Genetic alterations at diagnosis predict transplant outcomes for older patients with AML
ORLANDO — Genetic alterations at diagnosis predicted OS and leukemia-free survival for older individuals with acute myeloid leukemia who underwent allogeneic hematopoietic stem cell transplantation in first remission, according to study results presented at ASH Annual Meeting and Exposition.
Researchers created an integrated genetic and clinical model that identified distinct risk groups within this population
“Our data suggest patients classified as very high risk would perhaps benefit from strategies aimed at mitigating their high rate of relapse, either through conditioning intensity or novel maintenance strategies,” H. Moses Murdock, research fellow at Dana-Farber Cancer Institute and student at Perelman School of Medicine at University of Pennsylvania, said during a presentation. “Conversely, even in a cohort in which a majority of patients received reduced-intensity conditioning, patients we classified as low risk have very low rates of relapse and would benefit from approaches aimed at minimizing therapy-related toxicity.”
Older patients with AML often have a high prevalence of genomically poor-risk disease, often reflective of antecedent myelodysplastic syndrome. Allogeneic HSCT is a potentially curative treatment for AML; however, older age is associated with poorer outcomes.
Murdock and colleagues assembled a retrospective cohort of adults aged 60 years or older who underwent transplantation in first complete remission and examined how the genomics of AML at the time of diagnosis affected outcomes. Patients with acute promyelocytic leukemia or isolated extramedullary disease were excluded.
The cohort included 300 patients (median age, 66 years; range, 60-76; 59.3% men) from six institutions. About 41% of patients had Hematopoietic Cell Transplantation-specific Comorbidity Index scores of 3 or higher.
Nearly one-third of patients (30.3%) had secondary AML, and 40% of those patients received prior therapy with hypomethylating agents.
Per 2017 European LeukemiaNet criteria, 28.7% of patients had intermediate risk and 50.6% had adverse risk. Most patients (85%) received intensive induction chemotherapy.
Half (49.3%) of patients received transplant from matched unrelated donors, whereas 10.3% had unmatched unrelated donors, 18% had matched related donors and 2% had unmatched related donors. About one in five patients (19.7%) had alternative donors.
Two-thirds (65.7%) of patients received reduced-intensity conditioning, and only 9.3% of patients received myeloablative conditioning.
More than three-quarters (78%) of patients achieved complete remission with hematologic recovery, whereas 22% achieved complete remission with incomplete hematologic recovery.
Researchers reported median leukemia-free survival of 2.8 years, with median follow-up for survivors of 3.75 years.
Relapse was the primary mode of failure after transplantation. At 3 years, researchers reported a 36% cumulative incidence of relapse and a 23% cumulative incidence of nonrelapse mortality.
To link genetics to transplant outcomes, researchers performed targeted sequencing of 112 genes from diagnostic leukemia samples. They identified approximately 1,200 mutations in 63 genes.
Nearly all patients (96%) had at least one mutation. Eleven percent had TP53 mutations, 43% had secondary-type mutations in genes associated with prior myelodysplastic syndrome and 22% had NPM1 mutations. More than half of patients with NPM1 mutations had FLT3-internal tandem duplications.
Six percent of patients had DDX41 mutations. These are associated with germline predisposition to myeloid malignancies with long latency, Murdock said.
Murdock and colleagues used univariable and multivariable Cox models to evaluate the impact of gene mutations on leukemia-free survival, and they developed a hierarchical model of three molecular genetic risk groups.
They characterized patients with TP53 mutations, JAK2 mutations or FLT3-internal tandem duplication in the absence of NPM1 mutations as high risk.
Patients who had DNMT3A, DDX41 or NP1 mutations in the absence of FLT3-internal tandem duplication were characterized as intermediate risk.
All other patients were considered low risk.
Based on the molecular model, rates of 3-year leukemia-free survival were 8% in the high-risk group, 47% in the intermediate-risk group and 65% in the low-risk group (P < .001).
Researchers then performed multivariable analysis of clinical variables that affect posttransplant analysis. They identified two clinical variables — complete remission with hematologic recovery vs. complete remission with incomplete hematologic recovery, as well as adverse karyotype status — that were significant and integrated them into their risk model.
Using the integrated risk model, they reported 3-year leukemia-free survival rates of 5% for patients with very high risk (accounting for 16.4% of cohort, 29% for those with high risk (31.5% of cohort), 51% for those with intermediate risk (26.8% of cohort) and 70% for those with low risk (25.2% of cohort).
Nearly 80% of patients in the very high-risk group relapsed, and that was the primary contributor to poor outcomes in that group, Murdock said. In the other groups, outcomes were a composite of relapse and nonrelapse mortality.
“We show that an integrated genetic and clinical model is able to identify distinct risk groups among older adults undergoing allogeneic transplantation in first remission,” Murdock said. “The fact that remission quality was associated with outcome suggests that assessment of measurable residual disease may aid in guiding clinical management. Our work suggests ... that prospective clinical trials should perhaps consider genetic risk as we work to improve outcomes in this patient population.” – by Mark LeiserReference: Murdock HM, et al. Abstract 48. Presented at: ASH Annual Meeting and Exposition; Dec. 7-10, 2019; Orlando.
Disclosure: Murdock reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.