Tandem autologous-allogeneic stem cell transplantation as a feasible and effective procedure in high-risk lymphoma patients.

Although high-dose chemotherapy is the gold standard for the treatment of many relapsed or refractory lymphomas, the outcome remains unsatisfactory, particularly in some subsets of patients with adverse prognostic features. Here we report the outcome of 111 high-risk lymphoma patients treated with a tandem strategy involving debulking with HDC followed by autologous stem cell transplantation (ASCT) and subsequent adoptive immunotherapy consisting of allogeneic stem cell transplantation (SCT; tandem auto-allo). The response rate after ASCT was 86% and 34 patients (52% of responding patients) obtained complete remission before allogeneic SCT. After a median follow up of 38 months after allogeneic stem cell transplantation, the 3-year overall survival,, progression-free survival, non-relapse mortality and relapse/progression were 68% (95%CI: 59-77), 61% (95%CI: 52-70), 17% (95%CI: 10-25) and 22% (95%CI: 14-30), respectively. In multivariate analysis, the response to autologous stem cell transplantation was the only independent predictive factor of mortality (P=0.05), whereas autologous stem cell transplantation conditioning and the type of allogeneic donor did not significantly affect survival (P=0.40 and P=0.68, respectively). No survival difference was observed between Hodgkin and non-Hodgkin lymphoma patients (P=0.53). Salvage chemotherapy followed by high-dose therapy and autologous sem cell transplantation (ASCT) is recognized as the most effective strategy for relapsed or refractory Hodgkin lymphoma (HL) or aggressive nonHodgkin lymphoma (NHL). However, patients with some adverse prognostic features still have unsatisfactory outcomes after ASCT alone and may benefit from additional therapies. Short response duration after first-line therapy, B symptoms, advanced stage and/or extranodal disease at relapse and relapse in a previously irradiated field are among the most recognized adverse prognostic factors in relapsed/refractory HL patients, whereas relapse within one year of diagnosis, prior rituximab therapy and secondary IPI score have been reported in diffuse large B-cell lymphoma. Other prognostic factors have been identified for relapsed follicular and mantle cell lymphoma. Despite the identification of several adverse prognostic factors, the question about the best therapy for patients with refractory lymphoma is still open, and efforts are ongoing in an attempt to investigate the role and the timing of high-dose chemotherapy, allogeneic SCT, and investigational drugs. The aim of the present retrospective analysis is to report data on the feasibility, toxicity and outcome of tandem auto-allo in 111 adults with high-risk HL or NHL. Since it is known that the graft-versus-lymphoma (GvL) effect after allogeneic SCT is more effective when the tumor burden is minimal or not detected before transplantation, we explored a tandem strategy combining cytoreduction (through the administration of HDC followed by ASCT) and the GvL effect in those high-risk patients for whom ASCT is expected to produce unsatisfactory results. From June 2002 to September 2013, we identified 111 patients with a diagnosis of lymphoproliferative disease who received tandem auto-allo at any point during their therapeutic history at two institutions (Istituto Clinico Humanitas, Milan, Italy; Institut Paoli-Calmettes, Marseille, France), selected from the internal transplantation database. The data regarding patients’ age, sex, diagnosis, indication for tandem auto-allo, type and number of previous therapy or therapies, ASCT conditioning, interval between ASCT and allogeneic SCT, donor type and HCT-CI score were collected and analyzed as covariates in regression analyses; the hematopoietic cell transplantation-specific comorbidity index was reported or retrospectively calculated whenever possible. Firstline therapy was ABVD (HL patients), CHOP or CHOPlike regimens (patients with aggressive NHL, with the addition of rituximab in cases of malignant-cell positivity for CD20) or chemotherapy associations not including anthracyclines (i.e. R-CVP for indolent NHL). The salvage regimens were DHAP, IGEV or ICE with the addition of rituximab for CD20 lymphomas. As per institutional guidelines, BEAM or BEAM-like regimens were administered in Marseille whereas high-dose melphalan (HDMel) was administered in Milan. The allogeneic SCT conditioning regimens were classified as myeloablative (MAC), reduced intensity (RIC) or non-myeloablative (NMA) according to working definitions. The choice of the conditioning depended on donor type, patient’s clinical status, and any institutional protocols at the moment of patient enrollment. Regarding donor selection, when a patient lacked a suitable HLA-identical sibling, a search for a 10/10-matched or a 9/10-mismatched unrelated donor was initiated (only for patients aged ≤ 65 years at Istituto Clinico Humanitas). Beginning in 2010, in the absence of either an available HLA-identical sibling or an unrelated donor at the appropriate time interval, a haploidentical or cord blood donor was identified. Peripheral blood stem cells was the preferred source from HLAidentical and mismatched unrelated donors whereas haploidentical donors were scheduled to undergo bone marrow harvest under general anesthesia unless contraindicated. Response was assessed using the standard and revised Cheson criteria, these latter after the introduction of PET as a tool for response evaluation, occurring in 2003 and progressively used for disease evaluation of HL and aggressive NHL. The results pertaining to some patients in this cohort have been published elsewhere. Patients were followed-up until June 2014. The study was approved by the IRB of both institutions. The main patients’ and transplants’ characteristics are shown in Table 1. Ten patients were allocated to tandem auto-allo at diagnosis (n=3 mantle cell, n=3 transformed follicular, n=3 peripheral T-cell, n=1 NK lymphoma), based on disease aggressiveness, patient’s physical status and willingness, clinical judgment. The indication of tandem auto-allo was given before ASCT for all patients and did not depend on response after ASCT (Table 1). The median interval between ASCT and allogeneic SCT was 85 days (range: 36-235). After ASCT, median neutrophil engraftment occurred at day 13 (range: 8-41). NCI-CTC grade 3-4 mucositis occurred in 49 patients (44%) and at least one moderate to severe infectious disease was documented in 34 patients (31%), without significant differences between (B)EAM and HD-Mel (P=0.69 and P=0.21, respectively). After allogeneic SCT, median neutrophil engraftment occurred at day 18 (range 11-42), day 23 (range: 15-32) and day 14 (range: 7-26) after peripheral blood stem cells, bone marrow and cord blood, respectively. Two graft failures occurred in 2 patients after haploidentical transplantation. Three patients died before engraftment (2 haploidentical, 1 HLA-identical). Grade 34 mucositis occurred in 7 patients (2 after MAC, 5 after RIC). The rate of moderate to severe infections during hospitalization was 0%, 15% and 26% after MAC, RIC and NMA conditioning, respectively. At the time of