Minimal residual disease–directed therapy in acute myeloid leukemia

Abstract

Case 1: A 35-year-old man with a normal white blood cell (WBC) count (9.3 3 10 9 /L) was diagnosed with acute myeloid leukemia (AML) with a t(8;21)(q22;q22) translocation in 25/25 metaphases. The RUNX1-RUNX1T1 fusion gene was detected by real-time quantitative polymerase chain reaction (PCR), whereas studies for mutations involving KIT and FLT3 were negative. After 1 cycle of induction therapy with cytarabine/idarubicin according to the "713" schema, he achieved a morphologic complete remission (CR) with a 2-log reduction of RUNX1-RUNX1T1 transcript levels. The patient has an excellent performance status and no comorbidities. Should you recommend allogeneic hematopoietic cell transplantation (HCT)?Case 2: A 43-year-old woman was diagnosed with cytogenetically normal AML; molecular studies for gene mutations involving NPM1, CEBPA, and FLT3 were negative. After standard induction chemotherapy, she achieved a morphologic CR and then underwent 1 cycle of consolidation therapy with high-dose cytarabine. During the pre-HCT work-up in anticipation of matched related donor transplant, she is found to have evidence of minimal residual disease (MRD) by multiparameter flow cytometry (MFC); no prior MFC studies are available. She has no comorbidities other than arterial hypertension, and her performance status is excellent. Are you recommending additional cycle(s) of chemotherapy to attempt MRD eradication before HCT? IntroductionIn recent years, several methods have been developed to detect submicroscopic MRD in AML patients in morphologic remission.1-4 The existence of small numbers of leukemic cells among normal hematopoietic cells can be identified based on numeric or structural chromosomal changes, gene mutations, antigen receptor rearrangements, abnormal gene expression, altered cell growth, and immunophenotypic abnormalities. Thus far, most exploited for MRD detection and quantification in AML are MFC-and PCR-based approaches, which can achieve sensitivities up to 10 25 to 10 26. 1-5 MFC has gained popularity for the detection of MRD in AML because it can be applied to the vast majority of AML patients, although the identification of immunophenotypic abnormalities can be challenging, especially if a diagnostic specimen is not available or the disease has evolved over time. PCR-based approaches are typically limited to specific patient subsets, but recent methodologic advances (eg, based on next generation sequencing or digital PCR) allow leukemia-associated mutations to be tracked more comprehensively, thereby broadening the scope of molecular MRD detection (defined in this study as the detection of chimeric fusion genes, somatic mutations, or aberrant gene expression).For several reasons, including variations in health care provision and laboratory infrastructures between countries and, perhaps, the fluidity with which MRD detection methodologies are evolving, implementation of standardized MRD assessments into clinical practice has remained a major challenge. Nevertheless, increasing evidence indicates that the pre...

Characterization of children with FLT3-ITD acute myeloid leukemia: a report from the AIEOP AML-2002 study group

“…MRD, largely used in acute lymphoblastic leukemia and acute promyelocytic leukemia, 27,28 is gaining popularity also in AML 29 , and its monitoring is mainly based on MFC, 30 given the lack of large studies on molecular MRD measurements. 31 FLT3-ITD is one of the most common genetic alterations in childhood AML and has been reported to be associated with poor prognosis 13,14,17,32,33 . Even recently, FLT3-ITD AML patients showed just a slight improvement in outcome notwithstanding the more intensive chemotherapy adopted in different international protocols.…”

Universal monitoring of minimal residual disease in acute myeloid leukemia

“…Therefore, measuring MRD levels at key points during chemotherapy can steer decisions about intensity of subsequent chemotherapy and eligibility for allogeneic hematopoietic stem cell transplantation (1,57). Moreover, MRD is likely to become increasingly used as eligibility and response criteria in clinical trials of new anti-AML agents.…”

Maintenance therapy in acute myeloid leukemia: an evidence-based review of randomized trials

“…An unanswered question, particularly important in the post-HCT setting, is related to accurate identification of patients who are at high risk for relapse and would more likely benefit from maintenance. MRD testing before and/or after transplant may add to the discriminatory power of patient-, disease-, and transplant-related characteristics as predictors of relapse 81,82 and perhaps have an impact on maintenance therapy.…”