2025+专家共识：慢性髓性白血病慢性期治疗不耐受的定义

ABSTRACT

Introduction: Chronic myeloid leukemia in the chronic phase (CML-CP) has undergone therapeutic transformation with the advent of BCR::ABL1 roine kinase inhibitors (TKIs),improving 10-year survival rates from 20% to ~90%. These outcomes place increasing importance on maintaining quality of life (QoL), which can be compromised by adverse events (AEs) that may lead to decreased adherence or sub-therapeutic doses.Currently, there is no standardized definition of treatment intolerance, and treatment switches are based on individual physician practices.

Methods: A 13-member expert panel used a validated methodology (RAND/UCLA modified Delphi panel) to develop consensus on a definition of treatment intolerance in CML-CP. Panelists reviewed literature and provided 480 ratings on 96 unique patient scenarios that varied by TKI generation, line, and length of time on TKI treatment, frequency of AE interference on daily life, and TKI management strategies. Ratings were discussed at a meeting.

Results: After discussion, panelists agreed on 99% of scenarios.The group defined TKI treatment intolerance as patients whose AEs often interfered with daily activities,leading to TKI modifications. Panelists developed a tool to assess patient intolerance and recommendations for managing TKI therapy in the context of intolerance.

Discussion: Recognizing that treatment intolerance is influenced by laboratory findings,reported symptoms, and how patients experience their treatment, experts agreed on a patient-centered definition of TKI treatment intolerance in CML-CP. This definition represents a step forward in standardizing care for patients with CML-CP by presenting a balanced framework for managing TKI therapy, which will support shared decision-making.

ARTICLE HISTORY

Received 13 May 2025 Accepted 31 August 2025

KEYWORDS

Consensus; Delphi technique; chronic myeloid leukemia; chronic phase CML; tyrosine kinase inhibitors; adverse effects; activities of daily living;patient reported outcome measures

Introduction

Chronic myeloid leukemia(CML) in the chronic phase(CML-CP), the stage at which the majority of individuals with CML in Western nations are diagnosed, is characterized by the uncontrolled proliferation of maturing myeloid cells in the bone marrow, often with few symptoms [1]. Over the past 25 years, CML-CP has seen remark-able therapeutic advancements with the introduction of BCR::ABL1 tyrosine kinase inhibitors (TKIs). The six TKIs approved for CML in the United States (US) (imatinib [2], dasatinib [3], nilotinib [4], bosutinib [5], ponatinib [6],and ascidinib [7]) have transformed CML from a fatal disease to a manageable condition, with a life expectancy approaching that of the general population. Since 2001, the 10-year survival rate has risen from 20% to $\sim 90\%$ [2], but maintaining these outcomes requires oral therapy, sometimes with difficulty. As a result, therapeutic focus has shifted towards maximizing quality of life (QoL) and reducing long-term toxicities.

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Despite TKls' success, the definition of treatment intolerance remains underexplored. All TKls can cause general early toxicities (e.g. rash, nausea, fatigue) and drug-specific toxicities (e.g. dasatinib-induced pleural effusion [8, 9], nilotinib-related dyslipidemia, and arterial thrombosis [10, 11]) that may necessitate treatment switches. More than a quarter of patients on first-line therapy and up to a third on second-line therapy require a TKI switch [12]. Yet no unified metric defines when toxicity become intolerable [13, 14].Clinical trials have used differing definitions [13], inconsistently applied in clinical practice. Most research has focused on acute toxicities using the Common Terminology Criteria for Adverse Events (CTCAE),which defines intolerance as recurring grade 3 or 4 non-hematologic toxicity despite dose reduction and management [15]. However, lifelong daily therapy means even grade 1 or 2 toxicities can significantly impair QoL and require systematic management [16]. Moreover, treatment changes due to intolerance are subjective and influenced by patient and physician preferences.

Without a clear, standardized definition, clinicians and patients rely on individual judgment to determine whether side effects qualify as 'intolerance' This inconsistency can delay switching or trigger premature changes, compromising care. To address this gap, we used a rigorous, reproducible process to derive con-sensus on defining treatment intolerance in US adults with CML-CP experiencing low-grade toxicity (i.e. no severe toxicities or serious complications requiring immediate intervention). The aim was to generate a stan-dardized definition to improve treatment comparisons and guide clinical decision-making, prioritizing both efficacy and patient QoL.

Methods

This study used the RAND/UCLA modified Delphi panel method to define treatment intolerance in CML-CP(Figure 1). This formal group consensus process systematically and quantitatively combines expert opinions and evidence by asking panelists to rate, discuss, and re-rate items [17].

The panel consisted of 13 experts: nine hematologists/oncologists, one pharmacist, one advanced prac-tice registered nurse, one PhD researcher specializing in patient-reported outcomes in CML, and one patient with CML-CP. Clinicians averaged 13 years of experience in practice, treating approximately 200 patients with CML annually.

This study was funded by Novartis Pharmaceutical Corporation and was double-blinded. While work was ongoing, all but the moderator and panel chair were blinded to the sponsor's identity, and vice versa.

 Figure 1. Modified Delphi panel methodology.

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Unblinding occurred after results were submitted for conference presentation [18]. The sponsor had no input on the methodology or findings. Panels were compensated for their participation. As modified Delphi panels do not involve human subjects as defined in 45 CFR parts 46 [19], institutional review board approval was not required.

Panelists reviewed a summary of the relevant literature on CML-CP treatments, including first-, second-,and third-line TKIs, common toxicities, and strategies for long-term management. A targeted search of the PubMed database was conducted.The search strategy and a reference list of the studies reviewed is pro-vided in the Supplementary Appendix. The quality of the evidence was not formally appraised.

Through individual phone interviews to discuss CML-CP and TKI treatments, panelists collaboratively developed 96 unique patient scenarios varying by the clinical characteristics outlined in Table 1. Scen-arios included patients with hematologic and non-hematologic laboratory abnormalities(CTCAE v5.0 grades 1-3) [20] on any line of therapy. All patients in these scenarios had confirmed CML-CP, were adherent to TKI therapy, had no TKI resistance or serious complications requiring immediate intervention,experienced AEs that impacted QoL despite supportive care, and had been on therapy for at least three months (as experts agreed that changes should not be made within the first three months of therapy initiation).

For each scenario, panelists gave five ratings(Table 2), totaling 480 questions total. Using a 1-to-9 scale, panelists rated the appropriateness of modifying TKI therapy- ranging from no change, to dose hold or reduction, to switching or discontinuing after prior modifications. Panelists also rated whether they would consider the patient intolerant to therapy, before and after a hold or dose reduction.

Ratings were completed before and after a professionally moderated virtual panel meeting in June 2024.During the meeting, panelists received a document showing their individual ratings alongside the group's

Table 1. Clinical characteristics in patient scenarios.

|Characteristic|Definitiona| |---|---| |Treatment goal|● Treatment-free remission; these patients may have an eventual goal of discontinuing therapy. ● Patients on chronic therapy; these patients are likely to remain on therapy for the rest of their lives. ● Second generation[2G], including dasatinib, nilotinib, bosutinib. ● Third generation[3G]), including ponatinib, ascinibin, or panelist-preferred 3 G agent.b| |Line of TKI therapy|● First-line ● Later-line(anything beyond first-line e.g.second, third, fourth, etc.) ● Short(e.g.3-6 months) ● Intermediate(e.g.12-18 months) ● Long(e.g.2+ years)| |Length of time on TKI therapy|● Short(e.g.3-6 months) ● Intermediate(e.g.12-18 months) ● Long(e.g.2+ years)| |Frequency with which AEsc|Content of the item stem was informed by the‘Patient Reported Outcomes Measures Information System[PROMIS]-Ability to participate in social roles and activities' scale[21]| ||Rarely ● Sometimes ● Often| |Grade of laboratory abnormalities|CTCAE v5.0 definitions for non-hematologic and hematologic laboratory abnormalities: ● Grade 1| ||● Grade 1 ● Grade 2 ● Grade 3|

TKI, tyrosine kinase inhibitor; AEs, adverse events; CTCAE, Common Terminology Criteria for Adverse Events.

${}^{a}$ Except for the grade of laboratory abnormalities, definitions developed by panelists for the purpose of this study.${}^{a}$ At the time of the panel meeting(June 2024), panelists agreed to classify asminic as a 3G agent. However, some clinicians consider this to be an allosteric inhibitor [22,23]. Furthermore, a study published after the panel meeting supported the use of asminic in a first-line agent [24],prompting the FDA to grant accelerated approval for its use in adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia(Ph+ CML-CP) in October 2024 [25].

${}^{c}$ Panelists agreed that it was appropriate to consider the extent to which AEs interfered with daily activities rather than a specific description of an AE.

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Table 2. Rating scales.

|Question|Scale| |---|---| |After supportive measures have been attempted|| |1. Appropriateness of making no change to the TIK|1 =inappropriate,9 =appropriate| |2. Appropriateness of holding or dose reducing the TIK|1 =inappropriate,9 =appropriate| |3. Rate the patient's intolerance to therapy|1 =tolerant,9 = intolerant| |4. Appropriateness of switching or discontinuing TKI|1 =inappropriate,9 = appropriate| |5. Rate the patient's intolerance to therapy|1 =tolerant,9 = intolerant| |TKI: tyrosine kinase inhibitors.||

TKI: tyrosine kinase inhibitors.

median and range(example in the Supplementary Appendix). Discussion focused on areas of disagreement,defined as $\geq 2$ ratings of 1-3 and $\geq 2$ of 7-9 for the same scenario [21]. Items without disagreement were classified into three categories based on their median scores (1-3, 4-6, 7-9). Second-round ratings were ana-lyzed to develop consensus statements, as presented below.

Results

Following the discussion, agreement was reached on 99%(N = 474/480) of ratings compared to 83%(N = 400/480) in the first round. The following statements summarize how the panel defined TKl treatment intol-erance and related management strategies. They are intended to guide, not supersede, clinical judgment in treating adult patients with CML. Users should consider each patient's individual circumstances and share decision-making with patients and caregivers. Every case is different, and it would be impossible to include all clinical scenarios.

Definition of treatment intolerance and management of TKl

While the panel considered various clinical scenarios that may impact the definition of treatment intolerance(1) when often AEs interfere with a patient's daily activities (rarely, sometimes, often) and (2) the grade of laboratory abnormalities (grades 1, 2, 3).

The panelists also agreed that increasing AE interference with daily activities signifies increasing intolerer-ance to TKI treatment (Table 3).

Similarly, panelists agreed that patients with more severe (i.e. $\geq$ grade 3) laboratory abnormalities - hema-tologic and non-hematologic - could be considered intolerant to TKI treatment (Table 4).

The panel emphasized that AE features alone don't define treatment intolerance. Rather, because most patients require lifelong TKI therapy, a patient's own perspective on how AEs interfere with their daily activi-ties is central to defining intolerance. Common AEs (e.g. nausea,fatigue, joint pain, shortness of breath, and periorbital/ankle edema) may or may not interfere with daily activities depending on the individual. For example, mild nausea without loss of appetite may not interfere with the daily activities of one patient but may often interfere with the daily activities of another. One patient may not feel joint pain, muscle pain, or muscle spasms that limit movement interfere with their daily activities, whereas another patient

Table 3. Definition of TKl intolerance based on non-laboratory AEs.

|Frequency of AEs interference with daily activities within the past week|Intolerance to TKI therapy therapy|Appropriateness of making a change to TKI therapya| |---|---|---| |Rarely|Tolerant to treatment|Appropriate to keep TKI treatment unchanged| |Sometimes|May be intolerant to treatment|May be appropriate to make modifications to TKI therapy depending on patient and physician discussion(e.g. goal of therapy, line and generation of treatment, and length of time on current treatment could be considered)| |Often|Intolerant to treatment|Appropriate to change TKI treatment (i.e. hold or reduce the dose if patient continues to respond to therapy, switch to another TKI treatment after a hold and/or dose reduction has been attempted)|

TKI: tyrosine kinase inhibitors; AEs: adverse events.

${}^{a}$ In all scenarios, panelists considered patients who had been on therapy for at least three months and did not experience serious complications that required immediate intervention.

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Table 4. Definition of TKI intolerance based on laboratory abnormalities.

|Grade of hematologic and non-hematologic laboratory abnormality|Intolerance to TKI therapy|Appropriateness of making a change to TKI therapy|| |---|---|---|---| |Grade 1c|Tolerant to treatment|Appropriate to keep TKI treatment unchanged|| |Grade 1c|May be intolerant to treatment|May be appropriate to make modifications to TKI therapy depending on patient and physician discussion(e.g. goal of therapy,line and generation of treatment, and length of time on current treatment could be considered)|| |Recurrent or persistent grade 3d|Intolerant to treatment|Appropriate to change TKI treatment (i.e. switch to another TKI treatment, hold, or reduce the dose if patient continues to respond to therapy)||

$^{a}$ As defined by CTCAE v5.0.

$^{\text {bIn all scenarios, panelists considered patients who had been on therapy for at least three months and are not experiencing serious complications}$ that require immediate intervention.

$^{c}$ E.g. platelet count decreased LLN-75,000/mm3, ALT increased up to 3xULN.

${}^{d}$ For example, anemia requiring transfusion, pancreatic enzymes decreased/sequelae of absorption deficiency.

TKI: tyrosine kinase inhibitors.

may disagree. Similarly,fatigue relieved by rest may be manageable for a retired patient but not for someone more active.

Application of guidance in clinical practice

To apply this guidance, clinicians should directly ask patients:'In the last week, how often did [symptoms the patient reports] interfere with your daily activities - rarely, sometimes, or often?' The patient's response informs intolerance status. There exist validated tools for use in clinical trials [22, 23]. Based on these, the panel developed a patient-centric assessment tool as a part of this project to elicit this information in routine clinical practice (Figure 2).

In the last week, how often did the following symptoms (if experienced) interfere with your daily activities: rarely, sometimes, or often? Check the box that best describes your experience.

|How often did the symptom interfere with I did not your daily activities?your daily activities?|||| |---|---|---|---| |Symptom|Rarely|Sometimes|Often| |Gastrointestinal|||| |Diarrhea|□|□|□| |Constipation|□|□|□| |Nausea|□|□|□| |Vomiting|□|□|□| |Constitutional|||| |Fatigue|□|□|□| |Headache|□|□|□| |Rash|□|□|□| |Muscle spasms|□|□|□| |Muscle pain(myalgia)|□|□|□| |Joint pain|□|□|□| |Shortness of breath, coughing, and/or chest pain|□|□|□| |Swelling(edema)|□|□|□| |[List other symptoms as needed]|□|□|□|

Scoring for clinician use:

● Patients can be deemed tolerant to treatment if one or more AEs often interfere with daily activities within the past week.

● Patients can be deemed tolerant to treatment if AEs rarely interfere with daily activities within the past week.

● Patients whose AEs sometimes interfere with daily activities within the past week may be intolerant to treatment. Further discussion between physician, patient, and caregiver will determine tolerance.

Figure 2. Example of assessment tool.

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Discussion

Thirteen experts convened to develop a standardized definition of TKI treatment intolerance in CML-CP. The panel agreed on a patient-centered definition, with the impact of AEs on daily life and the severity of lab-oratory abnormalities (graded by CTCAE v5.0 [20]) emerging as critical factors. Panelists agreed that treat-ment intolerance is defined by (1) how often AEs interfere with a patient's daily activities (rarely,sometimes, often) and (2) the grade of laboratory abnormalities (grades 1, 2, 3). This definition aligns with the FDA's 1998 definition of tolerability, which defined intolerance by the degree to which AEs can be endured [24]. The panel also agreed that therapy should continue unchanged in tolerant patients and should be modified (e.g. dose hold, reduction, or switch) when intolerance is identified. The RAND/UCLA Modified Delphi panel method was used to develop a definition of TKI treatment intolerance in CML-CP.The method is a validated and reliable tool for quantifying expert opinion and has been used to develop society guidelines [25], disease classification systems [26], research agendas, and quality improvement inter-ventions [27, 28].

The panel emphasized individualized assessment and shared decision-making, recognizing that intoler-ance is shaped not only by symptoms and labs but also by patients' experiences. Published literature sup-ports this approach. A recent systematic review found that integrating patient-reported outcomes helps identify needs, reduces mortality risk, and improves QoL within 12 weeks[29]. Another study showed that patients often hesitate to report treatment challenges, underscoring the importance of eliciting feed-back[30]. Because most patients require lifelong TKI therapy, minimizing toxicity is essential. The panel's tool aims to help clinicians capture patient perspectives and manage therapy accordingly(see Figure S1 in the Supplementary Appendix for an example).

This definition builds on previous work. A 2010 review called for a consistent definition of imatinib intolerance to guide chronic toxicity management [13]. Similarly, the European LeukemiaNet guidelines recognized that even low-grade AEs could significantly affect QoL and adherence, advocating for a unified intolerance framework [14].The definition may complement existing CML-specific tools, such as the M.D. Anderson Symptom Inventory and PROMIS variants [22,23], by offering a CML-specific method to assess tolerability.

The patient-centric assessment tool developed as part of this panel (Figure 2) is meant to be used in routine clinical practice to facilitate conversation between patients and providers regarding treatment toler-ability. It is intended to support clinical decision-making, not supersede it.

This study had limitations. While the Delphi method is validated for expert consensus, it does not capture the full variability of patient experiences. No patient data were collected; the panel relied on artificial clinical scenarios.The resulting definition reflects the views of 13 US-based experts. Further validation in real-world settings is needed. A second panel comprising mostly patients could provide valuable insight into the frame-work's real-world applicability. Treatment intolerance is also linked to available treatment options and will need updating as new therapies emerge. Thus, the panel recommends a periodic review and refinement of the definition of TKI intolerance to align with the changing TKI landscape. Finally, because had access to all six approved TKIs, the guidelines may not apply in countries with fewer options.

This definition represents a significant step in standardizing CML-CP care. By combining patient perspec-tives with objective laboratory criteria, it offers a balanced framework for managing TKI therapy and addresses an unmet need in CML-CP- supporting not just survival, but a fulfilling life while on therapy.

Acknowledgements

All authors have met ICMJE authorship criteria. MSB is responsible for Data Curation, Formal Analysis, Investigation,Project Administration, Supervision, Visualization, and Writing (original draft, review and editing). HTDM is responsible for Data Curation, Formal Analysis, Visualization, and Writing (original draft, review and editing). EA, OC, KEF, JAG,MH,AMH,MJM,JPI,LAMR,ES,ST,JY and NPS are responsible for Resources, Investigation, and Writing (original draft,review and editing).

Author contributions

CRediT:Ehab Atallah: Investigation, Resources, Writing - original draft, Writing - review & editing; Michael S. Broder:Data curation, Formal analysis, Investigation, Project administration, Supervision, Visualization, Writing - original draft,

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Writing- review& editing; Onyee Chan: Investigation, Resources, Writing- original draft, Writing - review & editing;Kathryn E. Flynn:Investigation,Resources:Writing-original draft,Writing - review& editing;Jeffrey A. Gilreath:Inves-tigation,Resources:Writing-original draft,Writing - review& editing;Marisa Hine:Investigation,Resources:Writing -over original draft,Writing -review and original draft,Writing -review & editing;Marisa Hine:Investigation,Resources:Writing -editing;Marisa Hine:Investigation,Resources:Writing -review & editing;Marisa Hine:Inves-tigation,Resources:Writing-original draft,Writing - review& editing;Marisa Hine:Investigation,Resources:Writing -over original draft,Writing -review & editing;Marisa Hine:Investigation,Resources:Writing -review & editing;Hannah T.D.Mattson:Data curation,Formal analysis,Visualization,Writing-original draft,Writing -review& editing;Michael J. Mauro: Investigation,Resources, Writing -original draft, Writing -review & editing;Javier Pinilla-lbarz: Investigation,Resources,Writing -original draft, Writing -review & editing;Lindsay A.M. Rein:Investigation, Resources, Writing -original draft, Writing -original draft, Writing -review & editing; Evan Stemper: Investigation, Resources,Writing -original draft, Writing -review & editing; Srinivas Tantravahi: Investigation, Resources, Writing -original draft, Writing -review & editing; Jay Yang: Investigation, Resources, Writing -original draft, Writing -review &editing;Neil P. Shah: Investigation, Resources, Writing -original draft, Writing -review & editing.

Disclosure statement

All authors have completed ICMJE disclosure forms. All authors declare the following: support for the present manu-script: Novartis Pharmaceutical Corporation.

The authors declare the additional following potential conflicts of interest:

EA (Co-Author): Research support from Novartis. Grants/Contracts from Amgen and Xencor. Royalties/licenses from UpToDate. Consulting fees from Novartis,Syndax,Takeda,Pfizer, and Inhibikinase. Payment/honoraria from BMS,Syndax, and Abbvie. Payment for expert testimony from Strong and Hanni. Support for attending meetings/travel from Novartis. Participation on a Data Safety Monitoring Board or Advisory Board from Syndax. Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid from iCMLf.

MSB(Corresponding Author), HTDM (Co-Author): Employees of PHAR (now a part of ADVI Health) which was paid by Novartis to conduct the research described in this manuscript. PHAR also discloses relationships with the following enti-ties outside of the submitted work: Akcea, Amgen, Astellas, BioMarin Pharmaceuticals, Bristol-Myers Squibb, Celgene,Delfn Diagnostics, Dompe, Eisai, Exact Sciences Corporation, Genentech, Gilead, GRAIL, Greenwich Biosciences, Ionis,Janssen, Nobelpharma, Pfizer, Recordati, Regeneron, Sanofi US Services, and Takeda Paramuticals U.S.A.

OC (Co-Author): Consultancy fees from BMS, Abbvie, and PureTech. Honoraria/presentation from Aptitude Health,OncLive. Participation in Advisory Board at Takeda, BMS, and Syndax. Support for attending meetings and/or travel from Total Health Conferencing and Dava Oncology. Member, National Comprehensive Cancer Network (NCCN) CML guidelines panel.

KEF (Co-Author): Grants to institution from Novartis. Consulting fees from Novartis, Inhibrikase, and Pfizer. Participation in Advisory Board for Novartis.

JAG (Co-Author): Co-founder of Chemo Experts Foundation patient advocacy group.

MH (Co-Author): Consulting fees from Novartis.

AMH (Co-Author): Research support from Incyte, Cogent Biosciences, Ascentage Pharma, Blueprint Medicines,Syntrix Biosystems, Novartis, and PharaEssentia. Honoraria from PharmaEssentia and Blueprint medicines. Participation in a data safety monitoring board at Karyopharm. Participation in an Advisory Board at GKS, PharmaEssentia, Blueprint Medi-cines,Sobi, Incyte. Steering committee member at H Jean Khoury Cure CML Consortium.

MJM (Co-Author): Consulting fees from Novartis,BMS,Takeda,Terns,Enliven,and AbbVie. Research support from Novartis,Enliven, and Terns.

JPI (Co-Author): Consulting fees from Abbvie, Beigene, AstraZeneca, Lilly and BMS. Payment or honoraria for lectures,presentations, speakers' bureaus, manuscript writing or educational events from Abbvie, Beigene, AstraZeneca and Lilly.

LAMR (Co-Author): Grants/contracts made to institution for serving as lead Pl for clinical trials from Novartis, Cogent Biosciences,Pharmaessentia,Protagonist, Geron, Karyopharm,Sumitomo,Telios,Silence, Incyte, Merck, and Blueprints Medicine. Consulting fees from Novartis, Cogent, and Sobi. Honoraria from Abbvie, Cogent, Incyte, Morphosys, Sobi,and Sumitomo. Member of the H Jean Khoury Cure CML Consortium.

ES (Co-Author):None.

8  E. ATALLAH ET AL.

ST (Co-Author): Grants/contracts from Karyopharm Therapeutics. Consulting fees from Karyopharm Therapeutics,Novartis, GSK, Genentech, and Sobi.

JY (Co-Author): Consulting fees from Novartis, research funding from Ascentage Pharma and Kumquat Biosciences.

NPS (Co-Author): None.

Funding

This work was supported by Novartis Pharmaceutical Corporation.

Data availability statement

The data that support the findings of this study are available from the corresponding author, MSB, upon reasonable request.

ORCID

Ehab Atallah 10 http://orcid.org/0000-0002-9919-3564 Michael S. Broder 9 https://orcid.org/0000-0002-2049-5536 Onyee Chan 10 http://orcid.org/0000-0003-2872-1961 Kathryn E. Flynn http:orcid.org/0000-0002-4427-3583 Jeffrey A. Gilreath 10 https://orcid.org/0000-0002-4566-8448 Anthony. Hunter 3 https://orcid.org/0000-0002-9819-4151 Hannah T.D.Mattson 10 https://orcid.org/0000-0003-3153-3443 Michael J. Mauro 10 https://orcid.org/0000-0002-2251-4032 Javier Pinilla-lbarz 10 http://orcid.org/0000-0003-3170-9648 Lindsay A.M. Rein 10 http://orcid.org/0000-0002-9888-4814 Srinivas Tantravahi http://orcid.org/0000-0003-4899-3796 Neil P. Shah ①https://orcid.org/0000-0003-4398-3388

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