INTRODUCTION —
Hematopoietic cell transplantation (HCT) is an important component of treatment for relapsed and refractory (r/r) classic Hodgkin lymphoma (cHL).
This topic reviews HCT for r/r cHL in adults.
Related topics include:
●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 cHL treatment in adults and children (see "Overview of Hodgkin lymphoma in children and adolescents" and "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma")
DEFINITIONS —
HCT can be used to treat relapsed or refractory (r/r) cHL.
Key definitions include:
●Relapse – Relapse (recurrence) is the reappearance of HL at sites of prior disease and/or at new sites after achieving complete response (CR).
●Refractory – Refractory (resistant) disease is the failure to achieve CR with initial therapy (primary refractory) or after salvage therapy (secondary refractory).
●Salvage therapy – Salvage (rescue) chemotherapy is a treatment that minimizes the disease burden of r/r cHL prior to HCT, as discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma", section on 'Overview of management'.)
●Conditioning therapy – Preparative (conditioning) therapy is a systemic treatment that ablates residual cHL and permits bone marrow engraftment by autologous or allogeneic hematopoietic cells.
Preparative regimens can be myeloablative conditioning (MAC), nonmyeloablative (NMA) conditioning, or reduced-intensity conditioning (RIC) (table 1).
●Autologous HCT – Autologous HCT utilizes the patient's own hematopoietic cells (from peripheral blood or bone marrow) to rescue hematopoiesis after preparative therapy for HCT.
●Allogeneic HCT – Allogeneic HCT utilizes hematopoietic cells from another individual (eg, related donor, unrelated donor, or umbilical cord blood) for hematopoietic rescue.
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.
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 or refractory (r/r) cHL prior to autologous HCT (algorithm 1) is discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)
Our approach to management is consistent with guidelines of the American Society of Blood and Marrow Transplantation and the European Society for Blood and Marrow Transplantation [1,2].
Indications for autologous HCT — The indications for autologous HCT and its integration with other aspects of management of first relapse or primary refractory cHL in adults (algorithm 1) are discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma", section on 'Autologous HCT'.)As
Chemosensitivity of the tumor is critical for use of autologous HCT. Outcomes are superior when autologous transplantation is performed after a complete metabolic response by positron emission tomography (PET), but transplantation may be considered after a partial response, especially when immune checkpoint inhibitors are included as part of salvage programs. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma", section on 'Autologous HCT'.)
Eligibility for autologous HCT — Eligibility for autologous HCT may vary among centers.
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.
Eligibility and the risks and benefits of HCT must be discussed with the prospective patient and loved ones.
Additional discussion of eligibility for autologous HCT is provided separately. (See "Determining eligibility for autologous hematopoietic cell transplantation", section on 'Pretransplant evaluation'.)
Conditioning regimen — There is no consensus preparative (conditioning) regimen for autologous HCT in r/r cHL.
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".)
Acceptable options for preparative regimens (table 1) include:
●BEAM (BCNU [carmustine], etoposide, cytarabine, melphalan) is used by most centers.
●Acceptable alternative regimens include:
•CBV (cyclophosphamide, BCNU, etoposide)
•Bu/Cy (busulfan, cyclophosphamide)
Studies of preparative regimens for autologous HCT in cHL include:
●Compared with BEAM, alternative conditioning regimens (eg, CBV, Bu/Cy, total body radiation) were associated with higher mortality in a registry study of >1000 patients who underwent autologous HCT for cHL [3].
●Other retrospective studies reported that alternative conditioning regimens may be associated with better outcomes than BEAM but were more toxic [4,5].
Graft source — Apheresis-derived peripheral blood hematopoietic stem/progenitor cells are preferred because of faster engraftment, as discussed separately. (See "Hematopoietic cell transplantation (HCT): Sources of hematopoietic stem/progenitor cells".)
Consolidative radiation — To improve local control, we suggest consolidative involved-field radiation therapy (IFRT) for localized or bulky disease that was not previously radiated.
If it would entail significant radiation exposure to the bowels, care should be taken to exclude liver (to lessen the risk for hepatic sinusoidal obstruction syndrome [SOS]), lung (to avoid interstitial pneumonitis), and abdominal masses.
The timing of radiation therapy varies among centers; most centers administer IFRT after HCT, but it can also be given before HCT. No studies have compared outcomes with consolidative IFRT before versus after HCT.
A retrospective study reported no difference in overall survival (OS) but better disease-free survival (DFS) among 46 patients with relapsed cHL who received IFRT within two months of autologous HCT, compared with 46 matched patients who underwent autologous HCT without IFRT [6]. Other retrospective studies of autologous HCT report similar outcomes [6-11].
Maintenance therapy — Maintenance therapy may benefit certain patients after autologous HCT for r/r cHL.
Brentuximab vedotin — For brentuximab vedotin (BV)-naïve patients at higher risk of relapse after autologous HCT (described below), we suggest BV therapy based on improved progression-free survival (PFS).
There is no proven benefit for BV maintenance for patients at lower risk of relapse or who received BV as a component of initial treatment for cHL.
●Administration – We treat with BV 1.8 mg/kg (to a maximum dose of 180 mg) every 3 weeks beginning 30 to 45 days after HCT for up to 16 cycles. For patients who received BV as a component of salvage therapy, we treat with up to 10 cycles.
●Indications – At least one 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, are intolerant of BV, or have cHL progression while receiving BV.
For patients who received BV as a component of their first-line therapy for cHL, we limit BV maintenance to patients with high-risk criteria who relapsed >12 months after an initial response to BV.
●Adverse effects – Peripheral neuropathy is seen in more than one-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.
●Outcomes
•In the multicenter AETHERA trial, 329 BV-naïve patients with high-risk features who underwent autologous HCT were randomly assigned to maintenance therapy with BV versus placebo [12]. Compared with placebo, BV was associated with superior five-year PFS (59 versus 41 percent; hazard ratio [HR] 0.52 [95% CI 0.38-0.72]) [13]. OS did not differ between the two arms of the trial, but the conclusions are limited by the large number of patients who crossed over from the placebo arm to BV 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 a five-year follow-up, peripheral neuropathy improved in 90 percent and completely resolved in 73 percent.
•A study of 118 patients with high-risk features reported that only 14 percent received all planned doses; 72 percent of discontinuations were due to toxicity [14]. Two-year PFS did not differ when comparing patients who received >75 percent of all planned doses versus ≤50 percent of doses [14].
Other maintenance regimens — There is no proven benefit for other maintenance regimens, and we do not use them outside of a clinical trial.
A multicenter study with pembrolizumab 200 mg intravenously every 3 weeks for up to 8 cycles beginning within 21 days after autologous HCT hospital discharge reported 100 percent OS and 82 percent PFS after 18 months among 28 evaluable patients [15]. Toxicity included a grade 3 adverse effect in 30 percent of patients and a grade 2 immune-related adverse effect in 40 percent.
Tandem autologous HCT — There is no clear benefit for tandem (ie, sequential) autologous HCT for r/r cHL.
A matched cohort analysis of patients from two different studies reported that a single autologous HCT followed by BV maintenance was associated with better outcomes than tandem transplantation [16]. Other prospective studies demonstrated no clear benefits for tandem transplantation, even for patients with adverse prognostic features [17-20].
Prognostic factors for autologous HCT in cHL — Outcomes after autologous HCT are related to disease status prior to transplantation and response to salvage therapy.
Retrospective studies reported inferior outcomes with an incomplete metabolic response to salvage chemotherapy, B symptoms, shorter duration of remission (ie, <1 year), extranodal disease, ≥1 prior chemotherapy regimen, and poor performance status [21-42].
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. The prognostic model was validated in a separate cohort of 391 patients [27]. 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 or refractory (r/r) cHL prior to allogeneic HCT is discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)
Indications for allogeneic HCT — Allogeneic HCT is generally limited to medically eligible patients who relapse after brentuximab vedotin (BV) and autologous HCT and 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.
In settings where ICI is not available, allogeneic HCT may be considered for patients with r/r cHL after autologous HCT.
Allogeneic HCT in patients who were previously treated with ICI may be associated with an increased risk for acute graft-versus-host disease (GVHD), hyperacute GVHD, chronic GVHD, hepatic sinusoidal obstructive syndrome (SOS) after reduced-intensity conditioning (RIC), and glucocorticoid-requiring febrile syndrome.
Post-transplant cyclophosphamide can be considered for GVHD prophylaxis in this setting [43].
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) is a useful tool for assessing risk prior to allogeneic HCT [44].
There is no HCT-CI score that we consider an absolute exclusion to allogeneic HCT, but outcomes are less favorable for patients with an HCT-CI score ≥5; we discuss the higher risk and lower expectations of allogeneic HCT in this setting with the patient and loved ones.
●Medical fitness – Medical fitness for allogeneic HCT is discussed separately. (See "Allogeneic hematopoietic cell transplantation: Indications, eligibility, and prognosis".)
●Age – Most institutions restrict RIC/nonmyeloablative (NMA) HCT to patients ≤70 years old. For institutions that offer myeloablative conditioning (MAC) 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 [45]. Other studies have reported similar conclusions [46,47].
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.
ICI therapy appears to resensitize cHL to cytotoxic therapy, reinforcing its use in this setting [48,49].
Allogeneic HCT conditioning — RIC or NMA preparative regimens are preferred for allogeneic HCT in r/r cHL. Some institutions offer MAC HCT in this setting.
RIC and NMA preparative regimens (table 1) provide graft-versus-lymphoma effects with less toxicity than myeloablative regimens. The 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 [46,50-52]; some centers add alemtuzumab to this regimen [53,54].
RIC/NMA conditioning offers a survival advantage compared with MAC for allogeneic HCT in r/r cHL. As an example, a retrospective analysis of 168 patients reported that, compared with MAC HCT, RIC was associated with improved overall survival (OS; hazard ratio [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 [55]. Another retrospective comparison of 312 patients reported no significant difference in OS, event-free survival (EFS), relapse rate, or NRM between MAC versus RIC allogeneic HCT [56].
Informative studies regarding RIC/NMA conditioning allogeneic HCT for r/r cHL include:
●A prospective study of 78 patients reported 71 and 43 percent one-year and four-year OS, respectively, and 48 and 24 percent one-year and four-year PFS [57]. One-year NRM was 15 percent.
●Retrospective analysis of 191 patients who underwent RIC regimens reported three-year rates of OS, PFS, relapse, and NRM were 63, 39, 46, and 16 percent, respectively [58].
●A retrospective study of 143 patients reported 50 and 30 percent one-year OS and PFS, respectively, and 37 and 20 percent two-year OS and PFS [59]. 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 'Consolidative radiation' 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 — 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 [60].
POST-HCT SURVEILLANCE —
Patients are seen at periodic intervals to monitor disease status.
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
●Description – Autologous hematopoietic cell transplantation (HCT) can cure more than one-half of adult patients with classic Hodgkin lymphoma (cHL) who relapse after initial complete response (CR) or fail to achieve initial CR (primary refractory cHL).
Allogeneic HCT has a limited role in relapsed or refractory (r/r) cHL.
●Goal of transplantation – The goal of HCT in r/r cHL is to achieve long-term disease control/cure, improve the quality of life, and/or alleviate symptoms. (See 'Goal of transplantation in cHL' above.)
●Autologous HCT
•Indications – Indications for HCT and integration with other aspects of management of r/r cHL are discussed separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)
•Eligibility – Eligibility requires adequate organ function, performance status, and response to salvage therapy, as described above. (See 'Eligibility for autologous HCT' above.)
•Conditioning regimen – Most centers use BEAM (BCNU [carmustine], etoposide, cytarabine, melphalan) conditioning, but there are other acceptable options. (See 'Conditioning regimen' above.)
•Graft source – Apheresis-derived peripheral blood hematopoietic stem/progenitor cells are generally preferred. (See 'Graft source' above.)
•Post-HCT management
-Consolidative radiation therapy – We suggest post-HCT radiation therapy for localized or bulky disease that was not previously radiated, to improve local control (Grade 2C). (See 'Consolidative radiation' above.)
-Maintenance therapy – For brentuximab vedotin (BV)-naïve patients at higher risk of relapse after autologous HCT, we suggest BV maintenance therapy to prolong progression-free survival (Grade 2B).
Higher-risk features for relapse include ≥1 of the following: primary refractory cHL or relapse <12 months after initial therapy; less than CR to most recent salvage therapy; B symptoms at relapse; relapse with extranodal disease; and ≥2 salvage regimens.
There is no proven benefit for BV maintenance in patients without higher-risk features, who received BV as a component of initial treatment for cHL, who had disease progression while receiving BV, or who had BV intolerance.
●Allogeneic HCT – Allogeneic HCT is generally limited to medically eligible patients who relapse after BV and autologous HCT and have less than a CR with immune checkpoint inhibition. Eligibility, preferred conditioning regimens and donor source, and other aspects of allogeneic HCT for r/r cHL are discussed above. (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.