2026 ASH指南：青少年和年轻成人急性淋巴细胞白血病的一线治疗

指南血液内科· 白血病与骨髓增生 · 2026

Abstract:

Background: Adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) represent a unique population. Treatment regimens can vary significantly depending on whether they receive care in a pediatric or in an adult setting. They also have distinctive care needs, social risk factors, and disease behavior compared to other age groups. Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and other health care professionals in their decisions about the frontline management of ALL in AYAs. Methods: ASH formed a multidisciplinary guideline panel including hematologists, AYA psychosocial care specialists, pharmacists, methodologists, and patient representatives with efforts to minimize bias from conflicts of interest. An evidence review team at Brown University supported guideline development, including performing systematic evidence reviews up to November 2023. The panel prioritized clinical questions and outcomes according to importance for clinicians and patients. The panel used Grading of Recommendations Assessment, Development and Evaluation (GRADE), including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 15 recommendations and several good practice statements. Conclusions: Pediatric-inspired regimens containing asparaginase are recommended as frontline therapy compared to more traditional adult-inspired protocols, requiring significant supportive care and close follow up. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) isn't routinely recommended in first remission (CR1) but may be indicated for higher risk subsets or those with suboptimal responses to initial therapy. The use of targeted agents in frontline therapy is increasingly supported, though further research is needed to optimize this strategy.

# Conflict of interest: COI declared - see note

COI notes: All authors were members of the guideline panel, members of the systematic review team, or both. As such, they completed a disclosure of interest form, which was reviewed by ASH and is available as supplements 2 and 3.

Preprint server: No;

Author contributions and disclosures: "‡" = WS and JW contributed equally to this work and share co-senior authorship as the co-chairs of the guideline panel. "*= AC and JM contributed equally to this work and share co-first authorship of the guideline. All guideline panel members contributed to specific sub-sections of the text for the recommendations.; M.C., W.S., J.W., J.M., and A.D. organized and then revised these subsections into the first draft of this manuscript, and subsequently revised the manuscript based on authors' suggestions; all guideline panel members critically reviewed the manuscript and provided suggestions for improvement to strengthen the final version; members of the knowledge synthesis team (H.J.M., G.K., Y.S., I.S., E.B.) contributed evidence summaries to the guidelines; JW and WS were co-chairs of the guideline panel and led panel meetings; M.C. was the ex-officio representative from the ASH clinical practice guidelines oversight committee; and all authors approved of the content.

Non-author contributions and disclosures: No;

Agreement to Share Publication-Related Data and Data Sharing Statement:

Clinical trial registration information (if any):

# American Society of Hematology 2026 guidelines for Frontline Management of Acute Lymphoblastic Leukemia in Adolescents and Young Adults (ALL in AYAs)

# Young Adults (ALL in AYAs)

Adam S. DuVall$^{1}$,*, Jennifer McNeer$^{2}$,*, Matthew C. Cheung$^{3}$, Diego A. Adrianzen-Herrera$^{4}$, Anjali Advani$^{5}$, Mahmoud Aljurf$^{6}$, Anthony Audino$^{7}$, Lydia Benitez$^{8}$, Anastasia Deeter$^{9}$, Emily Dworkin$^{10}$, Olivia Hiltbrand$^{11}$, Leidy Isenalumhe$^{12}$, Loretta Li$^{13}$, Courtney Miller-Chism$^{14}$, Lee Mozessohn$^{15}$, Ashley P. Ng$^{16}$, Jeffrey J. Pu$^{17}$, Danielle Shafer$^{18}$, Fernando Vargas Madueno$^{19}$, Aaron Viny$^{20}$, Aman Wadhwa$^{21}$, Jay Yang$^{22}$, Sara Zarnegar-Lumley$^{23}$, Htun Ja Mai$^{24}$, Ghid Kanaan$^{25}$, Yuliia Sereda$^{26}$, Ian J. Saldanha$^{27}$, Ethan Balk$^{28}$, Wendy Stock$^{29}$,‡, Julie Wolfson$^{30}$,‡

"‡" = WS and JW contributed equally to this work and share co-senior authorship as the co-chairs of the guideline panel. "*" = AD and JM contributed equally to this work and share co-first authorship as co-writers of the guideline panel.

Correspondence

Matthew C. Cheung

Odette Cancer Centre, Sunnybrook Health Sciences Centre

2075 Bayview Ave, Toronto, ON, Canada, M4N 3M5

Phone: 416-480-4928

Fax: 416-480-6002

Email: `matthew.cheung@sunnybrook.ca`

1) Departments of Medicine and Pediatrics, University of Chicago, Chicago, IL, United States, duvalla@bsd.uchicago.edu, https://orcid.org/0000-0002-9163-8792

2) Department of Pediatrics, University of Utah/Primary Children's Hospital, Salt Lake City, UT, United States, jennifer.mcneer@hsc.utah.edu, https://orcid.org/0000-0002-4743-6325

3) Division of Medical Oncology and Hematology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, matthew.cheung@sunnybrook.ca, https://orcid.org/0000-0003-3193-5872

4) Division of Hematology Oncology, Department of Medicine, University of Vermont Larner College of Medicine, Burlington, VT, dadrianz@uvm.edu, https://orcid.org/0000-0003-0168-2165

5) Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, United States, advania@ccf.org, https://orcid.org/0000-0003-0015-5902

6) Hematology, Stem Cell Transplantation and Cellular Therapy Department, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia, maljurf@kfshrc.edu.sa, https://orcid.org/0009-0009-6898-8733

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

7) Division of Pediatric Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, OH, United States, anthony. audino@nationwidechildren. https://orcid.org/0000-0002-2597-1212 8) Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, United States, lbenitez@med.umich.edu, https://orcid.org/0000-0001-6828-8053 9) Texas Children's Hospital, Houston, TX, United States, aldeeter@texaschildren.org, (No ORCID ID) 10) Department of Pharmacy, University of Chicago Medicine, Chicago, IL, United States, emily.dworkin@uchicagomedicine.org, https://orcid.org/0009-0003-8459-7456 11) Columbus, OH, United States, olivia.fecteau@gmail.com 12) H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, United States, Leidy.Isenalumhe@moffitt.org, https://orcid.org/0009-0001-7537-8441 13) Division of Hematology, Oncology, Neuro-Oncology & Stem Cell Transplantation; Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, United States, lli@luriechildrens.org, https://orcid.org/0000-0002-3018-597X 14) Department of Medicine, Section of Hematology & Oncology, Baylor College of Medicine, Houston, TX, United States, cnmiller@bcm.edu, https://orcid.org/0000-0003-2284-491X 15) Division of Medical Oncology and Hematology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, ON, Canada, lee.mozessohn@sunnybrook.ca, https://orcid.org/0000-0003-3436-3849 16) Clinical Hematology Department, The Royal Melbourne Hospital and Peter MacCallum Cancer Centre, Parkville, VIC, Australia, ashley.ng@mh.org.au, https://orcid.org/0000-0001-9690-0879 17) Department of Medicine, VA Boston Medical Center and Brigham & Women's Hospital, Harvard Medical School, Boston, MA, United States, jeffreypu@gmail.com, https://orcid.org/0000-0001-7498-3159 18) Inova Schar Cancer Institute, Inova Fairfax Hospital, Falls Church, Virginia, United States, Danielle.Shafer@inova.org, https://orcid.org/0000-0003-1020-7569 19) Department of Malignant Hematology & Cellular Therapy, Moffitt Cancer Center at Memorial Healthcare System, Pembroke Pines, FL, United States, fvargasmadueno@mhs.net, https://orcid.org/0000-0001-6220-5579 20) Departments of Medicine, Division of Hematology & Oncology, and of Genetics & Development, Columbia Stem Cell Initiative, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, United States, adv2105@cumc.columbia.edu, https://orcid.org/0000-0001-7039-0110 21) Department of Pediatric Hematology & Oncology, University of Alabama at Birmingham, Birmingham, Alabama, United States, awadhwa@uabmc.edu, https://orcid.org/0000-0002-3245-2218 22) Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States, yangj@karmanos.org, https://orcid.org/0000-0003-0488-4336 23) Division of Hematology, Oncology, Neuro-Oncology & Stem Cell Transplantation; Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, United States; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, United States, szarnegarlumley@luriechildrens.org, https://orcid.org/0000-0002-5413-37 24) Center for Evidence Synthesis in Health, Brown University's School of Public Health, Providence, RI, United States, ja.maihtun@brown.edu, https://orcid.org/0009-0004-1357-1088 25) Center for Evidence Synthesis in Health, Brown University's School of Public Health, Providence, RI, United States, ghid_kanaan@brown.edu, https://orcid.org/0009-0003-4910-9656

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

26) Center for Evidence Synthesis in Health, Brown University's School of Public Health, Providence, RI, United States, sereda_yuliia@brown.edu, https://orcid.org/0000-0002-4017-4561 27) Center for Clinical Trials Evidence Synthesis, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States, isaldan1@jhu.edu, https://orcid.org/0000-0002-2062-3382 28) Center for Evidence Synthesis in Health, Brown University's School of Public Health, Providence, RI, United States, ethan_balk@brown.edu, https://orcid.org/0000-0002-4376-7290 29) Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, United States, https://orcid.org/0000-0002-8349-9200 30) Division of Pediatric Hematology-Oncology, Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, AL, United States, https://orcid.org/0000-0002-3711-2239

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Abstract

Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians and other health care professionals in their decisions about the frontline management of ALL in AYAs.

Methods: ASH formed a multidisciplinary guideline panel including hematologists, AYA psychosocial care specialists, pharmacists, methodologists, and patient representatives with efforts to minimize bias from conflicts of interest. An evidence review team at Brown University supported guideline development, including performing systematic evidence reviews up to November 2023. The panel prioritized clinical questions and outcomes according to importance for clinicians and patients. The panel used Grading of Recommendations Assessment, Development and Evaluation (GRADE), including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment.

Results: The panel agreed on 15 recommendations and several good practice statements.

Conclusions: Pediatric-inspired regimens containing asparaginase are recommended as frontline therapy compared to more traditional adult-inspired protocols, requiring significant supportive care and close follow up. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) isn't routinely recommended in first remission (CR1) but may be indicated for higher risk subsets or those with suboptimal responses to initial therapy. The use of targeted agents in frontline therapy is increasingly supported, though further research is needed to optimize this strategy.

Keywords

acute lymphoblastic leukemia; adolescents and young adults; hematology; practice guidelines; GRADE

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Summary of recommendations

These guidelines are based on original systematic reviews of evidence conducted under the direction of the methods team from Brown University. The panel followed best practice for guideline development recommended by the Institute of Medicine and the Guidelines International Network (GIN).$^{1}$⁻$^{3}$ The panel used the GRADE approach to assess the certainty of the evidence and formulate recommendations.$^{4}$⁻$^{10}$.

Interpretation of strong and conditional recommendations

The strength of a recommendation is expressed as either strong ("the guideline panel recommends..."), or conditional ("the guideline panel suggests...") and should be interpreted as described in Figure 1.

Figure 1.

|Recommendation Strength||||| |---|---|---|---|---| ||“Recommendations...”|“Recommended against...”|“Suggests...”|“Suggests against...”| |||||| |Interpretation of Strong Recommendations|Interpretation of Conditional Recommendations|||| |Pati e n t s|Most individuals in this situation would want the recommended course of action, and only a small proportion would not.||Most individuals in this situation would want the suggested course of action, but many would not. Decision aids may be useful in helping patients to make decisions consistent with their individual risks, values, and preferences.|| |Clin ic a n s|Most individuals should follow the recommended course of action. Formal decision aids are not likely to be needed to help individual patients make decisions consistent with their values and preferences.||Different choices will be appropriate for individual patients; clinicians must help each patient arrive at a management decision consistent with the patient's values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their individual risks, values, and preferences.|| |Poli cym ake rs|The recommendation can be adopted as policy in most situations. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator.|Policymaking will require substantial debate and involvement of various stakeholders. Performance measures should assess if decision making is appropriate.||| |Res earc|The recommendation is supported by credible research or other convincing judgments that make additional research unlikely to alter the recommendation. On occasion, a strong recommendation is based on low or very low|The recommendation is likely to be strengthened (for future updates or adaptation) by additional research. An evaluation of the conditions and criteria (and the related judgments, research evidence, and additional|||

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

![herS\n](1/parseimages/figureac3a0ee30da44eee87d79b779d98ae6b_0_1.png) certainty in the evidence. In such instances, further research may provide important information that alters the recommendations.

considerations) that determined the conditional (rather than strong) recommendation will help identify possible research gaps.

Interpretation of good practice statements

As described by the GRADE Guidance Group, good practice statements endorse interventions or practices that the guideline panel agreed have unequivocal net benefit yet may not be widely recognized or used.$^{4}$ Good practice statements in these guidelines are not based on a systematic review of available evidence. Nevertheless, they may be interpreted as strong recommendations.

Recommendations

Frontline Treatment Approach

Recommendation 1. For AYAs with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, the ASH guideline panel recommends pediatric-inspired (asparaginase-containing) regimens (strong recommendation based on moderate certainty in the evidence of effects (SABD1)

Asparaginase Management: Dosing

Recommendation 2. For AYAs with ALL receiving frontline pediatric-inspired (asparaginase-containing) regimens, the ASH guideline panel suggests that empiric dose capping and dose reductions are reasonable strategies to mitigate asparaginase-induced toxicities in AYAs without evidence of adversely impacting disease outcomes (conditional recommendation based on very low certainty in the evidence of effects 😊) *

Remarks:

$\bullet$ The panel defines dose capping as a maximum peg-asparaginase dose of 3750 international units (IU).

$\bullet$ The panel defines reduced dosing of pegaspargase as any weight-based dose below the dose of 2500 IU/m2 for individuals <22 years old or below the dose of 2000 IU/m2 for individuals 22 years and older.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

* See "Asparaginase Management: Good Practice Statement" for TDM guidance related to dose capping or reduction.

Asparaginase Management: Pre-medication

Recommendation 3. For AYAs with ALL receiving frontline pediatric-inspired (asparaginase-containing) regimens, the ASH guideline panel recommends the use of prophylactic premedication to prevent hypersensitivity reactions (strong recommendation based on very low certainty in the evidence of effects 😊) *

Remarks:

$\bullet$ Premedication is defined at a minimum as intravenous (IV) steroid premedication and may also include antihistamines and/or acetaminophen.

* See "Asparaginase Management: Good Practice Statement" for TDM guidance related to dose capping or reduction.

Good Practice Statement for Recommendation 2 and 3. The panel considers it good practice to use therapeutic drug monitoring (TDM) to ensure adequate asparagine depletion when dose capping and dose reductions are undertaken. TDM should also be utilized in the context of pre-medication to determine if hypersensitivity reactions are associated with antibody-mediated inactivation (i.e., undetectable nadir serum asparaginase activity [NSAA] levels) or to identify silent inactivation.

Remark:

$\bullet$ The panel recognizes that there is some heterogeneity in the target asparaginase activity levels across studies and when and how levels should be monitored. An in-depth discussion and evaluation of the optimal asparaginase activity level is beyond the scope of this effort. However, based on pharmacokinetic and clinical outcomes data, activity levels of 0.1 IU/mL or greater for at least 14 days are recommended to ensure adequate asparagine depletion.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Asparaginase Management: Venous Thromboembolism (VTE) prophylaxis

Recommendation 4. For AYAs with ALL receiving frontline pediatric-inspired (asparaginase-containing) regimens, the ASH guideline panel recommends against the routine use of cryoprecipitate replacement (or fibrinogen concentrate) outside the context of active bleeding (strong recommendation based on very low certainty in the evidence of effects

![00\n](1/parseimages/figure1492b8ee430745b8bb63f44e40446413_0_3.png) Recommendation 5. For AYAs with ALL receiving frontline pediatric-inspired (asparaginase-containing) regimens, the ASH guideline panel recommends against the routine use of unfractionated heparin (UFH) for venous thromboembolism (VTE) prophylaxis (strong recommendation based on very low certainty in the evidence of effects 😊 😞)

No recommendation. For AYAs with ALL receiving frontline pediatric-inspired (asparaginase-containing) regimens, the ASH guideline panel determined that the evidence is insufficient to issue a recommendation for or against routine VTE prophylaxis with low molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs).

Remark (for this group of VTE prophylaxis with asparaginase recommendations):

$\bullet$ The panel recognizes there is uncertainty in the timing and duration of VTE prophylaxis (induction, consolidation, intensification), LMWH dosing, and AT replacement targets. They also highlight the importance of risk models to identify patients at high-risk for developing VTE.

Asparaginase Management: Alternative formulations

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Erwinia-based asparaginase formulation over discontinuation of asparaginase therapy (strong recommendation based on very low certainty in the evidence of effects 😊)

Remarks:

$\bullet$ The panel was unable to provide a recommendation related to desensitization due to the lack of evidence comparing the effects of desensitization versus alternative asparaginase products.

$\bullet$ The ASH guideline panel concluded that the benefits, such as improved survival and disease control, outweighed the drawbacks, including the high costs and resources for Erwinia-based treatments.

Asparaginase Management: Rechallenging after toxicity

No recommendation. For AYAs with ALL receiving frontline pediatric-inspired (asparaginase-containing) regimens who have a non-hypersensitivity asparaginase-related toxicity, the ASH guideline panel determined that the evidence is insufficient to issue a recommendation on resuming asparaginase therapy.

Allogeneic Transplant in First Complete Remission (CR1)

Recommendation 7. For AYAs with ALL receiving frontline therapy and in first complete remission (CR1), the ASH guideline panel suggests against routinely proceeding with allogeneic hematopoietic stem cell transplantation (allo-HSCT) as consolidation (conditional recommendation based on very low certainty in the evidence of effects 😞)

Remark:

$\bullet$ For specific high-risk subgroups (especially those with minimal residual disease [MRD] persistence, induction failure, and high-risk biologic subsets), there may be a survival benefit from allo-HSCT in CR1.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Additional Therapies for Specific Subsets: Rituximab

Recommendation 8. For AYAs with CD20-positive B-cell acute lymphoblastic leukemia (B-ALL) receiving frontline therapy, the ASH guideline panel suggests the addition of rituximab to standard chemotherapy (conditional recommendation based on very low certainty in the evidence of effects 😊)

Remark:

$\bullet$ The panel recognizes the considerable uncertainty associated with rituximab dosing, frequency, and timing of administration, the minimum required level of CD20 expression, and the lack of data specific to younger AYA individuals.

Additional Therapies for Specific Subsets: Blinatumomab

Recommendation 9. For AYAs with B-cell acute lymphoblastic leukemia (B-ALL) receiving frontline therapy, the ASH guideline panel suggests the addition of blinatumomab for those who achieve morphologic remission, regardless of MRD status (conditional recommendation based on very low certainty in the evidence of effects 😊 😞)

Remarks:

$\bullet$ The panel recognizes there are limited data using blinatumomab within conventional pediatric-inspired (asparaginase-containing) chemotherapy backbones in AYAs.

$\bullet$ The panel further recognizes the evolution of evidence in this space, and that the recommendation may change with the availability of more data.

$\bullet$ Guidance for individuals with MRD persistence is addressed in Recommendation 15.

Additional Therapies for Specific Subsets: Inotuzomab Ozogamicin (Inotuzumab)

No recommendation. For AYAs with B-cell acute lymphoblastic leukemia (B-ALL) receiving frontline therapy, the ASH guideline panel determined that the evidence is insufficient to issue a recommendation for or against the addition of inotuzumab.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Additional Therapies for Specific Subsets: Nelarabine

No recommendation. For AYAs with T-cell acute lymphoblastic leukemia (T-ALL) receiving frontline therapy with all planned doses of asparaginase (including Capizzi methotrexate-based interim maintenance), the ASH guideline panel determined that the evidence is insufficient to issue a recommendation for or against the addition of nelarabine.

Remark:

$\bullet$ The panel noted that incorporating nelarabine may provide benefit among subgroups of AYAs including those with non-ETP subtype, CNS3 disease, and/or others who receive a high-dose methotrexate-based interim maintenance regimen.

Recommendation 10. For AYAs with T-cell lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, the ASH guideline panel suggests against the addition of nelarabine, due to insufficient evidence demonstrating efficacy for nelarabine in these patients (conditional recommendation based on very low certainty in the evidence of effects 😞 😞)

Additional Therapies for Specific Subsets: Bortezomib

Recommendation 11. For AYAs with T-cell acute lymphoblastic leukemia (T-ALL) receiving frontline therapy, the ASH guideline panel suggests against the addition of bortezomib into treatment regimens (conditional recommendation based on very low certainty in the evidence of effects 😊)

No recommendation. For AYAs with T-cell lymphoblastic lymphoma (T-LBL/LLy), the ASH guideline panel determined the evidence is insufficient to recommend for or against addition of bortezomib.

Remark:

$\bullet$ The panel noted that incorporating bortezomib may provide benefit amongst the youngest adolescents of the AYA population.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Treatment for Philadelphia Chromosome-Positive ALL

Recommendation 12. For AYAs with Philadelphia chromosome-positive (Ph-pos) ALL, the ASH guideline panel suggests reduced-intensity therapy with tyrosine kinase inhibitor (TKI) for remission induction over intensive chemotherapy with TKI. This should be followed by post-remission therapy. Options include intensive chemotherapy + TKI and/or immunotherapy + TKI. Either of these approaches may be consolidated by allogeneic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR1) (conditional recommendation based on very low certainty in the evidence of effects 😊 😊)

Remarks:

* All patients with Ph-pos ALL must receive CNS prophylaxis with concurrent intrathecal (IT) chemotherapy (see Recommendation 13).

$\bullet$ The panel recognizes that post-remission therapies (including allo-HSCT) are evolving given emerging data surrounding next-generation TKIs and novel/targeted immunotherapies.

$\bullet$ This recommendation may not be as applicable to the youngest AYA subgroup in which pediatric-inspired (asparaginase-containing) regimens would be applied; the panel appreciates that studies of pediatric-inspired backbones were not captured within the available dataset.

CNS Prophylaxis: Intrathecal (IT) chemotherapy regimens

Recommendation 13. For AYAs with ALL receiving frontline therapy, the ASH guideline panel suggests the use of either intrathecal (IT) methotrexate or triple intrathecal therapy (TIT) for CNS prophylaxis (conditional recommendation for either the intervention or comparison based on very low certainty in the evidence of effects 😊

Remark:

$\bullet$ Hydrocortisone can be used (in conjunction with IT methotrexate) for prevention of chemical arachnoiditis.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

CNS Prophylaxis: Cranial radiation

Recommendation 14. For AYAs with ALL receiving frontline therapy, the ASH guideline panel suggests against the routine use of cranial radiation for CNS prophylaxis for patients treated on a pediatric-inspired (asparaginase-containing) backbone (conditional recommendation against the intervention based on very low certainty in the evidence of effects 😊 😞)

Remark:

$\bullet$ There is uncertainty with respect to the use of cranial radiation for CNS prophylaxis for AYA individuals with T-ALL who are unable to receive nelarabine.

Approach for Minimal Residual Disease (MRD)

Recommendation 15. For patients with ALL with persistent MRD after ≥3 months of frontline therapy (induction plus a minimum of one block of post-remission therapy), the ASH guideline panel recommends a change in approach to treatment (see Recommendation 9) (strong recommendation for the intervention based on very low certainty in the evidence of effects 😊)

Remarks:

$\bullet$ The change in therapy could include several approaches including immunotherapy or allogeneic transplant (allo-HSCT). The optimal timing, choice of intervention(s), order, or combination of these approaches has not been defined.

$\bullet$ While T-ALL has not been studied individually, patients with T-ALL were included in the studies demonstrating the benefit of transplant for patients with MRD-positivity.

Good Practice Statement for Recommendation 15. Measurement of disease response using minimal residual disease (MRD) is considered standard of care in AYA ALL for both prognostic value and, in some cases, determination of treatment intensity.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Good practice statements

Good practice statement: Given the unique challenges of cancer in adolescence and young adulthood, it is good practice for AYAs with ALL to have their developmental needs evaluated, and their preferences and goals for treatment assessed within their unique developmental context. Whenever possible, their treatment should be delivered with these considerations in mind, providing scheduling flexibility when not otherwise contraindicated.

Good practice statement: Given the risk and prevalence of psychological comorbidities and adverse psychosocial outcomes during the cancer experience of AYAs with ALL, it is good practice to routinely screen for depression, anxiety, and other psychological comorbidities and implement multidisciplinary psychosocial support.

Good practice statement: Given the unique social needs of AYAs with ALL, it is good practice to assess and evaluate each patient's existing social supports and encourage connection with supportive communities where possible, through organized care coordination and resource navigation from a multidisciplinary team experienced in working with AYAs.

Good practice statement: Given the financial toxicity experienced by AYAs with ALL, it is good practice to provide financial counseling, resource navigation, and concrete resources through institutional means and/or in collaboration with larger regional/national organizations.

Good practice statement: Given the importance of sexual health and sexuality for AYAs with ALL, along with the dynamic changes experienced in these areas over time, it is good practice to discuss sexual health, sexual orientation, sexual preferences, and gender identity of each individual patient from the onset of diagnosis, again throughout the course of the individual's treatment, and into survivorship.

Good practice statement: Given the importance of fertility and how it is impacted by cancer and its therapy, it is good practice to provide AYAs with ALL access to comprehensive fertility care and consultation from, but not limited to, their oncology provider, fertility specialist, and fertility counselors prior to the initiation of therapy whenever possible, with continued involvement and care from this multidisciplinary team throughout therapy and into survivorship.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Good practice statement: Given that AYAs are underrepresented in cancer clinical trials, and improvement in survival over time has lagged in underrepresented populations of AYAs, it is good practice to offer AYAs treatment in appropriate clinical trials.

Good practice statement: It is good practice to introduce interdisciplinary palliative care teams as early as possible during treatment. Interdisciplinary and/or primary (i.e., delivered by the treating oncology team) palliative care should remain a focus of care throughout the care continuum, regardless of disease status.

Good practice statement: It is good practice to discuss goals of care and end-of-life concepts earlier in treatment, and before disease- or symptom-related crises arise. These discussions should be ongoing, tailored to the AYAs developmental and cognitive level, centered on the AYAs wishes, and should involve families and/or caregivers to the extent desired by the AYA. End-of-life care goals should be readdressed at key transition points during care (e.g., relapse).

Good practice statement: Considering differential outcomes for AYAs by location of care, in the context of their unique medical and developmental needs and the recommendations and statements included here, it is good practice to ensure AYAs with ALL have access to specialized care with professionals and institutions well-versed in AYA ALL whenever feasible.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Introduction

Aims of these guidelines and specific objectives

The purpose of these guidelines is to provide evidence-based recommendations on the frontline treatment of Acute Lymphoblastic Leukemia (ALL) in Adolescents and Young Adults (AYAs). The primary goals of these guidelines are to review, critically appraise, and implement evidence-based recommendations that address ongoing questions related to several aspects of treatment approach, disease assessment, and supportive care for this specific patient population. The appraisal and interpretation of available literature was conducted in the context of rapidly evolving diagnostic, monitoring, and therapeutic options. Through improved provider and patient education of the available evidence and evidence-based recommendations, these guidelines aim to provide clinical decision support for shared decision making between clinicians and patients that will result in optimal treatment choices.

The target audience includes patients, hematologists, general practitioners, internists, other clinicians and decision-makers. Policy makers interested in these guidelines include those involved in developing local, national or international plans with the goal of optimizing approaches to AYAs with ALL, given their unique circumstances; these include disease biology, therapeutic options, susceptibility to toxicities, and psychosocial challenges specific to AYAs with a new diagnosis of ALL. This document may also serve as the basis for adaptation by local, regional or national guideline panels.

Description of the health problem

AYA ALL remains a challenging malignancy to manage and while survival rates have significantly improved, a single standardized frontline treatment has not been established for treatment of ALL in AYAs. The National Cancer Institute (NCI) defines AYAs with cancer as individuals diagnosed with cancer between the ages of 15 and 39 years [https://www.cancer.gov/types/aya]. Considerable uncertainty persists regarding the optimal therapeutic approach to the AYA patient, with varying approaches between pediatric and adult practitioners. Regardless, treatment is intensive and lasts a long time with tremendous demands on the patient, caregivers, and families. This adds to the significant short and long

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Introduction

Aims of these guidelines and specific objectives

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

term psychosocial and socioeconomic burden caused by the disease itself. It is also crucial to consider the treatment-related toxicities and late effects of these treatments although related survival outcomes have improved.

Despite significant advancements in treatment, which have included the introduction of immunotherapy into frontline regimens, it is crucial to engage in a rigorous evaluation of the optimal approach and management of AYAs with ALL. ALL treatment backbones have evolved over the course of several decades with differences in approach not only related to pediatric-style or adult-style therapies, but also the incorporation of allogeneic hematopoietic stem cell transplantation (allo-HSCT), novel therapies, and measurement of minimal residual disease (MRD) response.

Nevertheless, distinctions between the approaches used more commonly by pediatric or adult hematologist-oncologists highlight an urgent need for harmonized, evidence-based guidelines to address gaps and inconsistencies in care for the AYA age group. This guideline attempts to focus on approaches tailored for AYAs, addressing the complexities of disease biology, treatment responses, psychosocial, and health system-related factors unique to this age group. By leveraging recent advancements in the field ranging from allo-HSCT and targeted therapies to detection of MRD, the panel aims to provide a framework for improving outcomes in this vulnerable population. By actively bridging adult and pediatric expertise and literature, the panel aims to ensure equitable access to novel therapies and provide a clearer roadmap for the frontline treatment of ALL in the unique AYA population.

The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used to systematically rate the quality of evidence and the strength of recommendations. A significant challenge was posed by the indirectness of the existing data; specifically, much of the evidence for AYA ALL is derived from studies focused on either pediatric or adult populations, with limited representation of AYAs. The lack of dedicated AYA-focused studies (described in more detail below) introduced uncertainty when extrapolating benefits and harms to the unique AYA population. Nonetheless, considering the importance of this issue, the panel attempted to use the best available evidence, albeit indirect, to appropriately tailor recommendations to the specific clinical niche of AYAs with ALL.

While the panel employed the widely accepted NCI definition of AYA, including patients age 15 to 39 at leukemia diagnosis, our group recognized that there were limited data that spanned the full AYA age-range; thus, there were nuances in considering regimens for the youngest AYA patients. For special populations, these nuances are noted in the sections below as relevant. The term "pediatric-inspired" regimen is used throughout the recommendations below; this refers to the implementation of a

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

pediatric regimen in an adult population where there have been subtle adaptations to the pediatric regimen over time. Further, when using this term, the panel is referring to both this adaptation and traditional high-risk pediatric regimens. For brevity, the abbreviation B-ALL within this document is used to represent Philadelphia chromosome-negative acute lymphoblastic leukemia (please see additional abbreviations in Appendix A).

Methods

The guideline panel developed and graded the recommendations and assessed the certainty of the supporting evidence following the GRADE approach.$^{5}$⁻$^{11}$ The overall guideline development process, including funding of the work, panel formation, management of conflicts of interest, internal and external review, and organizational approval, was guided by ASH policies and procedures derived from the Guideline International Network (GIN)-McMaster Guideline Development Checklist (http://cebgrade.mcmaster.ca/guidecheck.html)$^{12}$ and was intended to meet recommendations for trustworthy guidelines by the Institute of Medicine and the Guidelines International Network.$^{1}$⁻$^{3}$

Organization, panel composition, planning and coordination

The work of the two ALL in AYA panels was coordinated by ASH and The Brown University School of Public Health (funded by ASH under a paid agreement). Project oversight for both panels was provided by the ASH Guideline Oversight Subcommittee (represented by Dr. Matthew Cheung, the ex-officio member of the panel), which reported to the ASH Committee on Quality. ASH vetted and appointed individuals to the guideline panels. The two panels worked in parallel and collaborated in protocol development and other aspects of guideline development. The Brown University School of Public Health vetted and retained researchers to conduct systematic reviews of evidence and coordinate the guideline development process including the use of the GRADE approach. The membership of the panels and the methods team is described in Supplement 1.

The frontline panel included hematologists/oncologists specializing in either pediatric or adult ALL or both, each with relevant clinical and research experience, alongside pharmacists, a social worker, a clinical psychologist, and individuals with lived experience of ALL during the AYA period. One pediatric and one adult hematologist served as clinical co-chairs of the panel.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

In addition to synthesizing evidence systematically, Brown University School of Public Health, in collaboration with ASH staff, helped to train the panel members in guideline and systematic review methodology, led research question and protocol development discussions, organized research question eligibility criteria, coordinated outcome prioritization, developed summary tables, and participated in panel discussions synthesizing the evidence and developing recommendations and good practice statements (primarily to ensure that recommendations aligned with the evidence). The panel's work was done using web-based tools (www questionpro com and www gradepro org ) and face-to-face and online meetings.

Guideline funding and management of conflicts of interest

Development of these guidelines was wholly funded by ASH, a nonprofit medical specialty society that represents hematologists. Most members of the guideline panel were members of ASH. ASH staff supported panel appointments and coordinated meetings but had no role in choosing the guideline questions or determining the recommendations.

Members of the guideline panel received travel reimbursement for attendance at in-person meetings. The panelists received no other payments. Through the Brown University School of Public Health, researchers who contributed to the systematic evidence reviews received salary support or direct payment.

Conflicts of interest of all participants were managed according to ASH policies based on recommendations of the Institute of Medicine$^{13}$ and the Guidelines International Network.$^{2}$ Participants disclosed all financial and nonfinancial interests with for-profit healthcare companies, regardless of relevance to the guideline topic. ASH staff and the ASH Guideline Oversight Subcommittee reviewed the disclosures and composed the guideline panel to include a diversity of expertise and perspectives. Greatest attention was given to direct financial conflicts with for-profit companies that could be directly affected by the guidelines. During the guideline development process, panelists avoided significant direct financial relationships with for-profit healthcare companies, agreeing to keep the total value of all direct financial conflicts under $7,500 per year (excluding travel support for educational or academic purposes). Many panelists had relevant nonfinancial interests, such as published opinions on the guideline topic. None of the Brown University School of Public Health researchers who contributed to the systematic evidence reviews or who supported the guideline development process had any such conflicts.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Recusal was used to manage certain conflicts.$^{5,14-16}$ During discussions about recommendations, any panel member who was a current lead principal investigator in relevant research could participate in evidence and clinical context discussions; however, they were recused from making judgments or voting about individual domains (e.g., magnitude of desirable consequences) and the direction and strength of the recommendation. The Evidence-to-Decision framework for each recommendation describes which individuals were recused from making judgments about each recommendation.

On June 30, 2025, one panel member, (L.I.) disclosed that during the guideline development process they had received direct payments or other transfers of value from companies that could be affected by the guidelines in excess of the amount allowable. These disclosures occurred after the panel had agreed on recommendation statements. ASH staff and our Ex Officio representative from the GOS reviewed the guidelines in relation to these late disclosures and agreed that conflicts were unlikely to have influenced any of the recommendations.

Supplement 2 provides the complete disclosure-of-interest forms of all panel members. In part A of the forms, individuals disclosed direct financial interests for 2 years prior to appointment; in part B, indirect financial interests; and in part C, not mainly financial interests. Part D describes new interests disclosed by individuals after appointment. Part E summarizes ASH decisions about which interests were judged to be conflicts and how they were managed, including through recusal.

Supplement 3 provides the complete disclosure of interest forms of researchers who contributed to these guidelines.

Formulating specific clinical questions and determining outcomes of interest

The panel formulated a preliminary list of research topics for both the Frontline Management and Relapsed/Refractory Panels starting in August 2022. Based on this list, the Methods Team reformulated research topics into formal Population, Intervention, Comparator, and Outcomes (PICO) questions and drafted preliminary eligibility criteria for each question. Through a series of regular Zoom (R) conference calls with the full panel, calls with the co-chairs, and email communications, together with the Methods Team and ASH staff, the panels developed a list of 33 Research Questions (21 for the Frontline Management panel, 8 for the Relapse/Refractory Management panel, and 4 for both panels) with detailed eligibility criteria.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

We originally planned to draft recommendations during a 2-day in-person meeting in October 2023; however, the Methods Team instead presented evidence from randomized controlled trials (RCTs) and existing systematic reviews to the panels. Since up to about 600 additional studies were potentially eligible across all topics, the Co-Chairs instead reprioritized the research questions to a more feasible scope, focusing on topics that were likely to be most impactful for patient care. The final prioritized clinical questions for frontline management are presented in Table 1, derived from the original list determined by the panel, with minor wording changes.

The panel selected outcomes of interest for each question a priori, following the approach described in detail elsewhere (Saldanha et al., Manuscript in submission).$^{8}$ In brief, the panels prioritized outcomes in three steps. The co-chairs and methods team initially brainstormed all possible outcomes for each clinical question. Then, all panel members rated the relative importance of outcomes for decision making via a QuestionPro survey in April 2023, focusing attention on those considered most important for clinicians and patients, following the GRADE approach.$^{8}$ While acknowledging considerable variation in the impact on patient outcomes, the panel considered the outcomes listed as critical for clinical decision-making (Table 1). The outcomes rated highly by the panel and those identified as important based on the literature reviews were further refined and finalized during panel meetings until June 2023. When questions were re-prioritized in October 2023 in-person, the outcomes of importance remained the same as originally prioritized.

|Questions determined by the panel|Outcomes| |---|---| |For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?|Overall survival| |For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?|RFS/EFS/DFS/PFS/Relapse| |For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?|Complete remission| |For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?|MRD-negative status| |For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?|Fertility| |For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?|Quality of life| |For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?|Allogeneic HSCT| |For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?|Toxicity| |For patients (of any age) with ALL receiving frontline asparaginase, what are the comparative benefits and harms of changing asparaginase dose by: (1) following asparaginase levels (including monitoring frequency and|Overall survival| |For patients (of any age) with ALL receiving frontline asparaginase, what are the comparative benefits and harms of changing asparaginase dose by: (1) following asparaginase levels (including monitoring frequency and|RFS/EFS/DFS/PFS/Relapse| |For patients (of any age) with ALL receiving frontline asparaginase, what are the comparative benefits and harms of changing asparaginase dose by: (1) following asparaginase levels (including monitoring frequency and|Complete remission| |For patients (of any age) with ALL receiving frontline asparaginase, what are the comparative benefits and harms of changing asparaginase dose by: (1) following asparaginase levels (including monitoring frequency and|MRD-negative status|

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

timing) & changing asparaginase doses in response to those levels, (2) dose capping, (3) dose lowering (per BSA/m$^{2}$)?

For patients with ALL receiving asparaginase, what are the comparative benefits and harms of prophylactic premedication to prevent infusion reactions?

For patients with ALL receiving frontline asparaginase therapy, what are the comparative benefits and harms of different prophylaxis regimens to prevent hypercoagulation including: 1) anticoagulation for VTE (venous thromboembolism) prophylaxis (thromboprophylaxis) 2) monitoring (e.g., PT/PTT/INR/ATIII and fibrinogen levels) with reflex product replacement administration [or replacement recombinant antithrombin (AT)]?

For AYAs with ALL receiving frontline asparaginase who have an asparaginase-related reaction [allergic-type reaction], what are the comparative benefits and harms of desensitization versus use of alternative asparaginase products (Erwinia, Rylaze®)?

For AYAs with ALL receiving frontline asparaginase who have an asparaginase-related toxicity (e.g., coagulation-related side effect, pancreatitis, or hepatotoxicity), what are the comparative benefits and harms of resuming (or changing) asparaginase therapy?

For AYAs with ALL being treated with frontline therapy, what are the comparative benefits and harms of allogeneic hematopoietic stem cell transplantation versus no transplant (in first complete remission (CR1))?

For patients with B-cell (B-ALL) or T-cell acute lymphoblastic leukemia (T-ALL)/lymphoma (T-LBL/LLy) in frontline therapy, what are the comparative benefits and harms of inclusion (versus no inclusion) of targeted therapies? (e.g., inotuzumab ozogamicin, blinatumomab, rituximab, nelarabine, bortezomib)?

|Quality of life|Quality of life| |---|---| |Hospital admission|Hospital admission| |Toxicity|Toxicity| ||RFS/EFS/DFS/PFS/Relapse| |Silent inactivation|Silent inactivation| |Switches or discontinuation|| |Hospital admission|Hospital admission| |Toxicity|Toxicity|

Overall survival RFS/EFS/DFS/PFS/Relapse Asparaginase activity levels

Quality of life Hospital admission

Toxicity

RFS/EFS/DFS/PFS/Relapse

Hospital admission

Toxicity

RFS/EFS/DFS/PFS/Relapse

MRD-negative status

Fertility Quality of life

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

||Financial toxicity| |---|---| ||Toxicity| |For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?|Overall survival| |For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?|RFS/EFS/DFS/PFS/Relapse| |For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?|MRD-negative status| |For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?|Quality of life| |For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?|Adherence| |For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?|Allogeneic HSCT| |For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?|Financial toxicity| |For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?|Toxicity| |For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?|Overall survival| |For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?|RFS/EFS/DFS/PFS/Relapse| |For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?|CNS recurrence| |For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?|Neuro-cognitive impact| |For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?|Quality of life| |For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?|Caregiver burden| |For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?|Toxicity| |For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?|Overall survival| |For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?|RFS/EFS/DFS/PFS/Relapse| |For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?|Complete remission| |For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?|MRD-negative status| |For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?|Quality of life| |For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?|Allogeneic HSCT| |For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?|Toxicity|

Evidence review and development of recommendations

Under the direction of The Brown University School of Public Health, researchers followed standard, current methodology from the Agency for Healthcare Research and Quality (AHRQ) and outlined in the Cochrane Handbook for Systematic Reviews of Interventions (handbook.cochrane.org) for conducting systematic reviews and evaluating the evidence base.$^{4}$⁻$^{6}$,$^{8}$⁻$^{10}$,$^{17}$ The methodology team conducted a broad search for all 33 original Research Questions across both Frontline Management and Relapsed/Refractory Panels. All research questions were initially addressed by new systematic reviews. Literature searches were conducted in PubMed, Embase, PsycINFO, and CINAHL. The final searches were run on November 29, 2023, but additional studies were sought from reference lists of existing

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

systematic reviews. Panel members also suggested additional potentially eligible studies through August 2024. Citations were screened in duplicate using Abstrackr (http://abstrackr.cebm.brown.edu/), an abstract screening tool that uses machine learning to prioritize most-relevant studies based on the accept and reject labels provided by human screeners. Conflicts were adjudicated in team meetings. The full texts of potentially eligible studies were re-screened in duplicate, with conflicts adjudicated by a senior researcher.

For each prioritized research question, the Methods Team prepared one or more GRADE Evidence Tables, using the GRADEpro Guideline Development Tool (https://gradepro.org). Separate rows (and, thus, summaries of evidence and determination of certainty of evidence) were included for each outcome and reported separately at different time points. In addition, studies reporting different effect size measures (typically relative risks or hazard ratios) were summarized separately. For the purpose of entering data into the GRADE software, the Methods Team conducted restricted maximum likelihood (REML) meta-analyses when at least two studies had similar comparisons at the same time point using the same effect size measure. Proportions were meta-analized after double arcsine transformation. The methods team also assessed clarity and accuracy of study eligibility criteria, interventions, outcomes, and results reporting.

The certainty of the body of evidence (also known as quality of the evidence or confidence in the estimated effects) was assessed by the GRADE software (based on the following domains: risk of bias, precision, consistency and magnitude of the estimates of effects, directness of the evidence, risk of publication bias, presence of large effects, dose-response relationship, and an assessment of the effect of residual, opposing confounding) for each evaluated outcome (split by follow-up time and/or analytic measure). Study risk of bias was evaluated with the Cochrane Collaboration's risk of bias tool for randomized controlled trials,$^{17}$ and additional selected questions that addressed selection and analytic methods from ROBINS-I (Risk Of Bias In Non-randomized Studies - of Interventions).$^{18}$ To evaluate directness of the evidence and standardize/rationalize eligibility criteria across topics, the Co-Chairs for the frontline management and relapse/refractory panels defined six tiers of evidence that were agreed upon by the panels (Table 2).

|Tiers|Publication Year|Sample Size|Age, years|Directness| |---|---|---|---|---| |Tier 1|≥2000|N ≥10|AYA|Direct| |Tier 2|≥2000|N ≥10|Median 15-39|Serious indirect|

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

|Tier 3|≥2014|N ≥25|Median 10-14 or 40-65|Very serious indirect| |---|---|---|---|---| |Tier 4|≥2000|N ≥25|Median 10-14 or 40-65|Very serious indirect| |Tier 5|≥2014|N ≥25|Median <10 or >65|Very serious indirect| |Tier 6|≥2000|N ≥25|Median <10 or >65|Very serious indirect|

The certainty was categorized into four levels ranging from very low to high.$^{7,9,19}$ Within this report, these categories are represented by symbols, as described in Figure 2.

Figure 2.

|Evidence Certainty|Evidence Certainty| |---|---| |High Certainty|High Certainty| |++++|We are very confident that the true effect lies close to that of the estimate of the effect.| |Moderate Certainty|Moderate Certainty| |++○○|We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.| |Low Certainty|Low Certainty| |++○○|Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.| |Very Low Certainty|Very Low Certainty| |+○○○|We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of the effect.| |+○○○|We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of the effect.|

Interested readers may find more explanation about the GRADE approach to assessing and rating certainty in a body of evidence in other publications.$^{7}$,$^{9}$,$^{19}$

The panel began drafting clinical recommendations with a 2-day in-person meeting in October 2023, followed by a series of video conference calls to review evidence for the reprioritized research questions between February 2024 and September 2024. In separate virtual calls for each research question, the Brown University School of Public Health methods team leads presented the summarized data and GRADE evidence profiles to panel members, who provided feedback on clarity, completeness, and accuracy of the summarized data. For each question, the panel decided which Tiers of studies would be included, dependant on how many higher tier studies were identified (Table 3).

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

|Topic|Eligible Study Designs|N Studies|Eligible Study Tiers [Included Tiers]| |---|---|---|---| |1. Pediatric-inspired vs. adult-inspired regimens|Comparative; Prospective single-group|24|1 [1]| |2. Changing asparaginase dose by: 1) monitoring asparaginase levels, 2) dose capping, 3) dose lowering|Comparative; Single-group|9|1-6 [1,2,4,5]| |3. Prophylactic premedication to prevent asparaginase infusion reactions|Comparative|6|1-6 [1,5*]| |4. Prophylaxis against hypercoagulation, including: 1) anticoagulation, 2) hypercoagulation monitoring|Comparative|14|1-6 [2,3,5,6]| |5. After asparaginase-related reaction, desensitization vs. alternative asparaginase product|Comparative; Single-group|7|1-6 [3,4,5]| |6. After asparaginase-related toxicity, resuming or changing asparaginase product|Comparative|0|1-6| |7. Allogeneic hematopoietic stem cell transplantation versus no transplant|Comparative|7|1,2 [1,2]| |8. Targeted therapies (e.g., inotuzumab ozogamicin, blinatumomab, rituximab, nelarabine, bortezomib)|Comparative; Single-group|15|1-4| |Blinatumomab||2|[3,4]| |Nelarabine||8|[1,2,3,4]| |Bortezomib||1|[3]| |Rituximab||4|[2,3,4]| |9. Ph+ treatments: Reduced vs. Intensive chemotherapy, with TKI|Comparative; Single-group|25|1-3 [1,2,3]| |10. CNS prophylaxis regimens, including: 1) intrathecal chemotherapy regimens, 2) cranial|Comparative|15|1-6|

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

|radiation|||| |---|---|---|---| |Intrathecal chemotherapy||2|[5,6]| |Cranial radiation||13|[3,5,6]| |11. Changing the treatment regimen due to the detection of MRD|Comparative|5|1-6 [1,2,3]|

* 1 study did not report participant age data, so the Tier could not be determined.

The panel took a population perspective (considering a broad, well-resourced population) and came to consensus on the following: the certainty of the evidence, the balance of benefits and harms of the compared management options, and the assumptions about the values and preferences associated with the decision. The guideline panel also explicitly considered the extent of resource use associated with alternative management options. The panel prepared a GRADE “Evidence-to-Decision” (EtD) framework, using the GRADEpro Guideline Development Tool (https://gradepro.org).$^{5,6,11}$ The EtD table addressed effects of interventions, resource utilization, values and preferences (relative importance of benefits and harms), equity, acceptability, and feasibility. The panel did not explicitly solicit judgments for the certainty of evidence underlying resource requirements (costs) and cost effectiveness unless the panel raised these issues for discussion.

The panel agreed on the recommendations (including direction and strength), remarks, and qualifications by consensus or, in one instance, by voting (an 80% majority was required for a strong recommendation), based on the balance of all desirable and undesirable consequences. Between October 2024 to May 2025, the co-writers and co-chairs, with support from the methodology team, refined the manuscript sections drafted by panel members. The panel developed recommendations where feasible and appropriate based on the evidence and discussion among panel members. The final guidelines, including recommendations, were reviewed and approved by all members of the panel.

Interpretation of strong and conditional recommendations

The recommendations are labeled as either “strong” or “conditional” according to the GRADE approach. The words “the guideline panel recommends” are used for strong recommendations, and “the guideline panel suggests” for conditional recommendations. Figure 1 provides GRADE’s interpretation of strong and conditional recommendations by patients, clinicians, health care policy makers and researchers.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Document review

Draft recommendations were reviewed by all members of the panel, revised, and then made available online from September 27 to October 29, 2024, for external review by stakeholders, including allied organizations, other medical professionals, patients, and the public. Two individuals or organizations submitted comments across both guideline panels: Frontline and Relapsed/Refractory Management. Six individuals or organizations submitted comments specifically for the Frontline Management Panel. The document and deliverables were revised to address relevant comments, and any changes were communicated to each commenter between November 2024 and January 2025.

One comment suggested reconsidering the nelarabine recommendation in T-ALL and prompted extensive discussion; in particular, the comment highlighted the dearth of data that were AYA-specific data or in the setting of Capizzi-methotrexate, coupled with toxicity and cost. In response, the panel reviewed the data again in detail and adjusted the strength of the recommendation to reflect the uncertainty in the data, expanding on this in the remarks and further discussion. Consequently, the panel also reconsidered the AYA-specific data regarding bortezomib in T-LBL and revised this recommendation. Due to insufficient evidence both yielded "no recommendation" statements within the final publication. In a full panel meeting (November 20, 2024), the Frontline Management Panel reviewed and approved the changes which were then communicated to the relevant commenter.

By September 23, 2025, the ASH Guideline Oversight Subcommittee and the ASH Committee on Quality approved that the defined guideline development process was followed, and on October 1, 2025, the officers of the ASH Executive Committee approved submission of the guidelines for publication under the imprimatur of ASH. The guidelines were then subjected to peer review by Blood Advances.

How to use these guidelines

ASH guidelines are primarily intended to help clinicians and patients make shared decisions about diagnostic and treatment alternatives, with the goal of improving quality of patient care. Other purposes are to inform policy, education and advocacy, and to state future research needs.

These guidelines are not intended to serve or be construed as a standard of care. Clinicians must make decisions on the basis of the clinical presentation of each individual patient, ideally through a shared

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

process that considers the patient's values and preferences with respect to the anticipated outcomes of the chosen option. Decisions may be constrained by the realities of a specific clinical setting and local resources, including but not limited to institutional policies, time limitations, or availability of treatments. These guidelines may not include all appropriate methods of care for the clinical scenarios described. As science advances and new evidence becomes available, recommendations may become outdated. Following these guidelines cannot guarantee successful outcomes. ASH does not warrant or guarantee any products described in these guidelines.

Statements about the underlying values and preferences as well as qualifying remarks accompanying each recommendation are its integral parts and serve to facilitate more accurate interpretation. They should never be omitted when quoting or translating recommendations from these guidelines. The use of these guidelines is also facilitated by the links to the EtD frameworks and interactive summary of findings tables in each section.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Recommendations

Frontline Treatment Approach

For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?

Summary of the evidence

The panel considered a total of 24 studies for review,$^{20-46}$ all of which were Tier 1 and had a median age range in the AYA age, including one RCT and other comparative analyses of prospective and retrospective comparative cohorts. The definitions of therapeutic approaches (pediatric-inspired and adult-inspired) were established by the authors of the primary manuscripts. In general, pediatric-inspired regimens are those typically administered in a largely outpatient setting and include intensive asparaginase, while adult-style regimens are historically non asparaginase-including (or not containing intensive asparaginase) regimens that rely primarily on repeated inpatient hospitalizations for infusional myelosuppressive chemotherapy administration. The panel acknowledges that the available evidence lacks some of the most recent data on incorporation of targeted immunotherapy into frontline regimens for AYAs, although all efforts were made to incorporate newer data as they emerged.

The critical outcome was identified to be overall survival (OS), with event-free survival (EFS) and disease-free survival (DFS) also clinically important outcomes. While toxicities were considered important, limited data are available on comparative outcomes of toxicity; the panel also acknowledges that the dataset may not capture data on all outcomes of importance, including hospitalizations and quality of

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

life (QOL). A total of 23 included studies reported OS (or death),$^{20}$⁻$^{22}$,$^{24}$⁻$^{46}$ 13 of which were comparative and ten of which were single group. Eight comparative studies reported EFS (or an event),$^{21}$,$^{23}$,$^{24}$,$^{27}$,$^{32}$,$^{33}$,$^{40}$,$^{43}$ and six included comparisons of DFS or RFS.$^{21}$,$^{24}$,$^{28}$,$^{36}$,$^{42}$,$^{45}$ Given lack of direct evidence in the form of randomized controlled trials (RCT), the data from the comparative studies on the outcomes of interest were pooled to generate effect sizes of the impact of pediatric-inspired vs adult-inspired regimens. The evidence profile and EtD framework is available online at https://guidelines.ash/gradepro.org/staging/profiles/8 VaFSTSbs.

Benefits

The evidence reviewed by the panel demonstrates a significant decrease in mortality at 7 years (HR [hazard ratio] 0.53, 95% CI, 0.37 to 0.77) with pediatric-inspired regimens. Analyzing 2-year mortality with available studies, the HR non-significantly favored pediatric-inspired protocols suggesting late toxicity and/or relapse may play a role as well (HR 0.89, 95% CI, 0.47 to 1.69). EFS at 7 years also significantly favored pediatric inspired therapy (HR 0.45, 95% CI, 0.33 to 0.63) with a non-significant decrease in relapse at 2 years (HR 0.74, 95% CI 0.40 to 1.30).

Overall, the estimated desirable effects are large. Although the certainty of the evidence is very low (as per GRADE) owing to the sparseness of RCTs, the large number of comparative studies (most of which leveraged RCTs to make retrospective comparisons) and the median age of individuals within the studies (AYA range) were compelling for the panel. In particular, the panel considered the consistency of the results strongly favoring pediatric-inspired regimens and the low likelihood that additional future studies would change the results; as such, the panel decided to formally upgrade the certainty of evidence within the ETD framework to moderate certainty. The overwhelming majority of the panel felt a strong recommendation for pediatric-inspired therapy was warranted, while one dissenting voice felt a conditional recommendation was appropriate given the potential difficulty of implementing the recommendation in all settings. All panelists agreed that the potential magnitude of survival benefits is substantial and clinically meaningful to patients. Patient representatives on the panel placed the highest value on OS and mortality relative to other outcomes, with toxicity as an additional important outcome. The panel felt confident that the available effect estimates were representative of the true effect and that there was a low likelihood that future evidence would change the effect estimates. While understanding that some uncertainty regarding the strength of the evidence remains, they highlighted

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

the difficulty of conducting an RCT comparing these approaches in the context of the current data and the low likelihood that future RCTs will be conducted in this area.

Harms and burden

In considering the potential harms or undesirable effects of pediatric-inspired therapy for AYAs with ALL, toxic mortality, pancreatitis, and fertility were specifically considered of particular interest. Toxic mortality was included in only two comparative studies$^{23}$,$^{32}$ and pancreatitis in one,$^{32}$ and fertility rates were not addressed at all. Considering overall toxicity there was no statistically significant difference between regimens, but the HR for treatment-related mortality favored pediatric-inspired therapy (HR 0.68, 95% CI 0.10 to 4.41).

The burden of therapy in AYAs with ALL is difficult to measure objectively. All current intensive ALL regimens, regardless of approach (pediatric-inspired vs. adult-inspired) are long and arduous, require intensive supportive care from the health care team, and may incur significant debt on the patients and their caregivers due to out-of-pocket costs for prescriptions, travel, and lost productivity and job revenue. Implementation of pediatric-inspired regimens requires additional health system resources and infrastructure to ensure the safe and timely delivery of treatment modules in the outpatient setting; on the other hand, adult-inspired regimens are associated with different burdens, including repeated planned hospitalizations and similar challenges relating to delivering care on prescribed schedules. While both approaches pose challenges, in part due to the unique patient population and the prolonged treatment (nearly three years), with strong outcomes weighing in its favor, the panel ultimately recommends the use of pediatric-inspired therapy for AYAs with ALL.

Other EtD criteria and considerations

Survival outcomes (OS, EFS) were identified as the outcomes of utmost importance by both health care professionals and patient representatives on the panel, with a focus on toxicity as well. As described above, access to care, feasibility, and equity were considered and discussed at length as well.

The evidence includes only a single RCT, and relies largely on retrospective comparisons, some of which compare outcomes on pediatric vs adult trials that were prospectively conducted, and some compare single-institution/single-group outcomes to historical data. The panel recognizes this limitation, which

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

led to a prolonged consideration toward the weight of the recommendation, but given the consistent directionality of the available data, the panel decided a strong recommendation was warranted. There is also a lack of dedicated evidence on toxicity comparisons between regimens. The panel identified not only pancreatitis as a specific toxicity of interest, but also other asparaginase-related toxicity such as thrombosis and hypersensitivity. Also considered were fertility, steroid-associated toxicities, infectious complications, avascular necrosis, and unplanned hospitalizations. Some of these would be unlikely to be compared between pediatric- and adult-inspired regimens given less usage of certain agents (for example, asparaginase would unlikely be a component in most adult-inspired regimens). However, for toxicities that would be expected regardless of regimen, such as unplanned hospitalizations, the data do not currently exist.

An important area in which the current guidelines are lacking is the impact of immunotherapies on the outcomes of interest. Some of these agents will be discussed in other sections of these guidelines but given differential access to, and uptake of, these agents within pediatric versus adult studies, few comparative outcomes exist. This will be discussed in later sections. The panel acknowledges that these agents have the potential to dramatically reshape our approach to ALL in general, including in the AYA population. However, it should be noted that there is a lack of data integrating immunotherapy with pediatric-based regimens in the AYA population. It should also be noted that the ability to deliver these therapies to all patients may highlight further inequities in access to care.

Conclusions and research needs for this recommendation

Prioritizing survival outcomes (OS, EFS, and DFS) as critically important and considering toxicity as an important outcome, the panel concludes that the use of pediatric-inspired therapy results in superior outcomes for AYAs with newly diagnosed ALL. The certainty of evidence is low to very-low, with the largest limitation being the lack of RCTs, while the age specificity (AYAs) and comparative nature (including retrospective comparisons of RCTs) somewhat muted the limitations. The setting in which therapy is given is critical, as the burden on patients is high, with frequent trips to the treatment center for outpatient chemotherapy, as well as a need for high adherence to oral medications.

Implementation of such regimens without proper support structures in place introduces a risk of health inequities within an already at-risk population. Despite this, the panel concluded that the magnitude of survival benefits is substantial and clinically meaningful to patients and felt confident that the effect

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

estimates were reflective of true benefits. The composition of the panel was key for this discussion, as it included both pediatric and adult hematologist-oncologists and transplant physicians, pharmacists, social workers, and patients, and professionals who represented not only urban academic centers but also community and rural settings. The prioritization of survival benefit is likely to be acceptable to stakeholders and advocates as a rationale to dedicate system resources to enable hospitals, health systems, and healthcare professionals to accept and adopt pediatric-inspired regimens.

Future research in this area has the potential to address knowledge gaps related to outcomes of interest for which data do not currently exist, ranging from late effects of therapy and psychosocial outcomes (including fertility and health-related quality of life) to care delivery outcomes (unplanned hospitalization rates, and the impact of social determinants of health). Given the formative time during which AYAs are undergoing treatment, considerations for short- and long-term health, both physical and mental, are paramount. Furthermore, the panel acknowledges that the landscape of ALL treatment is changing rapidly and dramatically, with increasing roles of immunotherapies and other targeted agents within (and perhaps in place of) chemotherapy backbones. Modifications of current regimens may increase survival rates and change toxicity profiles, potentially providing great benefit to patients.

Asparaginase Management

For the Asparaginase Management sections that follow, the data presented and recommendations are related to pegaspargase (Peg-Asp), and not calaspargase pegol.

*Good Practice Statement for Recommendations 2-3. The panel considers it good practice to use therapeutic drug monitoring (TDM) to ensure adequate asparagine depletion when dose capping and dose reductions are undertaken. TDM should also be utilized in the context of pre-medication to determine if hypersensitivity reactions are associated with antibody-mediated inactivation (i.e., undetectable nadir serum asparaginase activity [NSAA] levels) or to identify silent inactivation.

$\bullet$ Remark: The panel recognizes that there is some heterogeneity in the target asparaginase activity levels across studies and when and how levels should be monitored. An in-depth discussion and evaluation of the optimal asparaginase activity level is beyond the scope of this effort. However, based on pharmacokinetic and clinical

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

outcomes data, activity levels of 0.1 IU/mL or greater for at least 14 days are recommended to ensure adequate asparagine depletion.

Asparaginase Dosing

For all patients (of any age) with ALL receiving frontline asparaginase, what are the comparative benefits and harms of changing asparaginase dose by: (1) following asparaginase levels (including monitoring frequency and timing) & changing asparaginase doses in response to those levels, (2) dose capping, (3) dose lowering (per BSA/m$^{2}$)?

Remarks:

$\bullet$ The panel defines dose capping as a maximum peg-asparaginase dose of 3750 international units (IU).

$\bullet$ The panel defines reduced dosing of pegaspargase as any weight-based dose below the dose of 2500 IU/m2 for individuals <22 or below the dose of 2000 IU/m2 for individuals 22 years and older.$^{47}$

* See "Asparaginase Management: Good Practice Statement" for TDM guidance related to dose capping or reduction.

Summary of the evidence

The panel reviewed a total of 9 comparative studies ranging from Tiers 1 to 5 to evaluate the benefits and harms of pegaspargase (PEG-asp) dose capping and reduced dosing of PEG-asp in AYA patients receiving upfront treatment on a pediatric-inspired (asparaginase-containing) protocol$^{22}$,$^{29}$,$^{42}$,$^{44}$,$^{48}$⁻$^{52}$,

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

among which seven had a median within the AYA age range. Among the comparative studies included, one was an RCT$^{49}$ and three were single center retrospective reviews.$^{48,51,52}$ The remaining five non-comparative studies were taken into consideration to further support the panel's recommendations.$^{22,29,42,44,50}$ The evidence profile and EtD framework is available online at https://guidelines.ash/gradepro.org/staging/profiles/jiscxt3g_wl.

Five studies provided direct evidence for the AYA population. The certainty of evidence was very low due to indirectness, imprecision, and risk of bias. The potential benefit of dose modification is mitigating toxicity, while the potential harm of this as an intervention is decreasing efficacy.

From the perspective of dose modification as an intervention, the potential benefit of the intervention is mitigating toxicity while the potential harm is decreasing efficacy. Overall, the panel felt the evidence available did not indicate any negative impact on survival outcomes when using dose capped or reduced dose PEG-asp. Notably, TDM was utilized in the vast majority, if not all, of the studies cited here, supporting the recommendation that when utilizing a dose-capping or dose-reduction strategy, it would be recommended to also pair that with TDM.

Benefits

The evidence reviewed by the panel did not demonstrate significant differences in rates of PEG-asp induced toxicities in AYA patients treated on pediatric-inspired regimens with reduced dose PEG-asp or capped dose PEG-asp compared to conventional dose PEG-asp.$^{48,49,51,52}$ In the non-comparative studies, rates of grade 3/4 toxicities, hepatotoxicity, pancreatitis and thrombosis were not significantly different when comparing low dose PEG-asp 1000 IU/m$^{2}$ vs. PEG-asp 2500 IU/m$^{2}$ (capped at 3750 IU) vs. PEG-asp 2500 IU/m$^{2}$ (without dose capping).$^{29,42,44,50}$

Comparison of rates of toxicity were difficult for the panel to assess given population heterogeneity and differences in adverse event definitions and reporting requirements between studies. The panel also notes that several studies utilized clinical characteristics such as older age, baseline liver dysfunction, diabetes and obesity to determine PEG-asp dosing.$^{48,51}$ The selection of patients with these “at risk” specific clinical characteristics for dose reduction/capping may indicate that giving high-risk patients lower PEG-asp doses may reduce the risk of toxicity since toxicity rates were no different from patients without risk factors who did not get PEG-asp dose reductions.

Overall, the benefits of decreased toxicity were considered moderate though the certainty of evidence was very low. The heterogeneity of patient populations and adverse event reporting made it difficult for

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

the panel to draw conclusions on toxicity rates with various PEG-asp dosing strategies. Given the available evidence, the panel felt that dose capping and reduced dose PEG-asp may help mitigate toxicities in AYA patients, especially in older AYAs and those with obesity, diabetes or underlying liver disease.

Harms and burden

Evidence reviewed by the panel did not demonstrate a difference in OS or EFS in patients treated with reduced dose pegaspargase or in patients who received capped dose PEG-asp compared to patients treated with conventional dosing.$^{48,49}$ Subgroup analyses did not identify any differences in treatment outcomes when looking at various clinical and biological subsets of patients.

Several large prospective European trials that included AYA patients utilized lower doses of PEG-asp (1000 IU/m$^{2}$) within pediatric-inspired regimens and reported survival outcomes comparable to prospective North American trials in AYA patients using higher doses of PEG-asp (2500 IU/m$^{2}$) within similar regimens.$^{22,29,42,44,50}$ Studies that evaluated differing dose strategies of asparaginase there were no significant difference in survival outcomes between low dose PEG-asp (1000 IU/m$^{2}$), dose capped PEG-asp (3750 IU) or conventional dose PEG-asp (2500 IU/m$^{2}$ with no cap).$^{48,49}$

Other EtD criteria and considerations

The panel placed a high value on OS and CR rates balanced with toxicities and quality of life. Although the available evidence did not capture all these outcomes, the panel did not feel this warranted a change in the strength or direction of the overall recommendation. The panel recognizes the very low certainty of evidence used to support this recommendation, and that the available data that is representative of the AYA population is sparse.

The panel felt reassured that the available evidence did not signal an adverse impact on survival outcomes such as OS and EFS. Furthermore, the data demonstrated that lower doses of PEG-asp achieve therapeutic asparaginase activity levels and asparagine depletion. Several additional single center retrospective reviews and prospective trials have also reported success with reduced dose PEG-asp achieving therapeutic asparaginase activity levels.$^{53-56}$ Based on this data and the expert opinion of the panel, it was felt that reducing PEG-asp dose as low as 1000 IU/m$^{2}$ is reasonable, especially when TDM is implemented.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Conclusions and research needs for this recommendation

The panel determined that there may be a benefit of PEG-asp dose capping or reduction in AYA patients. The panel recognizes the very low certainty of evidence but that based on the available evidence, it is reasonable to dose reduce or dose cap PEG-asp to mitigate toxicity without a detriment to survival or remission rates. This should especially be considered in patients who have risk factors for toxicity such as obesity, underlying liver dysfunction, and older age. TDM is encouraged if dose reductions or dose-capping is used to confirm adequate asparaginase activity levels for asparagine depletion.

Further research is needed to determine the optimal exposure to asparaginase and duration of asparagine depletion to maximize outcomes and minimize toxicity. This is true across all age groups but is of particular importance in the AYA population given the differences in disease biology and patient characteristics compared to pediatric and older adult patients. Asparaginase has proven to be highly efficacious but with a significant risk of serious toxicity, and validating this information is of utmost importance for patient care, including the risks and benefits of prolonged asparagine depletion. Ongoing studies are evaluating calaspargase in patients over the age of 18 years (NCT04817761, NCT05581030). However, these are only single-arm studies and will not provide comparative evidence on the benefits and harms of calaspargase compared to PEG-asp. Given the longer half-life of calaspargase and attendant potential for increased toxicities, clear understanding of any potential benefits and harms of this newer asparaginase preparation in the AYA population is needed.$^{57}$

Lastly, further research is needed on prevention and treatment of asparaginase induced toxicities as well as re-challenging with asparaginase after toxicity. Current evidence is sparse and primarily retrospective.$^{58-66}$ A majority of these data focus on the use of levocarnitine with or without vitamin B complex for prevention or treatment of hepatotoxicity.$^{61-66}$ A phase III trial comparing levocarnitine to no levocarnitine as hepatotoxicity prophylaxis is currently underway (NCT05602194).

Asparaginase Pre-medication

For patients with ALL receiving asparaginase, what are the comparative benefits and harms of prophylactic premedication to prevent infusion reactions?

Recommendation 3. For AYAs with ALL receiving frontline pediatric-inspired (asparaginase-containing) regimens, the ASH guideline panel recommends the use of prophylactic

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

premedication to prevent hypersensitivity reactions (strong recommendation based on very low certainty in the evidence of effects 😊) *

Remarks:

$\bullet$ Premedication is defined at a minimum as IV steroid premedication and may also include antihistamines and/or acetaminophen.

* See "Asparaginase Management: Good Practice Statement" for TDM guidance related to dose capping or reduction.

Summary of the evidence

The panel considered a total of six comparative studies for review,$^{44,67-71}$ which ranged from Tiers 1 to 5; one study included only AYAs,$^{44}$ while the median ages for 4 other studies were younger, and one was not reported. There were limited data overall with only two studies evaluating rates of switching asparaginase products to Erwinia based on premedication (versus none),$^{44,68}$ only one study directly comparing premedication versus none, one simply reporting rates of silent inactivation with premedication,$^{68}$ one addressing serum asparaginase activity,$^{68}$ one evaluating the cost associated with implementing premedication,$^{67}$ and two regarding cost savings associated with avoiding a switch to Erwinia as a consequence of a hypersensitivity reaction.$^{44,67}$ The evidence profile and EtD framework is available online at https://guidelines.ash.gradero.org/staging/profiles/7i6NAdBsfN0.

Benefits

Evidence reviewed by the panel demonstrated a reduction in the numbers of patients having asparaginase-related hypersensitivity reactions with premedication that included at least IV corticosteroid.$^{44,67,68}$ Moreover, the systematic review of grade 3 to 4 hypersensitivity reactions per patient demonstrated a statistically significant reduction in reactions with premedication (RR: 0.24, 95% CI 0.10 to 0.58).

The panel considered whether premedication could prevent hypersensitivity reactions that necessitated a switch to Erwinia, given the cost and inconvenience associated with Erwinia administration.$^{68,71}$ The evidence reviewed revealed decreased rates of Erwinia substitution with premedication with concurrent TDM (RR 0.40, 95% CI 0.27 to 0.59).$^{68,71}$ In addition, by avoiding Erwinia substitution, pre-medication was

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

associated with a cost savings ranging from $12,402 (USD) per premedicated patient$^{68}$ to $106,550.$^{70}$ Considering that premedication would also lead to fewer reaction-related hospital admissions and avoiding Erwinia would lead to fewer chemotherapy clinic visits, cost savings were projected to be larger than these estimates.

Overall, the estimated desirable effects are moderate though the certainty of evidence is very low owing to indirect evidence leading to a risk of bias. More specifically, five out of six studies in this review evaluated non-AYAs, none were randomized, and the chemotherapy backbones varied between studies. Despite these limitations, the panel felt that the moderate desirable effects favor premedication compared with no premedication to prevent asparaginase reactions.

Harms and burden

The panel determined that there is low-quality evidence to argue against the implementation of premedication prior to asparaginase administration to prevent infusion reactions. Four studies in this review evaluated silent inactivation with two of these studies reporting no instances of silent inactivation$^{67,71}$ and two studies each identifying a single episode in a patient receiving premedication.$^{44,68}$ As outlined in the Good Practice Statement, TDM should be made readily available as a tool to avoid missing silent inactivation of pegaspargase in the context of premedication.

While the estimated undesirable effects are trivial, the panel acknowledges the very low certainty of evidence owing to an indirect evidence base and risk of bias. Even though these studies included non-AYAs and were not randomized, the panel felt that these undesirable effects were unlikely to be different in AYAs.

Other EtD criteria and considerations

The panel acknowledges that although there is no research evidence on patient values, preferences, and acceptability of premedication to prevent asparaginase hypersensitivity reactions, many of the potential benefits are aligned with patient values. In addition to reduced rates of hypersensitivity reactions, decreasing the need for Erwinia substitution is of particular importance given the burden of increased clinic visits and injections. Moreover, the resources required for premedication were deemed acceptable and feasible for implementation with the potential for cost savings as reported in two of the

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

non-comparative studies.$^{44,67}$ It should be noted that although several studies did not show an increase in silent inactivation with premedication, TDM is important to detect silent inactivation which may be masked by premedication. If TDM is unavailable, consideration should be given to administering asparaginase without premedication to allow for the detection of hypersensitivity and silent inactivation.

Conclusions and research needs for this recommendation

The panel determined that there is a net benefit of premedication to prevent asparaginase hypersensitivity reactions and that this includes at least IV corticosteroids but may also contain antihistamines and/or acetaminophen. The panel recognized that the evidence was of very low certainty. Despite this, the panel was compelled by the many desirable effects including a lower incidence of hypersensitivity reactions and the associated cost savings. Moreover, there did not appear to be a significant adverse impact with the use of premedication. Following the considered judgment process of the panel and the recognition that the intervention could mitigate a life-threatening situation (hypersensitivity reaction), the panel supported a strong recommendation in favor of premedication despite the very low certainty of evidence.$^{72}$

Prophylaxis of Venous Thromboembolism (VTE) in the setting of asparaginase

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

bleeding (strong recommendation based on very low certainty in the evidence of effects 😞)

Recommendation 5. For AYAs with ALL receiving frontline pediatric-inspired (asparaginase-containing) regimens, the ASH guideline panel recommends against the routine use of unfractionated heparin (UFH) for venous thromboembolism (VTE) prophylaxis (strong recommendation based on very low certainty in the evidence of effects 😊)

No recommendation. For AYAs with ALL receiving frontline pediatric-inspired (asparaginase-containing) regimens, the ASH guideline panel determined that the evidence is insufficient to issue a recommendation for or against routine venous thromboembolism (VTE) prophylaxis with low molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs).

No recommendation. For AYAs with ALL receiving frontline pediatric-inspired (asparaginase-containing) regimens, the ASH Guideline Panel determined that the evidence is insufficient to issue a recommendation for or against routine AT replacement.

Remark (for this group of VTE prophylaxis with asparaginase recommendations):

The panel recognizes uncertainty in timing or duration of VTE prophylaxis (induction, consolidation, intensification), LMWH dosing, and AT replacement targets and importance of risk models to identify high-risk patients.

Summary of the evidence

The panel considered a total of 14 comparative studies for review,$^{73-86}$ including three RCTs; the studies ranged from Tiers 2 to 6. Seven studies had a median age within the pediatric range, and six studies had a median age between 30-41 years. There was one study with a median age in the AYA range. There was a great deal of heterogeneity in the evidence in terms of anti-thrombotic therapy (in addition to heterogeneity in duration and timing of such therapy), clinical features (type of thromboses), and sociodemographic characteristics of the study populations. The heterogeneity and limited data made it

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

difficult for the panel to endorse strong conclusions. The evidence profile and EtD framework is available online at https://guidelines.ash/gradepro.org/staging/profiles/Si_DjDua_CL).

Benefits

Evidence reviewed by the panel was insufficient to routinely recommend routine VTE prophylaxis with LMWH. LMWH prophylaxis following asparaginase was associated with significantly decreased rates of VTE both when compared to UFH (RR 0.37, 95% CI 0.14 to 0.96) and to no prophylaxis (RR 0.54, 95% CI 0.36 to 0.83). However, the heterogeneity and imprecision in the studies was too great to support specific recommendations. There was a non-significant decrease in VTEs with the DOAC, apixaban (RR 0.69, 95% CI 0.45 to 1.05) compared to no prophylaxis; similarly, the panel concluded there was no recommendation for using this class of agents in this situation.

The evidence reviewed by the panel was insufficient for routine recommendation of AT replacement in the setting of asparaginase. While the systematic review of 3 studies comparing AT replacement with no prophylaxis demonstrated a decreased incidence of VTE (RR 0.57, 95% CI 0.35-0.92), the studies utilized different AT dosing, monitoring, replacement schedules, as well as varying replacement thresholds.$^{73,74,77}$ Due to this substantial heterogeneity and the retrospective nature of the studies, the panel was unable to support specific recommendations for AT replacement in this situation.

Harms and burden

Despite the paucity of data, the panel recommends against the routine use of cryoprecipitate (or fibrinogen concentrate) based on a retrospective adult study in which both FFP or fibrinogen concentrates and AT replacement were recommended as routine practice during treatment,$^{83}$ and patients receiving fibrinogen concentrate outside the context of grade 3/4 bleeding had a higher incidence of VTE (17% vs 9%; OR, 2.2, 95% CI, 1.1 to 4.3, p=0.02).$^{83}$

With the evidence reviewed, the panel recommends against the use of UFH for VTE prophylaxis. In an RCT (THROMBOTECT), UFH was inferior to both AT replacement and LMWH$^{79}$ and in a retrospective study,$^{83}$ UFH was unexpectedly associated with an increased risk of VTE (13% vs 7%; OR 1.92, 95% CI, 1.03 to 3.58; p=.04) and a lower risk of grade 3/4 bleeding (OR 0.51, 95% CI, 0.35 to 0.75).

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Although bleeding poses a potential harm with any VTE prophylaxis, the studies reviewed inconsistently reported bleeding and its clinical significance but did not reveal an increase in significant bleeding events for either LMWH (RR 0.43, 95% CI 0.05 to 3.83) or DOACs (RR 2.60, 95% CI 0.94 to 7.19).

Other EtD criteria and considerations

The panel acknowledges that there is limited research evidence on patient values, preferences and acceptability of VTE prophylaxis. While the THROMBOTECT RCT randomized pediatric patients to LMWH, AT replacement, and UFH arms during induction,$^{79}$ 3% of patients refused randomization to AT replacement and UFH arms, and 33% refused LMWH randomization. It is key to consider that this may potentially be due, in part, to injection-associated discomfort. Regardless, adding another agent to an already complex regimen for a fragile population merits close consideration. The panel strongly endorses shared decision making in discussion of VTE prophylaxis, particularly in outpatient setting where patients may be asked to inject themselves.

Conclusions and research needs for these recommendations

The panel was compelled to issue a strong recommendation against the routine use of cryoprecipitate or fibrinogen concentrate replacement (outside the context of active bleeding), despite the very low certainty of underlying evidence. In weighing the potential desirable and undesirable effects of cryoprecipitate (or fibrinogen concentrate) replacement, the panel was specifically concerned of an increased risk of thrombosis documented in the one available study.$^{83}$ Following the considered judgment process of the panel and the recognition that the intervention (cryoprecipitate or fibrinogen concentrate) might be associated with greater harm, the panel supported a strong recommendation against the use of cryoprecipitate or fibrinogen concentrate outside the context of bleeding.$^{72}$ Similarly, the panel issued a strong recommendation against the use of UFH for VTE prophylaxis, despite the very low certainty evidence. Again, the balance of desirable and undesirable effects were considered by the panel; although there was a paucity of data, the available evidence did not support any reduction in the risk of VTE (compared to AT replacement and LMWH) and in one retrospective study, UFH was associated with an increased VTE risk. Following the considered judgment process of the panel and the

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

recognition that the intervention (UFH) might be associated with greater harm, the panel supported a strong recommendation against the use of UFH.$^{72}$

Despite not providing a recommendation on VTE prophylaxis with LMWH, DOAC, or AT replacement, the panel recognizes the need for guidance in this patient population and situation. We also recognize the care of a hospitalized patient may be different than the outpatient setting with respect to treatment decisions regarding VTE prophylaxis. Identification of higher risk populations and/or treatment protocols is a useful step in assessing risk/benefit of routine prophylaxis. The VTE risks in the studies varied and included presence of central venous catheter, asparaginase administration, induction versus other treatment phases, age and patient body mass index. In patients at higher risk for VTE, additional decisions include timing and dosing of VTE prophylaxis. VTE incidence is highest during and immediately after induction, particularly for cerebral venous sinus thromboses, but is not negligible in subsequent phases of intensive treatment (excluding maintenance). While the use of DOACs has expanded in oncology, their use as VTE prophylaxis in ALL is limited. In the PREVAPIX-ALL study, pediatric patients were only treated for 28 days, so the results may not be generalizable to the AYA population or for treatment periods beyond induction.$^{84}$ At this juncture, we endorse individualized shared decision making and consideration of VTE prophylaxis for higher risk patients.

Alternative asparaginase formulations

For AYAs with ALL receiving frontline asparaginase who have an asparaginase-related reaction (allergic-type reaction), what are the comparative benefits and harms of desensitization versus use of alternative asparaginase products (Erwinia, Rylaze)?

Recommendation 6. For AYAs with ALL receiving frontline pediatric-inspired (asparaginase-containing) regimens who develop an asparaginase-related allergic/hypersensitivity reaction with pegaspargase, the ASH guideline panel recommends that patients switch to an Erwinia-based asparaginase formulation over discontinuation of asparaginase therapy (strong recommendation based on very low certainty in the evidence of effects 😊 😞)

Remarks:

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

$\bullet$ The panel was unable to provide a recommendation related to desensitization due to the lack of evidence comparing effects of desensitization versus alternative asparaginase products.

Summary of the evidence

The panel considered one non-randomized comparative study [[Gupta 2020]] and six additional non-comparative single group studies, all with a median age of 10 years or younger.$^{87}$ The overall body of evidence was consistent, but the certainty of the evidence was very low due to indirectness and imprecision. The panel explored whether it was possible to make a recommendation regarding desensitization versus switching to Erwinia, but due to very low certainty of the evidence and the lack of comparative studies, the panel was unable to provide a recommendation relating to de-sensitization. The evidence profile and EtD framework is available online at

https://guidelines.ash/gradepro.org/staging/profiles/EuVECNpYS3c.

Benefits

Switching to Erwinia was not associated with differences in survival compared to those who completed all of their intended asparaginase doses (HR 0.8, 95% CI 0.4-1.4).$^{87}$ However, missing PEG-asparaginase doses without Erwinia substitution resulted in an inferior DFS (HR 1.5, 1.1-1.9, p=0.002) compared with receiving all PEG-asparaginase doses and this decrease in DFS was mitigated by substitution with Erwinia (HR 1.1 95% 0.8-1.7, versus receiving all PEG-asparaginase doses).$^{87}$ Although the certainty of evidence regarding survival benefit was considered low, the panel felt that the desirable effects were of critical importance. While not included in the summary of evidence considered due to indirectness of the research question, the panel placed high relevance on reports of poor outcomes in patients who have early discontinuation of PEG-asparaginase rather than using alternative formulations.$^{88}$

The systematic review demonstrated clearly that adequate asparagine depletion is achieved with Erwinia chrysanthemi-based asparaginase products, with very few cases of silent inactivation. Overall,

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

the certainty of these estimated effects is very low owing to indirectness in the studies, a small total body of evidence, and imprecision of the estimates.

Harms and burden

The panel recognized that patients receiving Erwinia chrysanthemi-based asparaginase formulations remain at risk for serious toxicities associated with asparaginase therapy including pancreatitis, thrombosis, hypersensitivity/anaphylaxis, and hepatotoxicity. In addition to adverse effects associated with Erwinia chrysanthemi-based asparaginase products, the panel recognizes the increased burden associated with inconvenience of multiple weekly injections that must be administered in a healthcare setting. Additionally, there is an increased cost associated with Erwinia chrisanthemi-based formulations, with studies demonstrating a cost benefit when a pre-medication strategy prior to peg-asparaginase is implemented along with careful stewardship of individual cases to avoid unnecessary switching of asparaginase formulations.

Given that the data presented were pooled from single group analyses, there is a low certainty in the estimate of the risk of adverse effects. However, given the available evidence the guideline panel considered the risk of adverse effects and burdens of alternative asparaginase formulations to be outweighed by the survival benefits achieved when switching to an alternative formulation rather than discontinuing asparaginase in this patient population.

Other EtD criteria and considerations

The panel places a high importance on the availability of continued access to the currently available alternative asparaginase formulation, Rylaze(R) (Erwinia chrysanthemi (recombinant-rywn)) given adverse outcomes during a time period where Erwinia was not reliably available.$^{87}$ The panel also acknowledges the preponderance of the evidence available to drive this recommendation is based on older non-commercially available products, and that the currently available product, Rylaze®, is a different formulation for which comparative outcomes data are limited. Nonetheless, adequate asparagine depletion has been reported with Rylaze®.$^{89}$

Conclusions and research needs for this recommendation

The guideline panel determined that there is a very low certainty to the evidence for a net health benefit/harm from using alternative asparaginase formulations, namely Rylaze®. However, based on the

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

body of available evidence, and the high value placed on DFS outcomes in the high-risk population that is represented by AYAs, the panel judged that there is a strong potential for improved outcomes (including survival) without an appreciable difference in adverse events. Following the considered judgment process of the panel and the recognition that the intervention (switch to an Erwinia-based asparaginase formulation) might offer benefit in a life-threatening situation and weighing the potential substantial desirable effects (improved DFS) over minimal undesirable effects, the panel decided to issue a strong recommendation despite the very low certainty evidence.$^{72}$

The panel identified the following research needs: Additional data regarding tolerability of the commercially available product, Rylaze®, in the AYA population given the product was studied in mostly young children; Comparative effects of de-sensitization and/or challenge compared to switching formulations.

Rechallenging after asparaginase toxicity

For AYAs with ALL receiving frontline asparaginase who have a non-hypersensitivity asparaginase-related toxicity (e.g., coagulation-related side effect, pancreatitis, or hepatotoxicity), what are the comparative benefits and harms of resuming (or changing) asparaginase therapy?

The panel recognizes that in the absence of a recommendation, clinicians will need to rely on existing guidance on toxicity management; potential resources for clinicians at present include published treatment protocols, product monographs, and narrative/consensus guidance documents.$^{90}$⁻$^{93}$

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Allogeneic Transplant in First Complete Remission (CR1)

For AYAs with ALL being treated with frontline therapy, what are the comparative benefits and harms of allogeneic hematopoietic stem cell transplantation (allo-HSCT) versus no transplant in first complete remission (CR1)?

$\bullet$ Remark: For specific high-risk subgroups (especially those with minimal residual disease [MRD] persistence, induction failure, high-risk biologic subsets), there may be a survival benefit from allo-HSCT in CR1.

Summary of the evidence

The panel considered a total of seven comparative studies (none were RCTs) for review,$^{94-100}$ all of which were Tier 1 or 2 (with a median age all within or near the AYA range) for evaluating the benefit and harms of allo-HSCT versus no allo-HCST in AYA ALL patients in CR1. One study evaluated patients with Ph+ ALL;$^{100}$ the other 6 evaluated patients with Ph- ALL. Ph+ ALL is separately addressed in the section on Treatment for Philadelphia Chromosome-Positive ALL and Recommendation 12, and is not considered part of the high-risk subgroups defined here. MRD persistence is further defined and addressed with the section on Approach to Minimal Residual Disease and Recommendation 15.

Among these six studies reporting Ph- ALL, all reported on the effect of allo-HSCT on mortality or OS,$^{94-99}$ on EFS,$^{97}$ five on DFS or RFS,$^{94,95,97-99}$ and five on relapse.$^{94,95,97-99}$. Ph+ ALL is addressed in Recommendation 12 and the evidence profiles and EtD framework are available online at https://guidelines.ash/gradepro.org/staging/profiles/bxJabROu5Ac.

Benefits

Evidence reviewed by the panel demonstrates a significant survival benefit in AYA ALL patients who did not undergo an allo-HSCT (5-year OS: HR 0.48, 95% CI, 0.24-0.95), with 262 fewer deaths estimated per 1000 patients. The survival benefit noted for those who did not receive allo-HSCT in CR1 was largely due

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

to an increased risk of treatment related mortality (TRM) for those receiving allo-HSCT, with a significantly higher four-year risk of TRM (HR 6.88, 95% CI, 3.02-15.7) and higher non-relapse mortality (all cause) at three, five and six years.$^{98}$ After six years, 553 more patients per 1000 who underwent allo-HSCT in CR1 suffered non-relapse mortality compared with those AYAs who were not transplanted in CR1 (HR 5.41, 95% CI 3.23-9.06).

The panel recognizes both the scarcity of data and the low-quality data specifically comparing OS and EFS in allo-HSCT compared to no allo-HSCT in CR1 among AYAs with ALL, largely limited by the lack of RCTs with this focus. The data are also limited by the definition of CR1 and lack of availability of MRD status in older studies, thus limiting any outcomes specific to MRD status and allo-HSCT in the AYA ALL population. The panel acknowledges that high-risk subgroups (e.g. MRD persistence, KMT2A rearranged, Ph-like ALL, hypodiploid ALL, TP53 mutant ALL, ETP ALL) may benefit from allo-HSCT in CR1.

Unfortunately, because little data exist on these high-risk subgroups, the desirable effects of transplant in CR1 are unknown and may be further tempered by the current strategies to attempt to "eradicate" MRD with targeted antibody therapy prior to moving forward with allo-HSCT in CR1.

Harms and burden

The most undesirable effect from the intervention (allo-HSCT) is treatment-related (specifically transplant-related) mortality (TRM) leading to worse OS, compared with relatively less treatment-related mortality noted in the chemotherapy regimens alone. Mortality at 6 years was significantly higher for AYAs who received allo-HSCT in CR1 (HR 2.00, 1.5-2.66), with 228 more deaths estimated per 1000 patients amongst the transplanted patients.

Although beyond the scope of the systematic review, the panel also considered the significant long-term morbidities specifically associated with transplantation including infertility, graft versus host disease, organ toxicity, and secondary malignancies that are particularly relevant to the AYA population. Similarly, the panel acknowledges the long-term effects of chemotherapy, including second cancers, which require more focused study in the AYA population.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Other EtD criteria and considerations

The panel acknowledges that underrepresented/disadvantaged populations are less likely to find a matched unrelated donor. Even patients with matched donors experience disparities; certain aspects of allogeneic HSCT may make outcomes strongly linked to racial disparities (donor availability), to socioeconomic factors such as the expense and complexities of the procedures, as well as other potential social barriers (need for caregivers, transportation, etc.). The panel further acknowledges that access to allo-HSCT and to intensive pediatric regimens is not universal and that geographically, economically, and socially isolated populations are more likely to experience greater barriers to access highly specialized comprehensive care essential to the successful treatment of AYAs with ALL.

Conclusions and research needs for this recommendation

For AYA patients with ALL in CR1 and receiving pediatric regimens as frontline therapy, the ASH Guideline Panel suggests not to routinely proceed with allogeneic HSCT in CR1, while recognizing there are data lacking for specific high-risk subgroups (e.g. MRD persistence, KMT2A rearranged, Ph-like ALL, hypodiploid ALL, TP53 mutant ALL, ETP ALL) for whom the benefits may outweigh the harms. In light of the scarcity and low certainty of the evidence regarding this outcome in AYAs with ALL, and the fact that some patient subgroups may benefit from allo-HSCT, the panel's recommendation against this intervention is conditional.

The panel recognizes the urgent need for additional clinical trials focused on allo-HSCT in the previously mentioned high-risk populations, including attention to long-term outcomes and late effects. Similarly, long term follow-up to assess the late effects of an intensive pediatric regimen is essential. Future studies are also needed to evaluate the impact of newer targeted therapies (including antigen-directed therapies such as blinatumomab and inotuzumab), TKIs, and new molecular-based therapies (e.g. menin inhibitors, BH3 mimetics) on early MRD eradication and the subsequent benefit of allo-HSCT in CR1. Prospective studies evaluating access to centers of excellence for AYA ALL care and allo-HSCT, are urgently needed to further inform this recommendation, as such access is often determined by factors including insurance status, socioeconomic status and other social determinants of health.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Additional Therapies for Specific Subsets

Rituximab

$\bullet$ Remark: The panel recognizes the considerable uncertainty associated with rituximab dosing frequency and timing of administration, the minimum required level of CD20 expression, and the lack of data specific to younger AYA individuals.

Summary of the evidence

Among the publications that evaluated the efficacy of rituximab in combination with chemotherapy for frontline management of pre-B-cell ALL, four comparative studies met criteria for review by the panel; two were RCTs, one was a single group study, and one was a non-randomized comparative study.$^{101-104}$ The studies ranged from tiers 2 to 4, with a median age from 37 to 46; three of the four studies reviewed had a median age outside the AYA age range. The prioritized outcomes of interest included EFS, OS, and allo-HSCT. The evidence profile and EtD framework is available online at https://guidelines.ash/gradepro.org/staging/profiles/deBc3uGzTEI.

Benefits

The panel noted superior EFS at 2 years, 30 months, and 4 years (HR=0.66, 95%CI 0.45-0.98) with the addition of rituximab to standard chemotherapy in CD20-positive ALL in one RCT,$^{101}$ while differences in EFS in the other RCT were not statistically significant.$^{102}$ Although the median age in the first trial was 40

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

years, in subgroup analyses there were no significant differences based on age (younger or older than 40 years). There was a lower risk of relapse in both an RCT (HR=0.52, 95%CI 0.31-0.89)$^{101}$ and in the non-randomized prospective study with a median age of 41 (RR=0.55, 95%CI 0.41-0.72).$^{104}$ Although there were no statistically significant differences in OS in the RCTs, there was a lower hazard of death following allo-HSCT in patients who received rituximab (HR=0.55, 95%CI 0.34-0.91).$^{101,102}$

No studies demonstrated significant differences in CR rates or MRD negativity following first induction or first consolidation.

Harms and burden

Adding Rituximab to chemotherapy did not significantly increase toxicity in frontline management of ALL; in particular there was no statistically significant increased risk of infections or cytopenias.$^{101,102}$ Nevertheless, the panel highlighted that the addition of rituximab to standard therapy may be associated with some undesirable effects, including infusion reactions, prolonged immunosuppression (including hypogammaglobulinemia and delayed-onset neutropenia) and loss of vaccine efficacy.

The addition of rituximab to various chemotherapy backbones has the potential to increase costs and impose additional burden on patients by increasing the number and duration of infusion appointments.

Other EtD criteria and considerations

The certainty of evidence for critical outcomes related to rituximab (including EFS and OS), were considered low to very low. The panel acknowledged that differences in the study designs (including dosing frequency and timing of rituximab administration and level of CD20 expression level of enrolled patients) may explain the differences in results (i.e., studies that use more doses showed more benefit whereas the only study that used 4 doses did not find a benefit).$^{102}$

The recommendation was informed by the patient panelists, who placed the highest value on overall survival/mortality relative to other outcomes. Thus, while the panel acknowledged that the available dataset may not have captured all outcomes of value for patients, that uncertainty was not felt to likely change the direction or strength of the recommendation.

The panel acknowledges that underrepresented/disadvantaged populations may be disproportionately impacted by the high costs associated with the potential cost/resource implications associated

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

with novel/targeted immunotherapies, including rituximab. The panel noted that some institutions may face barriers to providing inpatient novel therapies (including rituximab).

Conclusions and research needs for this recommendation

For AYA patients with CD20-positive ALL receiving frontline therapy, the potential benefit of rituximab appears to outweigh the risks. In particular, rituximab appears to decrease the risk of relapse. This recommendation is based on data that include, but are not limited to, an AYA population. Future studies that include AYAs (ideally with age-based sub-analyses) regarding the minimal threshold of CD20 expression, the optimal timing and dosing of rituximab, and the role of rituximab in the context of other evolving immune-based therapies would enhance the management of AYA ALL patients.

Blinatumomab

Remarks:

$\bullet$ The panel recognizes there are limited data using blinatumomab within conventional pediatric-inspired chemotherapy backbones.

$\bullet$ The panel further recognizes the evolution of evidence in this space, and that the recommendation may change with the availability of more data.

* Guidance for individuals with MRD persistence is addressed in Recommendation 15.

Summary of the evidence

Two comparative studies met criteria for the panel to review regarding the role of blinatumomab in frontline management of MRD-negative B-ALL;$^{105,106}$ the studies were within tiers 3-4, with median age ranges of 37 to 55 years. While one of these studies was prospective with a subset analysis restricted to individuals <55 years of age with MRD-negative disease, younger AYAs (<29 years) were excluded.$^{106}$ Importantly, the panel acknowledges that prospective randomized comparative studies are lacking for

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

the use of blinatumomab. $^{107}$ Considerations related to MRD-positive disease are addressed in Recommendation 15. The evidence profile and EtD framework is available online at https://guidelines.ash/gradepro.org/staging/profiles/VtHyq5pflfg.

Benefits

The panel noted the two referenced studies demonstrated improvement in RFS and OS with the addition of blinatumomab to an intensive chemotherapy backbone. At 3.5 years, there was superior OS (lower hazard of death, HR=0.16, 95%CI 0.05-0.47) and DFS (lower hazard of relapse/death: HR=0.53, 95%CI 0.32-0.87). The only study to evaluate a solely AYA population was a small non-randomized single institution study with an AYA subset (n=22, 18-39 years), in which a 3-year RFS 77% RFS and 86% OS were observed in interim analysis.$^{106}$

Harms and burden

The panel highlighted that blinatumomab is associated with notable toxicities. In the relevant RCT considered by the panel, the only statistically significant toxicity identified was ≥ grade 3 neurologic events (RR=4.20, 95%CI 1.79-9.85) with blinatumomab.<sup>106</sup> Other reported toxicities included infusion-related reactions, cytokine release syndrome (CRS), and development of hypogammaglobulinemia.

Other EtD criteria and considerations

The certainty of evidence in support of blinatumomab in the frontline setting was felt to be very low in the AYA setting.

The panel noted the potential substantial cost and resource implications associated with blinatumomab, including the requirement for hospitalization at the time of drug initiation, the need for 28-day continuous infusion cycles, and the potential of increasing the overall duration of therapy compared to regimens that do not include blinatumomab. In addition, the panel recognized that some institutions may face barriers to providing both inpatient immunotherapies as well as home-health care infrastructure required for prolonged continuous intravenous infusion. The panel also recognized patient acceptance and adherence to novel targeted therapies may be multifactorial, with these and similar considerations contributing to the overall therapeutic burden. The panel acknowledges that underrepresented and disadvantaged populations may also be disproportionately impacted by the high costs and complexity of blinatumomab administration.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

The panel recognized that this guideline is principally focused on management of AYA ALL in well-resourced countries and wished to highlight the potential for variable and inequitable global access to blinatumomab within clinical trials or as a component of standard therapy.

Conclusions and research needs for this recommendation

The panel acknowledges encouraging improvements in RFS and OS with the incorporation of blinatumomab within consolidation treatment for patients, regardless of MRD status. This includes patients who do not undergo allo-HSCT and patients with high-risk genomic features. The use of blinatumomab in MRD positive disease is addressed with a later recommendation (see recommendation 15).

Further prospective randomized studies specific to the AYA population and including pediatric-inspired chemotherapy backbones are required to establish definitive real-world evidence that supports the use of blinatumomab in the frontline management of ALL in AYA populations. The panel also acknowledges that formulations of blinatumomab that may improve equity of access and deliverability of therapy are desirable.

Inotuzumab ozogamicin (Inotuzumab)

Although two manuscripts were identified at the time the panel was convened, neither met criteria for review by the panel; one was below tier 6 (<25 patients) and the other was tier 5 (median age 68).$^{108}$,$^{109}$ There were insufficient data to further consider the addition of inotuzumab ozogamicin in CR1.

The panel recognizes that data in this area are emerging, including studies that may further clarify the toxicities associated with the addition of inotuzumab to multiagent chemotherapy (including trials NCT03150693 and NCT03959085), and that with time this recommendation may evolve.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Nelarabine

$\bullet$ Remark: The panel noted that incorporating nelarabine may provide benefit among subgroups of AYAs including those with non-ETP subtype, CNS3 disease, and/or others who receive a high-dose methotrexate-based interim maintenance regimen.

Summary of the evidence

The panel considered eight comparative studies that incorporated nelarabine into frontline therapy for T-ALL or T-LBL/LLy.$^{110}$⁻$^{117}$ The studies ranged from tiers 1-4, with a median age ranging from 10 to 46; although one study had a median age >40 years and three studies had median ages <14, one of the younger studies had an AYA-only sub-analysis, and an additional three studies had median ages between 15-39. The evidence profile and EtD framework is available online at https://guidelines.ash/gradepro.org/staging/profiles/ly9b_Czxjs.

Benefits

Among patients with T-ALL enrolled on an RCT with an asparaginase-containing chemotherapy backbone, a significant 5-year DFS benefit (RR=1.07, 95%CI 1.01-1.15) was observed for those randomized to receive nelarabine.116 However, there was no OS benefit, the median patient age was young, and in the AYA subgroup the DFS advantage was not maintained (survival ratio = 0.96; 95% CI 0.67-1.39, p=0.81).$^{115}$ While patients assigned to receive nelarabine across all arms in this trial were observed to have a significantly lower risk of CNS relapse (1.3% versus 6.9%), the panel recognized uncertainty related to whether patients benefited from nelarabine or the study-allocated approach to

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

methotrexate treatment. In particular, while all patients were randomized to receive (or not receive) nelarabine, all CNS3 patients were non-randomly assigned to high-dose methotrexate, while CNS1-2 patients were randomized to either high-dose or escalating (Capizzi) methotrexate. Although CNS3 patients randomized to nelarabine (all receiving high-dose methotrexate) had fewer CNS relapses (3.4% vs. 21.4%) and superior DFS (93.1% vs. 67.9%, p=0.014) than those who did not receive nelarabine, the cumulative incidence of CNS relapse among all patients was lower among those assigned to Capizzi (0.2%) than high-dose (2.1%) methotrexate.

With this in mind, the panel determined that the evidence was insufficient to issue a recommendation for or against the addition of nelarabine for AYAs with T-ALL receiving frontline therapy with all planned doses of asparaginase (including Capizzi methotrexate-based interim maintenance), while noting that some subgroups of AYAs may see some benefit to including nelarabine (non-ETP subtype, CNS3 disease, and/or others who receive a high-dose methotrexate-based interim maintenance regimen).

Among patients with T-LBL/LLy receiving nelarabine, neither an OS nor DFS benefit was observed.$^{110,111,117}$

Harms and burden

In the studies reviewed, no statistically significant differences in neurotoxicity were observed between cohorts receiving or not receiving nelarabine.$^{111,113,117}$ Nevertheless, the panel recognizes both a black box warning for nelarabine regarding neurotoxicity based on historical data,$^{118}$ and cases of nelarabine-associated rhabdomyolysis noted in post-marketing surveillance.$^{119,120}$

Other EtD criteria and considerations

The patient panelists discussed the high value that patients place on overall survival/mortality, rendering it of higher value than other outcomes. In addition, toxicities were considered important by patient panelists, even independent of long-term impact on QOL.

Considering the way in which it is administered (e.g. intravenously for five consecutive days), the incorporation of nelarabine into frontline therapy increases overall healthcare resource utilization. Additionally, use of these therapies requires increased financial burden on patients/families both for the therapy itself and for travel and other potential costs.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Conclusions and research needs for this recommendation

After review of the outlined evidence and feedback from public comment, the panel determined that the evidence is insufficient to issue a recommendation for or against the addition of nelarabine to frontline therapy for AYAs with T-ALL, while noting that there may be potential benefit among subgroups such as those with non-ETP T-ALL, CNS3 disease, and/or any others receiving a high-dose methotrexate-based interim maintenance regimen. The panel suggests against incorporating nelarabine into treatment regimens for patients with T-LBL/LLy.

For more definitive evidence, future work is necessary, including RCTs incorporating nelarabine into T-ALL therapy for the AYA population.

Bortezomib

No recommendation. For AYAs with T-cell lymphoblastic lymphoma (T-LBL/LLy), the ASH guideline panel determined the evidence is insufficient to recommend for or against addition of bortezomib.

$\bullet$ Remark: The panel noted that incorporating bortezomib may provide benefit amongst the youngest adolescents of the AYA population.

Summary of the evidence

One comparative study was eligible for panel consideration; this was a tier 3 study with a median age of 12 years and reported an RCT that incorporated bortezomib into a an asparaginase-containing regimen for patients with T-ALL/T-LBL/LLy.$^{121}$ The benefits of bortezomib were considered as a whole and separately for patients with T-ALL and T-LBL/LLy. The evidence profile and EtD framework is available online at https://guidelines.ash.gradero.org/staging/profiles/jxDJFpHhxG0.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Benefits

When considering T-ALL and T-LBL/LLy together, or T-ALL alone, there was not a statistically significant survival benefit for bortezomib (OS or DFS). While both 4-year OS (RR=1.13, 95%CI 1.03-1.24) and EFS (RR=1.12, 95%CI 1.01-1.27) were improved with the addition of bortezomib when considering T-LBL/LLy alone, the lack of enrollment of older AYAs coupled with the young median age (12 years) precluded a recommendation specific to the AYA population.

Harms and burden

There were no significant differences with respect to toxicities between patients receiving and not receiving bortezomib (overall AEs, grade ≥3 RR 1.05, 95%CI 0.97-1.12), including neuropathy and pulmonary toxicities.$^{121}$ When considering neuropathy in particular, which is known to be associated with bortezomib, there also is no significant difference between randomized groups.$^{121}$ Patients randomized to bortezomib were no more likely to experience grade 3-4 peripheral motor neuropathy than those randomized to chemotherapy alone (RR 0.66, 95%CI 0.4-1.06). Similarly, grade 3-4 peripheral sensory neuropathy was no more likely in those randomized to bortezomib (RR 1.31, 95%CI 0.82-2.11). Nevertheless, the panel acknowledges the known association between bortezomib and both neuropathy and pulmonary complications. These are more common with increasing age, especially when bortezomib is combined with vincristine. Given this concern of increasing toxicity with age and lack of data across the AYA age range, the panel could not issue a recommendation for AYAs with T-LBL/LLy of all ages but acknowledged that there may be benefit in the youngest AYAs with T-LBL/LLy.

Other EtD criteria and considerations

The patient panelist emphasized the high value placed on overall survival/mortality relative to other outcomes; this informed the recommendation against bortezomib in T-ALL and the lack of a recommendation in T-LBL/LLy.

Conclusions and research needs for this recommendation

For patients with T-ALL, the panel suggests against incorporating bortezomib into frontline therapy. For AYAs with T-LBL/LLy, the panel concluded that the evidence was insufficient to recommend for or against addition bortezomib to frontline therapy for all AYAs. The panel recognized that the available

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

study did not include older AYAs and thus, efficacy and toxicity in this population is unknown.

Incorporating bortezomib into treatment for the youngest adolescents with T-LBL/LLY however, may provide benefit amongst the youngest adolescents of the AYA population with T-LBL/LLy.

Future research is needed to evaluate the optimal treatment of AYA patients with T-ALL. It is imperative that this research includes AYA patients of the entire age spectrum, between the ages of 15 and 39.

Treatment for Philadelphia Chromosome-Positive ALL

For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits & harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumab ozogamicin) plus a TKI?

Remarks:

$\bullet$ All patients with Ph-pos ALL must receive CNS prophylaxis with concurrent intrathecal (IT) chemotherapy (see Recommendation 13).

$\bullet$ The panel recognizes that post-remission therapies (including allo-HSCT) are evolving given emerging data surrounding next-generation TKIs and novel/targeted immunotherapies.

$\bullet$ This recommendation may not be as applicable to the youngest AYA subgroup in which pediatric-inspired (asparaginase-containing) regimens would be applied; the

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

panel appreciates that studies of pediatric-inspired backbones were not captured within the available dataset.

Summary of the evidence

The panel considered a total of 25 studies for review,$^{122-146}$ ranging from Tiers 1 to 3. Three comparative studies with median age ranges of 40-47 years evaluated a TKI combined with either reduced intensity therapy (RIT) or intensive chemotherapy (IC) during remission induction.$^{144-146}$ These included one RCT comparing RIT plus the first-generation TKI imatinib to standard Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) chemotherapy during induction.$^{144}$ An additional 22 non-comparative single group studies were reviewed. Two had a median age in the AYA range, two had a median age of 10 years, and the remainder had median ages between 30 and 55 years. The indirect evidence of these studies was taken into consideration to further support the panel's recommendations. https://guidelines.ash/gradepro.org/staging/profiles/CrRFHtO0fWU.

Benefits

The bulk of the evidence reviewed by the panel did not focus solely on an AYA population and specifically did not include AYAs under the age of 18. Nevertheless, the studies reviewed by the panel demonstrated that induction with RIT plus TKI appears to be associated with reduced early treatment-related mortality and improved OS compared to IC with TKI. Specifically, patients treated with RIT plus TKI are less at risk for death within 60 days compared to those treated with a standard chemotherapy regimen (RR 0.25, 95% CI 0.07 to 0.85), and there is a trend toward higher likelihood of overall survival at five years using a RIT regimen (HR 1.17, 95% CI 0.84-1.62).$^{144}$ The panel determined there is low certainty evidence suggesting potential decreased short-term infections and adverse events (AEs) in AYA patients with Ph+ ALL treated with RIC plus TKI compared to IC plus TKI. The first induction cycle carries less infectious risk when RIT is used rather than IC (RR = 0.64, 95%CI, 0.49 to 0.83), and is accompanied by a trend toward lower rates of other grade 3-4 AEs during induction with RIT plus TKI compared to IC plus TKI (RR 0.90, 95% CI 0.69-1.19).$^{144}$

Overall, the estimated desirable effects are moderate though the certainty of the evidence is very low owing to the indirect evidence base and imprecision of the estimates including wide confidence intervals. Additionally, the studies reviewed included patient populations that were not AYA, and only

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

one study was an RCT. Most patients received post-remission therapy with chemotherapy, and many followed this by allo-HSCT; however, it was not possible to determine the relative effect of allo-HSCT on clinical outcomes. Nevertheless, given the benefits of desirable effects including reduced mortality and improved EFS and OS, the panel felt the evidence most likely favors the use of RIT plus TKI over IC plus TKI during remission induction. The panel recognizes that post-remission therapies (including allo-HSCT) are evolving given emerging data surrounding next-generation TKIs and novel/targeted immunotherapies.

Harms and burden

With an RIT regimen, the panel considered the risk of higher relapse rates. The data suggest, however, that RIT is not associated with an increased rate of early relapse in studies evaluating this outcome. There is a non-significant trend towards lower rates of pre- and post-allo-HSCT relapse rates with RIT plus TKI than with IC plus TKI (pre-allo-HSCT RR 0.26, 95% CI 0.03-2.18; post-allo-HSCT RR 0.65, 95% CI 0.2-2.11). Patients who received RIC plus TKI also trend towards reduced transplant-related mortality than those who received IC plus TKI (RR 0.35, 95% CI 0.1-1.18).

The panel acknowledges there is very low certainty regarding these data owing to indirectness, imprecision, and risk of bias. Comparisons between RIT and IC with respect to long-term toxicity and AEs following the remission induction period are limited by introduction of post-remission therapy and transplantation. Furthermore, conclusions regarding harm from the intervention of RIT rather than IC were limited by the lack of RCT or observational data addressing other important AEs considered by the panel, namely organ-specific side effects, quality of life, time spent in the inpatient setting and rate of hospitalization, and financial toxicity, among others.

Contextualizing the implications of one therapeutic strategy compared to another is essential to the understanding of potential harms despite the lack of direct evidence. The panel acknowledges that other factors also appear to favor the use of RIT plus TKI for induction, but these may not easily be quantitatively measured. These include the increased risk of infertility with high-dose chemotherapy (such as Hyper-CVAD) and the potential for cardiac toxicity from higher doses of anthracycline-based therapy. Both risks could possibly be lowered with reduced intensity regimens, although they are not eliminated. As data evolve regarding novel strategies for reduced intensity therapy, such as incorporation of targeted agents or transplant-sparing immunotherapy combinations, new approaches

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

may further reduce the risk of chemotherapy-related toxicity during chemotherapy cycles beyond remission induction (consolidation and maintenance).

Other EtD criteria and considerations

Overall survival and ability to achieve CR were recognized by the panel to be of highest value to patients in balance with toxicities and quality of life (QOL). Though the available data did not capture all outcomes of value for patients, namely QOL, the panel did not believe this uncertainty was enough to change the strength or direction of the recommendation. With the promising results of combined second (and now third) generation TKIs with blinatumomab and response-adapted transplant approaches,$^{109,141,147}$ the panel recognized that these approaches are likely to support the values important to patients.

The panel acknowledged that the comparison of chemotherapy intensity did not include intensive pediatric-inspired asparaginase-containing regimens or the incorporation of blinatumomab into these regimens, now utilized by national and international cooperative groups for the treatment of pediatric Ph+ ALL. The intensive pediatric treatment approach utilizes an MRD-guided post-remission risk-stratification strategy that results in fewer pediatric patients undergoing allo-HSCT compared to the adult RIT trials that informed our recommendation. Therefore, the recommendation may not be directly applicable to younger AYA patients or acceptable to clinicians treating this subgroup of patients.

Most patients in the available comparative studies received the first-generation TKI, imatinib, thereby limiting the panel's ability to analyze comparative efficacy, drug accessibility, or cost among TKI generations. In one retrospective study reviewed,$^{146}$ some patients received the second generation TKIs, dasatinib and nilotinib. The third generation TKI, ponatinib, may further avoid emergence of treatment resistance in Ph+ ALL, but results of treatment regimens incorporating ponatinib were not yet available during the generation of this guideline. The panel acknowledges that disadvantaged populations may be disproportionately impacted by higher costs of second and third-generation TKIs, limiting their broad access. The same limitations apply to consolidative treatment with targeted immunotherapies such as blinatumomab.

Conclusions and research needs for this recommendation

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

This panel determined that there may be a net benefit of RIT plus TKI over IC plus TKI for remission induction in AYA patients with Ph+ ALL. This recommendation places a high value on the potential benefits of RIT over more intensive chemotherapy. All patients should receive central nervous system prophylaxis as part of their treatment, with frequency and intensity depending on the type of regimen used, and with particular attention to those receiving a reduced-intensity approach.

Future research is needed to evaluate the optimal treatment of AYA patients with Ph+ ALL and efforts amongst pediatric and adult hematology cooperative groups should be made to broaden prospective studies to include the entire AYA age range. Although the induction question is relatively straightforward (despite low grade evidence), the best post-remission therapy approach is evolving. Excellent survival rates using TKI with blinatumomab without all-HSCT have recently been reported in adults with Ph+ ALL.$^{142}$ Longer-term follow-up of this study as well as results of ongoing prospective studies that include AYAs, and are testing third generation TKIs, targeted immunotherapy, with minimal or no traditional chemotherapy and no allo-HSCT, will be critical to strengthen our current guidelines. The role of CAR-T therapy in frontline treatment of Ph+ ALL also remains to be elucidated. Improved risk-stratification models to identify high-risk patients who might benefit from allo-HSCT in CR1 will also be helpful.

CNS Prophylaxis

For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?

Intrathecal chemotherapy regimens

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

$\bullet$ Remark: Hydrocortisone can be used (in conjunction with IT methotrexate) for prevention of chemical arachnoiditis.

Summary of the evidence

The panel reviewed 14 comparative studies that evaluated CNS prophylaxis regimens, ranging from Tiers 3 to 6 with a median age <10 years in all but one study. Among these, two RCTs compared triple intrathecal therapy (TIT: intrathecal methotrexate, cytarabine and hydrocortisone) with single agent intrathecal therapy (SIT: methotrexate) as post-induction CNS prophylaxis among patients without CNS involvement$^{148}$⁻$^{150}$ with a median follow-up of 5-6 years. One of these compared neurocognitive outcomes at 6 years between TIT with SIT.$^{148}$

For all outcomes, the certainty of the evidence was considered low to very low due to indirectness and imprecision of the data. Generalizability to the AYA population cannot be precisely determined as most patients included in the analysis were younger than AYA age. The evidence profile and EtD framework is available online at https://guidelines.ash/gradepro.org/staging/profiles/k4oMgZsVBLQ.

Benefits

A meta-analysis comparing the benefits of TIT vs SIT showed no differences in OS (RR 0.98, 95%CI 0.94 to 1.03), DFS (RR 0.97, 95%CI 0.71 to 1.33), or EFS (RR 0.98, 95%CI, 0.94 to 1.02), but did reveal a lower rate of isolated CNS relapse favoring TIT (RR 0.58, 95%CI, 0.40 to 0.83). One trial found higher rates of systemic relapse in patients receiving TIT with relapses that were generally harder to salvage.$^{149}$ The panel noted challenges in interpreting these results, however, as at least one was an older study utilizing a chemotherapy backbone with less systemic intensity than what is currently used.

The panel highlighted that the consequences of CNS relapse, and its treatment, are likely to be significant and under-recognized. Therefore, isolated CNS relapse was considered an important outcome independent of EFS and OS. Despite the lower risk of CNS relapse seen with TIT however, the panel could not conclude that TIT is clearly superior to SIT due to the lack of difference in EFS or OS.

Harms and burden

The panel was concerned about the potential for increased neurological toxicities and long-term cognitive impairment with the use of TIT compared with SIT. In studies directly comparing TIT to SIT,

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

there were no significant differences in encephalopathy, neurotoxicity or CNS toxicity outcomes while on treatment.$^{148,150}$ Long term follow-up of neurocognitive function found no meaningful differences between treatment arms across many measured metrics. There was a small difference noted in cognitive processing speed in favor of TIT. However, it is unclear if this outcome is clinically relevant and representative of actual neurocognitive function. In addition, these studies only included patients between 1 and 9.9 years of age, so the data were indirect for the AYA population. The panel recognized the importance of neurocognitive and neurotoxicity outcomes and their impact on future quality of life and work productivity. The panel highlighted that these concerns are often under-recognized and not routinely discussed at the outset of treatment. In our literature search, comparative and prospective studies in AYA patients with ALL focusing on the effects of CNS-directed therapies on long-term neurocognition were lacking.

The panel raised concerns about the more immediate side effects of IT therapy, including chemical arachnoiditis. Although the scope of this systematic review did not establish strategies that clearly reduce the risk of chemical arachnoiditis, the panel recognizes that there is a long-standing practice, particularly among adult oncology centers, to administer IT hydrocortisone in addition to IT methotrexate and/or IT cytarabine for this purpose. The panel felt it was reasonable to consider the addition of hydrocortisone to IT therapy. In addition, IT cytarabine can be used as an alternative for patients exhibiting intolerance to IT methotrexate, although there are no data to clearly determine if it is non-inferior. The panel also raised some concerns about the need for repeated sedation/anesthesia in younger AYA patients and its cumulative effects, including neurocognition. The consequences of these exposures were not captured in this analysis.

Conclusions and research needs for this recommendation

For AYA patients with ALL receiving frontline therapy, the ASH guidelines panel suggests the use of either single agent IT therapy (methotrexate) or triple IT therapy for CNS prophylaxis. The analysis did not demonstrate an EFS or OS benefit from TIT compared with SIT. There were also no clear differences in encephalopathy, neurotoxicity, CNS toxicity, and neurocognition. The panel felt that the available data favored neither intervention nor comparator.

Additional research studies in the AYA population directly comparing TIT to SIT would be beneficial, especially in the context of the evolving incorporation of immunotherapy into ALL treatment regimens. Analyzed outcomes should not only include CNS relapse, OS, and EFS, but also short-term and long-term

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

neurologic toxicities. Comparative studies looking at the long-term neurocognitive effects of therapy (and subsequent impact of CNS relapse) are lacking and should be considered a research priority.

Cranial Radiation

$\bullet$ Remark: There is uncertainty with respect to the use of cranial radiation for CNS prophylaxis for AYA individuals with T-ALL who are unable to receive nelarabine.

Summary of the evidence

The panel reviewed 12 studies$^{121}$,$^{151}$⁻$^{163}$ that evaluated CRT for CNS prophylaxis, with a median age <10 in all but one study. Only three studies provided randomized evidence comparing CRT use to no CRT use.$^{152}$,$^{159}$,$^{160}$ Overall, the panel recognized that there is considerable heterogeneity in the studies included with respect to other CNS-directed therapies, such as intrathecal and systemic (e.g., high-dose methotrexate) treatments. This heterogeneity limits the strength of the pooled analyses. Some studies were based on systemic backbone regimens that are less relevant to current practice (and not all of which were pediatric-inspired). The panel also noted that many of these studies were conducted in children under ten years old, rendering the evidence even more indirect. In all but one of the studies evaluated, risk of bias was serious to very serious, and all studies provided indirect evidence due to the ages of patients included. The evidence profile and EtD framework is available online at https://guidelines.ash/gradepro.org/staging/profiles/QELaX1fLG70.

Benefits

Among three randomized studies included in the meta-analysis, there was no difference in OS, DFS, or EFS in patients who did and did not receive CRT; of note, patients who did not receive CRT were treated with intensive intrathecal therapy and systemic chemotherapy that provides some CNS

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

penetration.$^{152,159,160}$ In specific, there was no OS difference between groups receiving or not receiving CRT at 8-10 years$^{152,160}$ (RR=1.02, 95% CI=0.97-1.07) or 25 years from diagnosis$^{9}$ (CRT: 78.5% vs. no CRT: 78.1%; HR=1.00, 95% CI=0.53-1.88)$^{121,156,157}$ In two non-randomized comparative studies there was also no benefit to OS (RR=1.00, 95% CI=0.99-1.01),$^{121,157}$ nor EFS or DFS with use of CRT. Overall, the panel agreed that there were no clear benefits to administering prophylactic CRT to patients without CNS involvement compared to the use of intrathecal chemotherapy and treatment regimens with systemic chemotherapy that provides CNS coverage.

Harms and burden

A significant concern with CRT use is the risk of poor neurocognitive outcomes. Eight studies described such outcomes and generally suggest that CRT use leads to worse function in this area. Domains of concern for deterioration included attention, processing speed, neuromotor abilities, visual learning and motor integration, and general academic achievement.$^{151,153-155,162,163}$ Importantly, these studies primarily included younger patients (under 15 years) during the period of CRT exposure. The panel recognized that the risks and burdens of neurocognitive deficits may be different among AYAs receiving CRT; however, data on both short- and long-term burdens of CRT use among AYAs are lacking. Nonetheless, given the lack of benefit coupled with potential harms associated with CRT use, the panel does not recommend routine use of prophylactic CRT among AYAs with ALL without CNS involvement.

Other EtD criteria and considerations

Of particular consideration is the evolving role of CRT as CNS prophylaxis in T-ALL, especially since most patients in the included studies were treated for B-ALL. All T-ALL patients enrolled on CALGB 10403$^{44}$ and all intermediate- and high-risk patients enrolled on COG AALL0434 were non-randomly assigned to receive prophylactic CRT as part of protocol therapy$^{113}$ and experienced favorable outcomes. However, the AALL0434 trial additionally randomized these patients to nelarabine or no nelarabine, and to high-dose or escalating (Capizzi-style) methotrexate (see Additional Therapies for Specific Subsets: Nelarabine section for additional detail regarding the role of nelarabine in CNS relapse).$^{113}$ The panel expressed uncertainty with respect to the role of CRT for CNS prophylaxis in T-ALL in the setting of nelarabine (either its use or omission), as treatment with and without CRT has not been formally tested. The panel also expressed uncertainty about the role of CRT for AYAs with T-ALL who are unable to receive nelarabine due to toxicity or other comorbidities.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Conclusions and research needs for this recommendation

When taken as a whole, the studies showed no clear benefit to administering prophylactic CRT to patients without CNS involvement, with the caveat that most of the patients considered in these studies were treated for B-ALL. Furthermore, while the risk of cognitive impairment due to CRT exposure is well-described among younger patients, the burden of this risk is less described among AYAs. As a result, studies describing late effects from CRT exposure may not be representative of the impact on AYAs or the risk-benefit ratio that AYA patients may place on the use of CRT to reduce CNS relapse risk. Finally, current radiation doses, protocols, and techniques may result in different toxicity rates and cognitive outcomes than those documented in the summarized older studies. Considerations for future work should include dedicated work on neurocognitive outcomes in patients undergoing CRT during the AYA years and could include prospective studies of the efficacy of nelarabine without CRT to prevent CNS relapses.

Approach to Minimal Residual Disease (MRD)

For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?

Remarks:

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

* While T-ALL has not been studied individually, patients with T-ALL were included in the studies demonstrating the benefit of transplant for patients with MRD-positivity.

Good Practice Statement for Recommendation 15. Measurement of disease response using MRD is considered standard of care in AYA ALL for both prognostic value and, in some cases, determination of treatment intensity.

Background

Quantitative measurement of MRD has both prognostic and therapeutic implications in ALL and is now considered a standard of care for disease assessment in patients with ALL. There are different methods of MRD measurement and prognostic implications of MRD levels are dependent on treatment approach and treatment timepoint. A few general definitions may be helpful. In most studies, the definition of MRD-positive disease is ≥0.01% when using quantitative flow cytometric or clone-specific MRD measurement. Conversely, MRD-negative disease is defined as <0.01% using these methods. Next-generation sequencing (NGS) techniques for MRD measurement are more sensitive than flow by approximately two logs (e.g. <0.0001%) and report an absolute copy number of the leukemia-specific IgH or TCR clonally rearranged cells representing the leukemia clone. The AYA guideline panel is aware of a forthcoming guideline from the College of American Pathologists and systematic review with expert recommendations in the application, interpretation, and actionability of MRD for pediatric and adult B-cell ALL (B-ALL) (https://www.cap.org/protocols-and-guidelines/cap-guidelines/current-cap-guidelines/evaluation-of-mrd-testing-in-all).

While this recommendation focused on the decision to alter therapy in MRD-positive patients following initial therapy, there are parallel considerations for MRD-negative patients addressed in recommendations above and these are referenced below.

Summary of the evidence

To determine the effects of changes in therapy based on MRD status in AYA patients with ALL, the panel reviewed a total of 5 comparative studies from tiers 2 to 3 and a median age ranging from 31 to 55 years.$^{99,106,164-166}$

Indirect evidence from an additional 9 non-comparative studies that are not included in the evidence profiles was discussed and taken into consideration by the panel.108,167-174

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

The evidence profiles for MRD+ and MRD- in CR1 and EtD framework are available online at https://guidelines.ash/gradepro.org/staging/profiles/juHAYkZOB0w.

Benefits

The panel reviewed five comparative studies that evaluated changes to therapy based on MRD-positivity after both induction therapy and at least one cycle of consolidation therapy in AYA ALL. $^{99,106,164-166}$

First, data were considered surrounding the addition of blinatumomab to therapy for patients in an MRD-positive remission. With the addition of blinatumomab in MRD-positivity, there was a decreased risk of relapse or death at 2.5 years adjusting for allo-HSCT (HR 0.47; 95% CI: 0.30-0.73)$^{169}$ and MRD-positive patients were more likely to be able to receive an allo-HSCT (44% vs. 78.5%; HR 1.78, 95% CI: 1.46-2.19). This was not accompanied by a statistically significant difference in OS (HR 0.68, 95% CI 0.42-1.09).

Data were also considered surrounding the receipt of allo-HSCT in MRD-positive patients. With allo-HSCT, there was a decreased risk of relapse (HR 0.34, 95% CI 0.20-0.58),$^{99,166}$ improved RFS at 5 years (HR 0.41, 95%CI 0.26-0.66),$^{99,166}$ improved DFS at 6 years (RR 7.19, 95% CI: 1.02-50.74),$^{166}$ and improved OS at 5 years (HR=0.40, 95% CI: 0.25-0.64).$^{99,166}$ However, non-relapse mortality was higher for MRD-positive patients who received an allo-HSCT (HR 2.39, 95% CI: 1.03-5.58).$^{165}$

Although evidence was sought to evaluate other changes to therapy based on MRD status (including inotuzumab), there were no additional data. Overall, the panel felt there was minimal comparative evidence for specific therapy augmentation approaches, and due to the uncertainty raised with study designs and indirectness, the overall certainty of the evidence was very low.

Therapy augmentation for MRD-negative patients is addressed in other recommendations. Specifically, Recommendation 9 addresses the addition of blinatumomab to post-remission therapy for MRD-negative patients and Recommendation 7 addresses allo-HSCT in MRD-negative patients in CR1.$^{99,106}$

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Harms and burden

Unfortunately, changes in therapy can result in undesirable effects (including serious toxicities and death) which must be considered. Patients receiving blinatumomab had increased grade ≥3 neurologic or psychiatric adverse events (AE) (RR=4.2, 95% CI, 1.79 – 9.85), but less grade ≥3 thrombocytopenia (RR=0.71, 95% CI: 0.55-0.92) than patients who received chemotherapy alone. MRD-positive patients who received an allo-HSCT experienced higher rates of non-relapse mortality (11.8% vs 4.9%; HR=2.39, 95% CI, 1.03-5.58) than those who did not receive an allo-HSCT.$^{165}$ Nevertheless, given the poor prognosis associated with persistent MRD positivity, the improved RFS with blinatumomab and improved RFS and OS with allo-HSCT as highlighted above were felt to outweigh potential undesirable effects.

Other EtD criteria and considerations

For changes in therapy guided by MRD status, the panel recognized mortality and OS as the highest value relative to other outcomes, while also acknowledging the importance of added toxicities for patients and the potential impact of any intervention on long-term quality of life (QOL). The available studies to examine changing therapy in the setting of MRD-positivity may not have captured all outcomes valuable to patients outside short-term AE and mortality, especially due to lack of data on QOL. Nevertheless, this uncertainty was not considered robust enough to change the strength or direction of the panel's recommendation regarding changes to treatment in the setting of persistent MRD-positivity. Though long-term effects of these therapies may become evident over time, it would not modify the value placed on the OS benefit in making this recommendation given the strength of the negative prognosis associated with MRD-positivity.

The totality of the evidence reviewed by the panel highlighted the need to escalate or change therapy from standard chemotherapy-based approaches for patients who remain MRD-positive while acknowledging that uncertainty remains as to the optimal approach to changing therapy in this situation. There was very low certainty regarding blinatumomab and allo-HSCT as interventions in light of minimal comparative evidence, single arm and historical control study designs, and the indirectness of the study population. For other potential interventions, such as inotuzumab, no prospective, comparative data from frontline studies are available. In addition, there was high uncertainty with respect to whether there is a specific treatment timepoint or MRD threshold level that would warrant escalation. There was also heterogeneity in the MRD assessment approach and technique. Furthermore,

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

there was no evidence surrounding the optimal number of post-remission cycles of blinatumomab, the best timing or sequence of blinatumomab and allo-HSCT as interventions, and/or how to incorporate other potential approaches to MRD-positivity after these interventions.

The panel noted the cost and resource implications associated with MRD testing and the incorporation of subsequent therapies including blinatumomab and/or allo-HSCT. In addition, the panel acknowledges that underrepresented or disadvantaged populations may be disproportionately negatively impacted by the high costs associated with MRD testing and subsequent escalation of care, including access to antibody-based or immunotherapies and/or pursuit of allo-HSCT. While this guideline is focused on the management of AYAs with ALL in well-resourced countries, the panel recognizes the potential for variable and inequitable access to MRD testing, novel targeted therapies, immunotherapies, and HSCT in other parts of the world.

Conclusions and research needs for this recommendation

The panel determined that there is a net benefit to changing the approach to treatment after 3 or more blocks of front-line therapy in AYA patients with ALL who have persistent MRD. This approach could include blinatumomab, inotuzumab, or allogeneic hematopoietic stem cell transplant. This recommendation places a high value on the potential benefits of changing the treatment approach. Even though the grade of available evidence is of very low certainty, there are comparative studies demonstrating improved relapse free and/or overall survival with both blinatumomab and allogeneic HSCT. Undesirable effects with this approach include toxicities related to these treatments: cytokine release syndrome and neurotoxicity with blinatumomab, cytopenias and hepatotoxicity with inotuzumab, infections and graft versus host disease with allogeneic HSCT. Although values and preferences are likely to vary, given the poor prognosis associated with persistent MRD and the fact that patients place the highest value on overall survival relative to other outcomes, it is likely that most patients value the uncertain benefits more than the uncertain harms. Following the considered judgment process of the panel and the recognition that the intervention (change in approach to therapy for persistent MRD) may offer benefit in a life-threatening situation (relapse), the panel supported a strong recommendation for this approach despite the very low certainty of evidence.$^{72}$ Changing treatment after 3 or more blocks of frontline therapy in patients with persistent MRD is an option likely to be acceptable to stakeholders. The optimal order or combination of these approaches is unknown.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Implementation of these changes may be challenging in under-resourced populations due to cost and access.

Future research is needed to better determine the optimal timing and choice of alternate therapies, as well as the order in which these treatments should be given. It remains unclear which patients still benefit from allogeneic HSCT if their MRD is cleared with blinatumomab or inotuzumab, and whether the above data is relevant to patients with low levels of MRD (measured by CloneSeq).

A new era is emerging suggesting a significant survival benefit with the addition of blinatumomab to post-remission frontline chemotherapy for MRD-negative as well as MRD-positive disease (see recommendation 9), and the panel recommendations are reflective of these developments. The issues of equitable access and financial toxicity that are highlighted for MRD-positive patients as described above apply, perhaps even more strongly, to the application of targeted immunotherapies in the MRD-negative frontline setting. Similarly, it is still unknown whether blinatumomab can or should be combined with other targeted agents and other immunotherapies, how treatment should be sequenced, how many cycles of blinatumomab are optimal and practical, the impact of these targeted immunotherapies on particular high risk molecular cytogenetic subsets (e.g. Ph-like and TP53 mutant disease), how best to apply CNS-directed therapy, whether or not there are still patients who will benefit from allogeneic stem cell transplant in CR1, and whether intensive chemotherapy and/or maintenance therapy can be shortened to potentially minimize treatment duration and long-term toxicities. Finally, the first studies addressing new targeting strategies for T-ALL in the frontline across the AYA age range are now underway or imminent, and this remains an important area of research for the future. These questions are mandates for this next exciting era in AYA ALL research.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Good Practice Statements

Good Practice Statement: Given the unique challenges of cancer in adolescence and young adulthood, it is good practice for AYAs with ALL to have their developmental needs evaluated, and their preferences and goals for treatment assessed within their unique developmental context. Whenever possible, their treatment should be delivered with consideration of their unique developmental stage, providing scheduling flexibility when not otherwise contraindicated.

Good Practice Statement: Given the risk and prevalence of psychological comorbidities and adverse psychosocial outcomes during the cancer experience of AYAs with ALL, it is good practice to routinely screen for depression, anxiety, and other psychological comorbidities and implement multidisciplinary psychosocial support.

Good Practice Statement: Given the unique social needs of AYAs with ALL, it is good practice to assess and evaluate each patient's existing social supports and encourage connection with supportive communities, where possible, through organized care coordination and resource navigation from a multidisciplinary team experienced in working with AYAs.

Good Practice Statement: Given the financial toxicity experienced by AYAs with ALL, it is good practice to provide financial counseling, resource navigation, and concrete resources through institutional means and/or in collaboration with larger regional and national organizations.

Good Practice Statement: Given the importance of sexual health and sexuality for AYAs with ALL along with the dynamic changes experienced in these areas over time, it is good practice to discuss sexual health, sexual orientation, sexual preferences, and gender identity of each individual patient from the onset of diagnosis, throughout the course of the individual's treatment, and into survivorship.

Good Practice Statement: Given the importance of fertility and how it is impacted by cancer and its therapy, it is good practice to provide AYAs with ALL access to comprehensive

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

fertility care in consultation with, but not limited to, their oncology provider, fertility specialist, and fertility counselors prior to the initiation of therapy whenever possible, with continued involvement and care from this multidisciplinary team throughout therapy and into survivorship.

Good Practice Statement: Given that AYAs are underrepresented in cancer clinical trials, and improvement in survival over time has lagged in underrepresented populations of AYAs, it is good practice to offer AYAs treatment in an appropriate clinical trial.

Good Practice Statement: It is good practice to introduce interdisciplinary palliative care teams as early as possible in treatment. Interdisciplinary and/or primary (i.e., delivered by the treating oncology team) palliative care should remain a focus of care throughout the care continuum, regardless of disease status.

Good Practice Statement: It is good practice to discuss goals of care and end-of-life concepts early in treatment, and before disease- or symptom-related crises arise. These discussions should be ongoing, tailored to the AYAs developmental and cognitive level, center on the AYAs wishes, and involve families and/or caregivers to the extent desired by the AYA. End-of-life care goals should be readdressed at key transition points during care (e.g., relapse).

Good Practice Statement: Considering differential outcomes for AYAs by location of care, in the context of their unique medical and developmental needs and the statements included here, it is good practice to ensure AYAs with ALL have access to specialized care with professionals and institutions well-versed in AYA ALL where feasible.

See Appendix B of the ALL in AYA guideline for expanded content related to these statements.

These statements are also published in the ALL AYA Relapsed/Refractory Management Manuscript (citation to RR manuscript) to ensure consistency across AYA guidance.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Limitations of these guidelines

The limitations of these guidelines are inherent in the low or very low certainty of the evidence we identified for many of the questions. In particular, the majority of existing data were considered indirect to the AYA population of interest for this guideline. The paucity of AYA-focused studies required the guideline panel to extrapolate estimates of benefits and harms from data that were more specific to either pediatric or adult populations and resulted in the lower certainty ratings associated with our recommendations.

Revision or adaptation of the guidelines

Plans for updating these guidelines

After publication of these guidelines, ASH will maintain them through surveillance for new evidence, ongoing review by experts, and regular revisions.$^{175}$

Updating or adapting recommendations locally

Adaptation of these guidelines will be necessary in many circumstances. These adaptations should be based on the associated EtD frameworks.$^{176}$

Priorities for research

Throughout the discussions above, the panel made distinct recommendations for research. However, beyond those specific recommendations there are some more pervasive gaps in evidence that were identified during the guideline development process. Considering these, the panel highlights further priorities for research.

Understanding the psychosocial impacts of therapy and therapy settings should be a priority, as AYAs are at a unique time in their social, emotional, and physical development from both the older adult population and pediatric population. AYAs also represent an overwhelming majority of patients with ALL who are of reproductive age. There is a paucity of data regarding therapy-related toxicity related to

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

reproductive organs; much of these data require decades to document, which renders decision-making among AYAs and leukemia clinicians incredibly challenging. There are advocacy efforts to encourage collection of relevant reproductive data points during oncology drug development, but it is crucial to consider collecting these data points at any point along the trajectory of evaluating therapy outcomes.$^{177}$ Specifically considering patients with ovaries who are diagnosed with ALL, there is controversy regarding the infiltration of the ovaries and whether it is safe or wise to harvest ovarian tissue and/or oocytes. Providers make recommendations regarding pregnancy and fertility without substantial data; while it is key that clinicians rely on the expertise of our colleagues in maternal fetal medicine and reproductive endocrinology and infertility, it is also vital to collect robust data to inform clinical management. Providers also make varying recommendations regarding sexual practices without robust assessments of sexual health nor evidence regarding potential risks, and there are a lack of data in this area. The unique position of AYAs in terms of the health system and how their care is delivered puts them at risk of financial toxicity and non-adherence to treatment recommendations, especially in the context of prolonged outpatient therapy. Research in these areas is desperately needed as well. Finally, the underlying theme to all the gaps in research noted and the overwhelming indirectness of the vast majority of the evidence leveraged for this endeavor, is the need for AYA-specific data in ALL. The panel recognizes that conducting AYA-specific studies may not always be plausible, and encourages all investigators to strongly consider reporting AYA subgroups of patients within their analyses and reports such that AYA clinicians and researchers can better understand the relevance of an intervention or outcome among AYAs, and at minimum to facilitate future meta-analyses that may improve our understanding and ability to identify the best approach to care for AYAs with ALL.

Acknowledgments

The authors are grateful to Dr. Hasmukh Jain's contributions during their service on the guideline panel.

The authors extend their appreciation to the Relapsed/Refractory Management Panel co-chairs, Drs. Kristen O'Dwyer and Sumit Gupta, for their valuable cross-panel collaboration and contributions in support of the frontline management recommendations.

The authors acknowledge methodology team members Eduardo Lucia Caputo, John Melson, and Teruhiko Terasawa for supporting the systematic reviews, and Gaelen Adam, Michael Zahradnik for supporting the in-person meeting.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

Authors also thank Dr. Megan Othus for the external statistical review and methodologic guidance.

The panel is eternally indebted to Rachel Cohen for her outstanding contributions and dedication to this guideline on behalf of ASH.

Authorship contributions

Contributions: All guideline panel members contributed to specific sub-sections of the text for the recommendations.; M.C., W.S., J.W., J.M., and A.D. organized and then revised these subsections into the first draft of this manuscript, and subsequently revised the manuscript based on authors' suggestions; all guideline panel members critically reviewed the manuscript and provided suggestions for improvement to strengthen the final version; members of the knowledge synthesis team (H.J.M., G.K., Y.S., I.S., E.B.) contributed evidence summaries to the guidelines; JW and WS were co-chairs of the guideline panel and led panel meetings; M.C. was the ex-officio representative from the ASH clinical practice guidelines oversight committee; and all authors approved of the content.

Disclosures of conflicts of interest

Conflict-of-interest disclosure: All authors were members of the guideline panel, members of the systematic review team, or both. As such, they completed a disclosure of interest form, which was reviewed by ASH and is available as supplements 2 and 3.

Correspondence

Correspondence: Matthew C. Cheung, Odette Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Toronto, ON, Canada, M4N 3M5; email: matthew.cheung@sunnybrook.ca.

ASH 2026 Guidelines: Frontline Management of ALL in AYAs

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Appendix A. List of Abbreviations

ALL – Acute lymphoblastic leukemia

Allo-HSCT – Allogeneic hematopoietic stem cell transplantation

AT – Antithrombin

AYAs – Adolescents and young adults (15–39 years old)

B-ALL – B-cell acute lymphoblastic leukemia (Philadelphia chromosome-negative acute lymphoblastic leukemia)

CNS – Central nervous system

CR1 – First complete remission

DOACs – Direct oral anticoagulants

ETP-ALL – Early T-cell precursor acute lymphoblastic leukemia

GRFS – GVHD Free and Relapse-Free Survival

HRQL – Health related quality of life

LMWH – Low molecular weight heparin

MRD-neg – Negative minimal residual disease

MRD-pos – Positive minimal residual disease

NSAA – Nadir serum asparaginase activity

Ph-pos Philadelphia chromosome-positive

PROs – Patient-reported outcomes

RIT – Reduced-intensity therapy

T-ALL – T-cell acute lymphoblastic leukemia

TBI – Total Body Irradiation

TDM – Therapeutic drug monitoring

TKIs – Tyrosine kinase inhibitors

T-LBL/LLy – T-cell lymphoblastic lymphoma

UFH – Unfractionated heparin

VTE – Venous thromboembolism

Appendix B. Broader Look at Psychosocial Care for AYAs

To comprehensively treat all AYAs with ALL, it is important to consider the domains of health beyond

medical complexity including the developmental, psychological, and social domains unique to this

population. In general, psychosocial support for individuals coping with cancer is associated with

improved emotional distress and quality of life.1,2 Below, we outline important practice considerations across key domains (this should not be considered an exhaustive list); these prioritize holistic treatment to improve function during treatment and maximize positive outcomes immediately post-treatment and into survivorship.

Developmental Needs of AYAs. Adolescence and young adulthood comprise a critical stage of human

development that is characterized by rapid cognitive, emotional, and social growth. During this

transition from childhood to adulthood, young people are tasked with navigating pubertal changes and cognitive development, exploring sexuality, developing a healthy body image, renegotiating boundaries with parents while increasing reliance on peers, forming a cohesive identity, achieving important legal

milestones, and making decisions about employment, education, and/or family.3

A cancer diagnosis, while impactful at any age, can be particularly disruptive to typical development

during the AYA period. AYAs who are diagnosed with cancer must navigate the same developmental

tasks as any other AYA, while also managing treatment-related disruptions across nearly every domain of development (e.g., educational/vocational, independence from parents, peer and dating

relationships, sexual functioning, and family planning). AYAs with cancer also face many

developmentally incongruent tasks, such as relinquishing newly found independence and bodily

autonomy, moving back into their parents’ homes, relying on parents or partners for caretaking tasks,

pausing educational and vocational aspirations, and confronting mortality – often for the first time.

AYA oncology is a unique discipline, as the psychosocial and developmental needs of this population is equivalent in importance to the biology of the disease itself. We acknowledge the significant individual variability in development between AYA patients and we emphasize the unique developmental needs

differ from the needs of other adult or pediatric patients.

Psychological Needs of AYAs. AYAs with ALL and other cancers are at highest risk of psychological

distress relative to those with cancer who are younger or older in age.4-6 They are more likely to

endorse clinically significant symptoms of anxiety, depression, post-traumatic stress, and other mental

health diagnoses, with symptoms often persisting well into survivorship.7 The increased risk of

psychological distress among AYAs has been attributed to the disruption that cancer and its therapy has on important unique developmental time periods leading to difficulty in mastering critical traumatic

exposures during the treatment process and difficulty in understanding the severity of their illness while sometimes lacking fully developed cognitive and emotional coping abilities.3,8 AYAs also endorse

psychological adjustment difficulties such as delayed social maturation, disrupted educational

attainment and vocational pursuits, job and insurance discrimination, financial difficulties, and

relationship and intimacy problems, all of which negatively impact broader psychosocial functioning.9,10 Furthermore, the AYA period intersects with a critical time point in the development of severe

psychopathology such as schizophrenia or bipolar disorder. For these disorders, symptoms may emerge between the late teens and mid-30s with the peak age of onset occurring in the early to mid-20s.

Collectively, these factors contribute to worsened psychosocial outcomes that are observed among AYA patients. Importantly, psychosocial functioning may adversely impact treatment outcomes as it may

impact the patient’s interest, willingness, or ability to access and/or complete oncology treatment which may increase their risk of treatment failure.

Despite the risk for adverse outcomes, it is also important to note that AYAs have remarkable capacity

for post-traumatic growth and resilience, particularly when they are provided appropriate supports

throughout treatment and survivorship.11 However, few seek out psychosocial supports when needed

due to significant stigma that can lead to embarrassment or unwillingness to report their concerns to

providers without significant prompting, while many of those who do seek out supports report

experiencing difficulties obtaining assistance.12

Social Needs of AYAs. The social needs of AYAs with ALL are intrinsically linked to both the

developmental and psychological needs of this population. For AYAs, their developmental need for

social connection and belongingness are in direct contradiction with the demands of treatment, which often calls for social isolation and separation. Additionally, treatment may prevent an AYA from

achieving or participating in important social (e.g., proms or friends’ weddings), educational (e.g.,

graduations), or vocational (e.g., advancing careers) milestones. Collectively, the impact of cancer and

its treatment on social development may contribute to or exacerbate psychological adjustment

difficulties; flexibility in health care delivery that affords AYAs as much opportunity to live as normal as possible and participate in as many developmental milestones as possible is beneficial.

Financial Needs of AYAs. An oncologic diagnosis during the AYA period intersects with a time where

most AYAs are building resources and learning financial independence. Such a diagnosis puts AYAs at a greater risk for insufficient insurance coverage and limited access to financial supports.13 There is

significant individual variability across AYAs in the amount and type of financial resources due to the

broad age and developmental range included in the AYA population. While the Affordable Care Act has expanded insurance coverage for some in the AYA group, AYAs (especially those 19-34) remain the most uninsured group in the US

(https://www.census.gov/content/dam/Census/library/visualizations/2022/demo/p60-278/figure2.pdf). Beyond the feasibility and cost of insurance, AYAs must also manage the burden of insurance copayments, meeting deductibles, and navigating the limitations of individual insurance plans for

comprehensive oncology care (e.g., fertility preservation and family planning, mental health care, and

treatment-related travel costs). Although AYAs may initially find conversations regarding the finances to be overwhelming, it is important that all AYAs have access to information regarding the financial

toxicities associated with treatment.

Sexual Health & Sexuality. Sexual health and sexuality are complicated but vital parts of human

existence that involve interactions between biopsychosocial, environmental, developmental, and

physical domains. Cancer and its therapy significantly impact both sexual functioning and non-sexual

physical intimacy of AYAs including self-image, physical desire, physical pain and comfort, fatigue, and

uncertainty of what may be safe for them and others throughout diagnosis and therapy. However,

discussions regarding sexual health and sexuality can be embarrassing for anyone of any age and

oncology providers report little training in these areas.14,15 Additionally, with their age and development, there may be changes to the AYAs sexual functioning, desires, and preferences throughout diagnosis,

treatment, and into survivorship.

Fertility Preservation. Cancer and its therapy can significantly impact an AYAs ability to build their family in their chosen manner through their impact on fertility. Additionally, each individual patient’s hopes

and desires and the impact of different therapies are unique, at times uncertain, and can also change

over time. However, it has been demonstrated that even discussions surrounding the impact of cancer and its therapy on fertility can ultimately reduce distress and improve quality of life. Unfortunately,

fertility preservation is not always possible with acute leukemias such as ALL given the level of illness on presentation requiring emergent therapy and/or financial or social barriers that are unable to be

overcome.

References

Zhang A, Zebrack B, Acquati C, et al. Technology-Assisted Psychosocial Interventions for

Childhood, Adolescent, and Young Adult Cancer Survivors: A Systematic Review and Meta-Analysis. J Adolesc Young Adult Oncol. Feb 2022;11(1):6-16. doi:10.1089/jayao.2021.0012

Zhang A, Wang K, Zebrack B, Tan CY, Walling E, Chugh R. Psychosocial, behavioral, and

supportive interventions for pediatric, adolescent, and young adult cancer survivors: A systematic review and meta-analysis. Crit Rev Oncol Hematol. Apr 2021;160:103291.

doi:10.1016/j.critrevonc.2021.103291

Zebrack BJ, Chesler MA, Penn A. Psychosocial support. In: Bleyer AW, Barr RD, eds. Cancer in adolescents and young adults. Springer; 2007:375-385.

Coccia PF, Altman J, Bhatia S, et al. Adolescent and young adult oncology. Clinical practice

guidelines in oncology. J Natl Compr Canc Netw. Sep 2012;10(9):1112-50. doi:10.6004/jnccn.2012.0117

Sansom-Daly UM, Wakefield CE. Distress and adjustment among adolescents and young adults with cancer: an empirical and conceptual review. Transl Pediatr. Oct 2013;2(4):167-97.

doi:10.3978/j.issn.2224-4336.2013.10.06

Rosenberg AR, Salsman JM. Resilience in adolescent and young adult oncology: Problems and prospects. Cancer. Apr 1 2024;130(7):1015-1018. doi:10.1002/cncr.35180

Osmani V, Horner L, Klug SJ, Tanaka LF. Prevalence and risk of psychological distress, anxiety and depression in adolescent and young adult (AYA) cancer survivors: A systematic review and metaanalysis. Cancer Med. Sep 2023;12(17):18354-18367. doi:10.1002/cam4.6435

Zebrack B, Isaacson S. Psychosocial care of adolescent and young adult patients with cancer and survivors. J Clin Oncol. Apr 10 2012;30(11):1221-6. doi:10.1200/JCO.2011.39.5467

Quinn GP, Goncalves V, Sehovic I, Bowman ML, Reed DR. Quality of life in adolescent and young adult cancer patients: a systematic review of the literature. Patient Relat Outcome Meas. 2015;6:19-51. doi:10.2147/PROM.S51658

10.

Levin NJ, Zebrack B, Cole SW. Psychosocial issues for adolescent and young adult cancer patients in a global context: A forward-looking approach. Pediatr Blood Cancer. Aug 2019;66(8):e27789.

doi:10.1002/pbc.27789

11.

Greup SR, Kaal SEJ, Jansen R, et al. Post-Traumatic Growth and Resilience in Adolescent and Young Adult Cancer Patients: An Overview. J Adolesc Young Adult Oncol. Feb 2018;7(1):1-14.

doi:10.1089/jayao.2017.0040

12.

Jones JM, Fitch M, Bongard J, et al. The Needs and Experiences of Post-Treatment Adolescent and Young Adult Cancer Survivors. J Clin Med. May 13 2020;9(5)doi:10.3390/jcm9051444

13.

Kirchhoff AC, Waters AR, Chevrier A, Wolfson JA. Access to Care for Adolescents and Young

Adults With Cancer in the United States: State of the Literature. J Clin Oncol. Feb 20 2024;42(6):642-652. doi:10.1200/JCO.23.01027

14.

Moerdler S, DuVall AS, Hayes-Lattin B, et al. Gaps in Adolescent and Young Adult Cancer Education in Oncology Fellowship Training. J Adolesc Young Adult Oncol. Feb 2024;13(1):97-104. doi:10.1089/jayao.2023.0056

15.

Frederick NN, Bingen K, Bober SL, et al. Pediatric oncology clinician communication about sexual health with adolescents and young adults: A report from the children's oncology group. Cancer Med.

Aug 2021;10(15):5110-5119. doi:10.1002/cam4.4077

表 1
Recommendation Strength
	“Recommendations...”	“Recommended against...”	“Suggests...”	“Suggests against...”

Interpretation of Strong Recommendations	Interpretation of Conditional Recommendations
Pati e n t s	Most individuals in this situation would want the recommended course of action, and only a small proportion would not.		Most individuals in this situation would want the suggested course of action, but many would not. Decision aids may be useful in helping patients to make decisions consistent with their individual risks, values, and preferences.
Clin ic a n s	Most individuals should follow the recommended course of action. Formal decision aids are not likely to be needed to help individual patients make decisions consistent with their values and preferences.		Different choices will be appropriate for individual patients; clinicians must help each patient arrive at a management decision consistent with the patient's values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their individual risks, values, and preferences.
Poli cym ake rs	The recommendation can be adopted as policy in most situations. Adherence to this recommendation according to the guideline could be used as a quality criterion or performance indicator.	Policymaking will require substantial debate and involvement of various stakeholders. Performance measures should assess if decision making is appropriate.
Res earc	The recommendation is supported by credible research or other convincing judgments that make additional research unlikely to alter the recommendation. On occasion, a strong recommendation is based on low or very low	The recommendation is likely to be strengthened (for future updates or adaptation) by additional research. An evaluation of the conditions and criteria (and the related judgments, research evidence, and additional

表 2
Questions determined by the panel	Outcomes
For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?	Overall survival
For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?	RFS/EFS/DFS/PFS/Relapse
For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?	Complete remission
For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?	MRD-negative status
For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?	Fertility
For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?	Quality of life
For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?	Allogeneic HSCT
For adolescents and young adults (AYAs) with B-cell or T-cell acute lymphoblastic leukemia (B-ALL/T-ALL)/T-cell acute lymphoblastic lymphoma (T-LBL/LLy) receiving frontline therapy, what are the comparative benefits and harms of asparaginase-containing regimens (e.g. CALGB 10403) versus non-asparaginase-containing regimens (e.g., Hyper-CVAD) for frontline therapy?	Toxicity
For patients (of any age) with ALL receiving frontline asparaginase, what are the comparative benefits and harms of changing asparaginase dose by: (1) following asparaginase levels (including monitoring frequency and	Overall survival
For patients (of any age) with ALL receiving frontline asparaginase, what are the comparative benefits and harms of changing asparaginase dose by: (1) following asparaginase levels (including monitoring frequency and	RFS/EFS/DFS/PFS/Relapse
For patients (of any age) with ALL receiving frontline asparaginase, what are the comparative benefits and harms of changing asparaginase dose by: (1) following asparaginase levels (including monitoring frequency and	Complete remission
For patients (of any age) with ALL receiving frontline asparaginase, what are the comparative benefits and harms of changing asparaginase dose by: (1) following asparaginase levels (including monitoring frequency and	MRD-negative status

表 3
Quality of life	Quality of life
Hospital admission	Hospital admission
Toxicity	Toxicity
	RFS/EFS/DFS/PFS/Relapse
Silent inactivation	Silent inactivation
Switches or discontinuation
Hospital admission	Hospital admission
Toxicity	Toxicity

表 4
	Financial toxicity
	Toxicity
For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?	Overall survival
For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?	RFS/EFS/DFS/PFS/Relapse
For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?	MRD-negative status
For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?	Quality of life
For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?	Adherence
For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?	Allogeneic HSCT
For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?	Financial toxicity
For patients with Philadelphia chromosome-positive (Ph-pos) ALL, what are the comparative benefits and harms of frontline treatment consisting of: (1) intensive chemotherapy plus a tyrosine kinase inhibitor (TKI), (2) reduced-intensity chemotherapy plus a TKI, (3) targeted immunotherapy (e.g., blinatumomab, inotuzumabozogamicin) plus a TKI?	Toxicity
For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?	Overall survival
For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?	RFS/EFS/DFS/PFS/Relapse
For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?	CNS recurrence
For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?	Neuro-cognitive impact
For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?	Quality of life
For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?	Caregiver burden
For patients with ALL without central nervous system (CNS) involvement at diagnosis, what are the comparative benefits and harms of different CNS prophylaxis regimens, including: (1) intrathecal chemotherapy regimens and (2) cranial radiation?	Toxicity
For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?	Overall survival
For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?	RFS/EFS/DFS/PFS/Relapse
For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?	Complete remission
For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?	MRD-negative status
For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?	Quality of life
For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?	Allogeneic HSCT
For patients with ALL receiving frontline therapy and being assessed for minimal residual disease (MRD), what are the comparative benefits and harms of changing the treatment regimen due to the detection of MRD, including incorporation of immunotherapy?	Toxicity

表 5
Tiers	Publication Year	Sample Size	Age, years	Directness
Tier 1	≥2000	N ≥10	AYA	Direct
Tier 2	≥2000	N ≥10	Median 15-39	Serious indirect

表 6
Tier 3	≥2014	N ≥25	Median 10-14 or 40-65	Very serious indirect
Tier 4	≥2000	N ≥25	Median 10-14 or 40-65	Very serious indirect
Tier 5	≥2014	N ≥25	Median <10 or >65	Very serious indirect
Tier 6	≥2000	N ≥25	Median <10 or >65	Very serious indirect

表 7
Evidence Certainty	Evidence Certainty
High Certainty	High Certainty
++++	We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate Certainty	Moderate Certainty
++○○	We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low Certainty	Low Certainty
++○○	Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.
Very Low Certainty	Very Low Certainty
+○○○	We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of the effect.
+○○○	We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of the effect.

表 8
Topic	Eligible Study Designs	N Studies	Eligible Study Tiers [Included Tiers]
1. Pediatric-inspired vs. adult-inspired regimens	Comparative; Prospective single-group	24	1 [1]
2. Changing asparaginase dose by: 1) monitoring asparaginase levels, 2) dose capping, 3) dose lowering	Comparative; Single-group	9	1-6 [1,2,4,5]
3. Prophylactic premedication to prevent asparaginase infusion reactions	Comparative	6	1-6 [1,5*]
4. Prophylaxis against hypercoagulation, including: 1) anticoagulation, 2) hypercoagulation monitoring	Comparative	14	1-6 [2,3,5,6]
5. After asparaginase-related reaction, desensitization vs. alternative asparaginase product	Comparative; Single-group	7	1-6 [3,4,5]
6. After asparaginase-related toxicity, resuming or changing asparaginase product	Comparative	0	1-6
7. Allogeneic hematopoietic stem cell transplantation versus no transplant	Comparative	7	1,2 [1,2]
8. Targeted therapies (e.g., inotuzumab ozogamicin, blinatumomab, rituximab, nelarabine, bortezomib)	Comparative; Single-group	15	1-4
Blinatumomab		2	[3,4]
Nelarabine		8	[1,2,3,4]
Bortezomib		1	[3]
Rituximab		4	[2,3,4]
9. Ph+ treatments: Reduced vs. Intensive chemotherapy, with TKI	Comparative; Single-group	25	1-3 [1,2,3]
10. CNS prophylaxis regimens, including: 1) intrathecal chemotherapy regimens, 2) cranial	Comparative	15	1-6

表 9
radiation
Intrathecal chemotherapy		2	[5,6]
Cranial radiation		13	[3,5,6]
11. Changing the treatment regimen due to the detection of MRD	Comparative	5	1-6 [1,2,3]

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引用 / 出处

2026 ASH指南：青少年和年轻成人急性淋巴细胞白血病的一线治疗. 2026.