Double Reduced-Intensity Allogeneic Hematopoietic Stem Cell Transplantation: French Society of Bone Marrow Graft Transplantation and Cellular Therapy Experience
Authors: Bay Jacques-Olivier , Cabrespine-Faugeras Aurelie , Tabrizi Reza , Bordigoni Pierre , Bilger Karin , Renaud Marc , Mialou Valerie , Robin Marie , Kuentz Mathieu , Chevallier Patrice , Dhedin Nathalie , Cahn Jean-Yves , Attal Michel , Blaise Didier , Michallet Mauricette 
Published: April 2020

Abstract
Purpose: Objective was to assess indication, feasibility and efficacy of double allograft with reduced intensity conditioning.
Patients and Methods: All double allogeneic hematopoietic stem cell transplantation (AHSCT) after reduced intensity regimen reported to Promise database were retrospectively studied. Because of the initial lack of clinical and biological data in the Registry, all centers were contacted to improve the database.
Results: 66 double mini-allografts were realized in 25 french transplant centers. At this time, 35 mini-allografts presented complete informations corresponding to 14 transplant centers. Diagnosis was LAM (n=15), aplasic anemia (n=5), MDS and/or MPS (n=5), LAL (n=2), Myeloma (n=2), ovarian cancer (n=1), LNH (n=2), LLC (n=1), LMC (n=1) and Hodgkin lymphoma (n=1). Median age at first transplantation was 49.3 years [12.75–64.9] with a median time from diagnosis to first transplant of 22.9 months [3.6–163.7]. Disease status before transplant was progression (n=5), partial response (n=3), complete response (n=18), induction failure (n=2) and chronic phase (n=2). The 5 aplasic anemias were not evaluable for this status. Most patients received fludarabine (n=31), SAL (n=22), busulfan (n=15) based regimen. Graft source was PBSC in 74% of grafts. Median age of donor was 42 years [4–68]. HLA relation of donor with patient was identical sibling (n=22), match unrelated (n=10) or mismatch unrelated (n=3). Second allograft indication was relapse (n=22), lost of graft (n=7), no engraftment (n=5) or residual disease (n=1). Eihgty percents of patients underwent a different conditioning. It was similar for only 7 patients (same n=1, increase SAL dose n=1, SAL addition n=2, dose reduction n=1). Median time between the two allografts was of 7.6 month [1.1–61.0]. Source of stem cells and donor were changed in 13.6% and 37% of allograft respectively. The median time to reach an absolute neutrophil count of 0.5 × 109/l and platelet count of 50 × 109/l was shorter after second allograft (21.4 days [12.4–759.5] versus 16.8 days [6.2–105.4] and 16.3 days [9.3– 71.3] versus 14.26 [3.1–83.7]) with no significant difference. Overall incidence of acute GvH was similar after the two allografts (34% versus 43%). However, acute GvH grade III–IV proportion seems to be higher after second allograft (8% versus 40%). Similarly, proportion of chronic GvH was 23% versus 27% with an increase of extensive GvH after second allograft (50% versus 66%). Response was improved by second allograft in five patients (15%) and allowed to engraftment in 3 patients (7%). To date, 8 patients are still alive. 14 patients died from progression and 11 of TRM (3 multiple organ failure, 5 respiratory failure, 2 fungal infection and 1 rejection) giving a TRM proportion of 31%. With a median follow-up of 57.1 months [21.9–128.8], the median overall survival (OS) was of 24 months [2–71]. Delay greater than 7.7 months and same source of stem cell between two mini-allografts improved OS (50 months versus 9 months, p = 0.0085 and 28 months versus 14 months, p=0.11).
Conclusions: Our preliminary results suggests response improvement after double AHSCT with reduced conditioning. However, TRM proportion was high.