Is it time to use minimal residual disease to stratify post-remission treatment for acute myeloid leukemia?

During the past several decades, the therapeutic approach to acute myeloid leukemia (AML) has evolved with the incorporation of cytogenetic and molecular aberrations to classify AML into favorable, intermediate and poor risk categories. This has facilitated post-remission treatment stratification including the use of allogeneic hematopoietic cell transplantation (allo-SCT) in first complete remission (CR1) [1]. At the same time, the definition of remission in AML has evolved from a purely morphology definition ( 5% blasts in the bone marrow with adequate counts recovery) to include cytogenetic and molecular complete remission [2]. The use of minimal residual disease (MRD) monitoring has facilitated the definition of molecular remissions and has refined prognostication in both chronic myeloid leukemia (CML) and, more recently, in acute lymphoblastic leukemia (ALL). The presence of MRD at pre-defined time points during therapy for ALL has been the strongest predictor for relapse or poor outcome, thereby guiding the recommendations for intensified post-remission therapies including treatment with allo-SCT (reviewed in Schrappe [3]). The clinical utility of MRD in AML is still evolving due to the heterogeneity of AML and the greater complexity of MRD assessment. In acute promyelocytic leukemia (APL), it has been clearly demonstrated that achievement of molecular remission in the bone marrow, using sensitive quantitative RT-PCR (qRTPCR) to detect PML-RARA transcripts, is a pre-requisite for long-term disease-free survival (DFS); thus, MRD monitoring has been adapted by all of the major APL treatment guidelines [4]. Similar to PML-RARA in APL, leukemia-specific fusion transcripts resulting from recurrent translocations can also be used in a limited number of other AML sub-sets, including the core binding factor (CBF) leukemia: the runtrelated transcription factor 1/runt-related transcription factor 1 translocated to 1 (RUNX1/RUNX1T1) transcripts in AML with t(8;21) and core-binding factor sub-unit beta–myosin heavy chain 11 (CBFB-MYH11) in inv (16) AML. In addition, qRT-PCR for the NPM1 mutation in normal karyotype AML has also been used for MRD monitoring. Other methods of MRD detection and monitoring in AML including multiparameter flow cytometry (MPFC) targeting a panel of leukemia associated immune-phenotypes [5] and qRT-PCR of the Wilms’ Tumor (WT1) gene [6] are being investigated but are not the focus of this commentary. Recently, MRD monitoring in AML has provided new insights on therapeutic choices, including post-remission risk-adapted therapy for patients with ‘good risk’ AML. In NPM1 mutated AML, Schnittger et al. [7] first demonstrated retrospectively that NPM1 level during treatment was the most relevant prognostic factor. Using qRT-PCR, a NPM1 level of  0.01% (%NPM1/ABL1) during first-line treatment and  0.1% undergoing second-line chemotherapy or alloSCT significantly predicted event-free survival. The predictive value of NPM1 MRD was subsequently confirmed in retrospective studies from the German–Austrian Acute Myeloid Leukemia Study Group [8] and the Study Alliance Leukemia (SAL) [9]. The clinical value of MRD monitoring in CBF AML initially was prospectively assessed in 278 patients (163 with t(8;21) and 115 cases with inv (16)) enrolled in the UK MRC AML 15 trial [10]. At remission, after course 1 of induction chemotherapy, a  3 log reduction in RUNX1-RUNX1T1 transcripts in bone marrow (BM) of t(8;21) patients and a  10 CBFB-MYH11 copy number in peripheral blood (PB) of inv (16) patients were the most useful prognostic variables for relapse. During follow-up, MRD cut-off thresholds in BM of  500 copies, in peripheral blood (PB) of  100 copies for t(8;21) patients and in BM of  50 copies and in PB of  10 copies for inv (16) patients, was associated with a 100% relapse rate. These results were confirmed in a prospective study from the French AML Intergroup [11], in which achievement of more than 3-log MRD reduction or absolute MRD level  0.1% (fusion gene/ABL1  100) before a second high dose consolidation, was the sole prognostic