Precision medicine in acute myeloid leukaemia (AML) is feasible in terms of providing cytogenetic and mutational data within 7 days, allowing their rapid incorporation into treatment decisions without increase in early mortality or adverse impact on overall survival (OS) according to the results from the Beat AML study published on 26 October 2020 in the Nature Medicine by John C. Byrd of the Ohio State University in Columbus, OH, USA and colleagues.
AML is the most common diagnosed leukaemia. It originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Recurrent mutations seen in older adults with AML are also seen in healthy patients with age-associated clonal haematopoiesis and myelodysplastic syndromes, with the added cumulative number equating to advanced disease evolution.
Use of next-generation sequencing has led to understanding of AML pathogenesis and prognosis, allowing for the characterisation of the mutational repertoire in patients with AML and the dominant leukaemic clone.
The mutations that contribute to AML pathogenesis have distinct functional roles, including disrupted apoptosis (TP53), production of oncometabolites (IDH1, IDH2) with resultant epigenetic remodelling, oncogenic signalling (FLT3, KIT, NRAS, KRAS, PTPN11), and epigenetic dysregulation (DNMT3A, TET2, WT1, ASXL1).
Molecular data in AML have been used predominately for prognostication and treatment after induction therapy and not for initial therapeutic decisions, outside of the use of FLT3 inhibitors.
Intensive chemotherapy for AML is associated with poor outcomes in the absence of allogeneic transplant with 15% of patients aged 18–59 years and 2% of those aged at least 60 years being disease-free at 10 years. Older patients treated with hypomethylating agents are not cured and have a median survival of 6.3 months.
Conventional treatment of AML involves rapid initiation of therapy, within days, to reduce the risk of death due to disease progression. Such rapidly initiated treatment precludes the ability to consider the mutational profile for treatment decisions.
In the ongoing Beat AML study, untreated patients with AML who are at least 60 years old were prospectively enrolled. Upon providing cytogenetic and mutational data within 7 days from sample receipt, the patients were assigned to treatment based on the dominant clone. The data presented in the article represents patient enrollment between November 2016 and January 2018.
In total, 487 patients with suspected AML were enrolled from whom 395 were eligible. Median age was 72 years (range, 60–92 years), 38% was at least 75 years old. Of those, 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 days and 224 (56.7%) were enrolled on the Beat AML sub-study. The remaining 171 patients elected standard of care, investigational therapy or palliative care. Nine patients died before treatment assignment.
Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving standard of care consisted of induction with cytarabine plus daunorubicin (7 + 3 or equivalent) or hypomethylation agent.
Thirty-day mortality was less frequent and OS was significantly longer for patients enrolled on the Beat AML sub-studies versus those who received standard of care.
The authors concluded that a precision medicine therapy strategy in AML is feasible.
The study was sponsored by the Leukemia & Lymphoma Society, which holds the investigational new drug application for this study. The Leukemia & Lymphoma Society is committed to making non-confidential, non-identifiable data available to individuals or teams focused on advancing the therapeutic efforts for patients with AML and related haematological malignancies.
Funding for the study was made possible by the Harry T. Mangurian Foundation, many other donors and the sites that enabled resources for rapid turnaround for cytogenetics and other monitoring requirements of patients.
The investigational new drug and ultimate design and implementation of this study came from integral collaboration of the Leukemia & Lymphoma Society team and the US Food and Drug Administration.
Sub-studies were supported by the pharmaceutical sponsors.
This work was also supported by the US National Cancer Institute (NCI) and in part through the National Institutes of Health/NCI Cancer Center Support grant.
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. Nature Medicine; Published online 26 October 2020. DOI: https://doi.org/10.1038/s41591-020-1089-8.