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Which are the most promising targets for minimal residual disease-directed therapy
in acute myeloid leukemia prior to allogeneic stem cell transplant?
Ferrata Storti Foundation
Haematologica 2019 Volume 104(8):1521-1531
Brian Ball and Eytan M. Stein
Memorial Sloan Kettering Cancer Center, New York, NY, USA
ABSTRACT
Minimal residual disease has emerged as an important prognostic factor for relapse and survival in acute myeloid leukemia. Eradication of minimal residual disease may increase the number of patients with long-term survival; however, to date, strategies that specif- ically target minimal residual disease are limited. Consensus guidelines on minimal residual disease detection by immunophenotypic and molecular methods are an essential initial step for clinical trials evaluating minimal residual disease. Here, we review promising targets of minimal residual dis- ease prior to allogeneic stem cell transplantation. Specifically, the focus of this review is on the rationale and clinical development of therapies target- ing: oncogenic driver mutations, apoptosis, methylation, and leukemic immune targets. We review the progress made in the clinical development of therapies against each target and the challenges that lie ahead.
Introduction
For over 45 years, standard therapy for fit patients with newly diagnosed acute myeloid leukemia (AML) has been induction chemotherapy with cytarabine and an anthracycline.1 Despite most patients achieving morphological remission with intensive chemotherapy, the prognosis for long-term survival in AML remains poor. Advances in multiparameter flow cytometry and molecular testing, including real-time quantitative polymerase chain reaction, digital polymerase chain reaction and next-generation sequencing, have enabled detection of minimal or measurable residual disease (MRD) far below a threshold of 5% blasts required for morpholog- ical remission.2 Among patients receiving induction chemotherapy, complete remission (CR) with persistent MRD occurs in a substantial 40% of patients.3 Mounting evidence has shown that the presence of MRD detectable prior to mye- loablative allogeneic stem cell transplantation (SCT) is associated with shorter sur- vival and increased risk of relapse that is similar to the risk in patients with active disease.4-7
Eradication of MRD prior to allogeneic SCT has the potential to increase long- term survival in AML. However, few studies have reported on the outcomes of patients converting from MRD-positive to MRD-negative disease after treatment with consolidation therapies. In the HOVON/SAKK AML 42A study, post-remis- sion treatment with either chemotherapy, autologous or allogeneic SCT led to a change from MRD-positive to MRD-negative status in 7/21 (33%) patients.8 In the GIMEMA study, late MRD clearance (induction positive, consolidation negative MRD status) was observed in 15/134 (11%) patients and was associated with sim- ilar rates of 5-year overall survival and relapse-free survival as those of patients with early MRD clearance (induction negative, consolidation negative MRD sta- tus). MRD status after consolidation was the only factor independently associated with both a shorter duration of relapse-free survival and overall survival in multi- variate analaysis, suggesting a more favorable outcome from MRD conversion after post-remission chemotherapy.9 Given the modest rates of MRD conversion with consolidation chemotherapy, more effective therapies capable of eradicating MRD prior to transplantation are urgently needed.
As a reservoir for relapse, MRD would ideally be targeted by therapies that
Correspondence:
EYTAN M. STEIN
steine@mskcc.org
Received: April 15, 2019. Accepted: July 1, 2019.
doi:10.3324/haematol.2018.208587
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/8/1521
©2019 Ferrata Storti Foundation
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