Recurrent lymphomas have become an increasingly therapeutic challenge. Allogeneic HCT has been more commonly used as a potential curative option due to recognition of the graft versus lymphoma effect with recent reports describing improved outcomes and limited treatment related adverse events (6
). However, progression or relapse after HCT remains common and a major cause of death (15
). Importantly, we found that some patients had prolonged survival following their relapse, particularly those with later relapse following the allograft. However, the overall prognosis for our patients with relapsed/progressive lymphoma following allogeneic HCT is poor with a median survival of only 5 months after HCT (2 months following relapse, similar to the few other reports (12
Prognostic factors that modify outcome after allogeneic HCT include low transplant comorbidity index (HCT-CI) scores, conditioning regimen, age, type of lymphoma, prior cytomegalovirus (CMV) infection and graft source (7
). In our study, the major prognostic factors that determined overall survival survival after HCT and survival following relapse include LDH at the time of relapse, ECOG performance status, stage and sites of relapse. The time of relapse after transplantation also affected post transplant survival, but not survival after the relapse. We observed no prognostic impact of graft source, conditioning regimen intensity or lymphoma histological subtype on survival after transplant relapse. Due to small number of patients, multivariate analysis was not performed. Most earlier reports of allogeneic HCT in lymphoma (4
) did not examine post relapse management, response or subsequent survival.
Several brief reports described salvage treatment in relapsed/progressive lymphoma following HCT; mostly relapse after autologous HCT (19
). A few series describe allogeneic HCT for those who respond to other salvage treatments. Reports of salvage therapies after allogeneic HCT are limited and there are no standard guidelines for the treatment of post-allograft relapse. Available potential treatment approaches include RIS, chemotherapy, rituximab, DLI (9
), second allogeneic HCT (30
), interleukin-2 (32
) or other novel agents (33
) yet reported outcomes are disappointing. One small series described salvage treatment for NHL after autologous (n=46) and allogeneic (n=12) HCT (16
). The median survival after allografting was only 7 months and no specific therapy was recommended.
Reduction of immunosuppressive is often a first step in patients without severe GVHD or highly aggressive NHL (11
). In our study, some patients with HL, T/NK cell or mantle cell NHL achieved CR with RIS alone while indolent B cell lymphoma and highly aggressive lymphoma such as Burkitt's lymphoma rarely responded to RIS, even with other therapies. A durable response to RIS observed in some patients might reflect a potent graft versus lymphoma effect, but we observed no correlation with specific histologies.
Rituximab, in addition to its application as an approved first line treatment for CD20+ NHL, has been increasingly used for relapsed/progressive lymphoma with promising efficacy and infrequent treatment-related adverse events (36
). Following HCT, several studies reported its efficacy as a single agent or in combination, mostly following autologous HCT (25
). We observed that rituximab could induce responses in some patients, even if previously treated with rituximab. Most of these patients had NHL (DLBCL 7, indolent 2, mantle cell 2) and one had HL. However, no study prospectively tested rituximab as a salvage treatment for prevention or therapy of relapse after allogeneic HCT.
Several chemotherapeutic regimens were used, but we could not compare the efficacy of different regimens due to small numbers and treatment heterogeneity. Moreover, the selection of chemotherapeutic regimen was influenced by many variables including previous response, performance status, histopathology and lymphoma burden. Notably, most of patients in our series who responded to chemotherapy had HL whereas those with NHL rarely responded unless treated concomitantly with rituximab. It is interesting to note that chemotherapy plus rituximab provided a therapeutic effect in this highly refractory patient subgroup who had exhausted several earlier treatment modalities. This might reflect a combined graft versus lymphoma effect from the concomitant reduction in immunosuppression. This was also was demonstrated by the promising responses to DLI in our study. However, this hypothesis will need further research to demonstrate its therapeutic potential.
DLI are used as a rescue treatment in relapsed lymphoma following allogeneic HCT with mixed results. Most early reports of DLI described favorable responses, but mostly in chronic myeloid leukemia (40
). Some recent reports include indolent NHL (10
). We observed promising responses after DLI in of 7 patients including HL and T cell NHL. In our series, the large number of UCB graft recipients could not receive DLI.
Second allogeneic HCT for lymphoma is rarely reported and has high treatment related mortality (30
). This may be due to patients' poor performance status, extensive previous treatment and refractory disease. Baron et al reported the feasibility of RIC allogeneic HCT in patients who had failed a first myeloablative HCT (autologous or allogeneic) (31
) with median overall survival of 813 days. However, the patients were heterogeneous and only 10 (of 147) had undergone a previous allogeneic HCT, none for NHL or HL. Another series describe only modest morbidity/mortality of second myeloablative allogeneic HCT in pediatric patients, especially age < 10 years (30
). Recently, Kenkre and colleagues demonstrated promising long-term survival from T-cell depleted allogeneic HSCT in multiply relapsed lymphoma (17
). However, there were only four patients who had a prior allotransplant preceding the allogeneic transplant reported. We might consider that a second allogeneic transplantation might be a feasible option if DLI is unavailable.
The prognosis and response to salvage treatment in relapse/progressive lymphoma following allogeneic HCT are rarely reported. Acknowledging the limits of retrospective analysis and heterogeneity of patients, histologies and treatments, we are encouraged that for some patients, especially those with later relapse, combination approaches can again achieve durable CR and prolonged survival. Improvements in supportive care and development of novel therapies may further improve outcome for such patients, but careful clinical study is needed to dissect the best approaches and identify those most likely to benefit.