Precision medicine treatment in acute myeloid leukemia using prospective genomic profiling: feasibility and preliminary efficacy of the Beat AML Master Trial

Amy Burd, Ross L Levine, Amy S Ruppert, Alice S Mims, Uma Borate, Eytan M Stein, Prapti Patel, Maria R Baer, Wendy Stock, Michael Deininger, William Blum, Gary Schiller, Rebecca Olin, Mark Litzow, James Foran, Tara L Lin, Brian Ball, Michael Boyiadzis, Elie Traer, Olatoyosi Odenike, Martha Arellano, Alison Walker, Vu H Duong, Tibor Kovacsovics, Robert Collins, Abigail B Shoben, Nyla A Heerema, Matthew C Foster, Jo-Anne Vergilio, Tim Brennan, Christine Vietz, Eric Severson, Molly Miller, Leonard Rosenberg, Sonja Marcus, Ashley Yocum, Timothy Chen, Mona Stefanos, Brian Druker, John C Byrd, Amy Burd, Ross L Levine, Amy S Ruppert, Alice S Mims, Uma Borate, Eytan M Stein, Prapti Patel, Maria R Baer, Wendy Stock, Michael Deininger, William Blum, Gary Schiller, Rebecca Olin, Mark Litzow, James Foran, Tara L Lin, Brian Ball, Michael Boyiadzis, Elie Traer, Olatoyosi Odenike, Martha Arellano, Alison Walker, Vu H Duong, Tibor Kovacsovics, Robert Collins, Abigail B Shoben, Nyla A Heerema, Matthew C Foster, Jo-Anne Vergilio, Tim Brennan, Christine Vietz, Eric Severson, Molly Miller, Leonard Rosenberg, Sonja Marcus, Ashley Yocum, Timothy Chen, Mona Stefanos, Brian Druker, John C Byrd

Abstract

Acute myeloid leukemia (AML) is the most common diagnosed leukemia. In older adults, AML confers an adverse outcome1,2. AML originates from a dominant mutation, then acquires collaborative transformative mutations leading to myeloid transformation and clinical/biological heterogeneity. Currently, AML treatment is initiated rapidly, precluding the ability to consider the mutational profile of a patient's leukemia for treatment decisions. Untreated patients with AML ≥ 60 years were prospectively enrolled on the ongoing Beat AML trial (ClinicalTrials.gov NCT03013998 ), which aims to provide cytogenetic and mutational data within 7 days (d) from sample receipt and before treatment selection, followed by treatment assignment to a sub-study based on the dominant clone. A total of 487 patients with suspected AML were enrolled; 395 were eligible. Median age was 72 years (range 60-92 years; 38% ≥75 years); 374 patients (94.7%) had genetic and cytogenetic analysis completed within 7 d and were centrally assigned to a Beat AML sub-study; 224 (56.7%) were enrolled on a Beat AML sub-study. The remaining 171 patients elected standard of care (SOC) (103), investigational therapy (28) or palliative care (40); 9 died before treatment assignment. Demographic, laboratory and molecular characteristics were not significantly different between patients on the Beat AML sub-studies and those receiving SOC (induction with cytarabine + daunorubicin (7 + 3 or equivalent) or hypomethylation agent). Thirty-day mortality was less frequent and overall survival was significantly longer for patients enrolled on the Beat AML sub-studies versus those who elected SOC. A precision medicine therapy strategy in AML is feasible within 7 d, allowing patients and physicians to rapidly incorporate genomic data into treatment decisions without increasing early death or adversely impacting overall survival.

Figures

Fig. 1 ∣. Overview of the Beat…
Fig. 1 ∣. Overview of the Beat AML trial.
a, AML prioritization by genomic or cytogenetic abnormality into groups. b, Patient distribution following enrollment on the Beat AML trial. c, Genomic assignment of eligible patients with AML by prioritization group. The asterisk denotes the hypermethylation group, which is defined by the TET2/WT1 mutations.
Fig. 2 ∣. Comutation oncoprint of eligible…
Fig. 2 ∣. Comutation oncoprint of eligible Beat AML trial patients.
Genes with genomic alterations (short variants and insertions/deletions) are listed in descending order of frequency and each column represents an individual patient. Red indicates that the alteration was present at an allele frequency of ≥30% and blue

Fig. 3 ∣. Overall survival estimates.

a…

Fig. 3 ∣. Overall survival estimates.

a , All eligible patients on the Beat AML…
Fig. 3 ∣. Overall survival estimates.
a, All eligible patients on the Beat AML trial. b, By treatment received including assigned Beat AML therapy, SOC (standard therapy), palliative care and alternative investigational therapy. Overall survival estimates were calculated with the Kaplan–Meier method and presented with 95% CIs constructed using the complementary log-log transformation. If a value could not be calculated, not evaluated is indicated. The 2 patients who did not consent to a Beat AML sub-study with unknown treatment were combined with the 38 patients who elected palliative care.
Fig. 3 ∣. Overall survival estimates.
Fig. 3 ∣. Overall survival estimates.
a, All eligible patients on the Beat AML trial. b, By treatment received including assigned Beat AML therapy, SOC (standard therapy), palliative care and alternative investigational therapy. Overall survival estimates were calculated with the Kaplan–Meier method and presented with 95% CIs constructed using the complementary log-log transformation. If a value could not be calculated, not evaluated is indicated. The 2 patients who did not consent to a Beat AML sub-study with unknown treatment were combined with the 38 patients who elected palliative care.

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