Advanced Stage and Relapsed/Refractory Hodgkin Lymphoma
Several studies have evaluated allo-HCT in relapsed/ refractory Hodgkin lymphoma. Early studies evaluating myeloablative allo-HCT for Hodgkin lymphoma showed excessive treatment-related mortality (up to 50%) and disappointingly low rates of long-term survival (< 25%).102,103 This was likely related to the fact that, in that era, most of the patients with Hodgkin lymphoma evaluated for allo-HCT were heavily pretreated and therefore at a higher risk for toxicity as well as lymphoma progression.
More recently, several studies have focused on the use of reduced-intensity conditioning (RIC) allo-HCT for relapsed and refractory Hodgkin lymphoma. This approach relies more on a “graft-versus-lymphoma” effect, the existence of which has been debated in Hodgkin lymphoma. Three single-center studies of RIC allo-HCT in patients with multiply recurrent Hodgkin lymphoma showed improved rates of treatment-related mortality (8%–16%) but still relatively low rates of long-term PFS (23%–39% at 2 to 4 years).104–106 Interestingly, in one of these studies the outcomes were more favorable for patients who underwent haploidentical (versus matched sibling or matched unrelated donor) transplants.105
Two large registry studies have also reported on the outcomes of RIC allo-HCT in patients with relapsed and refractory Hodgkin lymphoma.107,108 These studies also confirmed a modest improvement in outcomes compared with those seen historically with myeloablative transplants. Treatment-related mortality at 1 to 2 years was 23% to 33%, depending on whether a matched sibling donor versus an unrelated donor was used. However, long-term PFS (18%–20% at 2 to 5 years) and OS (28%–37% at 2 to 5 years) remained poor, primarily due to high rates of progressive lymphoma post-transplant. In both of these studies, patients were heavily pretreated (84%–96% had received 3 or more prior lines of chemotherapy, and 62%–89% received a prior auto-HCT), with 47% to 55% of patients chemo-resistant prior to transplant. Of note, both of these registry studies reflect patients who underwent transplant prior to the widespread use of brentuximab and PD-1 inhibitors.
,Based on the single-center and registry data above, a prospective multicenter European phase 2 trial was conducted to evaluate the benefit of RIC allo-HCT in Hodgkin lymphoma.109 Ninety-two patients (86% with prior auto-HCT, 90% with 3 or more prior lines of therapy) were enrolled and given salvage therapy. Those who had stable disease or better following salvage therapy remained on protocol (n = 78) and underwent RIC with fludarabine and melphalan, followed by allo-HCT (70% with matched sibling donors). Treatment-related mortality was 15% at 1 year. Relapse or progression occurred in 49% at 2 years (35% if chemo-sensitive prior to transplant). Chronic GVHD was associated with a decreased rate of relapse, supporting the existence of a graft-versus-lymphoma effect in Hodgkin lymphoma. Unfortunately, PFS among all allografted patients was still relatively poor (24% at 4 years). However, among patients in CR prior to allo-HCT, a 50% PFS was seen at 4 years. Therefore, even in a prospective multicenter study, RIC allo-HCT offered significant benefit with manageable toxicity in relapsed and refractory Hodgkin lymphoma patients with chemo-sensitive disease.
These studies suggest that outcomes with allo-HCT would improve further if implemented earlier in the course of disease and/or with a lower burden of disease at transplant. It has therefore been suggested that allo-HCT should be considered soon after failure of auto-HCT is documented. In a retrospective study by Sarina et al, 185 Hodgkin lymphoma patients who relapsed following auto-HCT were then immediately considered for reduced-intensity allo-HCT.110 Of these, 122 had a donor identified, and 104 (85%) actually underwent allo-HCT. These 104 patients were then compared to the other 81 patients who either had no donor identified or had a donor but did not receive the planned allo-HCT. Two-year PFS and OS were superior in the patients undergoing allo-HCT (39% versus 14% and 66% versus 42%, respectively, P < 0.001), with a median follow-up of 4 years. The presence of chronic GVHD again was associated with improved PFS and OS. Disease status prior to transplant remained highly predictive of PFS and OS by multivariate analysis. Two other smaller retrospective studies similarly found a survival benefit associated with allo-HCT compared with patients who underwent conventional salvage therapies alone.111,112 These studies, although subject to the usual limitations of retrospective analyses, suggest that the results with reduced-intensity allo-HCT are in fact enhanced if applied earlier in the disease course, and are superior to those with conventional therapy alone.
Currently, the exact role of allo-HSCT, including the optimal timing and optimal donor source (matched sibling versus haploidentical sibling versus matched unrelated donor), remain undefined for relapsed and refractory Hodgkin lymphoma. As discussed earlier, brentuximab is highly active in relapsed Hodgkin lymphoma patients, with a subset of patients still in CR at 5 years.67 For such patients, avoiding the risks of allo-HCT is a desirable goal.
