DNA sequencing could identify patients with AML at high risk for relapse after HSCT
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Key takeaways:
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Patients with AML in first remission before transplant who had certain persistent mutations appeared to have a greater risk for relapse and death.
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The results show the importance of testing prior to transplant.
Data derived from Dillon LW, et al. JAMA. 2023;doi:10.1001/jama.2023.1363.
Persistent FLT3-internal tandem duplication or NPM1 variants in the blood of patients with acute myeloid leukemia in first remission before transplant appeared associated with higher risk for relapse and death, according to a study in JAMA.
“Our hypothesis ... was confirmed in both a discovery and an independent validation cohort,” Christopher S. Hourigan, MD, DPhil, senior investigator of myeloid malignancies at National Heart, Lung, and Blood Institute, told Healio. “It shows there is hope that this high-risk [measurable residual disease] can be treated and, also, how powerful it is to be able to use highly sensitive tests to more accurately estimate residual tumor burden in patients in clinical remission. This sets the stage for a precision medicine approach for patients with AML undergoing transplant.”
Background and methodology
Genomic analysis at the time of AML diagnosis can help provide patients and clinicians with a variety of useful information, such as expected response to therapy, eligibility for specific molecularly targeted therapy and risk for subsequent relapse after initial complete remission.
Although initial remission maintenance for patients with AML is the most common indication for allogeneic hematopoietic stem cell transplantation, approximately 30% of patients experience disease recurrence after transplant, which is the most common cause of posttransplant death among this patient population.
The presence of measurable residual disease has been associated with higher relapse rates, however, testing has not been standardized.
In the current study, researchers sought to determine whether DNA sequencing used to identify residual variants in the blood of adults with AML in first remission before allogeneic HSCT could identify patients at an increased risk for relapse and shorter OS vs. those without such DNA variants.
Researchers performed DNA sequencing on pretransplant blood of 1,075 patients aged 18 years or older with AML associated with FLT3, NPM1, IDH1, IDH2 or KIT variants who had undergone their first allogeneic transplant during first remission.
OS and relapse served as the primary outcomes.
Results
Among the total tested population, 822 patients (median age, 57.1 years; 54% women) had the two most common AML variants, FLT3-ITD- and/or NPM1, detectable at initial diagnosis. Moreover, 142 still had residual traces of these mutations following therapy even though they had been classified as in remission.
Among 371 patients in the discovery cohort, 64 (17.3%) in remission prior to transplant with persistent NPM1 and/or FLT3-ITD variants had worse outcomes following transplant between 2013 and 2017.
Of the 451 patients in the validation cohort who underwent transplant in 2018 or 2019, 78 (17.3%) with residual NPM1 and/or FLT3-ITD had higher rates of relapse at 3 years (68% vs. 21%; HR = 4.32; 95% CI, 2.98-6.26) and decreased survival at 3 years (39% vs. 63%; HR = 2.43; 95% CI, 1.71-3.45) than those who did not have persistent variants.
Next steps
Further studies are needed to confirm observations in this initial trial; however, a personalized approach to treatment of this patient population could prove beneficial if done throughout the span of the treatment, according to researchers.
“A follow-on prospective clinical protocol named MEASURE has already opened and will enroll adult patients with AML in remission undergoing transplant at one of 17 major sites nationwide,” Hourigan told Healio. “This will validate the findings of the Pre-MEASURE study prospectively, determine if serial posttransplant monitoring can improve the performance of AML [next-generation sequencing]-MRD testing, and provide an evidence-based foundation for future multicenter clinical trials within the MEASURE network testing novel interventions to improve outcomes for these patients.”
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Dillon LW, et al. JAMA. 2023;doi:10.1001/jama.2023.1363.
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