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Minimal residual disease predicts relapse, mortality in standard-risk AML
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The presence of minimal residual disease, determined by quantification of NPM1-mutated transcripts, predicted increased risk for relapse and mortality among patients with standard-risk acute myeloid leukemia, according to research published in The New England Journal of Medicine.
“Although AML is genetically less complex than many other tumors, the condition is molecularly heterogeneous,” David Grimwade, MD, PhD, professor of molecular hematology at King’s College London, and colleagues from the U.K. National Cancer Research Institute AML Working Group wrote. “Despite improved understanding of the mutational landscape, treatment, decisions, particularly regarding allogeneic stem cell transplantation, remain guided by cytogenetic markers, and morphology-based assessment of remission.”
A predicted relapse risk of greater than 35% is widely considered to warrant hematopoietic stem cell transplantation (HSCT) during first remission, according to study background. However, it is uncertain whether patients with cytogenetically standard-risk AML — which affects nearly half of young adult patients — should undergo HSCT. The most common molecular lesion that occurs in this cohort is the NPM1 mutation.
Thus, Grimwade and colleagues sought to detect a leukemia-specific marker that could be used to identify submicroscopic disease during remission.
The researchers had access to 2,569 follow-up samples from 346 patients with NPM1-mutated AML (median age, 50 years; range, 6-68) enrolled in the AML17 trial conducted by the National Cancer Research Institute. The researchers used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease (MRD) in these samples, 902 of which were derived from bone marrow and 1,667 from peripheral blood. Further, they used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at diagnosis, along with 49 samples obtained at relapse.
Overall, researchers observed higher rates of MRD in bone marrow than peripheral blood samples. Still, a significantly greater proportion of patients with persistent NPM1-mutated transcripts in the peripheral blood after regeneration following the second cycle of chemotherapy — which accounted for 15% of patients — experienced relapse at 3 years (82% vs. 30%; HR = 4.8; 95% CI, 2.95-7.8), and significantly fewer achieved 3-year OS (24% vs. 75%; HR = 4.38; 95% CI, 2.57-7.47).
To assess whether MRD in the peripheral blood was an independent prognostic factor, researchers conducted univariate and multivariate analyses that included the results of sequencing analyses, which identified 161 unique genetic subgroups of patients.
Results of univariate analyses showed increased white cell count, DNMT3A and FLT3-internal tandem duplication mutations, and MRD in the peripheral blood increased risk for relapse, whereas only increased white cell count and MRD increased risk for mortality.
In multivariate analyses, MRD was the only independent prognostic factor for relapse (HR = 5.09; 95% CI, 2.84-9.13) and death (HR = 4.84; 95% CI, 2.57-9.15).
The researchers validated these findings in an independent cohort of 91 patients with NPM1 mutations. Results showed that MRD in the peripheral blood after the second chemotherapy cycle increased incidence of relapse (70% vs. 31%; P = .001) and lowered the rate of OS (40% vs. 87%; P = .001) at 2 years.
Twenty-one of 46 patients (46%) with MRD and 61 of 239 patients (26%) without MRD underwent HSCT (P = .006). However, results of a Mantel–Byar analysis showed no significant effect of transplantation among patients according to MRD status.
“Although we did not find a significant benefit of transplantation in patients with minimal residual disease, the number of patients in the analysis was small, since only one third of the patients underwent transplantation after a minimal-residual-disease sample was obtained following the second chemotherapy cycle,” Grimwade and colleagues wrote. “The question of whether outcomes might be improved by more rapid deployment of transplantation is being studied in the ongoing NCRI AML19 trial.”
The researchers then conducted sequential monitoring of samples from 243 patients in the development cohort who completed consolidation treatment. A rising NPM1-mutated transcript level predicted the occurrence of hematologic relapse among 53 patients in morphologic remission (median increment, 0.7 log10 per month; range, 0.3-2).
Further, although mutations associated with preleukemic clones remained detectable during remission after chemotherapy, NPM1 mutations were detected in nearly all patients (n = 69 of 70) during relapse, serving as a marker of disease status.
“Although it is recognized that the most informative sample source (peripheral blood or bone marrow) and time points may vary according to treatment protocol, these data lend support to a broadening of the scope of detection of minimal residual disease to assess response and to identify a group of patients with a poor prognosis who may be candidates for transplantation or new therapies,” Grimwade and colleagues concluded.
These data raise questions that should be addressed with additional research, Michael J. Burke, MD, a pediatric oncologist at Medical College of Wisconsin and Children’s Hospital of Wisconsin, wrote in an accompanying editorial.
“Will the addition of the assessment of minimal residual disease to risk stratification achieve better outcomes in adults with AML?” Burke wrote. “On the basis of this assessment, can we reassign treatment and thereby reduce the risk of relapse among patients who are not classified as being either at high risk or low risk? Time will tell, but this moment may prove to be a pivotal one in the assessment of minimal residual disease to assign treatment in patients with AML.” – by Cameron Kelsall
Disclosure: Grimwade reports grant support from Leukemia & Lymphoma Research, the National Institute for Health Research, and the Guy's & St. Thomas' Charity during the conduct of the study. Please see the full study for a list of all other researchers’ relevant financial disclosures. Burke reports no relevant financial disclosures.
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