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AML MRD Testing By NGS Identifies Adults At High Relapse Risk After Allogeneic Transplantation

June 16, 2022

Mid-July 2022

Measurable residual disease (MRD) testing using next-generation sequencing (NGS) in adult patients with acute myeloid leukemia (AML) in first complete remission (CR1) can predict those at highest risk of relapse after an allogeneic hematopoietic cell transplantation (alloHCT), according to the Pre-MEASURE study. Christopher S. Hourigan, DM, DPhil, of the National Institutes of Health, presented the results at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

The researchers conducted a large-scale study of 1,075 patients transplanted at one of 111 Center for International Blood and Marrow Transplant Research (CIBMTR) sites between 2013 and 2019, using independent discovery and validation cohorts, to establish the clinical utility of NGS-based AML MRD testing prior to alloHCT. To be eligible, patients must have received a first alloHCT while in CR1 from AML; have a reported mutation in FLT3, NPM1, IDH1, IDH2, and/or KIT prior to transplant; and a banked CR1 blood sample available from within 100 days prior to alloHCT. Testing of pre-alloHCT blood was conducted via ultra-deep next-generation DNA-sequencing, with a limit of detection validated down to 1/10,000 (0.01%).

A total of 296 patients (28%) relapsed within three years following alloHCT. Pre-alloHCT NGS-MRD results were positive in 319 patient blood samples (30%). On average, patients exhibited 1.28 mutations, with the most commonly detected being IDH2 (n=133), FLT3-ITD (n=111), and NPM1 (n=88). Following a prespecified analysis, the team found that detection of residual NPM1 or FLT3-ITD mutations in pre-alloHCT CR1 blood was associated with the highest risk of post-transplant relapse. Those testing positive immediately before alloHCT had increased relapse (three-month rate of 23% [16-30%] vs. 4% [3-5%] in MRDneg, p<0.001) and worse survival (three-year overall survival 36% [28-45%] vs. 66% [62-69%] in MRDneg, p<0.001) after alloHCT. In multivariable analysis, detection of pre-alloHCT NGS-MRD was the most important factor associated with post-transplant relapse (NPM1 3.0, FLT3-ITD 2.9) and survival.

Prior to Pre-MEASURE, Dr. Hourigan and colleagues had used a similar AML MRD by NGS approach on pre-alloHCT blood samples from the randomized phase III BMT-CTN 0901 trial, demonstrating worse survival for those with pre-alloHCT MRD who were randomized to reduced intensity conditioning (RIC). This new study, while larger, was not randomized and is unsuited to definitively answer that same question of the association between conditioning intensity and MRD status, Dr. Hourigan said. Despite this, he added that those patients with MRD who received non-Melphalan containing RIC in Pre-MEASURE also had the worst outcomes observed, with a three-year relapse rate of 87% (95% CI 75-100%). In comparison, Melphalan-based RIC had reduced rates of relapse (44% at three years, 95% CI 26-62%) and improved survival.

“This again reinforces the concept that AML MRD is not just ‘fate,’ but that appropriate intervention may improve clinical outcome,” Dr. Hourigan said.

According to Dr. Hourigan, this study is an essential step to make NGS-MRD testing the clinical standard of care and is just one part of a wider coordinated effort he is leading to advance AML MRD from research laboratories into clinical practice. He is co-principal investigator, together with Coleman Lindsley, MD, PhD, of Dana-Farber Cancer Institute and Jerald Radich, MD, of Fred Hutchinson Cancer Research Center, of the Foundation for the National Institutes of Health AML MRD biomarkers consortium with partners from the U.S. Food and Drug Administration and industry to develop AML MRD methods and is also co-chair of the laboratory committee of the National Cancer Institute’s Precision Medicine Initiative clinical trials portfolio, “MyeloMATCH.” Additionally, building on the results from this Pre-MEASURE study, Dr. Hourigan is the chair of an upcoming, prospective, 16-site national protocol “MEASURE” (NCT05224661) sponsored by the National Marrow Donor Program, to harmonize AML MRD testing nationally after alloHCT. 

“We are moving into a ‘get stuff done’ stage of precision medicine in hematology-oncology, including AML,” Dr. Hourigan said. “What motivates me as a physician-scientist is the idea that we can move to a point where AML MRD testing is something that is good for patients, not just papers.”

Any conflicts of interest declared by the authors can be found in the original abstract.

Reference

Hourigan CS, Dillon LW, Gui G, et al. Pre-MEASURE: multicenter evaluation of the prognostic significance of measurable residual disease testing prior to allogeneic transplantation for adult patients with AML in first remission. Abstract 7006. Presented at the 2022 ASCO Annual Meeting, June 7, 2022; Chicago, Illinois.

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