AML Hub Symposium | How does MRD impact outcome of stem cell transplantation in AML – now and in the future?

At the 46^th Annual Meeting of the European Society for Blood and Marrow Transplantation the AML Hub will hold a virtual Satellite Symposium (August 30, 2020, 8:30 A.M., Auditorium 1) on the impact of measurable residual disease (MRD) on stem cell transplantation (SCT) outcome in patients with acute myeloid leukemia (AML). During this Satellite Symposium, five international experts, Gert Ossenkoppele, Jacqueline Cloos, Christian Thiede, Adriano Venditti, and Charles Craddock, will discuss the latest developments and remaining challenges of MRD assessments in the context of SCT. Here we present an introductory overview of the theme which will be explored in more depth at the Satellite Symposium.

With intensive chemotherapy, most patients with AML will be able to achieve a morphologic complete remission (mCR). However, the challenge is to keep those patients in remission, as without further treatment relapse occurs in the majority of them. Growing evidence suggests that MRD, defined as the presence of residual leukemic cells in bone marrow or peripheral blood in patients who achieved mCR, is a predictor of relapse and outcome.¹ Determination of MRD is increasingly used to identify patients at high risk of relapse at an early time point and guide treatment decisions accordingly.^1,2

Despite its advantages, adoption of MRD assessments in standard clinical practice has been slow so far, partly due to a lack of standards regarding the use of various techniques, the source of cells and the best time-points for assessment, among others. In order to encourage the use of MRD and make it more accessible for clinical practice, the European LeukemiaNet (ELN) Working Party has recently provided guidelines to standardize approaches for MRD assessments in AML.³

The most commonly used methods to detect MRD are multiparameter flow cytometry (MPFC) and real-time quantitative polymerase chain reaction (PCR; qPCR). Two other methods are emerging: digital PCR and next-generation sequencing.³ Each methodology has its advantages and disadvantages and needs to be standardized, validated, and improved to be used to guide clinical decision making.

Regarding the time-points for MPFC-based MRD assessment, the ELN recommends to assess before treatment and after consolidation therapy, but not much is known about the optimal time-points during follow-up.³ Many studies have demonstrated that MPFC-based MRD assessment has a prognostic value, with MRD-negativity associated with better outcomes.^4-7 However, this technique is considered less sensitive compared to molecular techniques.

MRD assessment in the context of SCT

Evidence is accumulating that the presence of MRD assessed by MPFC immediately prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a predictor of post-transplant outcomes in AML.³ Patients who are MRD-negative before transplant both in the ablative and non-myeloablative setting perform much better than those who are MRD-positive.⁸ Patients who are MRD-positive prior to allo-HSCT show higher relapse incidences and shorter survival, irrespective of the intensity of conditioning regimens or the used MRD marker.^9-13

However, results from the GIMEMA AML1310 trial (NCT01452646) showed that in patients with intermediate-risk AML, who were MRD-positive before transplant, allo-HSCT improved OS and disease-free survival (DFS) to comparable levels of patients in the “favorable-risk" group. These data demonstrated that despite the adverse prognostic effect shown for pre-allo-HSCT MRD-positive patients, allo-HSCT can improve outcomes.

Another study, the RELAZA2 trial (NCT01462578), tested the clinical benefit of MRD-guided treatment after allo-HSCT in patients with AML and myelodysplastic syndromes. In this trial, patients in CR after allo-HSCT who developed MRD-positive disease received pre-emptive azacitidine treatment. This intervention prevented overt morphological relapses in about half of the MRD-positive patients and delayed relapse in the other half. These findings demonstrate that MRD-guided treatment with a hypomethylating agent could be an effective strategy to prevent or delay relapse in patients with MRD-positive AML.

Conclusions

In recent years, a growing interest in MRD determination is raising and this is not surprising, since MRD assessments may help to inform prognosis and treatment decisions. A large number of published studies have shown that patients with MRD-positive AML are at higher risk of relapse and experience shorter OS compared to MRD-negative patients. Latest data from clinical studies provide exciting prospects for the use of MRD in a more personalized approach to allo-HSCT in patients with AML.