Test Then Erase? Current Status and Future Opportunities for Measurable Residual Disease Testing in Acute Myeloid Leukemia

Measurable residual disease (MRD) in adults with acute myeloid leukemia (AML) in complete remission is an important prognostic marker, but detection methodology requires optimization. Persistence of mutated NPM1 or FLT3-ITD in the blood of adult patients with AML in first complete remission (CR1) prior to allogeneic hematopoietic cell transplant (alloHCT) associates with increased relapse and death after transplant. The prognostic implications of persistence of other common AML-associated mutations, such as IDH1, at this treatment landmark however remain incompletely defined. We performed testing for residual IDH1 variants (IDH1m) in pre-transplant CR1 blood of 148 adult patients undergoing alloHCT for IDH1-mutated AML at a CIBMTR reporting site between 2013 and 2019. No statistically significant post-transplant differences were observed between those testing IDH1m positive (n = 53, 36%) and negative pre-transplant (overall survival (OS): p = 0.4; relapse: p = 0.5). For patients with IDH1 mutated AML co-mutated with NPM1 and/or FLT3-ITD, only detection of persistent mutated NPM1 and/or FLT3-ITD was associated with significantly higher rates of relapse (p = 0.01). These data, from the largest study to date, do not support the detection of IDH1 mutation in CR1 blood prior to alloHCT as evidence of AML MRD for increased post-transplant relapse risk.

Measurable residual mutated IDH1 before allogeneic transplant for acute myeloid leukemia

Gui,

Ravindra,

Hegde

et al. 2024

Measurable residual mutated IDH2 before allogeneic transplant for acute myeloid leukemia

Gui,

Ravindra,

Hegde

et al. 2024

Routine genetic profiling of acute myeloid leukemia (AML) at initial diagnosis has allowed subgroup specific prognostication, drug development, and clinical management strategies. The optimal approach for treatment response assessment for AML subgroups has not yet however been determined. A nationwide cohort of 257 adult patients in first remission (CR1) from AML associated with an IDH2 mutation (IDH2m) undergoing allogeneic transplant during the period 2013–2019 in the United States had rates of relapse and survival three years after transplantation of 24% and 71%, respectively. Pre-transplant clinical flow cytometry assessment was not useful in stratifying patients based on risk of post-transplant relapse or death. DNA-sequencing was performed on CR1 blood collected within 100 days before transplant. Persistent detection of IDH2m was common (51%) and associated with increased relapse and death compared to testing negative. Co-mutation at initial diagnosis with mutated NPM1 and/or FLT3-ITD was common in this cohort (41%) and use of these validated MRD markers provided superior stratification compared to IDH2m testing. Patients testing negative for IDH2m prior to transplant had low relapse-related death, regardless of conditioning intensity. Post-transplant relapse rates for those with persistently detectable IDH2m in pre-transplant remission were lower after the FDA approval of enasidenib in August 2017.

Measurable residual disease testing and allogeneic hematopoietic cell transplantation for AML: adapting Pre-MEASURE to clinical practice

Shaffer,

Kebriaei,

de Lima

et al. 2024

Measurable residual disease (MRD) testing in patients with acute myelogenous leukemia (AML) represents a heterogenous assessment process designed to quantify leukemia-specific biomarkers that are not ascertainable by routine pathologic evaluation. The most common tools used to assess MRD are multiparameter flow cytometry (MPFC), and polymerase chain reaction (PCR) based tools, including quantitative or digital droplet PCR (qPCR, ddPCR), or next-generation sequencing (NGS) technologies. Collectively, MRD assessments have become an important clinical tool in the management of patients with AML. Despite progress, significant questions remain with respect to the appropriate timing, frequency, and methodology of MRD assessment, and whether or how to adapt therapy based on MRD results. Recent data from the Pre-MEASURE study, a retrospective cohort analysis of error corrected NGS based MRD assessment prior to allogeneic hematopoietic cell transplantation (alloHCT) in patients with AML, provides additional key information with respect to the emerging role of NGS-based technology in MRD assessment. In the context of this review, we evaluate the Pre-MEASURE study as well as other recent, high-quality assessments of MRD in AML. Our focus is to provide a practical assessment of the use of emerging MRD technologies in patients with AML with an emphasis on the role of peri-transplant MRD for the practicing clinician.