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Relapse after transplant for Acute Leukemia - the role of Measurable Residual Disease (MRD) and Sorafenib therapy

by
Arnon Nagler, Vice Chair & Mohamad Mohty, Chair, Acute Leukaemia Working Party

Relapse is the major obstacle for successful allogeneic stem cell transplantation (HSCT) in Acute Leukemia ranging between 20-50% depending mainly on the leukemia risk but also on the transplant conditioning, graft manipulations and others.

The best way to address this critical issue is by prevention of relapse preemptively or prophylactically especially in high risk leukemia with very close monitoring and new available compounds. This strategy should be MRD driven.

Measurable residual disease (MRD) is probably the most important prognostic factor in modern acute leukemia therapy. In last few years it is becoming well established that the presence of MRD following initial induction treatment as well as post consolidation courses is a powerful independent prognosticator of patient outcome in both ALL and AML. Similarly, several studies, published lately in top rank journals, emphasized the importance of pre-transplantation MRD status in predicting allogeneic stem cell transplantation (HSCT) outcome in patients with acute leukemia. This was shown initially for acute leukemia patients undergoing HSCT from siblings or unrelated donors with both myeloablative (MAC) and non myeloablative (RIC) conditioning. MRD positivity measured by either flow cytometry or PCR (in ALL and also AML cases with suitable mutations like NPM1) and recently by next generation sequencing (NGS) correlates with high relapse rates and lower leukemia free survival and overall survival. Moreover, data are recently emerging that there is no difference in HSCT outcome between AML patients undergoing transplants while in clinical relapse versus those with positive MRD pre-transplantation. Of note in a study published lately HSCT results were better for AML patients transplanted while in CR2 with negative pre transplant MRD than in patients transplanted in CR1 but with positive MRD.

The Acute Leukaemia Working Party (ALWP) of the EBMT focused on these topics in last few years demonstrating the role of MRD for haploidentical HSCT, in patients with ALL and those with AML, patients transplanted in CR2. We also analyzed  the role of MRD in MAC versus RIC and also with or without ATG. These data show that in patients with AML < 50 y with MRD positivity pre HSCT a MAC protocol is preferable and that ATG does not increase relapse even in high risk AML with MRD positivity. As for prevention of relapse of high risk AML post HSCT the ALWP has published previously on epigenetic and prophylactic donor lymphocyte infusion (DLI) based approaches. Most importantly in a seminal contribution at ASH 2018 a randomized study investigating sorafenib versus placebo in FLT3 positive AML patients after stem cell transplantation could show a significant benefit in PFS and OS for patients treated with sorafenib. These results are in line with EBMT data published recently in Haematologica (Bazarbazi A et al) which confirms the importance of sorafenib (kinase inhibitor) administered post HSCT for prevention of relapse improving HSCT outcome in AML.

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