Advanced Stage and Relapsed/Refractory Hodgkin Lymphoma
PD-1 (IMMUNE CHECKPOINT) INHIBITORS
As discussed earlier, PD-L1/PD-L2 copy number alterations represent a disease-defining feature of cHL. Alterations in chromosome 9p24.1 increase the expression of PD-1 ligands PD-L1 and PD-L2. Nivolumab and pembrolizumab are PD-1-blocking antibodies, which have recently been FDA approved for relapsed and refractory cHL. In a study with 23 patients, with 78% of them relapsing after auto-HCT and 78% relapsing after brentuximab, nivolumab produced an objective response in 87% of the patients, with 17% achieving CR and 70% achieving PR. The rate of PFS was 86% at 24 weeks.68 Pembrolizumab, another PD-1 antagonist, was also tested in relapsed and refractory Hodgkin lymphoma. In the KEYNOTE-087 study (n = 210), pembrolizumab produced an ORR of 64% to 70% in 3 different cohorts of relapsed and refractory cHL patients. Overall CR rate was 22%.69 In general, these agents are well tolerated, although patients must be monitored closely for
inflammatory/autoimmune-type toxicities including skin rash, diarrhea/colitis, transaminitis, endocrine abnormalities, and pneumonitis. Prompt recognition and initiation of corticosteroids is essential in managing these toxicities. Of note, PD-1 inhibitors should be given very cautiously to patients with a prior history of allo-HCT, since 30% to 55% of such patients will experience acute graft-versus-host disease (GVHD) in this setting. In 2 retrospective studies, the response rate was very high at 77% to 95%; however, 10% to 26% of all patients treated with PD-1 inhibitors post-allo-HCT died from GVHD induced by PD-1 inhibition.70,71 These risks and benefits therefore need to be carefully weighed in the post-allo-HCT setting. In another recent study, the outcomes were reported for 39 patients who underwent allo-HCT after prior therapy with a PD-1 inhibitor. Three patients (7.7%) developed lethal acute GVHD, suggesting there may be an increased risk of GVHD in patients undergoing allo-HCT after prior PD-1 inhibitor therapy.72
AUTOLOGOUS STEM CELL TRANSPLANTATION
Several studies have shown an improved disease-free survival (DFS) or FFS in patients with relapsed cHL treated by auto-HCT as compared to those receiving conventional chemotherapy alone.55,73,74 Overall, for relapsed disease, one can expect an approximately 50% to 60% chance for DFS at 5 years post-transplant. In a retrospective, matched-pair analysis, FFP was 62% for auto-HCT patients, compared to 32% for conventional chemotherapy patients. OS, however, was similar for the 2 groups (47%–54%). Patients failing induction therapy or relapsing within 1 year were seen to benefit the most from auto-HCT, including an OS benefit.74
,A European prospective randomized trial was conducted comparing conventional salvage therapy to auto-HCT. In this study, 161 patients with relapsed Hodgkin lymphoma were treated with 2 cycles of dexa-BEAM. Those with chemo-sensitive disease were then randomized to either 2 more cycles of dexa-BEAM or high-dose BEAM with auto-HCT. Auto-HCT was associated with an approximately 55% FFTF at 3 years, versus 34% with conventional chemotherapy alone.55 This benefit again was most apparent for patients relapsing within 1 year of completion of primary therapy, although an OS benefit was not seen with auto-HCT. For patients with late relapse (>1 year after completion of primary therapy), auto-HCT was associated with an approximately 75% FFTF at 3 years, versus 50% with chemotherapy alone. One other small randomized trial of auto-HCT in relapsed and refractory Hodgkin lymphoma also showed an improved 3-year EFS in favor of auto-HCT (53% versus 10%), again with no difference in OS.73
The lack of OS benefit seen in these studies suggests that auto-HCT at first or second relapse provides comparable outcomes. Auto-HCT offers the benefit of avoiding the long-term toxicities associated with multiple salvage regimens and the anxiety associated with multiple relapses. In addition, the treatment-related mortality with auto-HCT is now in the 1% to 2% range in younger patients, at centers that perform the procedure routinely. For all of these reasons, auto-HCT is commonly recommended by physicians for Hodgkin lymphoma patients in first or second relapse. In most cases, transplant is favored in first relapse, since waiting until second relapse may be associated with a lower chance of achieving CR and difficulty collecting sufficient hematopoietic stem cells. For patients with early relapse or primary refractory disease, an even stronger case can be made for auto-HCT as the best option to achieve sustained control of the disease. For patients with late relapse, conventional salvage therapy alone may be a reasonable option, particularly in older or frail patients, or those with significant comorbid conditions.
The optimal conditioning regimen for autoHCT for relapsed and refractory Hodgkin lymphoma remains undefined. No randomized trials have been performed comparing conditioning regimens for relapsed and refractory Hodgkin lymphoma. One retrospective study compared 92 patients with Hodgkin lymphoma who underwent auto-HCT using a total-body irradiation (TBI) regimen versus a chemotherapy-alone regimen. No difference in 5-year OS or EFS was seen.75 Given the lack of benefit seen with TBI, along with reports of increased rates of secondary malignancies and myelodysplasia with TBI,76 chemotherapy-alone conditioning regimens are most widely employed. For example, in the United States, either the BEAM or CBV (cyclophosphamide, carmustine, etoposide) regimens are used in over 80% of cases.77 This practice was justified in a Center for International Blood and Marrow Transplant Research (CIBMTR) retrospective study comparing outcomes by conditioning regimens, in which no regimen performed better than BEAM or CBV.78
IFRT is often given as an adjunctive therapy to sites of initial and/or relapsed disease following auto-HCT. Although a relatively common practice, whether this truly enhances outcomes beyond that obtained with auto-HCT alone is unclear. Two retrospective studies have shown some benefit in terms of improvement in OS at 3 to 5 years in the group that received IFRT (70%–73% versus 40%–56%).79,80 Given the retrospective nature and small size of these studies, a prospective study would be needed to properly define the potential role for IFRT following auto-HCT in relapsed/refractory Hodgkin lymphoma. Another retrospective study (n = 73) that evaluated peri-transplant IFRT in Hodgkin lymphoma patients receiving auto transplant found no improvement in survival for patients who received peri-transplant IFRT. This study, however, did show a survival benefit in the subgroup of patients with limited stage disease.81
