Possible Role for Comprehensive Molecular ProfilingBased Treatment Selection in Newly Diagnosed AML, Study Suggests – Cancer Therapy Advisor

The feasibility of a precision medicinebased approach was demonstrated for patients with newly diagnosed acute myeloid leukemia (AML), according to findings from a phase 1/2 clinical trial reported in Nature Medicine.

The current standard of care for the treatment of patients diagnosed with AML involves prompt initiation of intensive induction chemotherapy, such as 7 days of standard-dose cytarabine and 3 days of daunorubicin, or administration of a hypomethylating agent for those deemed unable to tolerate standard induction therapy, to prevent rapid progression of disease in this predominantly older patient population.

Hence, time for comprehensive molecular characterization of the disease is not built into typical treatment protocols for patients with newly diagnosed AML. However, long-term outcomes of patients with newly diagnosed AML treated with intensive chemotherapy without autologous hematopoietic stem cell transplantation have been shown to be poor, and hypomethylating agents are not a curative approach in the setting of AML.

This nonrandomized, open-label, multicenter, umbrella protocol study sponsored by the Leukemia & Lymphoma Society (BEAT AML Master Trial; ClinicalTrials.gov Identifier: NCT03013998) enrolled adult patients with suspected AML prior to the administration of frontline treatment.

During a 7-day period prior to treatment assignment, bone marrow biopsy specimens of eligible patients were subjected to cytogenetic analysis, comprehensive molecular profiling using next-generation sequencing, and a FLT3-ITD ratio testing. On the basis of these results, patients with a dominant AML clone characterized by an actionable alteration were assigned to 1 of multiple molecularly defined substudy treatment arms, whereas those without evidence of such an alteration were assigned to the marker-negative subgroup.

In describing the purpose of this study, the investigators stated that they collaboratively implemented a new prospective clinical trial approach aimed at facilitating frontline treatment assignments to specific genomic-defined AML subtypes.

Of the 395 eligible patients, approximately 95% were assigned to treatment within 7 days of bone marrow biopsy collection. Of note, only 26 of these patients exhibited evidence of rapid disease progression necessitating initiation of therapy during the 7-day testing window.

The most common mutational drivers identified were DNMT3A (22.7%), TET2 (19.6%), TP53 (19.1%), ASXL1 (19.1%) and SRSF2 (18.4%).

Regarding molecularly based treatment assignment, the study authors commented that these data show that there were few co-occurring dominant mutations that could have been used for an alternative therapeutic assignment.

Only 224 (56.7%) of patients agreed to receive treatment according to their assigned BEAT AML substudy treatment arm, with 103, 28, and 38 patients selecting standard-of-care treatment, alternative investigational therapy, and palliative care, respectively.

Patients were encouraged to select an alternative therapy (alternative investigational therapy, [standard of care] or palliative care) if the patient with their health-care providers deemed this a better option, the study investigators noted.

A key finding from this study was the 30-day mortality of patients starting at initial study enrollment was 3.7% for patients enrolled on the BEAT AML trial protocol and 20.4% for those who choose to receive standard-of-care therapy.

Furthermore, rates of 1-year overall survival were 54.7%, 27.6%, 11%, and 57.4% for patients treated on the BEAT AML protocol, or with standard-of-care therapy, palliative care, and alternative investigational therapy, respectively.

However, the study investigators noted that while our study demonstrates the feasibility of precise molecular treatment assignment in older adults with AML, it does not clearly differentiate the benefit of treatment assignment based on a molecular target from better outcome that occurs simply from enrolling on a clinical trial.

They also emphasized that this approach requires a detailed team-coordinated effort by investigators, patients and caregivers, genomic laboratories, cytogenetic laboratories and a central treatment assignment team.

In their concluding remarks, the researchers commented that randomization of specific large genomic groups to targeted therapy versus [standard of care] or, in less common genomic groups, comparison of treatment with targeted therapy to either real-world data or synthetic controls, will be required to determine the comparative effectiveness of a precision medicine-based approach vs standard-of-care therapy in patients with newly diagnosed AML.

Reference

Burd A, Levine RL, Ruppert AS, et al. Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial. Nat Med. Published online October 26, 2020. doi:10.1038/s41591-020-1089-8

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Possible Role for Comprehensive Molecular ProfilingBased Treatment Selection in Newly Diagnosed AML, Study Suggests - Cancer Therapy Advisor

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