1. Fuerst, Mark L.

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SAN DIEGO-Rapid genetic screening could soon become an integral part of acute myeloid leukemia (AML) diagnostics. Clinicians could match each patient with the therapy best suited for his or her specific disease.


A new study demonstrates that doctors could determine which molecular subtype of AML a patient has before beginning treatment and to use this information to pick an approach that best matches the individual patient.


AML is a highly heterogeneous disease and is the most commonly diagnosed and most lethal adult leukemia. "Our hypothesis is that we can improve outcomes by matching patients to the increasing number of available targeted therapies," said lead author Amy Burd, PhD, Vice President for Research Strategy at The Leukemia & Lymphoma Society (LLS).


Burd presented the findings of the study at a press conference at the 2018 ASH Annual Meeting (Abstract 559).


Study Specifics

AML is a rapidly progressing cancer, and treatment typically starts on the day of diagnosis. Clinicians have been reluctant to wait the 2-3 weeks for results of genomic analysis. Current practice dictates that all patients receive the same treatment regimen initially without learning which AML subtype the patient has.


The LLS-led Beat AML Master trial was designed to assess whether a multi-center clinical trial could use genetic profiling to assign patients to molecularly defined, subtype-specific therapies within 7 days, and to delineate the role of new therapies in the first-line treatment of AML. The goal was to improve outcomes in older patients with AML through the use of mechanism-based novel therapies using precision medicine, Burd noted.


In recent years, there have been renewed efforts to improve the standard treatment for AML, which has not significantly advanced in about 4 decades. Many experimental new therapies target specific AML subtypes. The ability to determine a patient's AML subtype is crucial to realizing the full benefits of these therapies, she said.


"In line with FDA recommendations, we used broad eligibility criteria to capture the majority of AML patients," Burd stated. The patient inclusion criteria were:


* age 60 years or older at time of diagnosis;


* previously untreated AML with no prior treatment other than hydroxyurea;


* prior therapy for myelodysplastic syndrome, myeloproliferative disease, or aplastic anemia is permitted, but not with hypomethylating agents; and


* ability to give informed consent.



Patients were profiled using local cytogenetics and a next-generation sequencing assay with all molecular data required for treatment assignment obtained within 7 days. Therapy was assignment based on the best option for patient curability and the dominant clone on variant allele frequency analysis.


The reported findings include data from 285 patients, median age 72 years, with suspected or confirmed AML. "Can we assign patients to therapy within 7 calendar days of samples arriving at reference lab?" asked Burd. Her emphatic answer was "Yes." Virtually all (95.8%) of the patients were assigned within 7 days.


To date, 146 patients have continued on to the study's second phase, in which they were treated on a clinical trial for experimental AML therapies targeting their disease subtype. The remaining patients did not continue on to the study's second phase for a variety of reasons, including choosing standard AML therapy after molecular profiling, enrolling in a different trial, or deciding not to pursue therapy. Waiting for a few days to start therapy after receiving a diagnosis also gave patients time to make informed decisions about their therapy. "This supports a patient-centric approach," Burd explained.


The study is designed to incorporate new experimental therapies as they are developed. It began in 2016 with three treatment arms and has now grown to include 11 arms testing therapies developed by seven different pharmaceutical companies. "Treatment decision is always guided by what is best for the patient," she said.


Initial results from some of these studies suggest patients benefit from therapies specifically chosen based on their individual disease subtype. Burd provided updates of several studies. The phase Ib dose-escalation study with BI836858 plus azacitidine (Abstract 4053) has been completed and the phase II recommended dose is 80 mg. The phase II study of enasidenib in IDH2-mutant patients (Abstract 287) has been expanded. The overall response rate is 44.4 percent (12 of 27 patients). One study has been discontinued, a phase I study of samalizumab with the standard 7 + 3 regimen in core binding factor AML.


In conclusion, Burd noted: "Implementation of a rapid treatment assignment umbrella study in elderly AML is feasible with 95 percent of patients assigned to treatment in less than 7 days. Early death and disease progression prior to treatment assignment is uncommon outside of mixed-lineage leukemia rearranged AML. The majority of patients assigned to protocol therapy proceed to trial with increasing frequency as new protocols open. Promising efficacy has been observed in several of the treatment arms to date.


"I think the future of treatment for AML will include point-of-care screening to determine what type of AML the patient has and then make the treatment decision based on that information. Being able to do genetic screening rapidly and efficiently is critical to making a decision for that patient within 7 days. This study demonstrates that the precision medicine approach is feasible and effective."


Mark L. Fuerst is a contributing writer.


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