 good partial remission, although prolonged cytopenias after the fourth cycle prohibited additional chemotherapy. He had no fully HLA-matched sibling donor (HLA-MSD) or HLA-matched unrelated donor (HLA-MUD) available. Thus, he underwent reduced intensity allo-HCT using posttransplant cyclophosphamide graft-versus-host disease (GVHD) prophylaxis from his haploidentical brother and remains in remission without active GVHD 4 years after allo-HCT.
Allogeneic stem cell transplantation offers potential long-term disease control for relapsed chemosensitive FL, but it is generally not considered unless auto-HCT fails or patients are otherwise unable to undergo or are unlikely to benefit from auto-HCT. When performed in first relapse or beyond, retrospective data would suggest that, although the GVL effect may confer a disease-free survival (DFS) advantage compared with auto-HCT, higher NRM and treatment-related mortality (TRM) abrogate much of the differences in OS. However, comparisons of outcomes following allo-HCT with other therapies can be challenging based on varied patient and disease characteristics.
The first large registry trial performed in the prerituximab era evaluated 904 patients reported to the International Bone Marrow Transplant Registry between 2000 and 2009. It compared the outcomes of 131 (14%) patients receiving purged auto-HCT, 597 (67%) patients receiving unpurged auto-HCT, and 176 (19%) patients receiving myeloablative allo-HCT for FL.27 Although myeloablative allo-HCT conferred a 5-year DFS advantage of 45% vs 31% to 39% for auto-HCT, this was offset by higher 5-year TRM of 30% vs 8% to 14% for auto-HCT. Therefore, no survival benefit was seen in this study, with 5-year OS rates of 51% (allo-HCT) vs 55% to 62% (auto-HCT).
Because of the high rates of NRM and TRM seen in earlier studies using myeloablative conditioning regimens, increased efforts were undertaken to decrease toxicities and expand treatment options for older less-fit patients. Most allo-HCTs now use reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning regimens. In the rituximab era, a comprehensive analysis from the National Cancer Care Network Lymphoma Outcomes Project evaluated the outcomes of 184 patients with R/R FL, of whom 136 (74%) received an auto-HCT and 48 (26%) received an allo-HCT.28 RIC was the conditioning regimen used for most allo-HCTs. The 100-day NRM for auto-HCT and allo-HCT was 1% and 6%, respectively (P <.0001), whereas 3-year NRM was 3% and 24%, respectively (P <.0001). For auto-HCT and allo-HCT, cumulative rates of relapse, progression, and/or transformation were 32% vs 16%, respectively (P =.03), and 3-year OS rates were 87% vs 61%, respectively (P <.0001).
The Blood and Marrow Transplant Clinical Trials Network did attempt to prospectively compare outcomes of patients with relapsed chemotherapy-sensitive FL assigned to receive RIC allo-HCT vs auto-HCT, but slow accrual led to early study closure. However, after a median follow-up of 3 years, the reported OS in the 8 patients receiving RIC (fludarabine, cyclophosphamide, rituximab) allo-HCT was 100% compared with 73% in the 22 patients receiving an auto-HCT. The 3-year PFS was also superior in the allo-HCT cohort (86% vs 63%). Interestingly, the investigators found a higher 1-year and 3-year TRM for auto-HCT compared with prior studies (15% and 21.8%, respectively); however, given the premature closure of this study and the small number of enrolled patients, definitive conclusions could not be drawn.31 Cumulatively, these studies show allo-HCT as a potentially curative option for relapsed FL because of the lower disease relapse rates compared with auto-HCT (Table 2); however, TRM rates >30%, even with RIC or NMA, in some series may offset this benefit. Furthermore, multiple pre-HCT factors, logistics, and donor availability often dictate whether auto-HCT or allo-HCT is considered at the time of relapse.
NRM, % (follow-up, y).
PFS/DFS, % (follow-up, y).
mm-URD, mismatched unrelated donor; NCCN, National Cancer Care Network.
Early closure from low accrual.
The European Society for Blood and Marrow Transplantation and the CIBMTR conducted a retrospective analysis of 1567 patients, the largest cohort ever studied, to ascertain the role for allo-HCT in relapsed FL treated between 2001 and 2011 and to determine the factors associated with outcomes.34 Despite differences in clinical practice between European and US transplant centers, the adjusted 5-year PFS was 52% for both; OS was 62% and 61%, respectively, for the European Society for Blood and Marrow Transplantation and CIBMTR patients; and 5-year cumulative incidence of TRM was 29%. After multivariate analysis, grade 3 histology, age at transplantation (continuous variable), prior lines of chemotherapy, chemorefractory disease, poor performance status, and myeloablative conditioning regimens were found to be adverse prognostic factors. There was no difference in outcomes found between HLA-MSDs and HLA-MUDs in this large cohort of patients. The investigators concluded that allo-HCT should be considered earlier in a patient’s FL course, particularly before multiple lines of chemotherapy are administered, chemorefractoriness develops, or performance status declines.
The contribution of rituximab-containing RIC regimens has also been described in 2 recent publications. The first analyzed the outcomes of >1400 transplanted patients (histologies included diffuse large B-cell lymphoma, FL, mantle cell lymphoma, and MZL) between 2008 and 2014 in the CIBMTR database. A 3-year PFS benefit was identified for individuals receiving a rituximab-containing RIC regimen compared with a nonrituximab-based approach (56% vs 47%, P =.005), even after multivariate analysis; however, no difference in OS was identified after multivariate analysis (risk ratio, 0.84; 95% CI, 0.69-1.02; P =.08).35 A subsequent analysis limited to FL patients did not identify this PFS benefit when comparing fludarabine, cyclophosphamide, and rituximab (FCR) conditioning with fludarabine and busulfan conditioning (3-year PFS, 74% vs 71%, respectively; P =.65).35 The 3-year OS rate was higher in the FCR group but the difference was not statistically significantly different (81% v. 73%, P =.18) because both regimens afforded excellent survival; however, the risk of chronic GVHD was reduced with FCR compared with fludarabine and busulfan (risk ratio, 0.52; 95% CI, 0.36-0.77; P =.001).36 Taken together, these studies suggest a PFS benefit for rituximab-containing RIC for NHL as a disease group; however, this benefit is not seen when restricted to FL as a subtype. The OS data are still reassuring and compare favorably with selected studies (Table 2).
When HLA-MSDs are unavailable, HLA-MUDs are relied upon; however, availability is often driven by racial/ethnic background and timing. Haploidentical related donors can overcome potential barriers in identifying HLA-MUDs, but initial concerns were raised regarding the higher risk for NRM, disease relapse, and delayed immune reconstitution from efforts used to mitigate rejection and potential GVHD.37 Posttransplantation cyclophosphamide (PT-Cy) helps to mitigate the morbid effects of GVHD, and this approach was evaluated in a group of 987 lymphoma patients receiving an allo-HCT from a haploidentical related donor (Haplo-HCT, n = 180) or an HLA-MSD (n = 807), of whom 232 were treated for FL.38 All Haplo-HCT patients received PT-Cy, with or without a calcineurin inhibitor and mycophenolate mofetil; compared with their HLA-MSD counterparts, the 3-year PFS and OS were not significantly different between the groups: 48% vs 48% (P =.96) and 61% vs 62% (P =.82) for Haplo-HCT and HLA-MSD, respectively. The cumulative incidence of grade 2 to 4 acute GVHD at day 100 also did not differ: 27% for Haplo-HCT and 25% for HLA-MSD (P =.84). However, the cumulative incidence of chronic GVHD at 1 year after Haplo-HCT was reduced to 12% compared with 45% in HLA-MSD (P <.001), suggesting that Haplo-HCT followed by PT-Cy may decrease the risk for chronic GVHD and remains a viable approach to transplant should HLA-MSD or HLA-MUD be unavailable.
The decision to transplant R/R indolent NHL can be challenging in light of multiple targeted agents now approved in this setting and the rapid evolution of treatment options in this field. These approaches also have to be balanced with the short- and long-term toxicities of transplant. Table 3 lists scenarios in which an auto-HCT