Variable Outcome of Allogeneic Stem Cell Transplant According to the Different Levels of Pre-Transplant Minimal Residual Disease, in Adult Patients with Acute Myeloid Leukemia
Authors: Buccisano Francesco , Maurillo Luca , Piciocchi Alfonso , Del Principe Maria Ilaria , De Angelis Gottardo , Di Veroli Ambra , Cerretti Raffaella , Cefalo Mariagiovanna , Ditto Concetta , Picardi Alessandra , Cudillo Laura , Mariotti Benedetta , Lo Coco Francesco , Arcese William , Amadori Sergio , Venditti Adriano 
Published: October 2019

Abstract
Despite advances in treatment and supportive therapies, outcome of acute myeloid leukemia (AML) remains dismal with approximately 40% of younger and less than 20% of elderly patients becoming long-term survivors. Stem cell transplantation (SCT) is a well-established post-remission therapeutic option, and in both its variants, autologous (AuSCT) and allogeneic (ASCT), it is often incorporated in modern treatment programs for it may reliably improve long-term prognosis. Ten years ago we demonstrated that the levels of minimal residual disease (MRD) before autologous stem cell transplant (AuSCT), assessed at the post-consolidation time point by multiparametric flow cytometry (MFC), affected outcome (1). Moreover, we have preliminarily observed that in MRD positive (MRDpos) patients, allogeneic stem cell transplant (ASCT) attenuates the negative prognostic impact of pre-transplant MRD positivity by conferring a significant survival advantage in terms of either overall (OS) or disease free survival (DFS) (2). At variance with this, others have shown that even in the setting of ASCT, pre-transplant MRD positivity is associated with a poor prognosis regardless of the graft-versus-leukemia (GVL) effect (3). The aim of the present analysis was to evaluate, in 81 MRDpos patients submitted to ASCT (45) or AuSCT (36), the impact on clinical outcome of different MRD levels. As previously reported, counting 3.5x10-4 (0.035%) residual leukemic cells (RLCs) or more in the bone marrow (BM) upon full hematological recovery after consolidation cycle, was regarded as a condition of MRD positivity. Patients with or above 3.5x10-4 RLC were arbitrarily divided into 3 different cohorts: 1) ≥0.035%≤0.1% (13 patients, 6 ASCT and 7 AuSCT); 2) >0.1%≤1% (52 patients, 31 ASCT and 21 AuSCT); 3) >1% (16 patients, 8 ASCT and 8 AuSCT). In the category no. 2, ASCT gave a significant 5-years OS (64,9% vs 17,9%, p<0.001) and DFS (66,5% vs <10%, p<0.001) advantage. In the category no. 3, even if the low numbers suggest caution in drawing any conclusions, the patients showed a similar poor outcome both after AuSCT or ASCT. In multivariable analysis, backward, forward and stepwise regressions confirmed the role of ASCT vs. AuSCT (OS: HR 0.53, SDF 95% 0.30-0.95, p=0.039; DFS: HR 0.40, SDF 95% 0.23-0.70, p=0.001) and MRDpos vs MRDneg status (OS: HR 1.89, SDF 95% 1.03-3.46, p=0.032; DFS: HR 2.20, SDF 95% 1.24-3.93, p=0.007). These preliminary results indicate that in pre-transplant MRD positive patients the log-term outcome of ASCT may be different according to the amount of RLC. In low tumor burden (< 1%) MRD positive patients, conditioning regimens and GVL effect can still offer a chance of cure similarly to MRD negative patients. In high tumor burden (>1%) MRD positive patients, ASCT does not guarantee a long-term control of leukemia and further reduction of relapse risk is expected to be facilitated by novel strategies.

Disclosures
No relevant conflicts of interest to declare.