Improved MRD Detection Methods Aid in Posttransplant AML

AML cells | Image Credit: © LASZLO - www.stock.adobe.com

Predicting relapse after allogeneic stem cell transplant (alloHCT) for acute myeloid leukemia (AML) in first complete remission (CR1) may be limited by measurable residual disease (MRD) detection methods used in the pretransplant setting. Relapse occurs in approximately 30% of these patients and is the leading cause of posttransplant death. MRD detection prior to alloHCT is a strong predictor of relapse; however, many patients testing negative for MRD by currently used methods will still experience relapse. Adaptation of improved methods of MRD detection are needed to better define this population at risk. Current practice-changing efforts are underway in the Laboratory of Myeloid Malignancies at the National Institutes of Health (NIH) led by Dr Christopher Hourigan to establish molecular MRD testing as the future standard and to build robust evidence supporting the transformation of MRD test positivity into an actionable event. A major goal is to validate AML MRD biomarkers that can then be integrated in therapeutic clinical trials to guide decision-making. Laura Dillon, PhD, FACMG, lead scientist in Dr Hourigan’s laboratory, will address these issues in the upcoming ”Update on Molecular Monitoring in AML” presentation on Wednesday, September 6, 2023, at 8 am.

Heterogeneity of AML

The inherent heterogeneity of AML, with multiple clones harboring different cytogenetic and molecular compositions, poses a challenge for unified MRD assessment. The current European LeukemiaNet (ELN) MRD guidelines from 2021 recommend MRD assessment using multiparameter flow cytometry (MFC-MRD) using a baseline sample to establish the individual leukemia-associated immunophenotype when able, and otherwise using a different-from-normal approach.¹ The benefit of MFC-MRD is the ability to use this in the majority of AML subtypes, with cost of relatively low sensitivity (1/1000 events) and lack of standardization with lab variability. In those with validated molecular markers [NPM1, t(8;21), inv(16), t(15;17)] quantitative polymerase chain reaction is recommended with greater sensitivity (1/100,000 events). Current MRD testing is not centralized or standardized, leading to inconsistent results and possibly inconsistent prognostication. MRD assessment is used in combination with baseline disease characteristics/ELN risk stratification to gauge individual patient prognoses. With several recent novel drug approvals, prognostication of disease using current ELN risk stratification has also been challenged as the majority of these patients were treated with prior approaches. With the advent of venetoclax (Venclexta), targeted agents for FLT3- and IDH1/2-mutated AML, and the current development of menin-inhibitors for NPM1-mutated or KMT2A-rearranged AML, we anticipate updates to the ELN risk stratification in those treated with less intensive or targeted therapies, as well as paired biomarker MRD detection assays. Deeper genomic MRD detection methods in various subgroups of disease, along with different treatment approaches, will likely shape future prognostic models.

The recent Pre-MEASURE retrospective observational study demonstrated the ability of ultra-deep next-generation DNA-sequencing (NGS) MRD testing (with sensitivity of 1/10,000) to predict those at highest risk for relapse after alloHCT for AML in CR1.² This study evaluated 1075 pretransplant peripheral blood samples of patients transplanted at 111 Center of International Blood and Marrow Transplantation Research (CIBMTR) sites with reported mutations in FLT3, NPM1, IDH1, IDH2, or KIT. Pretransplant residual detection of NPM1 and/or FLT3-ITD [internal tandem duplication] in both the discovery and validation cohorts were associated with higher rates of relapse at 3 years (68% vs 21%; HR, 4.32; P < .001) and decreased survival at 3 years (39% vs 63%; HR, 2.43; P < .001).

Christopher S. Hourigan, DM DPhil, and colleagues have shown in the BMT CTN 0901 study (NCT01339910), which evaluated ultra-deep NGS MRD testing for commonly mutated genes in 190 pretransplant blood samples of patients with AML in CR prior to being randomly assigned to either reduced intensity conditioning (RIC) or myeloablative conditioning (MAC).³ This study showed higher relapse rates and lower survival in those with pretransplant molecular MRD who received RIC rather than MAC. Survival of those with molecular MRD receiving MAC, and those without molecular MRD receiving MAC or RIC, were the same. This exemplifies one way in which we can currently intervene on MRD with preferential use of MAC when feasible.

“Work from our group and others from the past few years has demonstrated the potential for translating MRD in AML from the literature to clinically actionable information to improve outcomes for patients,” Dillon said. “In order to move the field forward, large-scale collaborative efforts for AML MRD assay harmonization and well-designed randomized clinical trials are needed.”

Subsequently, Hourigan designed the ongoing prospective multicenter national prospective MEASURE study (NCT05224661), sponsored by the Center for International Blood and Marrow Transplant Research, which is currently recruiting at 18 major transplant centers across the United States. Diagnostic samples are obtained for genomic sequencing, and subsequent pre- and posttransplant samples will be evaluated for MRD with molecular detection methods. Additionally, Hourigan is co-lead on the Foundation for the National Institutes of Health AML MRD Biomarkers Consortium, a public-private partnership aimed at validating new methods of molecular MRD detection in AML. Data from both of these initiatives could be practice changing.

_References

_{1. Heuser M, Freeman SD, Ossenkoppele GJ, et al. 2021 Update on MRD in acute myeloid leukemia: a consensus document from the European LeukemiaNet MRD Working Party. Blood. 2021;138(26):2753-2767. doi:10.1182/blood.2021013626}

_{2. Dillon LW, Gui G, Page KM, et al. DNA sequencing to detect residual disease in adults with acute myeloid leukemia prior to hematopoietic cell transplant. JAMA. 2023;329(9):745-755. doi:10.1001/jama.2023.1363}

_{3. Hourigan CS, Dillon LW, Gui G, et al. Impact of conditioning intensity of allogeneic transplantation for acute myeloid leukemia with genomic evidence of residual disease. J Clin Oncol. 2020;38(12):1273-1283. doi:10.1200/JCO.19.03011.}