Myeloablative conditioning may improve survival for certain patients with acute myeloid leukemia
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Myeloablative conditioning prior to allogeneic hematopoietic stem cell transplantation may result in improved survival compared with reduced-intensity conditioning for patients with acute myeloid leukemia with genomic evidence of measurable residual disease, according to results of a randomized phase 3 study published in Journal of Clinical Oncology.
“AML is a cancer that is typically widely disseminated at diagnosis; however, unlike many other metastatic cancers, cytotoxic chemotherapy is often effective at achieving morphologic complete remission,” Christopher S. Hourigan, MD, DPhil, investigator in the myeloid malignancies section of the National Heart, Lung, and Blood Institute of the NIH, and colleagues wrote. “Allogeneic hematopoietic cell transplantation is a standard post-remission strategy to prevent relapse in patients with AML. This approach is suboptimally effective, however, with death as a result of AML representing the most common form of transplant treatment failure.”
Measurable residual disease (MRD) status of patients with AML in morphologic complete remission prior to allogeneic HSCT can predict post-transplantation outcomes; however, it remained unclear whether modulating the intensity of the preparative conditioning regimen for those who test positive for MRD can prevent relapse and improve survival.
Hourigan and colleagues conducted ultra-deep, error-corrected sequencing of preconditioning blood samples from 190 adults with AML in morphologic complete response who had been randomly assigned in a previous phase 3 trial to myeloablative conditioning (n = 95; median age, 54.9 years; range, 21.9-66) or reduced-intensity conditioning (n = 95; median age, 54.7 years; range, 21.9-65.9).
The researchers sequenced blood for 13 commonly mutated genes in AML. They detected no mutations in 32% of patients who received myeloablative conditioning and 37% of those who underwent reduced-intensity conditioning.
The groups had similar 3-year OS rates (56% vs. 63%). However, among patients with a detectable mutation, those assigned reduced intensity vs. myeloablative conditioning had a higher 3-year cumulative incidence of relapse (67% vs. 19%; P < .001) and inferior 3-year OS (43% vs. 61%; P = .02).
Multivariable analysis of next-generation sequencing-positive patients, adjusted for disease risk and donor group, showed significant associations between reduced-intensity conditioning and increased relapse (HR = 6.38; 95% CI, 3.37-12.1), decreased RFS (HR = 2.94; 95% CI, 1.84-4.69) and decreased OS (HR = 1.97; 95% CI, 1.17-3.30) compared with myeloablative conditioning.
Models of AML MRD also showed benefits of myeloablative conditioning vs. reduced-intensity conditioning among those with detectable mutations.
“Future studies should confirm the hypothesis that reduced-intensity conditioning remains a reasonable approach in AML, even in those eligible for myeloablative conditioning, when no genomic evidence of residual disease is detected,” Hourigan and colleagues wrote. “It is conceivable that future work with broader sequencing, at the same depth, could better identify those for whom reduced-intensity conditioning is the preferable approach. Larger data sets may also allow determination of what type and level of residual leukemic clones are susceptible to which conditioning intensity and lead to a better understanding of the impact of allogeneic immune effects in relapse prevention.” – by John DeRosier
Disclosures: Hourigan reports research funding to his institution from Merck Sharp & Dohme and Sellas Life Sciences. Please see the study for all other authors’ relevant financial disclosures.
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