Reduced Intensity Vs. Standard Conditioning Followed By Allogeneic Stem Cell Transplantation for Patients with MDS or Secondary AML: A Prospective, Randomized Phase III Study of the Chronic Malignancies Working Party of the EBMT (RICMAC-Trial)

Introduction

Retrospective studies in MDS/sAML suggest that reducing the intensity of the conditioning regimen prior to allogeneic stem cell transplantation reduces the risk of non-relapse mortality but is associated with a higher risk of relapse, but prospective randomized studies for MDS are lacking so far.

Patients and Methods

Within the Chronic Malignancies Working Party (CMWP) of EBMT, we performed a prospective randomized trial comparing a busulfan based (Busulfan 8mg/kg orally or equivalent dosis intravenously (iv) plus fludarabin 180mg/m²) reduced intensity conditioning regimen (RIC) and a standard myeloablative busulfan (Busulfan 16mg/kg orally or equivalent dosis iv plus cyclophosphamide 120mg/kg) based regimen (MAC) in patients with MDS or sAML (<20 % blasts). Between May 2004 and December 2012, 129 patients were included from 18 centers and 7 nations and 127 could be analysed. Major inclusion criteria were: MDS (according to FAB: RA, RARS, RAEB, RAEB-t), CMML, and sAML, blasts less than 20 %, matched related or unrelated donor (HLA 8/8, 1 mismatch was allowed), age 18 - 60 years (for unrelated) and 18 - 65 years (for HLA-identical sibling). Included patients were stratified according related vs unrelated donor and blast count < or > than 5%. The primary endpoint of the study was 1 year non-relapse mortality.The median age of the patients was 51.4 years (r.19-64y). Donors were HLA-identical sibling (n=34), matched unrelated (n=59) and mismatched related or unrelated (n=30). The patients were well distributed in both arms regarding age, gender, IPSS risk profile, number of blasts at transplantation, donor source and mismatch donor.

Results

Leukocyte count more than 1.0 x 10e9/L and platelet count more than 50x10e9/L at day 28 was reached in 90 % and 70% after RIC and in 92% and 77% after MAC, respectively Acute GvHD II-IV was noted in 29% after RIC and 32% after MAC. Chronic GvHD was seen in 61% after RIC and 64% after MAC. The cumulative incidence (CI) of non-relapse mortality (NRM) after 1 year was 17% (95% CI 8-26%) after RIC and 28% (95% CI 16-39%) after MAC (p=0.18). The CI of NRM at 1 year after HLA-identical sibling transplantation was lower than after unrelated transplantation after RIC (0% vs 23%, p=0.06) as well after MAC (17% vs 32%; p=0.18) The CI of relapse at 2 years was 18% (95% CI 8-27%) after RIC and 15% (95% CI 5-24%) after MAC (p=0.5), resulting in a 2 year relapse-free and overall survival of 61% (95% CI 48-73%) and 74% (95% CI 63-86%) after RIC and 56% (95% CI 43-69%) and 61% (95% CI 48-73%) after MAC (p=0.50 and p= 0.07, respectively).

Conclusion

This prospective randomized trial of EBMT provide evidence that RIC resulted in at least similar 2 year relapse-free and overall survival as in MAC for patients with MDS and sAML and less than 20% blasts.