Version May 2024
INTRODUCTION — Hematopoietic cell transplantation (HCT) is an important component of treatment for relapsed and refractory (r/r) classic Hodgkin lymphoma (cHL).
This topic will review HCT for r/r cHL. The following topics are discussed separately:
●Management of r/r cHL (see "Treatment of relapsed or refractory classic Hodgkin lymphoma")
●Management of patients with r/r cHL who are not eligible for HCT (see "Treatment of relapsed or refractory classic Hodgkin lymphoma")
●Overviews of treatment of cHL in adults and in children (see "Overview of Hodgkin lymphoma in children and adolescents" and "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma")
●Monitoring of the patient with cHL during and after treatment (see "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment")
Suggestions in this topic are consistent with guidelines of the American Society of Blood and Marrow Transplantation and the European Society for Blood and Marrow Transplantation [1,2].
DEFINITIONS — Definitions regarding HCT for relapsed and refractory (r/r) cHL include:
●Relapse (recurrence) is the reappearance of HL at sites of prior disease and/or at new sites after achieving complete response (CR).
●Refractory (resistant) disease is the failure to achieve CR with initial therapy (primary refractory) or after salvage therapy (secondary refractory).
●Salvage (rescue) chemotherapy is treatment to minimize the disease burden of r/r cHL prior to HCT. Discussion of salvage therapy is presented separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)
●Preparative (conditioning) therapy is systemic treatment to ablate residual cHL and permit bone marrow engraftment by autologous or allogeneic hematopoietic cells. Conditioning regimens can be myeloablative versus nonmyeloablative (NMA) or reduced intensity conditioning (RIC). Preparative regimens (table 1) are discussed below and separately. (See 'Autologous HCT conditioning' below and 'Allogeneic HCT conditioning' below and "Preparative regimens for hematopoietic cell transplantation".)
●Autologous HCT utilizes the patient's own hematopoietic cells (from peripheral blood or bone marrow) to rescue hematopoiesis after preparative therapy for HCT. Indications, eligibility, and other aspects of autologous HCT for r/r cHL are discussed below. (See 'Autologous transplantation' below.)
●Allogeneic HCT utilizes hematopoietic cells from another individual (eg, related donor, unrelated donor, or umbilical cord blood) for hematopoietic rescue. Indications, eligibility, and other aspects of allogeneic HCT for r/r cHL are discussed below. (See 'Allogeneic transplantation' below.)
GOAL OF TRANSPLANTATION IN cHL — The goal of HCT in relapsed or refractory (r/r) cHL is to achieve long-term disease control (ie, cure) when possible. For patients who do not achieve cure, HCT can prolong life, improve the quality of life, and/or alleviate symptoms.
Goals of HCT are influenced by the status of disease (ie, primary refractory/first relapse versus subsequent relapses), response to salvage treatment, eligibility for autologous versus allogeneic HCT, and the patient's personal goals, as described in the sections below.
Integration of HCT with other aspects of management of r/r HL is described separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)
AUTOLOGOUS TRANSPLANTATION — Management of relapsed/refractory (r/r) cHL prior to autologous HCT (algorithm 1) is discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)
Indications for autologous HCT — Autologous HCT is the treatment of choice for most patients with first relapse of HL or primary refractory cHL.
Indications for autologous HCT in first relapse or primary refractory cHL (algorithm 1) and integration of HCT with other aspects of management are discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma", section on 'Autologous HCT' and "Treatment of relapsed or refractory classic Hodgkin lymphoma".)
For children with r/r cHL, our suggestions and published guidelines for autologous HCT are the same as for adults, based on a limited number of studies and extrapolation from adult data [1,3]. Other aspects of management of r/r cHL in children and adolescents are described separately. (See "Overview of Hodgkin lymphoma in children and adolescents", section on 'Relapsed or refractory disease'.)
Eligibility for autologous HCT — There is no universal agreement regarding eligibility criteria for autologous HCT in r/r cHL. Eligibility and the risks and benefits of HCT must be discussed with the prospective patient and loved ones.
Our eligibility criteria for autologous HCT in r/r cHL include:
●Performance status – Eastern Cooperative Oncology Group (ECOG) performance status ≤2 (table 2).
●Medical fitness – Adequate cardiac, pulmonary, kidney, and liver function, and appropriate psychosocial support.
●Age – Age limits for autologous HCT vary by institution and are not absolute, but some experts suggest autologous HCT for patients ≤70 or ≤75 years of age.
Additional discussion regarding eligibility for autologous HCT is provided separately. (See "Determining eligibility for autologous hematopoietic cell transplantation", section on 'Pretransplant evaluation'.)
Autologous HCT conditioning — No specific preparative regimen is considered the standard of care for autologous HCT in r/r cHL. Autologous HCT can be performed in the inpatient setting or as an outpatient (if a caregiver is available and transportation and other resource needs can be met). Prospective trials have not directly compared different preparative regimens and settings for autologous HCT.
The choice of conditioning regimen is influenced by patient comorbidities, short- and long-term toxicities, and institutional preferences, as discussed separately. (See "Preparative regimens for hematopoietic cell transplantation".)
Our preferences for preparative regimens (table 1) are:
●We (and most groups) favor BEAM (BCNU, etoposide, cytarabine, melphalan)
●Acceptable alternative regimens include:
•CBV (cyclophosphamide, BCNU, etoposide)
•Bu/Cy (busulfan, cyclophosphamide)
Informative studies regarding preparative (conditioning) regimens for autologous HCT in cHL include:
●A registry study that included more than 1000 patients who underwent autologous HCT for cHL reported that, compared with BEAM conditioning, alternative regimens (eg, CBV, Bu/Cy, total body radiation) were associated with higher mortality [4].
●Two retrospective studies suggested that, compared with BEAM, other regimens may provide superior event-free survival (EFS) and/or overall survival (OS) but caused increased toxicity, but neither study included patients >65 years old [5,6].
Source of autologous cells — No studies have directly compared peripheral blood versus bone marrow as the source of autologous hematopoietic cells for HCT in r/r cHL.
We and most groups favor apheresis-derived peripheral blood hematopoietic cells because of faster engraftment, as discussed separately. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)
Radiation of localized or bulky disease — When relapse includes localized or bulky disease, involved-field radiation therapy (IFRT) can reduce the risk of relapse in patients who did not previously receive radiation therapy.
We suggest IFRT for patients with localized or bulky disease that was not previously radiated, but care should be taken to exclude liver and lung (to lessen the possibility of hepatic sinusoidal obstruction syndrome [veno-occlusive disease] and interstitial pneumonitis, respectively) and abdominal masses, if it would entail significant radiation exposure to the bowels. The timing of radiation therapy depends on physician/institutional preference; most centers administer IFRT after HCT, but it can also be given before HCT.
Outcomes of patients who received IFRT appear to be superior to those who did not receive IFRT, but no studies have compared the timing of consolidation IFRT (ie, before versus after HCT).
A retrospective study reported superior disease-free survival (DFS), but not OS, in 46 patients with relapsed HL who received IFRT within two months of autologous HCT, compared with 46 matched patients who underwent autologous HCT without IFRT [7]. Other retrospective studies of autologous HCT report similar outcomes [7-12].
Maintenance therapy — Maintenance therapy may benefit certain patients after autologous HCT for r/r cHL.
Brentuximab vedotin maintenance — For patients who undergo autologous HCT and are at higher risk of relapse (described below), brentuximab vedotin (BV) maintenance therapy improves progression-free survival (PFS) when compared with observation alone. There is no proven benefit for BV maintenance for patients at lower risk of relapse or for patients who received BV as a component of initial treatment for cHL.
We suggest brentuximab vedotin 1.8 mg/kg (to a maximum dose of 180 mg) every three weeks beginning 30 to 45 days after HCT for up to 16 cycles (10 cycles for those who received BV as salvage therapy) for patients with at least one but preferably two of the following high-risk features:
●Primary refractory cHL or relapse <12 months after initial therapy
●Less than complete response (CR) to most recent salvage therapy
●B symptoms at relapse
●Relapse with extranodal disease
●Two or more salvage therapies
We do not administer BV maintenance to patients who do not meet these high-risk criteria, were intolerant of BV, or if cHL progressed while receiving BV. For patients who received BV as a component of initial therapy, we limit BV maintenance to those who meet high-risk criteria and relapsed >12 months after an adequate initial response to BV. Peripheral neuropathy is seen in more than half of patients treated with maintenance BV, but it improves or resolves in most after discontinuation; motor neuropathy and neutropenia are seen in one-quarter to one-third of patients.
In the multicenter AETHERA trial, 329 BV-naïve patients who underwent autologous HCT with the high-risk features described above were randomly assigned to maintenance therapy with BV versus placebo [13]. Compared with placebo, BV was associated with superior five-year PFS (59 versus 41 percent; HR 0.52; 95% CI 0.38-0.72) [14]. OS did not differ between the two arms of the trial, but the analysis was limited by the large number of patients on the placebo arm who crossed over to BV treatment after progression. BV was associated with more peripheral sensory neuropathy (56 versus 16 percent, respectively), peripheral motor neuropathy (23 versus 2 percent), and neutropenia (35 versus 12 percent). With five-year follow-up, peripheral neuropathy improved in 90 percent and completely resolved in 73 percent.
PD-1 blockade maintenance — Maintenance therapy with a PD-1 inhibitor may provide clinical benefit following autologous HCT for r/r cHL. Use of PD-1 inhibitors for other aspects of treatment of r/r cHL is discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma", section on 'PD-1 blockade'.)
A multicenter study administered pembrolizumab 200 mg intravenously every three weeks for up to eight cycles beginning within 21 days post autologous HCT hospital discharge [15]. At 18 months, the PFS was 82 percent and OS was 100 percent among 28 evaluable patients. Toxicity was manageable, with 30 percent experiencing ≥1 grade 3 adverse event (AE) and 40 percent ≥1 grade 2 immune-related AE. While promising, maintenance therapy with PD-1 blockade must be validated in other studies before suggesting its use.
Tandem autologous HCT — No randomized studies have directly compared tandem (ie, sequential) autologous HCT with single autologous HCT for r/r cHL. However, uncontrolled prospective studies have demonstrated no clear benefits for tandem transplantation, even for patients with adverse prognostic features [16-19].
We do not offer tandem autologous HCT for r/r cHL outside of the setting of a clinical trial.
Prognostic factors for autologous HCT in cHL — No studies have prospectively evaluated prognostic factors for autologous HCT in r/r cHL. Retrospective studies have reported that worse outcomes were associated with incomplete positron emission tomography (PET) response to salvage chemotherapy, presence of B symptoms, short duration of remission (ie, less than one year), extranodal disease, more than one prior chemotherapy regimen, and poor performance status [20-41].
A prognostic model to predict PFS after HCT was developed based on the outcomes of 337 patients with r/r cHL who underwent autologous HCT, and was validated in a separate cohort of 391 patients [26]. A multivariate model identified the following four major risk factors at the time of HCT with each factor assigned a relative weight:
●Poor performance status (Karnofsky performance score <90) (table 3) – 1 point
●Chemotherapy-resistant disease – 1 point
●>3 prior chemotherapy regimens – 2 points
●Extranodal disease – 2 points
Three risk groups were identified based on the sum of the total score: low risk (score 0), intermediate risk (score 1 to 3), and high risk (score 4 to 6); the four-year PFS rates for these groups were 71, 60, and 42 percent, respectively.
ALLOGENEIC TRANSPLANTATION — Management of multiply relapsed/refractory (r/r) cHL prior to allogeneic HCT is discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)
Indications for allogeneic HCT — We generally limit allogeneic HCT to medically-eligible patients who were previously treated with brentuximab vedotin (BV) and autologous HCT and who had only a partial response or progressive disease after immune checkpoint inhibition (ICI). We generally do not proceed with allogeneic HCT for patients who had a complete response (CR) with ICI.
Allogeneic HCT in patients who were previously treated with pembrolizumab may be associated with an increased risk for acute graft-versus-host disease (GVHD), hyperacute GVHD, chronic GVHD, hepatic sinusoidal obstructive syndrome (SOS, also called veno-occlusive disease) after reduced intensity conditioning, and glucocorticoid-requiring febrile syndrome (with an identified infectious disease).
In settings where ICI is not available, allogeneic HCT may be considered for patients with r/r cHL following autologous HCT.
Eligibility for allogeneic HCT — Age, medical fitness, and risk category inform eligibility for allogeneic HCT in r/r cHL, but criteria vary between institutions. Our approach follows:
●Risk category – Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI) (www.hctci.org) is a useful tool for assessing risk prior to allogeneic HCT [42]. There is no HCT-CI score that we consider an absolute exclusion to allogeneic HCT, but outcomes are less favorable for patients with HCT-CI score ≥5, and we discuss the higher risk and lower expectations of HCT in this setting with the patient and loved ones.
●Medical fitness – Medical fitness for allogeneic HCT is discussed separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)
●Age – Most institutions restrict reduced intensity conditioning (RIC)/nonmyeloablative (NMA) HCT to patients ≤70 years old. For institutions that offer myeloablative HCT in this setting, allogeneic HCT is typically limited to patients ≤60 years old.
Allogeneic donor source — We favor related-donor allogeneic hematopoietic cells for allogeneic HCT for r/r cHL, when available. Details of donor selection for allogeneic HCT are provided separately. (See "Donor selection for hematopoietic cell transplantation".)
A systematic review concluded that all donor sources, including related, unrelated, and haploidentical donors, and umbilical cord blood were reasonable options for allogeneic HCT in patients with cHL [43]. Other studies have reported similar conclusions [44,45].
Bridging therapy — There should be adequate disease control prior to transplant. C-MOPP (cyclophosphamide, vincristine, procarbazine, prednisone) or another alkylator-based chemotherapy can be used as bridging therapy to achieve disease control.
Allogeneic HCT conditioning — RIC or NMA preparative regimens are preferred for allogeneic HCT in r/r cHL. Some institutions offer myeloablative allogeneic HCT in this setting.
RIC and NMA preparative regimens (table 1) provide graft-versus-lymphoma effects with less toxicity than myeloablative regimens. Selection of RIC versus NMA conditioning is based on institutional preferences, and is discussed separately. (See "Preparative regimens for hematopoietic cell transplantation", section on 'NMA and RIC regimens'.)
Our preferred RIC regimen is fludarabine and melphalan [44,46-48]; some centers add alemtuzumab to this regimen [49,50].
RIC/NMA conditioning offers a survival advantage when compared with myeloablative approaches for allogeneic HCT in r/r cHL. As an example, a retrospective analysis of 168 patients reported that, compared with myeloablative HCT, RIC was associated with improved overall survival (OS; HR 2.1, 95% CI 1.3-3.3) and lower nonrelapse mortality (NRM; HR 2.9, 95% CI 1.6-5.0), despite an increased risk of relapse or progression [51]. Another retrospective comparison of 312 patients reported no significant difference between myeloablative and RIC allogeneic HCT with regard to relapse rate, NRM, event-free survival (EFS), or OS [52].
Informative studies regarding RIC/NMA conditioning allogenic HCT for r/r cHL include:
●A prospective Spanish study of 78 patients reported one-year and four-year PFS rates were 48 and 24 percent, respectively, and the one-year and four-year OS rates were 71 and 43 percent, respectively [53]. NRM at one year was 15 percent.
●Retrospective analysis of 191 French patients who underwent RIC regimens reported three-year rates of OS, PFS, relapse, and NRM were 63, 39, 46, and 16 percent, respectively [54].
A retrospective study of 143 patients reported PFS and OS of 30 and 50 percent at one year, and 20 and 37 percent at two years [55]. Rates of treatment-related mortality at 100 days and two years were 15 and 33 percent, respectively.
Post-HCT management — Following allogeneic HCT, we offer radiation therapy to localized or bulky disease that was not previously radiated, and we offer maintenance BV therapy to BV-naïve patients, as described above. (See 'Radiation of localized or bulky disease' above and 'Maintenance therapy' above.)
Management of GVHD is discussed separately. (See "Treatment of acute graft-versus-host disease".)
Surveillance after allogeneic HCT is discussed below. (See 'Post-HCT surveillance' below.)
Prognostic factors for allogeneic HCT — Only limited data regarding prognostic factors after allogeneic HCT for r/r cHL are available. A systematic review and meta-analysis of 42 studies reported that achieving remission prior to allogeneic HCT was associated with improved OS at two years and improved relapse-free survival at one year [56].
POST-HCT SURVEILLANCE — Patients are seen at periodic intervals to monitor disease status, as described separately. (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment".)
Transplant recipients are at risk of developing therapy-related complications for years after treatment, as described separately. (See "Second malignancies after treatment of classic Hodgkin lymphoma" and "Long-term care of the adult hematopoietic cell transplantation survivor" and "Approach to the adult survivor of classic Hodgkin lymphoma".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Autologous bone marrow transplant (The Basics)" and "Patient education: Allogeneic bone marrow transplant (The Basics)")
●Beyond the Basics topics (see "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)" and "Patient education: Hodgkin lymphoma in adults (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Autologous hematopoietic cell transplantation (HCT) can cure more than half of patients with classic Hodgkin lymphoma (cHL) that relapsed after initial complete response (CR) or failed to achieve initial CR (primary refractory cHL). (See 'Definitions' above and 'Goal of transplantation in cHL' above.)
Allogeneic HCT can cure a subset of patients with subsequent relapses of cHL, and extend survival, improve the quality of life, and/or alleviate symptoms for others.
●Indications for HCT and integration of HCT with other aspects of management of relapsed/refractory cHL is discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)
●Eligibility for HCT depends on the choice of autologous versus allogeneic HCT, medical fitness, age, and response to salvage therapy, as described above. (See 'Eligibility for autologous HCT' above and 'Eligibility for allogeneic HCT' above.)
●For autologous HCT, we offer BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning (table 1) and peripheral blood as the source of hematopoietic cells, as discussed above. (See 'Autologous transplantation' above.)
●For previously unirradiated localized or bulky disease we suggest involved-field radiation therapy (IFRT) after HCT rather than observation alone (Grade 2C). This suggestion is based on limited evidence that radiation after autologous HCT is associated with improved disease control but has no impact on overall survival. (See 'Radiation of localized or bulky disease' above.)
●For brentuximab-naïve patients at high risk of relapse or progression (ie, primary refractory disease, relapse <12 months after initial therapy, or relapsed with extranodal disease) we suggest maintenance therapy with brentuximab vedotin (BV) rather than observation alone until progression (Grade 2B). This suggestion is based on more favorable progression-free survival with BV maintenance coupled with acceptable toxicity. For patients who received BV as a component of initial therapy, we limit BV maintenance to those who meet high-risk criteria and relapsed >12 months after an adequate initial response to BV.
●We limit allogeneic HCT to medically-eligible patients who were previously treated with BV and autologous HCT and who had only a partial response or progressive disease after immune checkpoint inhibition (ICI); we generally do not proceed with allogeneic HCT for patients who had a CR with ICI. (See 'Allogeneic transplantation' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges George P Canellos, MD, Peter M Mauch, MD, and Ginna G Laport, MD, who contributed to earlier versions of this topic review.
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