Abstract
BackgroundOlder patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome. Beat AML is a Leukemia and Lymphoma Society-sponsored, multicenter umbrella study that algorithmically segregates AML patients based upon cytogenetic and dominant molecular abnormalities (variant allele frequencies (VAF) ≥ 0.2) into different cohorts to select for targeted therapies. During the conception of the Beat AML design, a historical dataset was needed to help in the design of the genomic algorithm for patient assignment and serve as the basis for the statistical design of individual genomic treatment substudies for the Beat AML study.MethodsWe classified 563 newly diagnosed older AML patients treated with standard intensive chemotherapy on trials conducted by Cancer and Leukemia Group B based on the same genomic algorithm and assessed clinical outcomes.ResultsOur classification identified core-binding factor and NPM1-mutated/FLT3-ITD-negative groups as having the best outcomes, with 30-day early death (ED) rates of 0 and 20%, respectively, and median overall survival (OS) of > 1 year and 3-year OS rates of ≥ 20%. All other genomic groups had ED rates of 17–42%, median OS ≤ 1 year and 3-year OS rates of ≤ 15%.ConclusionsBy classifying patients through this genomic algorithm, outcomes were poor and not unexpected from a non-algorithmic, non-dominant VAF approach. The exception is 30-day ED rate typically is not available for intensive induction for individual genomic groups and therefore difficult to compare outcomes with targeted therapeutics. This Alliance data supported the use of this algorithm for patient assignment at the initiation of the Beat AML study. This outcome data was also used for statistical design for Beat AML substudies for individual genomic groups to determine goals for improvement from intensive induction and hopefully lead to more rapid approval of new therapies.Trial registration ClinicalTrials.gov Identifiers: NCT00048958 (CALGB 8461), NCT00900224 (CALGB 20202), NCT00003190 (CALGB 9720), NCT00085124 (CALGB 10201), NCT00742625 (CALGB 10502), NCT01420926 (CALGB 11002), NCT00039377 (CALGB 10801), and NCT01253070 (CALGB 11001).
Highlights
Older patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome
There were 75 (13%) patients assigned to the core-binding factor (CBF) group, 107 (19%) to the NPM1m/FLT3ITD‒ group, 13 (2%) to the KMT2A group, 59 (10%) to the IDH2 mutated (IDH2m) group, 35 (6%) to the IDH1 mutated (IDH1m) group, 50 (9%) to the TP53 mutated (TP53m) group, 28 (5%) to the complex karyotype/TP53 Wild-type (TP53wt) group, 99 (18%) to the FLT3-ITD or FLT3-TKD (FLT3m) group, and 42 (7%) to the TET2 Mutated (TET2m) or WT1 Mutated (WT1m) group
Cytogenetic and molecular genetic characteristics of patients classified into genetic groups Baseline clinical characteristics among groups were similar with the following exceptions: (1) CBF and NPM1m/FLT3-ITD—patients had almost an equal maleto-female ratios whereas other groups had predominance of male patients; (2) platelet counts were highest in the IDH1m group; (3) the white blood cell counts were highest in the FLT3m, KMT2A and NPM1m/FLT3-ITD— groups; and (4) percentage of bone marrow (BM) blasts were highest in the KMT2A, IDH1m, and the FLT3m groups (Table 3)
Summary
Older patients (≥ 60 years) with acute myeloid leukemia (AML) often have multiple, sequentially acquired, somatic mutations that drive leukemogenesis and are associated with poor outcome. Acute myeloid leukemia (AML) is not a single entity but a multitude of diseases that differ with regard to pretreatment genetic features including cytogenetics and gene mutations [1,2,3] Despite this disease heterogeneity, initial AML treatment approaches have been essentially the same for the past forty years, with patients either receiving intensive induction approaches (i.e., 7 + 3) or palliative treatment including hypomethylating agents (HMA), subcutaneous cytarabine, supportive care, or hospice care. Venetoclax, glasdegib, ivosidenib, and liposomal daunorubicin/cytarabine are approved by the Food and Drug Administration for certain older patient populations or for patients with comorbidities that prevent them from tolerating intensive induction therapy These treatments lead to improved outcomes, including increased complete remission (CR) rates, diseasefree survival (DFS), and overall survival (OS) for some AML patient populations, currently none of these therapies are considered curative unless the patients are able to undergo allogeneic stem cell transplantation in initial CR. Vasu et al showed that a 10-year DFS rate of older AML patients treated with intensive induction who were not able to receive allogeneic transplantation in first CR was 2.4% [18]
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