Long-Term Overall and Event-Free Survival after RIC Allogeneic Transplantation in Acute Leukemias in a Single Centre - Impact of Age and Donor Type?
Authors: Wittnebel Sebastian , Lewalle Philippe , Michiels Sandra , Anoun Soumaya , Bailly Benjamin , Vercruyssen Marie , Dallemagne Julie , Buntinx Sarah , Huynh Phuong , Crombez Patrick , Jaivenois Marie France , Bron Dominique 
Published: October 2019

Abstract
BACKGROUND: Between January 2007 and December 2014, we transplanted 143 patients (Pts) using RIC- conditioning allogeneic transplant. 71 were transplanted for acute leukemias (AML and ALL) and high risk myelodysplastic syndromes (MDS) not eligible for myeloablative transplantation. Clinicians are usually scared to transplant older patients with MUD because of the higher risk of Treatment-related mortality (TRM). We thus reviewed retrospectively the impact of donor / recipient ages and donor-choice (familial related donor (RD) versus matched unrelated donors (MUD)) on the post-transplant outcome of the pts.
POPULATION AND METHODS: We retrospectively studied in our cohort of 71 leukemia pts evaluable after RIC transplant, the overall survival (OS) and event-free survival (EFS), according to recipient ages (≤ 54yo vs ≥55yo) and donor types (RD vs MUD).
Conditioning consisted of combinations of Busulfan-Fludarabin-ATG or Endoxan-Fludarabine-ATG. Immunosuppression was a combination of cyclosporine (CSA)/mycofenolate mofetil (MMF), Tacrolimus (TAC)/ MMF or TAC/ Sirolimus. Chimerism analyses were performed on d30, d90 and d180. Both study-groups were well balanced concerning transplant conditioning regimens, (ATG or not) RD vs MUD donors, type of leukemia and status of the disease at transplant. Our local EBMT database was the source for this analysis.
RESULTS: 34 de novo AML (20 ≤54 yr and 14 ≥55 yr), 30 secondary AML and MDS (15 ≤54 yr and 15 ≥55 yr) and 7 ALL (5 ≤54 yr and 2 ≥55 yr) were enrolled in our trial. 24 pts received HLA identical RD in the group ≤54yr and 14 pts in the group ≥55 yr. The others pts received MUD transplant from HLA 9 or 10/10 donors (16 in the group ≤ 54yr and 17 in the group ≥ 55yr). The median follow-up was 22 (3-93) months. Engraftment rate was 100% in the studied cohort. TRM before d100 was 18,3% (15% ≤54 yo and 22,6% ≥ 55yo). Grade II-IV Acute GVHD (aGVHD) at d90 (16,6%) and Chronic GVHD rates (24%) were similar in both age populations. 5 yrs OS was not different according to the age of the recipient (≤54 yr versus ≥55 yr)(p = 0.9). However, there is a clear, difference in 5years OS when stratifying the two age groups according to donor-types, especially for older patients (≥55 yr) with MUD transplant. (pts ≤ 54yr : OS: RD: 31,6%; and MUD: 38%; pts ≥ 55yr : OS: RD: 27,8% and MUD 44,2%). This trend in a better OS in older MUD pts could be explained partially by a lower relapse-rate in the group ≥ 55 yr with a MUD as shown by EFS/5yrs (pts ≤ 54 yr : RD: 32%; ≤ 54yr MUD: 19%; pts ≥ 55yr RD: 21% and ≥ 55yr MUD 38,5 %). As reported already in transplanted CLL patients, this suggests a greater GVHD/GVL-effect in the MUD transplantation. We then further investigated the age of the donors and its correlation with aGVHD and cGVHD. In the RD RIC transplant group, median age of the donors was 49 yrs (range 35-69 years) with 37.5% of aGVHD and 42% of cGVHD. In the MUD RIC transplant cohort, donor median age was 31 yrs (20-55 years) with 12% of aGVHD and 32% of cGVHD. We previously reported that the number of CD8+ T cells and naïve CD4+ T cells decreases with the age of the donor, also supporting a better control of the disease with younger donors. This combination of younger donor age, lower aGVHD and a similar rate of cGVHD clearly explains the better outcome in pts transplanted with MUD. Our data requires confirmation in a larger series of patients.
CONCLUSION: our observations confirm that: 1) RIC transplantation is a curative approach in acute leukemia whatever the age when the pts are fit enough to tolerate the transplant. 2) despite a higher TRM compared to younger patients, older patients seem to particularly benefit from MUD in terms of OS. 3) an increased EFS is observed in older pts transplanted with MUD (also younger) donors more likely due to a greater GVHD/GvL effect in the MUD setting.

Disclosures
No relevant conflicts of interest to declare.