Feasibility and Efficacy of Tandem Autologous-Allogeneic Transplantation in a Cohort of 111 Patients Affected By High-Risk Hodgkin's and Non-Hodgkin's Lymphoma
Authors: Crocchiolo Roberto , Castagna Luca , Fuerst Sabine , El Cheikh Jean , Sarina Barbara , Bramanti Stefania , Granata Angela , Morabito Lucio , Giordano Laura , Garciaz Sylvain , Coso Diane , Bouabdallah Reda , Balzarotti Monica , Chabannon Christian , Carlo-Stella Carmelo , Santoro Armando , Blaise Didier 
Published: October 2019

Abstract

Introduction: although high-dose chemotherapy (HDC) is the golden standard for the treatment of many relapsed or refractory lymphomas, the outcome is still unsatisfactory especially in some subsets of patients with adverse prognostic features. To improve these results, we treated high-risk patients with a tandem strategy associating debulking with HDC followed by autologous stem cell transplantation (ASCT) and subsequent adoptive immunotherapy consisting in allogeneic SCT (tandem auto-allo). We report here the outcome of 111 lymphoma patients undergoing this procedure; in addition, the role of two ASCT conditioning regimens is discussed.
Patients and Methods: adult patients consecutively treated at two centers (Milan, Italy and Marseille, France) were included. Criteria for receiving tandem auto-allo were: refractory disease after first-line therapy, less than CR after first salvage treatment, histology of transformed follicular, mantle-, T- and NK-cell lymphoma, relapse after prior ASCT, multiple relapses. Disease evaluation was performed by using PET scan starting from 2003.
Results: 111 consecutive patients with HL or NHL were transplanted from June 2002 to September 2013. Main characteristics are shown in Table 1. Median interval between ASCT and allogeneic SCT was 85 days (range: 36-235). Sixty-two patients (56%) received BEAM (8 of them without BCNU) and 46 (41%) high-dose Melphalan (HD-Mel, 100-200 mg/m2); 3 patients received other regimens. Main characteristics were not significantly different between BEAM and HD-Mel groups with the exception of the use of more alternative donor (i.e. non HLA-identical) in the HD-Mel group: 33% vs. 13%, p=0.01. Disease status before ASCT was: CR (n=47), PR (n=38), SD (n=10), PD (n=16). Grade 3-4 mucositis occurred in 49 patients (44%) and documented infections during hospital stay in 30 (27%), without differences between BEAM and HD-Mel groups, p=0.57 and p=0.14. Disease status before allogeneic SCT was: CR (n=79), PR (n=22), SD (n=5), PD (n=5). Among the 64 patients with active disease before ASCT, the overall response rate was 87% (n=56 responders) and the rate of CR was 53% (n=34), these latter adding to the 45 (out of the 47) patients in CR before ASCT; nine patients (8%) progressed between ASCT and allogeneic SCT. Again, no differences were observed in terms of response among BEAM and HD-Mel group (p=0.28). Allogeneic SCT was performed after NMA (n=43), RIC (n=66) or MA (n=2) conditioning; donor was either HLA-identical (n=86), MUD 9/10 (n=2), haploidentical (n=20) or cord blood (n=3). After a median follow-up of 38 months after allogeneic SCT, 3-y OS of entire cohort was 68% (95% CI: 59-77), 3-y PFS was 61% (52-70), rates of acute GvHD grade 2-4 and chronic GvHD were 28% and 38% respectively. TRM rate was 18% (n=20). Last relapse event occurred at day +853. No difference between BEAM and HD-Mel group was observed for OS (73% and 64% respectively, p=0.40) or TRM (19% and 13%, p=0.44). CR before allogeneic SCT confirms to a major prognostic factors for OS (Figure 1), whereas donor type did not significantly impact on survival (p=0.68). No survival difference was observed between HL and NHL (p=0.53). Conclusions: tandem auto-allo confirms to be a feasible and effective therapeutic strategy in those lymphoma patients whose prognosis is expected to be unsatisfactory with ASCT alone. BEAM vs. HD-Mel appeared to be similar in terms of extrahematological toxicity, disease response and survival. Disease status before allogeneic SCT confirms to be a significant prognostic factor, underlying the importance of high-dose chemotherapy followed by ASCT as further tumor shrinking before allogeneic immunotherapy in this setting of high-risk patients.
Table 1. Main patients’ and transplant characteristics Variable Value % N 111 100% Pt's age (median) 44 range:16-69 Gender M 66 59% F 45 41% Disease HL 44 40% DLBCL 12 11% FL 21 19% Transf FL 9 8% MCL 9 8% MZL 1 1% T lymph 13 12% Grey zone 1 1% NK lymphoma 1 1% Indication for tandem auto-allo 1ary refractory 28 25% no CR after salvage 43 39% histology 10 9% relapse after prior ASCT 6 5% multiple relapse 24 22% Prior therapy lines (median) 2 range: 0-7 Prior radiotherapy 26 23% ASCT conditioning BEAM 54 49% EAM 8 7% HD-Mel 100 1 1% HD-Mel 140 12 11% HD-Mel 200 33 30% other 3 3% Allogeneic stem cell donor HLA-id sibling 62 56% MUD 10/10 24 22% MUD 9/10 2 2% haplo 20 18% cord blood 3 3%
Figure 1. OS according to disease status after ASCT. Figure 1. OS according to disease status after ASCT.

Disclosures
No relevant conflicts of interest to declare.