2023+JSH实践指南：血液恶性肿瘤—淋巴瘤-10.霍奇金淋巴瘤（HL）

JSH practical guidelines for hematological malignancies, 2023:II.Lymphoma 10. Hodgkin lymphoma(HL)

Shigeru Kusumoto $^{10}$ ·Akihiro Tomita $^{2}$

Received: 23 April 2025 / Revised: 4 September 2025 / Accepted: 24 September 2025 © The Author(s), under exclusive licence to Japanese Society of Hematology 2025

©The Author(s), under exclusive licence to Japanese Society of Hematology 2025

Overview

Hodgkin lymphoma (HL) accounts for approximately 10%to 30% of all malignant lymphomas in Western countries,and approximately 3% to 6% in Japan.

It has a bimodal incidence pattern across age groups with one peak in young adults (20 s) and the other in middle-aged adults (50 to 60 years old).

Many patients are initially asymptomatic or have painless superficial lymphadenopathy. Approximately 75% of cases are detected from cervical and supraclavicular lymphad-enopathy. A mediastinal mass is detected in approximately 60% of patients with nodular sclerosis HL.

Hematologic findings include leukocytosis, lymphope-nia, eosinophilia, anemia, elevated alkaline phosphatase,elevated erythrocyte sedimentation rate(ESR), elevated C-reactive protein, and reduced cell-mediated immunity.

Histopathologically, HL is a lymphoma characterized by proliferation of tumor cells, such as Hodgkin/Reed-Stern-berg(HRS) cells and lymphocyte-predominant(LP) cells(“popcorn” cells). In the 2017 WHO Classification, HL is classified into two subtypes: nodular lymphocyte-predom-inant Hodgkin lymphoma(NLPHL) and classic Hodgkin lymphoma(CHL)[1, 2]. HRS cells are characteristic of CHL, and LP cells of NLPHL. CHL is further classified into four additional subtypes: nodular sclerosis, lymphocyte-rich,mixed cellularity, and lymphocyte-depleted.

<BeginOfPara>HL is classified into stages I through IV using the Ann Arbor staging system.

# Prognostic factors in limited-stage CHL

Table 1 shows prognostic factors in limited-stage(stages I and II) CHL. Note that different research groups emphasize different prognostic factors [3-5].

(From References 3-5).

# Prognostic factors in advanced-stage CHL

The International Prognostic Score (IPS) is used as a prog-nostic model for advanced-stage CHL [36] It is based on seven prognostic factors identified using time to progression (TTP) as an endpoint in an analysis of 4695 patients aged 15 to 65 years with advanced-stage CHL treated with a regimen, such as MOPP regimen (mechlore-thamine [not approved in Japan], vincristine, procarbazine,and prednisolone) or ABVD regimen (doxorubicin, bleomy-cin, vinblastine, and dacarbazine). It is considered possible to predict TTP from the number of these factors a patient has. In this system, the projected five-year rate of freedom from disease progression is 84% for a patient with no unfa-vorable prognostic factors, compared with a poor 42% for patients with 5 or more factors.

References

<EndOfPara>1)Stein H,et al.Hodgkin lymphomas. Swerdlow SH,et al.eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, IARC; 2017: pp424-42.

2)Nogová L, et al. Lymphocyte-predominant and classical Hodgkin's lymphoma: a comprehensive analysis from the German Hodgkin Study Group. J Clin Oncol. 2008; 26(3):434-9.(3iiiDiii)

3)Noordijk EM, et al. Combined-modality therapy for clinical stage I or II Hodgkin's lymphoma: long-term results of the European Organisation for Research and Treatment of

区 Shigeru Kusumoto

<EndOfPara>skusumot@aichi-cc.jp

1 Department of Hematology and Cell Therapy, Aichi Cancer Center, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681,Japan

2 Department of Hematology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan

S.Kusumoto,A.Tomita

Table 1 Prognostic factors in limited-stage CHL identified by various research groups

|Research group|GHSG|EORTC|NCIC/ECOG|NCCN2023| |---|---|---|---|---| |Favorable disease|Stage I or II No risk factors|Stage I or II (supradiaphragmatic disease) No risk factors|Stage I or IIA No risk factors|Stage I or II One or more risk factors| |Unfavorable disease|Stage I or II One or more risk factors Considered advanced-stage if stage IIB with bulky medi- astinal mass or extranodal involvement|Stage I or II (supradiaphragmatic disease) One or more risk factors|Stage I or IIA One or more risk factors Considered advanced- stage if presenting with bulky or intra-abdomi-nal mass|Stage I or II One or more risk factors| |Risk factors|1. Mediastinal mass (ratio to maximum thorax diam- eter≥1/3) 2. Extranodal involvement|1. Mediastinal mass (ratio to maximum thorax diam- eter≥0.35) 2.Age≥50 years|1.Age≥40 years 2. Elevated ESR(≥50)3. Four or more lymph node regions 4. Mixed cellularity or lymphocyte-depleted classic Hodgkin lym- phoma|1. Mediastinal mass (ratio to maximum thorax diam-eter>0.33) 2. Elevated ESR(≥50) 3. B symptoms 4. Four or more lymph node regions 5. Mass exceeding 10cm|

GHSG German Hodgkin Study Group, EORTC European Organization for Research and Treatment of Cancer, NCIC National Cancer Institute of Canada, ECOG Eastern Cooperative Oncology Group, NCCN National Comprehensive Cancer Network

Cancer H7 randomized controlled trials. J Clin Oncol. 2006;24(19):3128-35.(1iiA)

4)Engert A, et al.; German Hodgkin's Lymphoma Study Group. Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group. J Clin Oncol.2003;21(19):3601-8.(1iiDiii)

5)Meyer RM,et al.; National Cancer Institute of Canada Clinical Trials Group, et al. Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma:National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol.2005;23(21):4634-42.(1iiDiii)

6)Hasenclever D, et al. A prognostic score for advanced Hodgkin's disease. International Prognostic Factors Pro-ject on Advanced Hodgkin's Disease. N Engl J Med. 1998;339(21):1506-14.(3iiDiiii)

JSH practical guidelines for hematological malignancies, 2023:II. Lymphoma 10. Hodgkin...

Algorithm

case of CHL, treatment with radiotherapy alone is not rec-ommended for limited- nor advanced-stage disease. Chemo-therapy alone or chemotherapy plus radiotherapy is recom-mended. In the case of NLPHL, involved-site radiotherapy(ISRT) is the standard therapy for limited-stage disease(CQ5).

Treatment for HI. differs between CHI, and NI.PHI. In the

 *Patients with non-bulkly disease

 *When response-adapted therapy based on interim PET is not used, 6 or 8 cycles of ABVD is an option.

S.Kusumoto,A.Tomita

The standard chemotherapy is the ABVD regimen (doxo-rubicin, bleomycin, vinblastine, and dacarbazine). Combi-nation of the AVD regimen (doxorubicin, vinblastine, and dacarbazine) with bentreximab vedotin (BV), the anti-CD30 antibody-drug conjugate, has recently become available as a treatment option for advanced-stage CHL.

Systematic lymphoid irradiation by extended-field radio-therapy(EFRT), major examples of which are mantle irra-diation, subtotal lymphoid irradiation, and total lymphoid irradiation, is not recommended alone nor in combination with chemotherapy. ISRT is recommended for combination with chemotherapy.

Limited-stage disease

Combined modality therapy(CMT) with chemotherapy and radiotherapy is performed as primary therapy for limited-stage CHL(CQ1). The ABVD regimen is one of the main regimens currently used for this purpose(CQ1). Limited-stage CHL treated with four cycles of ABVD followed by ISRT has a 10-year progression-free survival(PFS) rate of over 90%.Chemotherapy-only treatment approaches are also an option that avoid issues with late effects of radiotherapy, particularly late mortality from second cancers(e.g., lung, breast, and gas-trointestinal cancers) and cardiovascular disease(CQ2). It is also feasible to reduce the number of chemotherapy cycles or the radiation dose to reduce adverse events in patients with limited-stage CHL with no unfavorable prognostic factors.Four cycles of ABVD followed by 30 Gy of ISRT is rec-ommended for patients with unfavorable disease(CQ4), but two cycles of ABVD followed by 20 Gy of ISRT is another recommended treatment option for patients with favorable disease(CQ3). In CMT, response assessment is performed after completion of ABVD, and patients without obvious pro-gressive disease(PD) are treated with ISRT as planned, thus concluding the treatment sequence. When treating relapsed

$\text{patients, it is commonly to select the same regimens used for}$advanced-stage relapsed patients. Response-adapted therapy based on interim positron emission tomography (PET) during primary therapy is a promising treatment option for patients with unfavorable disease (CQ8).

Advanced-stage disease

The recommended primary therapies for advanced-stage CHL are six or eight cycles of ABVD or six cycles of BV+AVD (CQ6, CQ7). Response-adapted therapy based on interim PET during primary therapy is also a promis-ing treatment option for patients with advanced-stage dis-ease(CQ8). It is recommended to conclude treatment if PET shows a complete metabolic response(CMR) at the end of chemotherapy(CQ9). Addition of ISRT should be considered if computed tomography (CT) shows a complete response(CR) or partial response (PR), but PET does not show a CMR(CQ9). Salvage chemotherapy is performed for patients who have stable disease (SD) or worse on primary chemotherapy or relapse after chemotherapy (CQ10), and high-dose chemo-therapy with autologous hematopoietic stem cell transplan-tation (HSCT) is recommended for patients aged 65 years or younger who respond to salvage chemotherapy and have adequate organ function (CQ11). For relapsed or refrac-tory disease, typical salvage chemotherapy (e.g.,ICE,GDP,DHAP,ESHAP, or CHASE) as well as BV and the anti-PD-1 antibodies nivolumab and pembrolizumab have demonstrated efficacy (CQ10,12). Allogeneic HSCT may be an option for patients who respond to salvage chemotherapy after relapsing after autologous HSCT, but eligibility for allogeneic HSCT should be carefully considered (CQ13).

CQ1 Is CMT with chemotherapy and radiotherapy recommended as the standard therapy for newly diag-nosed limited-stage CHL?

Recommendation grade: Category 1

CMT is the standard therapy for limited-stage CHL in both patients with favorable and unfavorable disease.

JSH practical guidelines for hematological malignancies, 2023:II. Lymphoma 10. Hodgkin...

Explanation

A randomized phase III trial (H8-F) that compared CMT with three cycles of MOPP/ABV(mechlorethamine, vincristine, pro-carbazine, and prednisolone/doxorubicin, blecomycin, and vin-blastine) plus involved-field radiotherapy (IFRT) against subtotal nodal radiotherapy (STNR) alone for patients with newly diag-nosed favorable limited-stage CHL showed that CMT yielded significantly better 5-year event-free survival (EFS) and 10-year OS rates [1]. A three-arm trial (H8-U) that compared four cycles of MOPP/ABV+IFRT, six cycles of MOPP/ABV+IFRT, and four cycles of MOPP/ABV+STNR for patients with unfavora-ble prognostic features showed no significant differences in 5-year EFS or 10-year OS rates between the three groups. ${ }^{1}$

In the H7-F trial, which compared six cycles of EBVP(epirubicin, bleomycin, vinblastine, and prednisolone) plus IFRT versus STNR alone for patients with newly diagnosed favorable limited-stage CHL, the 10-year EFS rate was sig-nificantly better with CMT[2]. In the H7-U trial, which compared six cycles of EBVP+IFRT against six cycles of MOPP/ABV+IFRT in patients with unfavorable disease, the 10-year EFS rate was significantly better in patients who received CMT with MOPP/ABV.

<BeginOfPara>In the German Hodgkin Study Group (GHSG) HD7 trial, which compared radiotherapy alone (EFRT+IFRT) against CMT with two cycles of ABVD plus EFRT and IFRT in patients with newly diagnosed favorable limited-stage CHL, [3] CMT showed a significantly superior 15-year PFS rate (73% vs. 52%)[4]. OS did not differ significantly between treatments.

Reduction of the radiation field size is also being investi-gated as a way to reduce adverse events. In the HD8 trial, a randomized controlled trial (RCT) that investigated two cycles of COPP (cyclophosphamide, vincristine, procarbazine, and prednisolone) plus ABVD (COPP/ABVD) followed by EFRT or IFRT in patients with newly diagnosed unfavorable limited-stage CHL, [5] the 5-year freedom from treatment failure (FFTF) rate was comparable and OS did not differ significantly. Acute toxic-ity was lower with IFRT than with EFRT. ISRT, which uses a smaller radiation field that more precisely targets tumors to mini-mize radiation damage to normal tissue, has recently become recommended for CHL as well [6, 7].

On the basis of these results, CMT can be considered a suitable standard therapy for newly diagnosed limited-stage CHL. However, the standard CMT approach currently rec-ommended uses ISRT rather than IFRT as the radiotherapy technique.

References

1)Fermé C, et al. Chemotherapy plus involved-field radia-tion in early-stage Hodgkin's disease. N Engl J Med.2007;357(19):1916-27.(1iiD1)

2)Noordijk EM, et al. Combined-modality therapy for clinical stage I or II Hodgkin's lymphoma: long-term results of the European Organisation for Research and Treatment of Cancer H7 randomized controlled trials. J Clin Oncol. 2006;24(19):3128-35.(1iiA)

3)Engert A, et al. Two cycles of doxorubicin, bleomy-cin, vinblastine, and dacarbazine plus extended-field radio-therapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial.J Clin Oncol.2007;25(23):3495-502.(1iiDiii)

4)Sasse S, et al. Long-Term Follow-Up of Contemporary Treatment in Early-Stage Hodgkin Lymphoma: Updated Head10, and HD11 Trials. J Clin Oncol. 2017; 35(18):1999-2007.(1iiA)

5)Engert A, et al. Involved-field radiotherapy is equally effective and less toxic compared with extended-field radio-therapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group.J Clin Oncol.2003;21(19):3601-8.(1iiDiii)

6)Specht L,et al. Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group(ILROG). Int J Radiat Oncol Biol Phys. 2014; 89(4): 854-62.

7)Wirth A, et al. Involved Site Radiation Therapy in Adult Lymphomas: An Overview of International Lym-phoma Radiation Oncology Group Guidelines. Int J Radiat Oncol Biol Phys. 2020; 107(5): 909-33.(3iiiDiii)

CQ2 Is treatment with six cycles of ABVD recom-mended for newly diagnosed non-bulky limited-stage CHL?

S.Kusumoto,A.Tomita

Explanation

Although CMT achieves a 5-year PFS rate of approximately 85% or better in patients with newly diagnosed limited-stage CHL, late effects of radiotherapy, such as cardiovascular disorders and second cancers, are an issue, particularly in younger patients. To address this, studies have investigated the benefit of chemotherapy alone without radiotherapy.

A study of six cycles of ABVD in children with newly diagnosed non-bulky limited-stage CHL showed a 5-year PFS rate of around 85% to 92%, which was comparable to that observed with CMT[1, 2]. In an RCT of low-dose IFRT versus no IFRT in patients with non-bulky limited-stage CHL who achieved CR on COPP/ABV, the 3-year EFS rate was better with IFRT, but OS did not differ significantly[3]. A trial that compared six cycles of ABVD plus IFRTTR(IFRT and modified EFRT) against six cycles of ABVD for non-bulky stage I to IIIA CHL showed no significant differ-ence in the 5-year FPP or OS rate,[4]. but the authors note that a larger trial might demonstrate the benefit of CMT.

An RCT(HD.6 trial) by the National Cancer Institute of Canada(NCIC) Clinical Trials Group was designed with an ABVD group consisting of four to six cycles of ABVD for patients with non-bulky limited-stage CHL, either favorable or unfavorable, and an STNR group consisting of STNR alone for patients with favorable disease or two cycles of ABVD+STNR for those with unfavorable disease[5]. The 12-year rate of freedom from disease progression(FFDP)was significantly better with STNR, but OS was significantly better with ABVD. This was attributed to the fact that the ABVD group had fewer deaths from causes other than the primary disease, such as second cancers.

The incidence of cardiovascular events and second can-cers as late effects of radiotherapy increases over time,even 10 to 40 years after treatment completion,[6-8] and is approximately 4 to 6 times higher than the rate observed in the general population. It is believed that even reducing the radiation dose from 40 to 30 Gy is insufficient to pre-vent these late effects[6]. An observational study of 3905 patients treated for CHL in the Netherlands from 1965 to 2000(87.8% of whom received radiotherapy) showed that the cumulative incidence of second cancer at 40 years after treatment was 48.5%[8]. However, it should be noted that these data are relatively old, from the time when larger radia-tion field sizes were used, and limited evidence is available on late effects after radiotherapy using the currently recom-mended standard field sizes.

On the basis of the above, chemotherapy with six cycles of ABVD without radiotherapy can be considered a treat-ment option for non-bulky limited-stage CHL because it minimizes risk of late effects.

Response-adapted therapy based on interim PET has also been investigated. The RATHL trial investigated the non-inferiority of omitting bleomycin for patients with unfavorable limited-stage CHL or advanced-stage CHL who had a negative interim PET after two cycles of ABVD(PET-2) (AVD was an option for cycles three through six in PET-2-negative patients)[9]. This evidence indicates that when selecting six cycles of ABVD for non-bulky limited-stage CHL, switching to AVD for cycles three to six may be an option for PET-2-negative patients. Options for PET-2-positive patients are four cycles of escalated BEACOPC(bleomycin, etoposide, doxorubicin, cyclo-phosphamide, vincristine, procarbazine, and prednisolone)for patients with unfavorable CHL who are younger than 60 years, [9] and four cycles of ABVD plus 30 Gy of ISRT for patients with favorable CHL who are 60 years or older or have a favorable prognosis[10]. If response-adapted therapy based on interim PET is not selected, six cycles of ABVD is an option.

References

1)Rueda Domínguez A, et al. Treatment of stage I and II Hodgkin's lymphoma with ABVD chemotherapy: results after 7 years of a prospective study. Ann Oncol. 2004;15(12):1798-804.(3iiDiii)

2)Canellos GP,et al.Treatment of favorable, limited-stage Hodgkin's lymphoma with chemotherapy without con-solidation by radiation therapy. J Clin Oncol.2010;28(9):1611-5.(3iiiDiii)

3)Nachman JB, et al. Randomized comparison of low-dose involved-field radiotherapy and no radiotherapy for children with Hodgkin's disease who achieve a complete response to chemotherapy. J Clin Oncol.2002;20(18):3765-71.(iiDi)

4)Straus DJ,et al. Results of a prospective randomized clinical trial of doxorubicin, bleomycin, vinblastine, and dacarbazine(ABVD) followed by radiation therapy(RT)versus ABVD alone for stages I, II, and IIIA nonbulky Hodgkin disease. Blood.2004;104(12):3483-9.(1iiDiii)

5)Meyer RM, et al. ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma. N Engl J Med.2012;366(5):399-408.(1iiA)

6)Brusamolino E,et al.Long-term events in adult patients with clinical stage IA-IIA nonbulky Hodgkin's lymphoma treated with four cycles of doxorubicin, bleomycin, vin-blastine, and dacarbazine and adjuvant radiotherapy: a sin-gle-institution 15-year follow-up. Clin Cancer Res. 2006;12(21):6487-93.(3iiDiv)

7)De Bruin ML, et al. Breast cancer risk in female survi-vors of Hodgkin's lymphoma: lower risk after smaller radia-tion volumes. J Clin Oncol. 2009;27(26):4239-46.(3iiC)

JSH practical guidelines for hematological malignancies, 2023:II. Lymphoma 10. Hodgkin...

8)Schaapveld M, et al. Second Cancer Risk Up to 40 Years after Treatment for Hodgkin's Lymphoma. N Engl J Med.2015;373(26):2499-511.(3iC)

9)Johnson P, et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin's Lymphoma. N Engl J Med.2016;374(25):2419-29.(iiiA)

10)André MPE,et al.Early Positron Emission Tomog-raphy Response-Adapted Treatment in Stage I and II Hodg-kin Lymphoma: Final Results of the Randomized EORTC/LYSA/FIL H10 Trial.J Clin Oncol.2017;35(16):1786-94.(1iiA)

CQ3 Is CMT with two cycles of ABVD followed by ISRT recommended for patients with newly diagnosed favorable limited-stage CHL?

<EndOfPara>favorable limited-stage CHL received two cycles of ABVD,after which an interim PET was performed, and then those with a negative PET received either one additional cycle of ABVD plus 30 Gy of involved-node radiotherapy (INRT)or two cycles of ABVD alone [4]. The trial failed to demon-strate the non-inferiority of ABVD alone to ABVD + INRT in terms of 5-year PFS rates, indicating radiotherapy can-not be omitted even in patients with a negative interim PET after two cycles of ABVD. In the randomized GHSG HD16 trial, patients with favorable limited-stage CHL received two cycles of ABVD, and PET-negative patients either received 20 Gy of IFRT or were observed without treatment [5]. The 5-year PFS rate was significantly higher with CMT than with ABVD alone. This finding indicates that radiotherapy is still

<BeginOfPara>Recommendation grade: Category 2A

Two cycles of ABVD followed by ISRT is one of the recommended treatment options for patients with favorable limited-stage CHL.

Explanation

Long-term survival can be expected in patients with newly diagnosed favorable limited-stage CHL. Clinical trials are investigating reduction of chemotherapy cycles, drug doses,and radiation doses with the aim of reducing adverse events.

The GHSG HD10 trial was a randomized phase III trial with a 2×2 factorial design that compared two or four cycles of ABVD followed by 20 Gy or 30 Gy of IFRT for newly diagnosed favorable limited-stage CHL [1,2]. Neither the 5-year FFTF nor 5-year OS rates differed significantly.Adverse events and acute toxicities were the highest with four cycles of ABVD plus 30 Gy of IFRT. These efficacy and adverse event results suggested that two cycles of ABVD plus 20 Gy of IFRT would become the standard therapy for favorable limited-stage CHL.

The GHSG HD13 trial investigated omission of drugs from the ABVD regimen in patients with favorable limited-stage CHL[3]. This randomized phase III trial compared two cycles of ABVD, ABV, AVD, or AV followed by 30 Gy of IFRT, and found that the 5-year FFTF rate was signifi-cantly inferior for ABV and AV and inferior for AVD com-pared to ABVD. As a result, ABVD was determined to be the standard therapy.

Other trials have investigated reduction of treatment intensity based on interim PET results. In the H10F trial by the European Organisation of Research and Treatment of Cancer(EORTC), Lymphoma Study Association(LYSA),and Fondazione Italiana Linfomi(FIL), patients with

necessary for patients with a negative interim PET after two cycles of ABVD. ISRT is recommended as the standard local radiotherapy technique for CHL instead of IFRT[6,7].

Consequently, CMT with two cycles of ABVD plus 20 Gy of ISRT can be considered the recommended treatment for patients with newly diagnosed favorable limited-stage CHL. However, it is important to note that this evidence is exclusively from favorable patients without any of the risk factors in limited-stage CHL(mediastinal mass, extranodal involvement, elevated ESR, or involvement of $\geq 3$ lymph node regions) specified in the GHSG HD10 trial. ${ }^{1}$

References

1)Engert A, et al. Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma. N Engl J Med.2010;363(7):640-52.(1iiDiii)

2)Sasse S,et al.Longer-Term Follow-Up of Contemporary Treatment in Early-Stage Hodgkin Lymphoma: Updated Analyses of the German Hodgkin Study Group HD7, HD8,HD10, and HD11 Trials. J Clin Oncol. 2017; 35(18): 1999-2007.(1iiDiii)

3)Behringer K,et al.Omission of dacarbazine or bleomy-cin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma(GHSG HD13): an open-label, randomised, non-inferiority trial. Lancet.2015;385(9976):1418-27.(1iiDiii)

S.Kusumoto,A.Tomita

4)André MPE, et al. Early Positron Emission Tomogra-phy Response-Adapted Treatment in Stage I and II Hodg-kin Lymphoma: Final Results of the Randomized EORTC/LYSA/FIL H10 Trial.J Clin Oncol.2017;35(16):1786-94.(1iiDiii)

The GHSG HD11 trial, which aimed to reduce the IFRT dose by increasing chemotherapy intensity in patients with newly diagnosed unfavorable limited-stage CHL,[3, 4]compared four cycles of ABVD or four cycles of stand-ard BEACOPP followed by 20 or 30 Gy of IFRT in a 2 x2 factorial design. Based on efficacy and toxicity outcomes,ABVD+30 Gy of IFRT was concluded to be the standard therapy. In the HD14 trial that investigated the efficacy of escalated BEACOPP,[5, 6] 5-year FFTF and PFS rates were significantly better with two cycles of escalated BEACOPP plus two cycles of ABVD and 30 Gy of IFRT than with four cycles of ABVD plus 30 Gy of IFRT(OS was comparable).Since that point, escalated BEACOPP has been considered the standard therapy within the GHSG. A trial conducted to confirm the efficacy of CMT with the intensive Stanford V regimen for limited-stage CHL with bulky mediastinal mass failed to confirm superiority over ABVD[7]. The HD.6 trial by the NCIC Clinical Trials Group compared CMT with two cycles of ABVD+35 Gy of STNR against four to six cycles of ABVD in patients with newly diagnosed unfavorable

5)Fuchs M,et al. Positron Emission Tomography-Guided Treatment in Early-Stage Favorable Hodgkin Lymphoma:Final Results of the International, Randomized Phase III HD16 Trial by the German Hodgkin Study Group. J Clin Oncol.2019;37(31):2835-45.(1iiDiii)

6)Specht L,et al.Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group(ILROG). Int J Radiat Oncol Biol Phys.2014;89(4):854-62.

7)Wirth A,et al. Involved Site Radiation Therapy in Adult Lymphomas: An Overview of International Lym-phoma Radiation Oncology Group Guidelines. Int J Radiat Oncol Biol Phys. 2020; 107(5): 909-33.(3iiiDiii)

CQ4 What treatments are recommended for newly diagnosed unfavorable limited-stage CHL?

Recommendation grade: Category 2A CMT with four cycles of ABVD+ISRT is recommended for patients with unfavorable limited-stage CHL.

Recommendation grade: Category 2B

Response-adapted therapy based on interim PET (CQ8) is another recommended option.

Explanation

In a randomized phase III trial (GHSG HD8) in which patients with newly diagnosed unfavorable limited-stage CHL received two cycles of COPP/ABVD followed by either 30 Gy of EFRT or 30 Gy of IFRT,[1] IFRT was non-inferior to EFRT in terms of 5-year FFTF and OS rates, and had a lower incidence of adverse events. These results established CMT with IFRT as the standard therapy. In the H8-U trial(EORTC, GELA), which aimed to reduce treatment intensity in patients with newly diagnosed unfavorable limited-stage CHL,[2] patients were randomized to receive MOPP/ABV for six cycles followed by IFRT, four cycles followed by IFRT, or four cycles followed by STNR. Neither EFS nor OS differed significantly between protocols, and thus four cycles of chemotherapy followed by IFRT was concluded to be the standard therapy.

limited-stage CHL. CMT yielded a significantly better 12-year FFDP rate, but ABVD alone yielded a significantly better OS. As toxicity associated with CMT contributed to these trial results, careful interpretation is required consider-ing the recent shift to recommending ISRT as the standard radiotherapy technique for CHL[8,9].

Some trials investigated response-adapted therapy based on interim PET after chemotherapy in patients with unfa-vorable limited-stage CHL, in which radiotherapy is omit-ted in PET-negative patients to reduce adverse events, and treatment is intensified in PET-positive patients to boost efficacy (CQ8) [10,11]. The RATHL trial investigated the non-inferiority of omitting bleomycin for unfavorable lim-ited- or advanced-stage CHL with a negative PET-2 (AVD was an option for cycles three through six in PET-2-negative patients) [12]. In a trial of BV+AVD for newly diagnosed unfavorable limited-stage CHL, four cohorts of patients with a negative PET after four cycles of BV+AVD (PET-4) were

JSH practical guidelines for hematological malignancies, 2023: II. Lymphoma 10. Hodgkin...

assigned to receive 30 Gy of ISRT, 20 Gy of ISRT, 30 Gy of consolidation-volume radiotherapy, or no radiotherapy [13].Both CR and 2-year PFS rates were favorable, exceeding 90%, and adverse events were within an acceptable range,suggesting that radiotherapy could be reduced or omitted in PET-4-negative patients. However, as the evidence for BV+AVD in limited-stage CHL is not based on RCTs, it is preferable to limit its use to clinical trials.

Consequently, CMT with four cycles of ABVD+30 Gy of ISRT can be considered the recommended treatment for patients with newly diagnosed unfavorable limited-stage CHL. The recommended options for response-adapted therapy based on interim PET after two cycles of ABVD are as follows: four cycles of AVD for PET-2-negative patients, four cycles of escalated BEACOPPP for PET-2-positive patients younger than 60 years, and four cycles of ABVD plus 30 Gy of ISRT for PET-2-positive patients aged 60 years or older. ISRT can also be omitted for patients who are PET-4-negative after two cycles of escalated BEACOPP plus two cycles of ABVD.

References

1)Engert A, et al. Involved-field radiotherapy is equally effective and less toxic compared with extended-field radio-therapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group.J Clin Oncol.2003;21(19):3601-8.(1iiA)

2)Fermé C, et al. Chemotherapy plus involved-field radia-tion in early-stage Hodgkin's disease. N Engl J Med.2007;357(19):1916-27.(1iiD1)

3)Eich HT,et al.Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the Ger-man Hodgkin Study Group HD11 trial. J Clin Oncol. 2010;28(27):4199-206.(ii1Diii)

4)Sasse S,et al. Long-Term Follow-Up of Contemporary Treatment in Early-Stage Hodgkin Lymphoma: Updated Analyses of the German Hodgkin Study Group HD7, HD8,HD10, and HD11 Trials. J Clin Oncol. 2017;35(18):1999-2007. (1iiDiii)

5)von Tresckow B, et al. Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the Ger-man Hodgkin Study Group HD14 trial. J Clin Oncol.2012;30(9):907-13.(1iiDiii)

6)Gilessen S, et al. Intensified treatment of patients with early stage, unfavourable Hodgkin lymphoma: long-term follow-up of a randomised, international phase 3 trial of the German Hodgkin Study Group(GHSG HD14). Lancet Hae-matol.2021;8(4):e278-88.(1iiDiii)

7)Advani RH, et al. Randomized Phase III Trial Compar-ing ABVD Plus Radiotherapy With the Stanford V Regi-men in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial. J Clin Oncol 2015;33(17):1936-42.(1ii-Diii)

8)Specht L,et al. Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group(ILROG). Int J Radiat Oncol Biol Phys.2014;89(4):854-62.

9)Wirth A,et al. Involved Site Radiation Therapy in Adult Lymphomas: An Overview of International Lym-phoma Radiation Oncology Group Guidelines. Int J Radiat Oncol Biol Phys.2020; 107(5): 909-33.

10)André MPE, et al. Early Positron Emission Tomog-raphy Response-Adapted Treatment in Stage I and II Hodg-kin Lymphoma: Final Results of the Randomized EORTC/LYSA/FIL H10 Trial.J Clin Oncol.2017;35(16):1786-94.(1iiDiii)

11)Borchmann P, et al. PET-guided omission of radio-therapy in early-stage unfavourable Hodgkin lymphoma(GHSG HD17): a multicentre, open-label, randomised,phase 3 trial. Lancet Oncol. 2021; 22(2): 223-34.(1iiDiii)

12)Johnson P, et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin's Lymphoma.N Engl J Med.2016;374(25):2419-29.(1iiDiii)

13)Kumar A,et al. Brentuximab Vedotin Combined With Chemotherapy in Patients With Newly Diagnosed Early-Stage, Unfavorable-Risk Hodgkin Lymphoma. J Clin Oncol.2021;39(20):2257-65.(2Diii)

CQ5 What treatments are recommended for NLPHL?

S.Kusumoto,A.Tomita

Explanation

NLPHL is less common than the nodular sclerosis and mixed cellularity subtypes of CHL, and thus no prospective trials have been conducted exclusively in NLPHL. In a retrospective analy-sis of patients with stage IA NLPHL without risk factors who were enrolled in various GHSG clinical trials (including HD4,HD7, HD10, and LPHL IA), [1, 2] EFRT, IFRT, and CMT all had good outcomes, and IFRT alone was considered the stand-ard therapy because it had the lowest risk of treatment-related toxicity. Since that point, ISRT has been recommended in place of IFRT as the standard local radiotherapy technique for CHL,[3,4] and studies have provided evidence for ISRT in NLPHL[5]. A U.S. retrospective analysis of treatment outcomes for limited-stage NLPHL showed that radiation field size had no effect on the efficacy of radiotherapy, and that CMT was not superior to radiotherapy alone, and consequently concluded that radiotherapy with a limited radiation field is the standard therapy[6] A retrospective analysis of limited-stage NLPHL outcomes by the International Lymphoma Radiation Oncology Group(ILROG) [7] similarly confirmed the superiority of radiother-apy alone, but also noted the benefit of CMT in some patients with risk factors. Although several retrospective analyses have demonstrated the efficacy of CMT with ABVD+radiotherapy,[8-10] specific indications for CMT remain unclear.

Other studies have shown that long-term survival can be expected in patients with in a single node lesion completely resected, [11] and that watch and wait for a defined period after diagnosis is feasible in certain patients and may not affect the survival prognosis [12]. However, further research is warranted because all of these results are from retrospec-tive analysis.

References

1)Eichenauer DA, et al. Long-Term Course of Patients With Stage IA Nodular Lymphocyte-Predominant Hodgkin Lym-phoma: A Report From the German Hodgkin Study Group.J Clin Oncol.2015;33(26):2857-62.(3iiiDiii)

2)Nogová L,et al.Extended field radiotherapy,combined modality treatment or involved field radiotherapy for patients with stage IA lymphocyte-predominant Hodgkin's lym-phoma: a retrospective analysis from the German Hodgkin

Study Group (GHSG). Ann Oncol. 2005; 16(10):1683-7.(3iiiDii)

3)Specht L,et al. Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group(ILROG). Int J Radiat Oncol Biol Phys.2014;89(4):854-62.

4)Wirth A,et al. Involved Site Radiation Therapy in Adult Lymphomas: An Overview of International Lym-phoma Radiation Oncology Group Guidelines. Int J Radiat Oncol Biol Phys.2020; 107(5): 909-33.(3iiiDiii)

5)Pinnix CC,et al.Favorable outcomes with de-escalated radiation therapy for limited-stage nodular lymphocyte-prominant Hodgkin lymphoma. Blood Adv. 2019; 3(9):1356-67.(3iiiDiii)

6)Chen RC,et al.Early-stage,lymphocyte-predominant Hodgkin's lymphoma: patient outcomes from a large, single-institution series with long follow-up. J Clin Oncol. 2010;28(1): 136-41.(3iiiA)

7)Binkley MS, et al. Stage I-II nodular lymphocyte-pre-dominant Hodgkin lymphoma: a multi-institutional study of adult patients by ILROG. Blood.2020;135(26):2365-74.(3iiiDiii)

8)Eichenauer DA,et al. Long-Term Follow-Up of Patients With Nodular Lymphocyte-Predominant Hodgkin Lym-phoma Treated in the HD7 to HD15 Trials: A Report From the German Hodgkin Study Group. J Clin Oncol. 2020;38(7):698-705.(3iiiDiii)

9)Savage KJ, et al. Treating limited-stage nodular lym-phocyte predominant Hodgkin lymphoma similarly to classi-cal Hodgkin lymphoma with ABVD may improve outcome.Blood.2011;118(17):4585-90.(3iiiA)

10)Cheng PTM, et al. Outcome of limited-stage nodu-lar lymphocyte-predominant Hodgkin lymphoma and the impact of a PET-adapted approach. Blood Adv. 2021; 5(18):3647-55.(3iiiDiii)

11)Appel BE, et al. Minimal Treatment of Low-Risk,Pediatric Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the Children's Oncology Group. J Clin Oncol.2016;34(20):2372-9.(3iiiDi)

12)Borchmann S, et al. Active surveillance for nodular lymphocyte-predominant Hodgkin lymphoma. Blood 2019;133(20):2121-9.(3iiDiii)

CQ6 What treatments are recommended for newly diagnosed advanced-stage CHL?

SHJ practical guidelines for hematological malignancies, 2023: II. Lymphoma 10. Hodgkin...

Explanation

Newly diagnosed advanced-stage CHL has inferior treat-ment outcomes compared with limited-stage CHL [1]. Either response-adapted therapy based on interim PET (ABVD or ABVD/escalated BEACOPP) or BV + AVD is recommended as standard therapy for newly diagnosed advanced-stage CHL.

The standard therapy used for newly diagnosed advanced-stage CHL is ABVD in Japan and the United States, [2, 3]and escalated BEACOPP in Germany and elsewhere in Europe [4]. Despite its toxicity, escalated BEACOPP yields superior PFS to ABVD, [4] but only extends OS to a limited degree in patients scheduled to undergo autologous HSCT after relapse [5].

Interim PET is also a useful prognostic tool in CHL(see CQ8 for details): in several clinical trials, patients with newly diagnosed advanced-stage CHL were evaluated by interim PET after two cycles of ABVD (PET-2), and those with a positive scan were switched to escalated BEACOPP,whereas those with a negative scan received ABVD or AVD(with bleomycin omitted).

In a Japan Clinical Oncology Group trial (JCOG1305)in patients aged 60 years or younger with advanced-stage CHL, PET-2-positive patients received six cycles of esca-lated BEACOPP, and PET-2-negative patients received four cycles of ABVD (six cycles in total). Patients with PR and residual lesions in a single area after chemotherapy then received ISRT. The primary endpoints of 2-year PFS rates in all eligible patients and PET-2-positive patients were 84.8%and 84.2%, respectively, exceeding the pre-specified thresh-olds of 75% and 35%, respectively.6

Three non-Japanese trials (RATHL, SWOG S0816, and GITIL/FIL HD0607) similarly demonstrated favorable 2- or 3-year PFS rates of 60% to 65% after switching PET-2-posi-tive patients to escalated BEACOPPP [7-9]. Although the RATHL trial, which was a randomized trial of ABVD and AVD in PET-2-negative patients, failed to achieve the ini-tially specified non-inferiority margin, [7] several guide-lines state that switching to AVD is a treatment option for PET-2-negative patients [10,11]. The choice of whether to omit bleomycin in PET-2-negative patients is considered important, especially in older patients (>60 years) and in younger patients with risk factors for pulmonary toxicity from bleomycin [12].

The JCOG Lymphoma Study Group has published results from clinical trials aimed at reducing adverse events. A single-arm phase II trial investigated ABVd, which uses a lower dose of dacarbazine, in patients with limited-stage(stage II) and advanced-stage CHL, with the aim of reducing the gastrointestinal toxicity of ABVD. The regimen dem-onstrated efficacy, with a CR rate of 81% and 5-year PFS

<EndOfPara>rate of 78.4%, and adverse events were within the accept-able range[1, 13]. Patients who receive ABV, which omits dacarbazine, had poorer PFS than patients with the same baseline characteristics, confirming that dacarbazine should not be omitted[14].

In a phase III RCT of $BV+AVD$ versus ABVD for pre-viously untreated advanced-stage CHL,[14] $BV+AVD$ yielded a significantly better 2-year modified PFS rate than ABVD, and a long-term follow-up analysis at 5 years showed similar results [15]. A subsequent long-term follow-up analysis at approximately 6 years showed that $BV+AVD$ extends OS, [16] but concerns have been raised about second cancers and bleomycin-related pulmonary toxicity in light of differences in OS events [17] Each regimen has a different adverse event profile: attention must be paid to bleomycin-related pulmonary toxicity in ABVD, and febrile neutropenia in $BV+AVD$ . Primary prophylaxis with granulocyte colony-stimulating factor is recommended for $BV+AVD$ .

In older CHL patients(>60 years), in contrast, escalated BEACOPP is not indicated, and BV+AVD provides limited benefit (see CQ7). Therefore, six or eight cycles of ABVD may be an option when response-adapted therapy based on interim PET will not be used.

References

1)Makita S, et al. Clinical features and outcomes of 139 Japanese patients with Hodgkin lymphoma. Int J Hematol.2016;104(2):236-44.(3iiiDiii)

2)Ogura M, et al. Phase II study of ABVD therapy for newly diagnosed clinical stage II-IV Hodgkin lymphoma:Japan Clinical Oncology Group study(JCOG 9305). Int J Hematol. 2010; 92(5): 713-24. (3iiiDiv)

3)Canellos GP, et al. Chemotherapy of advanced Hodg-kin's disease with MOPB, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992; 327(21): 1478-84.(1iiA)

4)Engert A, et al. Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin's lym-phoma: 10 years of follow-up of the GHSG HD9 study. J Clin Oncol. 2009 Sep 20; 27(27):4548-54.(1iiDi)

5)Viviani S, et al. ABVD versus BEACOPP for Hodg-kin's lymphoma when high-dose salvage is planned. N Engl J Med.2011;365(3):203-12.(iiDi)

6)Kusumoto S, et al. Interim PET-guided ABVD or ABVD/escalated BEACOPP for newly diagnosed advanced-stage classic Hodgkin lymphoma(JCOG1305).Cancer Sci. 2024 Oct;115(10):3384-3393.(3iiiDiv)

7)Johnson P, et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin's Lymphoma.N Engl J Med.2016;374(25):2419-29.(1iiDiii)

S. Kusumoto, A. Tomita

8)Press OW, et al. US Intergroup Trial of Response-Adapted Therapy for Stage III to IV Hodgkin Lymphoma Using Early Interim Fluorodeoxyglucose-Positron Emis-sion Tomography Imaging: Southwest Oncology Group S0816. J Clin Oncol. 2016; 34(17): 2020-7.(3iiiDiii)

9)Gallamini A, et al. Early Chemotherapy Intensi-fication With Escalated BEACOPP in Patients With Advanced-Stage Hodgkin Lymphoma With a Posi-tive Interim Positron Emission Tomography/Computed-Tomography Scan After Two ABVD Cycles: Long-Term Results of the GITIL/FIL HD 0607 Trial. J Clin Oncol.2018;36(5):454-62.(3iiiDiii)

10)NCCN guideline 2022 Hodgkin Lymphoma.

11)Guideline for the first-line management of Classical Hodgkin Lymphoma- A British Society for Haematology guideline.

12)UpToDate. Initial treatment of advanced (stage III-IV)classic Hodgkin lymphoma.

13)Ogura M, et al. Phase II study of ABV(doxorubicin with increased dose, bleomycin and vinblastine) therapy in newly diagnosed advanced-stage Hodgkin lymphoma: Japan Clinical Oncology Group study(JCOG9705). Leuk Lym-phoma.2013;54(1):46-52.(3iiiDiii)

14)Connors JM, et al. Brentuximab Vedotin with Chemo-therapy for Stage III or IV Hodgkin's Lymphoma. N Engl J Med.2018;378(4):331-44.(iiDi)

15)Straus DJ,et al. Brentuximab vednotin tochem for therapy for stage III or IV classical Hodgkin lymphoma(ECHELON-1): 5-year update of an international, open-label, randomised, phase 3 trial. Lancet Haematol. 2021;8(6):e410-21.(1iiD1)

16)Ansell SM, et al. Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin's Lymphoma. N Engl J Med.2022 Jul 28; 387(4):310-20.(1iiDi)

17)Longo DL, et al. A Better Treatment for Advanced-Stage Hodgkin's Lymphoma? N Engl J Med.2022 Jul 28;387(4):370-2.

CQ7 What treatments are recommended for newly diagnosed advanced-stage CHL in older patients(≥60 years)?

Explanation

<EndOfPara>Activities of daily living(ADL)impairment and comorbidi-ties should be considered in treatment selection for older patients with CHL. In a real-world retrospective analysis of treatments provided to older CHL patients aged 60 years or older(including approximately 60% with advanced-stage disease),[1] approximately 10% of patients had ADL loss,and approximately 20% had some kind of clinically signifi-cant medical comorbidity. PFS and OS were significantly better with conventional chemotherapy (ABVD, AVD, or BV-AVD) than with other treatments. In addition, patients with impaired ADL had a poor prognosis, and patients with comorbidities had a high rate of treatment discontinuation due to toxicity. In addition, a large retrospective observa-tional study in patients aged 65 years or older with newly diagnosed CHL (about half with advanced-stage disease) [2]showed that treating at a lower intensity than standard ther-apy may increase the risk of lymphoma-related mortality.

The main regimens are ABVD and related therapies, and regimens that incorporate BV have also been investigated.In a retrospective analysis of ABVD for CHL patients aged 60 years or older, the CR rate was approximately 80%, but approximately 20% of patients experienced grade 3 or higher pulmonary toxicity(including fatal cases), which suggests that use of bleomycin in particular should be considered with sufficient care. In a subgroup analysis of older patients aged 60 years or older in a phase III trial that compared the efficacy of ABVD versus BV+AVD for newly diagnosed advanced-stage CHL,[3] modified PFS did not differ signifi-cantly between regimens. Adverse events, which included pulmonary toxicity with ABVD and febrile neutropenia and peripheral neuropathy with BV+AVD, occurred at a high rate, indicating a need for attention. Sufficient evidence for these treatments has not yet been gathered, and further studies are warranted. In the meantime, it is advisable to carefully select treatment for each individual patient, with consideration to comorbidities.

Other regimens that have been investigated for older patients with CHL include BV alone, [4] BV plus

<BeginOfPara>Recommendation grade: Category 2B

A(B)VD or BV+AVD is recommended for older patients with advanced-stage CHL, but comorbidities should be considered in treatment selection, and attention must be paid to adverse

comorbidities should be considered in treatment selection, and attention must be paid to adverse events.

JSH practical guidelines for hematological malignancies, 2023:II. Lymphoma 10. Hodgkin...

dacarbazine,[5] BV/AVD/BV,[6] PVAG(prednisolone,vinblastine, doxorubicin, and gemcitabine,[7] and CHOP(cyclophosphamide, doxorubicin, vincristine, and prednis-o-lone)[8]. Although these regimens have shown some effi-cacy and their toxicity is considered to be within an accept-able range, none has demonstrated equivalent or superior benefit compared with ABVD. Concerns about potentially high treatment-related toxicity have also been raised for regi-mens, such as intensive Stanford V regimen [9] and standard BEACOPP. ${ }^{10}$

References

1)Orellana-Noia VM, et al. Multicenter analysis of geriatric fitness and real-world outcomes in older patients with classi-cal Hodgkin lymphoma. Blood Adv.2021;5(18):3623-32.(3iiiDiii)

2)Rodday AM,et al. Association of Treatment Intensity With Survival in Older Patients With Hodgkin Lymphoma.JAMA Netw Open.2021;4(10):e2128373.(3iB)

3)Evens AM,et al. Older patients(aged $\geq$ 60 years) with previously untreated advanced-stage classical Hodgkin lym-phoma: a detailed analysis from the phase III ECHELON-1 study. Haematologica.2022;107(5):1086-94.(3iiiDi)

4)Forero-Torres A, et al. Phase 2 study of frontline Brentuximab vedotin monotherapy in Hodgkin lymphoma patients aged 60 years and older. Blood. 2015; 126(26):2798-804.(3iiiDiv)

${}^{5}$ )Friedberg JW,et al.Frontline bentuximab vedotin in combination with dacarbazine or bendamustine in patients aged $\geq$ 60 years with HL. Blood. 2017; 130(26): 2829-37.(3iiiDiv)

6)Evens AM,et al. Multicenter Phase II Study of Sequen-tial Brentuximab Vedotin and Doxorubicin, Vinblastine,and Dacarbazine Chemotherapy for Older Patients With Untreated Classical Hodgkin Lymphoma. J Clin Oncol.2018;36(30):3015-22.(3iiiDiv)

7)Boll B,et al. Phase 2 study of PVAG(prednisone, vin-blastine, doxorubicin, gemcitabine) in elderly patients with early unfavorable or advanced stage Hodgkin lymphoma.Blood.2011;118(24):6292-8.(3iiiDiv)

8)Kolstad A, et al. Standard CHOP-21 as first line therapy for elderly patients with Hodgkin's lymphoma. Leuk Lym-phoma.2007;48(3):570-6.(3iiiDiv)

9)Evens AM,et al.The efficacy and tolerability of adria-mycin, bleomycin, vinblastine, dacarbazine and Stanford V in older Hodgkin lymphoma patients: a comprehensive analysis from the North American intergroup trial E2496.Br J Haematol.2013; 161(1):76-86.(3iiiDiii)

10)Ballova V,et al. A prospectively randomized trial car-ried out by the German Hodgkin Study Group(GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD(study HD9elderly).Ann Oncol.2005; 16(1):124-31.(1iiDii)

CQ8 Is response-adapted therapy based on results of FDG-PET during primary therapy(interim PET) recom-mended for newly diagnosed CHL?

Recommendation grade: Category 2A

Response-adapted therapy based on interim PET is a recommended option for newly diagnosed unfavorable limited-stage CHL and for advanced-stage CHL.

S.Kusumoto,A.Tomita

Explanation

Findings from fluorodeoxyglucose-positron emission tomogra-phy (FDG-PET) during treatment (interim PET) have shown prognostic utility in CHL,[1-4] and clinical trials have investi-gated response-adapted therapy, where the regimen is changed on the basis of response assessment by interim PET. Several trials have investigated omission of local radiotherapy in patients with newly diagnosed favorable limited-stage CHL with a nega-tive interim PET after two or three cycles of ABVD (PET-2 or PET-3), but all failed to confirm non-inferiority [5-9]. However,the GHSG HD17 trial validated the non-inferiority of omitting local radiotherapy in patients with newly diagnosed unfavora-ble limited-stage CHL with a negative interim PET after two cycles of escalated BEACOPP plus two cycles of ABVD [10].Another trial in newly diagnosed bulky limited-stage CHL reported excellent outcomes for response-adapted therapy where patients with a negative PET-2 received four cycles of ABVD, and those with a positive PET-2 received four cycles of escalated BEACOPP plus 30.6 Gy of IFRT [11]. In addition,in trials where patients with newly diagnosed advanced-stage CHL were switched to escalated BEACOPP after a positive PET-2, the PFS rates of patients who were switched were better at 60\% to 65\%, compared to just 15\% to 30\% in historical con-trols who received six to eight cycles of ABVD (in the RATHL,SWOG S0816, and GITIL/FIL HD0607 trials) [12-14]. The abovementioned RATHL trial investigated the non-inferiority of omitting bleomycin for patients with unfavorable limited- or advanced-stage CHL with a negative PET-2 (four cycles of AVD was also available as an option for patients with a negative interim PET) [12]. In the JCOG1305 trial in Japanese patients with advanced-stage CHL, which had a similar design to the abovementioned SWOG S0816 trial, PET-2-positive patients received six cycles of escalated BEACOPP, and PET-2-nega-tive patients received four cycles of ABVD (six cycles in total).Patients with PR and a single residual lesion after chemotherapy then received ISRT. The primary endpoints of 2-year PFS rates in all eligible patients and PET-2-positive patients were 84.8\%and 84.2\%, respectively, exceeding the prespecified thresholds of 75\% and 30\%[15].

On the basis of the above evidence, response-adapted therapy based on interim PET is a recommended option for newly diagnosed unfavorable limited-stage CHL and for advanced-stage CHL.

However, the evidence for escalated BEACOPP as response-adapted therapy based on interim PET in PET-2-positive patients does not apply to CHL patients older than 60 years. In addition, the SWOG S0816 trial reported concerns regarding the low negative predictive value of interim PET and the risk of second cancers after escalated BEACOPP, [16] and further long-term follow-up data, including from other trials, are awaited. In addition,

trials of response-adapted therapy based on interim PET after escalated BEACOPP in advanced-stage CHL have shown a benefit to reducing treatment intensity in patients with a negative interim PET[17-19].

References

1)Gallamini A,et al.Early interim 2-[18F] fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study.J Clin Oncol.2007;25(24):3746-52.(3iiiDiii)

2)Markova J, et al. FDG-PET for assessment of early treatment response after four cycles of chemotherapy in patients with advanced-stage Hodgkin's lymphoma has a high negative predictive value. Ann Oncol. 2009; 20(7):1270-4.(3iiiDiii)

3)Barrington SF, et al. Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imag-ing Working Group. J Clin Oncol. 2014;32(27):3048-58.

4)Aldin A, et al. Interim PET-results for prognosis in adults with Hodgkin lymphoma: a systematic review and meta-analysis of prognostic factor studies. Cochrane Data-base Syst Rev.2020;1(1):CD012643.

5)Radford J,et al.Results of a trial of PET-directed ther-apy for early-stage Hodgkin's lymphoma. N Engl J Med.2015;372(17):1598-607.(1iiDiii)

6)André MPE, et al. Early Positron Emission Tomogra-phy Response-Adapted Treatment in Stage I and II Hodg-kin Lymphoma: Final Results of the Randomized EORTC/LYSA/FIL H10 Trial. J Clin Oncol.2017;35(16):1786-94.(1iiDiii)

7)Fuchs M,et al. Positron Emission Tomography-Guided Treatment in Early-Stage Favorable Hodgkin Lymphoma:Final Results of the International, Randomized Phase III HD16 Trial by the German Hodgkin Study Group.J Clin Oncol.2019;37(31):2835-45.(iiiiDiii)

8)Barrington SF, et al. Positron Emission Tomography Score Has Greater Prognostic Significance Than Pretreat-ment Risk Stratification in Early-Stage Hodgkin Lymphoma in the UK RAPID Study. J Clin Oncol. 2019; 37(20): 1732-41.(3iiiDiii)

9)Shaikh PM, et al. Consolidation radiotherapy fol-lowing positron emission tomography complete response in early-stage Hodgkin lymphoma: a meta-analysis. Leuk Lymphoma.2020;61(7):1610-7.(3iiiDiii)

10)Borchmann P,et al.PET-guided omission of radio-therapy in early-stage unfavourable Hodgkin lymphoma(GHSG HD17): a multicentre, open-label, randomised,phase 3 trial. Lancet Oncol. 2021; 22(2): 223-34.(1iiDiii)

11)LaCasce AS, et al. Positron Emission Tomography-Adapted Therapy in Bulky Stage I/II Classic Hodgkin

JSH practical guidelines for hematological malignancies, 2023: II. Lymphoma 10. Hodgkin...

Lymphoma: CALGB 50801(Alliance).J Clin Oncol.2023; 41(5):1023-34.(3iiiDiii)

12)Johnson P, et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced Hodgkin's Lymphoma.N Engl J Med.2016;374(25):2419-29.(iiiiiiii)

13)Press OW, et al. US Intergroup Trial of Response-Adapted Therapy for Stage III to IV Hodgkin Lymphoma-Using Early Interim Fluorodeoxyglucose-Positron Emission Tomography Imaging: Southwest Oncology Group S0816.J Clin Oncol. 2016; 34(17): 2020-7.(3iiiDiii)

14)Gallamini A, et al. Early Chemotherapy Intensification With Escalated BEACOPP in Patients With Advanced-Stage Hodgkin Lymphoma With a Positive Interim Positron Emission Tomography/Computed Tomography Scan After Two ABVD Cycles: Long-Term Results of the GITIL/FIL HD 0607 Trial.J Clin Oncol.2018;36(5):454-62.(3iiiDiii)

15)Kusumoto S, et al. Interim PET-guided ABVD or ABVD/escalated BEACOPP for newly diagnosed advanced-stage classic Hodgkin lymphoma(JCOG1305). Cancer Sci.2024 Oct;115(10):3384-3393.(3iiiDiv)

16)Stephens DM, et al. Five-year follow-up of SWOG S0816: limitations and values of a PET-adapted approach with stage III/IV Hodgkin lymphoma. Blood.2019;134(15):1238-46.(3iiiDiii)

17)Borchmann P, et al. Progression-free survival of early interim PET-positive patients with advanced stage Hodg-kin's lymphoma treated with BEACOPPescalated alone or in combination with rituximab(HD18): an open-label, inter-national, randomised phase 3 study by the German Hodgkin Study Group. Lancet Oncol. 2017; 18(4): 454-63.(1iiDiii)

18)Borchmann P,et al.PET-guided treatment in patients with advanced-stage Hodgkin's lymphoma(HD18): final results of an open-label, international, randomised phase 3 trial by the German Hodgkin Study Group. Lancet. 2017; 390(10114):2790-802.(1iiDiii)

19)Casasnovas RO, et al. PET-adapted treatment for newly diagnosed advanced Hodgkin lymphoma(AHL2011):a randomised, multicentre, non-inferiority, phase 3 study.Lancet Oncol. 2019; 20(2): 202-15.(iiDiiii)

CQ9 Is consolidative ISRT recommended for newly diagnosed advanced-stage CHL?

Explanation

In addition to CT, FDG-PET/CT is now commonly to assess response to chemotherapy for CHL. Studies conducted before the FDG-PET/CT era showed that local radiotherapy did not improve prognosis when used as consolidation ther-apy for patients with a CR to chemotherapy, but did improve prognosis when used to treat residual disease[1-4]. How-ever, some studies showed that local radiotherapy after CR or additional chemotherapy after CR improved prognosis[5,6]. ISRT has been recommended as the standard local radiotherapy technique for CHL[7,8].

In the GHSG HD15 trial, patients with newly diagnosed advanced-stage CHL were randomized to receive eight cycles of escalated BEACOPPP, six cycles of escalated BEACOPPP, eight cycles of BEACOPP-14, and those in any group who had residual PET-positive lesions exceeding 2.5 cm after chemotherapy were given an additional 30 Gy of radiotherapy. The 5-year FFTF rate(primary endpoint)was better for six cycles of escalated BEACOPP. PET-nega-tive patients with a PR and those with CR/CRu had compa-rable 4-year PFS rates, whereas PET-positive patients with a PR had a worse 4-year PFS rate[9, 10]. This evidence suggests that additional ISRT is unnecessary for patients with newly diagnosed advanced-stage CHL who show a PR on CT after chemotherapy but a CMR on PET.

In the HD0607 trial, patients with newly diagnosed advanced-stage CHL with a mass lesion of 5 cm or larger and CMR on interim PET after both two cycles (PET-2)and six cycles (PET-6) of ABVD were randomly assigned to consolidative local radiotherapy or no radiotherapy. The 6-year PFS rates (primary endpoint) did not differ between those who received and did not receive radiotherapy [11].Similarly, in the FIL HD0801 trial, patients with newly diagnosed advanced-stage CHL with a mass lesion of 5 cm or larger or larger before treatment and CMR on both PET-2 and PET-6 after ABVD were randomized to radiotherapy or no radiotherapy. The 2-year EFS rates (primary endpoint) did not differ between those who received and did not receive radiotherapy [12]. These two trials showed that consoli-dative local radiotherapy can be omitted in patients with

S.Kusumoto,A.Tomita

advanced-stage CHL who have a mass lesion of 5 cm or larger at initial presentation if they show a CMR on PET-2 and PET-6.

Accordingly, ISRT is not recommended for patients with newly diagnosed advanced-stage CHL who show a CMR to chemotherapy.

References

1)Aleman BM, et al. Involved-field radiotherapy for advanced Hodgkin's lymphoma. N Engl J Med.2003;348(24):2396-406.(1iiDiii)

2)Borchmann P, et al. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin's lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol.2011;29(32):4234-42.(1iiDiii)

3)Fabian CJ, et al. Low-dose involved field radiation after chemotherapy in advanced Hodgkin disease. A Southwest Oncology Group randomized study. Ann Intern Med. 1994;120(11):903-12.(1iiA)

4)Johnson PW, et al. Consolidation radiotherapy in patients with advanced Hodgkin's lymphoma: survival data from the UKLG LY09 randomized controlled trial(ISRCTN97144519).J Clin Oncol.2010;28(20):3352-9.(3iiiDiii)

5)Laskar S, et al. Consolidation radiation after complete remission in Hodgkin's disease following six cycles of doxo-Rubicin, bleomycin, vinblastine, and dacarbazine chemother-apy: is there a need? J Clin Oncol. 2004; 22(1): 62-8.(1iiA)

<BeginOfPara>6)Fermé C, et al. Comparison of chemotherapy to radiotherapy as consolidation of complete or good partial

<EndOfPara>response after six cycles of chemotherapy for patients with advanced Hodgkin's disease: results of the groupe d'études des lymphomes de l'Adulte H89 trial. Blood.2000;95(7):2246-52.(1iiDii)

7)Specht L,et al. Modern radiation therapy for Hodg-kin lymphoma: field and dose guidelines from the interna-tional lymphoma radiation oncology group(ILROG). Int J Radiat Oncol Biol Phys.2014;89(4):854-62.

8)Wirth A,et al. Involved Site Radiation Therapy in Adult Lymphomas: An Overview of International Lym-phoma Radiation Oncology Group Guidelines. Int J Radiat Oncol Biol Phys.2020; 107(5): 909-33.(3iiiDiii)

9)Kobe C, et al. Positron emission tomography has a high negative predictive value for progression or early relapse for patients with residual disease after first-line chemotherapy in advanced-stage Hodgkin lymphoma.Blood.2008;112(10):3989-94.(1iiDiii)

10)Engert A, et al. Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma(HD15 trial): a randomised,open-label, phase 3 non-inferiority trial. Lancet. 2012;379(9828): 1791-9.(iiiiDiii)

11)Gallamini A, et al. Consolidation Radiotherapy Could Be Sely Omitted in Advanced Hodgkin Lym-phoma With Large Nodal Mass in Complete Metabolic Response After ABVD: Final Analysis of the Randomized GITIL/FIL HD0607 Trial.J Clin Oncol.2020;38(33):3905-13.(iiiiDiii)

12)Ricardi U, et al. Role of radiotherapy to bulky sites of advanced Hodgkin lymphoma treated with ABVD: final results of FIL HD0801 trial. Blood Adv. 2021; 5(21):4504-14.(1iiDi)

CQ10 What treatments are recommended for relapsed or refractory CHL?

Recommendation grade: Category 2B

Conventional salvage chemotherapy (e.g., ICE, GDP, DHAP, CHASE, or gemcitabine alone), an anti-CD30 antibody-drug conjugate (BV), or an anti-PD-1 antibody (nivolumab or pembrolizumab) can be selected, with consideration to age and other eligibility factors for autologous HSCT as well as duration of response (DoR) and adverse events with prior therapy.

JSH practical guidelines for hematological malignancies, 2023:II. Lymphoma 10. Hodgkin...

Explanation

Salvage chemotherapy options for relapsed or refractory CHL include conventional chemotherapy (e.g., ICE, [1]GDP, [2] DHAP, [3] CHASE, [4] or single-agent gemcit-abine [5]), an anti-CD30 antibody-drug conjugate (BV),[6-9] or anti-PD-1 antibodies (nivolumab [10-14] or pem-brolizumab [15-18]). As evidence regarding the relative superiority of salvage chemotherapy regimens is very lim-ited, [18] regimen selection should be based on age and other eligibility factors for autologous HSCT, DoR and adverse events with prior therapy, and the goal of salvage chemotherapy.

Salvage chemotherapy for first-relapsed or primary refractory CHL in younger therapy (<60 years) is discussed in CQ11 and CQ12.

As the goal of salvage therapy for transplant-ineligible patients with first-relapsed or primary refractory CHL is to extend survival and palliate symptoms, BV, nivolumab, or pembrolizumab is selected more often than conventional chemotherapy.

In a phase II trial of single-agent BV (1.8 mg/kg, every 3 weeks, for up to 16 cycles) in CHL relapsed on or refrac-tory to autologous HSCT, the primary endpoint of overall response rate (ORR) was 75\%, the CR rate was 34\%, and 3-year PFS and OS rates in complete responders were 58\%and 73%, respectively [6-8]. The most common adverse events were peripheral sensory neuropathy, nausea, fatigue,neutropenia, and diarrhea. In phase II trial of single-agent BV in older patients ( $\geq 60$ years) with first-relapsed or pri-mary refractory CHL, the ORR was 53\%, CR rate was 24\%,and median PFS and OS were 8.8 months and 21.7 months,respectively, at a median follow-up of 24.9 months [9].Older patients who received single-agent BV had a limited DoR, and experienced adverse events, such as infection and peripheral neuropathy, indicating poor tolerability.

In a phase II trial of single-agent nivolumab (3 mg/kg,every 2 weeks, until progression) in CHL relapsed after autologous HSCT, the primary endpoint of ORR was 69%,and median DoR was 16.6 months [12]. Lipase increases,neutropenia, and ALTI increases were reported as grade 3 or higher treatment-related adverse events. In a phase II trial of single-agent nivolumab in 17 Japanese patients with relapsed or refractory CHL, the ORR was 88% and the median DoR was 8.5 months [13, 14]. The patient population skewed relatively old, with a median age of 63 years, and certain adverse events such as lung disorders were observed, but safe treatment with nivolumab was possible.

<BeginOfPara>In a phase II trial of single-agent pembrolizumab(200 mg/body, every 3 weeks, for a maximum of 2 years) in relapsed or refractory CHL, the ORR was 72%, CR rate was 28%, and the overall median DoR was 16.5 months [16,17].

Another RCT compared the efficacy of single-agent pem-brolizumab versus single-agent BV in patients with relapsed or refractory CHL who were ineligible for autologous HSCT or had already undergone autologous HSCT. At a median follow-up of 25.7 months, median PFS was significantly superior with pembrolizumab than with BV (13.2 months vs.8.3 months) (OS was not analyzed) [18]. Grade 3 or higher adverse events differed between drugs: pneumonitis was more common with pembrolizumab, whereas neutropenia and peripheral neuropathy were more common with BV.

Treatment with an anti-PD-1 antibody before or after allogeneic HSCT has been shown to increase the risk of immune-related complications, including acute graft-ver-sus-host disease(GVHD),[19, 20] which is important to consider when selecting salvage chemotherapy for younger patients with CHL.

References

1)Moskowitz CH, et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood.2001;97(3):616-23.(3iiiDiv)

2)Baetz T,et al.Gemcitabine,dexamethasone and cis-platin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin's disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group. Ann Oncol.2003; 14(12): 1762-7.(3iiiDiv)

3)Josting A, et al. Cologne high-dose sequential chemo-therapy in relapsed and refractory Hodgkin lymphoma:results of a large multicenter study of the German Hodgkin Lymphoma Study Group(GHSG). Ann Oncol.2005;16(1):116-23.(3iiiDiv)

4)Ogura M, et al. Pilot phase I/II study of new salvage therapy (CHASE) for refractory or relapsed malignant lym-phoma. Int J Hematol. 2003; 77(5): 503-11. (3iiiDiv)

5)Santoro A, et al. Gemcitabine in the treatment of refrac-tory Hodgkin's disease: results of a multicenter phase II study.J Clin Oncol.2000; 18(13):2615-9.(2Div)

6)Younes A, et al. Results of a pivotal phase II study of bentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma. J Clin Oncol. 2012; 30(18): 2183-9.(2Div)

7)Gopal AK, et al. Durable remissions in a pivotal phase 2 study of bentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood.2015;125(8):1236-43.(2Div)

8)Chen R,et al. Five-year survival and durability results of bentuximab vedotin in patients with relapsed or refrac-tory Hodgkin lymphoma. Blood. 2016; 128(12): 1562-6.(2Div)

S.Kusumoto,A.Tomita

9)Stefoni V, et al. Brentuximab vedotin in the treatment of elderly Hodgkin lymphoma patients at first relapse or with primary refractory disease: a phase II study of FIL ONLUS.Haematologica. 2020; 105(10):e512.(2Div)

10)Ansell SM, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med.2015; 372(4):311-9.(2Div)

11)Younes A, et al. Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell trans-plantation and brentuximab vedotin: a multicentre, multi-cohort, single-arm phase 2 trial. Lancet Oncol. 2016; 17(9):1283-94.(2Div)

12)Armand P, et al. Nivolumab for Relapsed/Refractory Classic Hodgkin lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial. J Clin Oncol.2018;36(14):1428-39.(2Div)

13)Maruyama D, et al. Multicenter phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma. Cancer Sci.2017;108(5):1007-12.(2Div)

<BeginOfPara>14)Maruyama D, et al. Final results of a phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma. Jpn J Clin Oncol 2020; 50(11):1265-73.(2Div)

<EndOfPara>15)Armand P, et al. Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lym-phoma After Brentuximab Vedotin Failure. J Clin Oncol.2016;34(31):3733-9.(2Div)

${}^{16}$ )Chen R,et al.Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma.J Clin Oncol.2017;35(19):2125-32.(2Div)

17)Chen R,et al. Pembrolizumab in relapsed or refractory Hodgkin lymphoma: 2-year follow-up of KEYNOTE-087.Blood.2019;134(14):1144-53.(2Div)

18)Kuruvilla J, et al. Pembrolizumab versus bentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma(KEYNOTE-204): an interim analysis of a multicentre, ran-domised, open-label, phase 3 study. Lancet Oncol. 2021;22(4):512-24.(ii1iiDiii)

19)Herbaux C,et al.Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lym-phoma. Blood.2017;129(18):2471-8.(3iiiDiv)

20)Haverkos BM, et al. PD-1 blockade for relapsed lym-phoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood. 2017; 130(2):221-8.(3iiiDiv)

CQ11 Is high-dose chemotherapy with autologous HSCT recommended for younger(< 60 years) patients with relapsed CHL?

Recommendation grade: Category 2A

High-dose chemotherapy with autologous HSCT is recommended for younger patients with CHL in first relapse who respond to salvage chemotherapy.

SHJ practical guidelines for hematological malignancies, 2023: II. Lymphoma 10. Hodgkin...

Explanation

Clinical trials have compared high-dose chemotherapy with autologous HSCT (HDC/AHSCT) against standard-dose salvage chemotherapy in patients with relapsed CHL.A joint study by the GHSG and the European Group for Blood and Marrow Transplantation(EBMT) compared four cycles of salvage chemotherapy with Dexa-BEAM(dexamethasone and BEAM [carmustine (not approved in Japan), etoposide, cytarabine, and melphalan]) against two cycles of Dexa-BEAM followed by high-dose BEAM/AHSCT [1]. In the subset of patients judged to be sensitive to salvage chemotherapy, the FFTF rate was significantly better with HDC/AHSCT, but there was no significant dif-ference in the OS rate. However, HDC/AHSCT was not demonstrated to be superior in patients in second or sub-sequent relapse. In addition, a British National Lymphoma Investigation (BNLI) trial that compared standard-dose salvage chemotherapy against HDC/AHSCT, though it only enrolled 40 patients and ended prematurely, showed that high-dose chemotherapy with autologous HSCT yielded better EFS and PFS [2]. Studies have also shown that HDC/AHSCT is beneficial (for patients in first relapse and non-responders to primary therapy) by retrospective analyses, [3] and that long-term survival after HSCT is difficult to attain in patients who are not sensitive to pre-transplantation chemotherapy [4]. On the basis of the above evidence, HDC/AHSCT is recommended for younger patients (<60 years) with CHL in first relapse who have responded to salvage chemotherapy. Many insti-tutions set the upper age limit for HSCT between 65 and 70 years, and the eligibility of HSCT should be carefully considered in patients aged 70 years and older.

A double-blind RCT that evaluated the benefit of BV consolidation after HDC/AHSCT in patients at high risk of relapse after transplantation (refractory to primary therapy,relapsed within 1 year of primary therapy, or had extranodal involvement before salvage chemotherapy) showed that PFS was significantly superior with BV than placebo [5]. How-ever, OS did not differ between groups because the placebo group was allowed to receive BV after relapse. Follow-up data from 5 years later showed that the effects of BV treat-ment after autologous HSCT were durable, persisting for approximately 1 year [6]. As none of the patients in this trial had ever received BV before, there is no evidence regarding whether the same effect could be obtained in patients who received treatment including BV before HSCT. Evidence on conditioning regimens for HDC/AHSCT is limited, but BEAM is widely used in Western countries [7].

A retrospective analysis by GHSG showed a favorable prognosis in patients with relapse of limited-stage CHL,

especially favorable limited-stage CHL, even without HDC/AHSCT [8, 9].

In summary, there is no evidence for the benefit of HDC/AHSCT in patients relapsed on CMT with a short course of chemotherapy for newly diagnosed limited-stage disease,and thus the eligibility of HSCT should be carefully consid-ered in such patients.

References

1)Schmitz N, et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemo-sensitive Hodgkin's disease: a randomised trial. Lancet. 2002;359(9323): 2065-71.(1iiiiiii)

2)Linch DC, et al. Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodg-kin's disease: results of a BNLI randomised trial. Lancet.1993;341(8852):1051-4.(3iiiDi)

3)Yuen AR, et al. Comparison between conventional sal-vage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin's disease. Blood. 1997;89(3):814-22. $\overline{(3iiiA)}$

4)Sirohi B, et al. Long-term outcome of autologous stem-cell transplantation in relapsed or refractory Hodgkin's lym-phoma. Ann Oncol. 2008; 19(7): 1312-9.(3iiiA)

5)Moskowitz CH, et al. Brentuximab vedotin as consoli-dation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or pro-gression(AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2015; 385(9980): 1853-62.(1iDiii)

6)Moskowitz CH, et al. Five-year PFS from the AETHERA trial of brentuximab vedotin for Hodgkin lymphoma at high risk of progression or relapse. Blood.2018;132(25):2639-42.(1iDiii)

7)Chen YB, et al. Impact of conditioning regimen on out-comes for patients with lymphoma undergoing high-dose ther-apy with autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2015; 21(6): 1046-53.(3iiiDiv)

8)Brckelmann PJ, et al. Relapse After Early-Stage,Favorable Hodgkin lymphoma: Disease Characteristics and Outcomes With Conventional or High-Dose Chemotherapy. J Clin Oncol.2021;39(2):107-15.(3iiiDiii)

9)Brockelmann PJ,et al. Clinical outcomes of relapsed and refractory Hodgkin lymphoma patients after contemporary first-line treatment: a German Hodgkin Study Group analysis.Leukemia.2022;36(3):772-80.(3iiiDiii)

CQ12 What salvage chemotherapy regimens are recom-mended before high-dose chemotherapy with autologous HSCT for younger patients (<60 years) with first-relapsed CHL?

S.Kusumoto,A.Tomita

Recommendation grade: Category 2B

Conventional salvage chemotherapy regimens (e.g., ICE, GDP, DHAP, ESHAP, or CHASE) are recommended as salvage therapy for patients who respond to primary therapy.

In contrast, BV, nivolumab, or pembrolizumab is recommended as salvage chemotherapy for patients who are refractory to primary therapy or who do not respond adequately to conventional salvage chemotherapy.

Explanation

High-dose chemotherapy with autologous HSCT (HDC/AHSCT) is recommended for younger patients (<60 years) with CHL in first relapse who respond to salvage chemotherapy. Refer to CQ11 for details.

In patients who have responded to primary therapy for CHL(relapsed≥1 year after achieving CR), a conventional salvage chemotherapy regimen(e.g., ICE,[1] GDP,[2] DHAP,[3] ESHAP,[4] or CHASE5) is recommended as salvage chemo-therapy before HDC/AHSCT. In patients who are refractory to primary therapy for CHL or who do not respond adequately

to conventional salvage chemotherapy, in contrast, BV,[6]nivolumab, [7] or pembrolizumab [6] is recommended as salvage therapy before HDC/AHSCT.

Recent studies have investigated addition of conventional salvage chemotherapy after BV depending on response,[8,9] and combining BV with chemotherapy (ICE, [10]ESHAP,[11] bendamustine, [12] or gemcitabine [13]) or with nivolumab [14, 15] as salvage therapy before HDC/AHSCT. However,regimens that involve concurrent admin-istration of BV with other agents should not be used in routine practice because they are not covered by Japanese National Health Insurance and there is no evidence for them in Japanese patients.

References

1)Moskowitz CH,et al. A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood. 2001;97(3):616-23.(3iiiDiv)

2)Baetz T,et al. Gemcitabine, dexamethasone and cis-platin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin's disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group.Ann Oncol.2003; 14(12): 1762-7.(3iiiDiv)

<BeginOfPara>3)Josting A, et al. Time-intensified dexamethasone/cis-platin/cytarabine: an effective salvage therapy with low

<EndOfPara>to toxicity in patients with relapsed and refractory Hodgkin's disease. Ann Oncol.2002;13(10):1628-35.(3iiiDiv)

$^{4}$ Aparicio J, et al. ESHAP is an active regimen for relapsing Hodgkin's disease. Ann Oncol. 1999; 10(5): 593-5.(3iiiDiv)

$^{5}$ )Ogura M, et al. Pilot phase I/II study of new salvage therapy (CHASE) for refractory or relapsed malignant lym-phoma. Int J Hematol. 2003; 77(5): 503-11.

6)Kuruvilla J, et al. Pembrolizumab versus bentuximab vedotin in relapsed or refractory classical Hodgkin lym-phoma(KEYNOTE-204): an interim analysis of a multi-centre,randomised, open-label, phase 3 study.Lancet Oncol.2021;22(4):512-24.(1iiDiii)

7>Merryman RW, et al. Autologous stem cell transplanta-tion after anti-PD-1 therapy for multiply relapsed or refrac-tory Hodgkin lymphoma. Blood Adv. 2021; 5(6): 1648-59.(3iiiA)

8)Moskowitz AJ, et al. PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-ran-domised, open-label, single-centre, phase 2 study. Lancet Oncol.2015;16(3):284-92.(3iiiDiv)

9)Chen R,et al.Results of a Multicenter Phase II Trial of Brentuximab Vedotin as Second-Line Therapy before Autol-ogous Transplantation in Relapsed/Refractory Hodgkin Lymphoma. Biol Blood Marrow Transplant. 2015; 21(12):2136-40.(3iiiDiv)

10)Lynch RC,et al. Dose-dense bentuximab vedotin plus ifosfamide, carboplatin, and etoposide for second-line treat-ment of relapsed or refractory classical Hodgkin lymphoma:

JSH practical guidelines for hematological malignancies, 2023:II. Lymphoma 10. Hodgkin...

a single centre, phase 1/2 study. Lancet Haematol. 2021;8(8):e562-71.(3iiiDiv)

11)Garcia-Sanz R, et al. Brentuximab vedotin and ESHAP is highly effective as second-line therapy for Hodg-kin lymphoma patients(long-term results of a trial by the Spanish GELTAMO Group). Ann Oncol. 2019; 30(4):612-20.(3iiiDiv)

12)LaCasce AS,et al. Brentuximab vedotin plus benda-ustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma. Blood. 2018; 132(1): 40-8.(3iiiDiv)

13)Cole PD, et al. Brentuximab vedotin with gemcit-abine for paediatric and young adult patients with relapsed or refractory Hodgkin's lymphoma(AHOD1221): a Chil-dren's Oncology Group, multicentre single-arm, phase 1-2 trial. Lancet Oncol. 2018; 19(9): 1229-38.(3iiiDiv)

14)Herrera AF,et al.Interim results of bentuximab vedo-tin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma. Blood.2018;131(11):1183-94.(3iiiDiv)

15)Advani RH, et al. Brentuximab vedotin in combina-tion with nivolumab in relapsed or refractory Hodgkin lym-phoma: 3-year study results. Blood. 2021; 138(6): 427-38.(iiiDiv)

CQ13 Is allogeneic HSCT recommended for patients with CHL relapsed after high-dose chemotherapy with autologous HSCT?

Explanation

Allogeneic HSCT is a potentially curative treatment option that should be considered in patients with CHL relapsed after HDC/AHSCT, provided that they respond to salvage chemotherapy and have adequate organ function[1-6].

In allogeneic HSCT, the risk of post-transplant relapse and treatment-related mortality varies greatly depending on transplant-related factors, including response status at the time of HSCT,[7] organ dysfunction caused by previ-ous treatments, and donor source selection[7-10]. Conse-quently, eligibility for HSCT should be considered on an individual basis. HSCT from an HLA-haploidentical-related donor, particularly when combined with post-transplant cyclophosphamide(PTCY), has demonstrated favorable outcomes in Western countries. Many institutions set the upper age limit for HSCT between 65 and 70 years, and eligibility should be considered carefully in patients aged 70 years and older.

In allogeneic HSCT for CHL, reduced-intensity condi-tioning or nonmyeloablative conditioning reduces the risk of transplant-related mortality[9-13].

Use of an anti-PD-1 antibody (nivolumab or pembroli-zumab) before or after allogeneic HSCT has also been associated with increased risk of post-transplant immune-related adverse events, including GVHD[14-16]. GVHD

Recommendation grade: Category 2B

Allogeneic HSCT may be a treatment option for CHL patients who have relapsed after high-dose chemotherapy with autologous HSCT but respond to salvage chemotherapy. However, eligibility for allogeneic HSCT should be carefully considered.

S.Kusumoto,A.Tomita

prophylaxis that includes PTCY has demonstrated benefit in patients who received an anti-PD-1 antibody before allo-geneic HSCT, regardless of whether a haploidentical donor was used [17].

References

1)Guidelines Committee of the 2018 Annual Meeting of the Japan Society for Hematopoietic Cell Transplantation, ed.Hematopoietic Cell Transplantation Guidelines for Lymphoma(Adult), 3rd Edition. Japan Society for Hematopoietic Cell Transplantation.2019.

2)Crump M. Management of Hodgkin lymphoma in relapse after autologous stem cell transplant. Hematology Am Soc Hematol Educ Program. 2008: 326-33.(3iiiA)

3)Kewalramani T, et al. Progressive disease following autologous transplantation in patients with chemosensitive relapsed or primary refractory Hodgkin's disease or aggres-sive non-Hodgkin's lymphoma. Bone Marrow Transplant.2003;32(7):673-9.(3iiiA)

4)Sarina B, et al. Allogeneic transplantation improves the overall and progression-free survival of Hodgkin lymphoma patients relapsing after autologous transplantation: a retro-spective study based on the time of HLA typing and donor availability. Blood. 2010; 115(18): 3671-7.(3iiiA)

5)Kako S,et al.The role of hematopoietic stem cell trans-plantation for relapsed and refractory Hodgkin lymphoma.Am J Hematol.2015;90(2):132-8.

6)Rashidi A, et al. Allogenic hematopoietic stem cell transplantation in Hodgkin lymphoma: a systematic review and meta-analysis. Bone Marrow Transplant. 2016; 51(4):521-8.(3iiiA)

7)Marcais A, et al. Impact of disease status and stem cell source on the results of reduced intensity conditioning trans-plant for Hodgkin's lymphoma: a retrospective study from the French Society of Bone Marrow Transplantation and Cellular Therapy(SFGM-TC). Haematologica. 2013; 98(9):1467-75.(3iiiA)

8)Thompson PA,et al. Double umbilical cord blood trans-plant is effective therapy for relapsed or refractory Hodgkin lymphoma. Leuk Lymphoma. 2016; 57(7): 1607-15.(3iiiA)

9)Ahmed S, et al. Lower Graft-versus-Host Disease and Relapse Risk in Post-Transplant Cyclophosphamide-Based Haploidentical versus Matched Sibling Donor Reduced-Intensity Conditioning Transplant for Hodgkin Lymphoma.Biol Blood Marrow Transplant. 2019; 25(9): 1859-68.(3iiiA)

10)Burroughs LM, et al. Comparison of outcomes of HLA-matched related, unrelated, or HLA-haploidentical related hematopoietic cell transplantation following nonmyeloablative conditioning for relapsed or refractory Hodgkin lymphoma. Biol Blood Marrow Transplant.2008;14(11):1279-87.(3iiiA)

11)Sureda A, et al. Reduced-intensity conditioning com-pared with conventional allogeneic stem-cell transplantation in relapsed or refractory Hodgkin's lymphoma: an analysis from the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2008; 26(3): 455-62.(3iiiA)

12)Robinson SP,et al. Reduced intensity conditioning allogeneic stem cell transplantation for Hodgkin's lym-phoma: identification of prognostic factors predicting out-come. Haematologica.2009;94(2):230-8.(3iiiA)

13)Sureda A, et al. Allogeneic stem cell transplantation after reduced intensity conditioning in patients with relapsed or refractory Hodgkin's lymphoma. Results of the HDR-ALLO study- a prospective clinical trial by the Grupo Espanol de Linfomas/Trasplante de Médula Osea(GEL/TAMO) and the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Haematologica.2012;97(2):310-7.(3iiiA)

14)Merryman RW,et al.Safety and efficacy of allogeneic hematopoietic stem cell transplant after PD-1 blockade in relapsed/refractory lymphoma. Blood. 2017; 129(10): 1380-8.(3iiiA)

15)Herbaux C, et al. Efficacy and tolerability of nivolumab after allogeneic transplantation for relapsed Hodgkin lymphoma. Blood. 2017; 129(18): 2471-8.(iiiiiDiv)

16)Haverkos BM,et al.PD-1 blockade for relapsed lym-phoma post-allogeneic hematopoietic cell transplant: high response rate but frequent GVHD. Blood. 2017; 130(2):221-8.(iiiDiv)

17)Merryman RW,et al.Allogeneic transplantation after PD-1 blockade for classic Hodgkin lymphoma. Leukemia.2021;35(9):2672-83.(3iiiA)

Declarations

Conflict of interest SK has received per diem, including speaking fees,from Chugai Pharmaceutical, Janssen Pharmaceutical, and Ono Phar-maceutical; and has received research funding from Daiichi Sankyo.AT has received per diem, including speaking fees, from Chugai Phar-maceutical, Takeda Pharmaceuticals, Ono Pharmaceutical, and Astra-Zeneca; has received research funding from Perseus Proteomics; and has received scholarship or grant donations from Chugai Pharmaceuti-cal, Eisai, and Ono Pharmaceutical.

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