Initial Report of the Beat AML Umbrella Study for Previously Untreated AML: Evidence of Feasibility and Early Success in Molecularly Driven Phase 1 and 2 Studies

A multitude of somatic genomic alterations contribute to the pathogenesis of acute myeloid leukemia (AML). Despite these important biologic insights, current therapeutic approaches to AML remain limited, particularly in adults ≥ 60. The Leukemia & Lymphoma Society (LLS)-led Beat AML trial was designed to assess whether a multi-center clinical trial could use genetic profiling to assign patients (pts) to molecularly defined, subtype-specific therapies within 7 days, and to delineate the role of new therapies in the first-line treatment of AML, with the goal of improving outcomes in older pts with AML through the use of mechanism based novel therapies.

Pt eligibility included age ≥ 60 years with non-APML AML, no CNS leukemia, no prior hypomethylating agent (HMA) therapy and no clinical need for emergent therapy. Eligible pts were profiled using local cytogenetics and next generation sequencing (NGS) assay (Foundation Medicine, Inc.) with all molecular data required for treatment assignment (TA) obtained ≤ 7 days. TA was made centrally using a prioritization schema incorporating cytogenetics [t(8;21], inv(16), MLL rearrangement, complex karyotype ≥ 3 abn) and somatic mutations present in a dominant AML clone with a variant allele frequency (VAF) >0.3. If no cytogenetic abnormality or mutation with VAF ≥ 0.3 was observed, VAF ≥ 0.2 was used for TA. The trial opened with 3 arms but currently has 11 treatment arms with 7 novel agents (NA) shown in Table 1. Treatment among different arms include either NA followed by combination of NA + HMA if no response, upfront combination of NA + HMA, or NA + intensive chemotherapy for select groups. Current treatment prioritization and TA based upon enrollment are shown in Table 2.

Enrollment began November 2016 with a data cut off of April 30, 2018. At data cutoff, 268 pts have enrolled with a median age of 72 years (range: 60 to 92) and 38% being ≥ 75 years; 43% were female; median WBC was 4.8 x 10⁹/L (range: 0.5 to 194.1) and WBC > 50 x 10⁹/L in 9.3%; median Hgb was 8.4 g/dL (range: 3.9 to 15); median platelet count was 61 x 10⁹/L (range: 7 to 649). Of the 268 patients, 210 had AML with TA. 53 pts were ineligible for enrollment, most commonly due to an alternative diagnosis, and 5 pts have a treatment decision pending. All pts had cytogenetic results available by 7 days. We achieved TA within 7 days in 106 of the 109 (97.2%) pts in the feasibility phase, and 200/210 (95.2%) of the overall cohort, meeting feasibility requirements. Of the 10 pts with delayed treatment assignment, 1 pt had suboptimal specimen quality whereas 9 pts had delayed TA due to technical (7/10) or instrumentation failure (2/10). All pts had cytogenetics available by 7 days. TA is shown in Table 2. These data confirm the feasibility of a precision medicine TA trial in newly diagnosed pts with AML.

The Beat AML trial is dynamic by design, with different arms opening over time and all trial arms designed to detect for substantive clinical efficacy. As shown in Figure 1, of the 210 eligible AML pts enrolled, 7 pts (3.3%) died during the first 7 days prior to TA, 12 pts (5.7%) received alternative treatments prior to TA and 81 pts (38.6%) received an alternative treatment after TA. At time of analysis, weekly safety calls assessed that 23 pts went on an alternative clinical trial deemed better for them than Beat AML, and 40 pts received other standard-of-care therapies, 13 pts received palliative care and 5 pts were not specified. Special events of interest (disease worsening or progression) were assessed in 19 (9.0%) of pts. Of those going onto treatment, 110 pts (52.4%) received treatment on one of the Beat AML sub-studies. At time of abstract submission, one sub-study had completed phase 2 enrollment with positive results using monotherapy as measured by CR/CRi attainment (Study S3 with enasidenib +/- HMA: 43% CR/Cri rate) and is currently in expansion to further assess efficacy of this NA in newly diagnosed AML. Three additional studies have completed phase 1b dose escalation for combined NA + HMA therapy. An update including overall (for all enrolled pts) survival, sub-study-specific survival, and survival of patients receiving alternative treatment will be presented. Our data support the feasibility of a rapid precision medicine approach in older pts with previously untreated AML. The Beat AML trial is a model for dynamic, mechanism- based clinical trials in blood cancers where genomic analysis may inform, accelerate, and improve drug development.

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