Search

Olutasidenib, a potent, selective, oral, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML). Here we report efficacy and safety of olutasidenib in 18 patients with m IDH1 AML who were relapsed (10), refractory (6) or had complete remission with incomplete hematologic recovery (CRi; 2) to a venetoclax combination. Of the 16 patients who were R/R, 4 (25%) achieved complete remission (CR), one (6.3%) achieved CR with partial hematologic recovery (CRh), and 7 (43.8%) achieved a composite complete remission (CRc). Median time to CRc was 1.9 months (range 1-2.8). As of data cutoff (18 June 2021), median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ months). Both patients with CRi at study entry achieved a CR. Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with m IDH1 AML previously treated with venetoclax.

Hematopoiesis is hierarchical, and it has been postulated that acute myeloid leukemia (AML) is organized similarly with leukemia stem cells (LSCs) residing at the apex. Limited cells acquired by fluorescence activated cell sorting in tandem with targeted amplicon-based sequencing (LC-FACSeq) enables identification of mutations in small subpopulations of cells, such as LSCs. Leveraging this, we studied clonal compositions of immunophenotypically-defined compartments in AML through genomic and functional analyses at diagnosis, remission and relapse in 88 AML patients. Mutations involving DNA methylation pathways, transcription factors and spliceosomal machinery did not differ across compartments, while signaling pathway mutations were less frequent in putative LSCs. We also provide insights into TP53-mutated AML by demonstrating stepwise acquisition of mutations beginning from the preleukemic hematopoietic stem cell stage. In 10 analyzed cases, acquisition of additional mutations and del(17p) led to genetic and functional heterogeneity within the LSC pool with subclones harboring varying degrees of clonogenic potential. Finally, we use LC-FACSeq to track clonal evolution in serial samples, which can also be a powerful tool to direct targeted therapy against measurable residual disease. Therefore, studying clinically significant small subpopulations of cells can improve our understanding of AML biology and offers advantages over bulk sequencing to monitor the evolution of disease., (© 2021. The Author(s).)

Background: 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. 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., Methods: We 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., Results: Our 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%., Conclusions: By 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).

The European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) have become an important tool to assess patients' prognosis and guide treatment. We tested the prognostic impact of the 2017 ELN classification in a large cohort of 863 AML patients aged <60 years similarly treated on Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology studies. Based on multivariable models within each ELN genetic-risk group, we identified additional gene mutations that may refine the 2017 ELN risk classification. BCOR- or SETBP1-mutated favorable-risk patients with non-core-binding factor AML and IDH-mutated adverse-risk patients had intermediate-risk outcomes. Outcomes of NPM1/WT1 co-mutated patients and those of ZRSR2-mutated patients resembled outcome of adverse-risk patients. Moreover, FLT3-ITD high allelic ratio conferred adverse rather than intermediate-risk irrespective of the NPM1 mutation status, and DNMT3A mutations associated with very poor survival. Application of these refinements reclassified 9% of current favorable-risk patients and 53% of current intermediate-risk patients to the adverse-risk group, with similar poor survival as current adverse-risk patients. Furthermore, 4% of current favorable-risk patients and 9% of adverse-risk patients were reclassified to the intermediate-risk group.

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.

Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839., (© 2020 by The American Society of Hematology.)

Targeted mutation assessment of 81 genes in 1021 adults with de novo acute myeloid leukemia (AML) identified recurrent mutations in the neurofibromin 1 (NF1) gene in 52 (5.1%) patients, including 36 (5.2%) younger and 16 (4.8%) older patients, which suggests NF1 belongs to the 20 most frequently mutated genes in adult AML. NF1 mutations were found throughout the gene, and comprised missense, frameshift, and nonsense mutations. One mutation hotspot, at amino acid threonine 676 (Thr676), was found in 27% of AML patients with NF1 mutations. NF1-mutated patients belonged more often to the adverse European LeukemiaNet (ELN) risk category than NF1 wild-type patients. Among patients aged <60 years, the presence of NF1 Thr676 mutations was associated with lower complete remission (CR) rates (P = 0.04) and shorter overall survival (OS; P = 0.01), as was the presence of any NF1 mutation in patients in the adverse ELN risk category (CR, P = 0.05; OS, P < 0.001). CR rates were also lower in NF1-mutated patients aged ≥60 years compared with NF1 wild-type patients (P = 0.001). In summary, our findings provide novel insights into the frequency of NF1 mutations in AML, and are suggestive of an adverse prognostic impact in patients treated with standard chemotherapy.

Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENA monotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML. This trial is registered at www.clinicaltrials.gov as #NCT03013998.

Next-generation sequencing (NGS) to identify pathogenic mutations is an integral part of acute myeloid leukemia (AML) therapeutic decision-making. The concordance in identifying pathogenic mutations among different NGS platforms at different diagnostic laboratories has been studied in solid tumors but not in myeloid malignancies to date. To determine this interlaboratory concordance, we collected a total of 194 AML bone marrow or peripheral blood samples from newly diagnosed patients with AML enrolled in the Beat AML Master Trial (BAMT) at 2 academic institutions. We analyzed the diagnostic samples from patients with AML for the detection of pathogenic myeloid mutations in 8 genes (DNMT3A, FLT3, IDH1, IDH2, NPM1, TET2, TP53, and WT1) locally using the Hematologic Neoplasm Mutation Panel (50-gene myeloid indication filter) (site 1) or the GeneTrails Comprehensive Heme Panel (site 2) at the 2 institutions and compared them with the central results from the diagnostic laboratory for the BAMT, Foundation Medicine, Inc. The overall percent agreement was over 95% each in all 8 genes, with almost perfect agreement (κ > 0.906) in all but WT1, which had substantial agreement (κ = 0.848) when controlling for site. The minimal discrepancies were due to reporting variants of unknown significance (VUS) for the WT1 and TP53 genes. These results indicate that the various NGS methods used to analyze samples from patients with AML enrolled in the BAMT show high concordance, a reassuring finding given the wide use of NGS for therapeutic decision-making in AML.

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.