Kinetics of Chimerism Conversion to Total Donor Profile: Impact on Transplant Outcome after Reduced Intensity Conditioning Allogeneic Transplantation.
Authors: Michallet Mauricette , Le Quoc-Hung , Michallet Anne-Sophie , Nicolini Franck E. , Thiebaut Anne , Tavernier Emmanuelle , Rafii Hanadi , Mahmoudi Samira , Revesz Daniela , Praire Aline , Gadolet Elodie , Dubois Valerie , Gebuhrer Lucette 
Published: October 2019

Abstract
Allogeneic hematopoietic stem cell (HSC) transplantation after reduced intensity conditioning regimen (RICT) is increasingly used worldwide. Chimerism evaluation by short tandem repeat analysises is fundamental in this strategy to document donor cell engraftment and to indicate DLI after transplant. The signification and impact on transplant outcome of conversion kinetics to total donor profile is until now unknown. We performed a retrospective analysis in 85 patients [(53 males and 32 females, median age = 49 years (18–65)] who underwent RICT. The principal aim of our study was to analyze the impact of convertion delay to total donor on overall and event-free survivals (OS and EFS) within 90 days after transplant without any donor lymphocyte infusion (DLI) intervention. Diagnosis before transplantation were acute leukemia (n = 18), myelodysplasia (n = 6), chronic myeloid leukemia (n = 5), chronic lymphoid leukemia (n = 7), non hodgkin lymphoma (n = 10), hodgkin disease (n = 7), multiple myeloma (n = 21), aplastic anemia (n = 2), and solid tumor (n = 9). Before RICT, 36 patients were already transplanted, 18 patients were in complete remission (CR), 33 in partial response (PR) and 34 in evolutive disease (ED). As conditioning regimen, 32 received TBI (from 2 to 6 grays) associated to either fludarabine or cyclophosphamide, 44 fludarabine+busulfan+anti-thymocyte globulins (ATG), 6 cyclophospamide+ATG and 3 idarubicine+aracytine+fludarabine. As HSC, 26 patients received bone marrow [median nucleated cells = 2.6x108/kg (1.29–5.8)] and 59 peripheral blood stem cells [median CD34+ cells = 5.82x106/kg (2.3–5.8)] from 78 HLA identical sibling donors and 7 HLA identical unrelated donors. After transplant, 49 patients developed an acute GvHD (18 grade I, 17 grade II, 6 grade III, 8 grade IV) and 33 patients a chronic GvHD (22 limited, 11 extensive). At time of the last follow-up, 43 patients had relapsed after transplant while 35 are alive and 50 died (27 from relapse and 23 from transplant-related toxicity). Regarding chimerism post-transplant, we divided the population into 4 groups : group 1: who converted to total donor in less than 30 days (n = 44), group 2: who converted to total donor in more than 30 days (from 55 to 90 days) ( n = 11), group 3: who did never convert to total donor (n = 21 ) and group 4: who rapidly converted to total donor but returned during evolution after transplant into mixed chimerism (n = 10). The probability of OS and EFS at 2 years were 38% (95%CI 37–52) and 20.8 (13–34) respectively. OS and EFS at 2 years of 37.4% (95%CI 24–58) and 13.2 (95%CI 5.2–33.8) in the group 1, 77% (95%CI 53.5–100) and 56.6% (95%CI 31.3–100) in the group 2, 35.6% (95%CI 18.9–67) and 19.4% (95%CI 6.6–56.6) in the group 3 and 0% and not reached in the group 4. In conclusion, chimerism kinetics seems to have an impact on transplant outcome. A slow conversion to total donor profile seems benefit showing the importance to present a transient mixed chimerism status permitting tolerance.