Pollyea, Daniel Aaron

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. 1 The NCCN Guidelines Panel for AML convenes annually to update recommendations for the diagnosis and treatment of AML in adults. These recommendations are based on a review of recently published clinical trials that have led to significant improvements in treatment or have yielded new information regarding biologic factors that may have prognostic importance. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding the monitoring and management of measurable (minimal) residual disease.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

Abstract Despite much of the past 2 years being engulfed by the devastating consequences of the SAR‐CoV‐2 pandemic, significant progress, even breathtaking, occurred in the field of chronic myeloid malignancies. Some of this was show‐cased at the 15th Post‐American Society of Hematology (ASH) and the 25th John Goldman workshops on myeloproliferative neoplasms (MPN) held on 9th‐10th December 2020 and 7th‐10th October 2021, respectively. The inaugural Post‐ASH MPN workshop was set out in 2006 by John Goldman (deceased) and Tariq Mughal to answer emerging translational hematology and therapeutics of patients with these malignancies. Rather than present a resume of the discussions, this perspective focuses on some of the pivotal translational hematology and therapeutic insights in these diseases.

Abstract BACKGROUND: Recurrent isocitrate dehydrogenase (IDH) 1 mutations are observed in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), a potent, selective, oral, small-molecule inhibitor of the mutant IDH1 (mIDH1) protein, is a promising therapeutic candidate for the treatment of patients with mIDH1 AML. Through inhibition of mIDH1, ivosidenib suppresses the abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from the first-in-human phase 1 study of ivosidenib in patients with mIDH1 advanced hematologic malignancies including relapsed/refractory (R/R) AML (NCT02074839). This is the first report of data from the 4 expansion cohorts, with a total of 258 patients treated on study. METHODS: The ongoing phase 1 study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib in mIDH1 hematologic malignancies. Enrollment was completed on May 8, 2017. During dose escalation, patients received ivosidenib as a single agent orally once daily (QD) or twice daily (BID) in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the recommended dose to be tested in 4 expansion cohorts: R/R AML (Arms 1 and 4, where Arm 1 patients are those with relapse after transplantation, second or later relapse, resistance to initial induction or reinduction treatment, or relapse within 1 year of initial treatment, and Arm 4 patients have R/R AML but are not eligible for Arm 1); untreated AML (Arm 2); and other advanced hematologic malignancies including myelodysplastic syndrome (MDS) (Arm 3). Updated safety data will be presented for all patients. Efficacy outcomes will be presented for all R/R AML patients treated at 500 mg QD across the dose escalation and expansion cohorts who received their first dose of ivosidenib at least 6 months prior to the analysis cut-off date of May 12, 2017, as well as for the poorest prognosis Arm 1 subset. Efficacy data for all treated patients from the other expansion cohorts (untreated AML and other advanced hematologic malignancies including MDS) will also be presented. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) were treated with ivosidenib. As of May 12, 2017, 62 of 258 (24%) patients were continuing on treatment. The median duration of exposure to ivosidenib was 3.5 months (range 0.1-33.5). Twenty-two (8.5%) patients discontinued treatment to proceed to allogeneic stem cell transplantation. Treatment was well tolerated; the most common adverse events (AEs) (n=258) of any grade irrespective of causality occurring in ≥20% of patients were diarrhea (33%), leukocytosis (30%), nausea (30%), fatigue (29%), febrile neutropenia (25%), dyspnea (24%), anemia (23%), QT prolongation (23%), peripheral edema (22%), pyrexia (21%), and decreased appetite (20%). The majority of these AEs were grades 1-2 and reported as unrelated to treatment. Differentiation syndrome (DS) was observed in 29 of 258 (11.2%) patients, including grade ≥3 DS in 14 (5.4%); study drug was held owing to DS in 11 patients (4.3%), and no instances of DS led to permanent treatment discontinuation or death. The primary efficacy endpoint for R/R AML is the CR+CRh rate, i.e., the rate of complete remission (CR according to modified IWG 2003 criteria plus CR with partial hematologic recovery, defined as CR except absolute neutrophil count >0.5 × 109/L [500/µL] and platelet count >50 × 109/L [50,000/µL]). Among 125 Arm 1 R/R AML patients receiving ivosidenib 500 mg QD across dose escalation and expansion who received their first dose at least 6 months prior to the analysis cutoff date, the CR+CRh rate was 30.4% (95% CI 22.5%, 39.3%), including CR in 27 (21.6%) and CRh in 11 (8.8%) patients. Median duration of CR+CRh was 8.2 months (95% CI 5.5, 12.0), and duration of CR was 9.3 months (95% CI 5.6, 18.3). The overall response rate (CR+CRi/CRp+PR+MLFS) was 41.6% (95% CI 32.9%, 50.8%) (52/125 patients). CONCLUSION: Ivosidenib monotherapy is well tolerated in patients with mIDH1 AML and other advanced hematologic malignancies. In a high-risk, molecularly defined R/R AML patient population with unmet medical need, ivosidenib induced durable remissions and improved patient outcomes. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 AML. Disclosures DiNardo: Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. De Botton: Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Servier: Honoraria; Agios: Honoraria, Research Funding. Stein: GSK: Other: Advisory Board, Research Funding; Constellation Pharma: Research Funding; Seattle Genetics: Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Pfizer: Consultancy, Other: Travel expenses; Novartis: Consultancy, Research Funding. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Mims: Novartis: Honoraria. Pollyea: Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding. Altman: Syros: Consultancy; NCCN: Other: Educational speaker; BMS: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Ceplene: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy; ASH: Other: Educational speaker. Collins: Celgene Corporation: Research Funding; Agios: Research Funding; Arog: Research Funding; BMS: Research Funding. Mannis: Curis: Honoraria; Juno: Research Funding; Agios: Research Funding; Amgen: Honoraria. Uy: GlycoMimetics: Consultancy; Novartis: Consultancy, Other: Travel Suppport; Boehringer Ingelheim: Consultancy. Fathi: Juno: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Erba: Celgene: Consultancy, Other: Chair, Scientific Steering Committee , Speakers Bureau; Incyte: all research support paid to University of Alabama, Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Daiichi Sankyo: Consultancy, Other: all research support paid to University of Alabama, Research Funding; ImmunoGen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; MacroGen: Consultancy; Ono: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Sunesis: Consultancy; Millennium/Takeda: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Agios: Other: all research support paid to University of Alabama, Research Funding; Juno: Other: all research support paid to University of Alabama, Research Funding; Astellas: Other: all research support paid to University of Alabama, Research Funding; Celator: Other: all research support paid to University of Alabama, Research Funding; Janssen: Other: all research support paid to University of Alabama, Research Funding; Glycomimetics: Other: Chair, Data and Safety Monitoring Committee. Traer: ImmunoGen: Consultancy; Tolero: Consultancy; Notable Labs: Equity Ownership. Stuart: Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Consultancy, Honoraria; Agios: Research Funding; Celator/Jazz: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bayer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; ONO: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; MedImmune: Research Funding; Cantex: Research Funding; Astellas: Research Funding. Arellano: Cephalon Oncology: Research Funding. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees. Yen: Agios: Employment, Equity Ownership. Kapsalis: Agios: Employment, Equity Ownership. Liu: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Goldwasser: Agios: Employment, Equity Ownership. Agresta: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Attar: Agios: Employment, Equity Ownership. Stone: Novartis: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Fuji Film: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Pfizer: Consultancy; Arog: Consultancy; Ono: Consultancy; Agios: Consultancy; Sumitomo: Consultancy. Kantarjian: ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Novartis: Research Funding.

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

Abstract INTRODUCTION Recurrent somatic mutations in the metabolic enzymes isocitrate dehydrogenase 1 and 2 (IDH1/2) confer gain-of-function activity in cancer cells, resulting in accumulation of the oncometabolite, D-2-hydroxyglutarate (2-HG). High levels of 2-HG result in epigenetic changes and impaired cellular differentiation. IDH mutations have been identified in multiple solid tumors and hematologic malignancies. Approximately 6-10% and 9-13% of adults with acute myeloid leukemia (AML) carry mutations in IDH1 (mIDH1) or IDH2 (mIDH2), respectively. AG-120 is a first-in-class, oral, potent, reversible, selective inhibitor of the IDH1 mutant enzyme under evaluation in multiple ongoing single agent and combination clinical trials [NCT02074839, NCT02073994, NCT02632708, NCT02677922]. This is the first report of IDH1 mutation clearance assessed by variant allele frequency (VAF) analysis using next-generation sequencing (NGS) in patients treated on the dose escalation portion of the first-in-human phase 1 study [NCT02074839]. METHODS Patients with advanced mIDH1-positive hematologic malignancies received AG-120 as a single agent orally once daily (QD) or twice daily (BID) continuously in 28-day cycles. Primary objectives were determination of safety, maximum tolerated dose (MTD), and selection of a dose schedule for expansion cohorts and future studies. Secondary objectives included clinical activity assessed by investigators using modified 2003 International Working Group Criteria in AML. Determination of mIDH1 VAF was performed using the FoundationOne® Heme test on mononuclear cells from the bone marrow or peripheral blood at screening and subsequent time points on study. This NGS assay reports IDH1 mutations for samples with VAF ≥1%, with median coverage 500X. Patients with IDH1 mutational clearance (IDH1-MC) were defined as having mIDH1 at baseline and at least one on-study sample with no reported mIDH1. RESULTS Seventy-eight patients were treated in the dose escalation portion, which is now closed to enrollment. As of the data cut-off of May 12, 2016, the median duration on treatment was 3.2 months and 9 (11.5%) patients remain on treatment, with an additional 8 (10.3%) patients transitioned to stem cell transplant. Doses ranged from 300-1200 mg QD with 1 cohort at 100 mg BID. Though the MTD was not reached, the recommended phase 2 dose was determined to be 500 mg QD. The majority of adverse events (AEs) were grade 1 and 2, the most common (≥30%) being diarrhea, fatigue, and nausea; the most common grade ≥3 AEs (≥15%) were febrile neutropenia, anemia, leukocytosis and pneumonia. The most common serious AEs were febrile neutropenia (16.7%) and pneumonia (12.8%). The overall response rate (ORR) was 38.5% (n=30), with 17.9% (n=14) achieving a complete remission (CR). Longitudinal mIDH1 VAF data were available for 51 patients; of these, 22% (n=11) achieved a CR. IDH1-MC was observed in 27.3% (3/11) patients who achieved CR (Figure 1). In contrast, only 1/40 patients who did not achieve CR experienced IDH1-MC. This occurred in a patient with an initially low mIDH1 VAF who had clinical progression despite IDH1-MC (Figure 1, bottom right). In all 3 patients with CR who achieved IDH1-MC, an initial increase in mIDH1 VAF, or early peak, was observed prior to IDH1-MC, suggesting that early clonal expansion might have occurred as part of the mechanism of action of AG-120. CONCLUSION This is the first demonstration that treatment with single agent AG-120 can result in mIDH1 clearance as determined by NGS. Further analysis of the mutational profiles is planned. AG-120, a potent, selective, oral inhibitor of mIDH1 continues to demonstrate a well-tolerated safety profile in patients with advanced hematologic malignancies, and induced objective single-agent durable responses. The data continue to support the efficacy and safety of single agent AG-120 and provide evidence that the underlying biology of the disease is altered by treatment. Figure 1. VAF analysis using FoundationOne® Heme NGS assay in 4 AML patients with IDH1-MC treated with AG-120 Figure subscript: Y-axis is mIDH1 VAF, x-axis is days on treatment. Text indicates investigator-assessed clinical response. CR, complete remission; CRi, CR with incomplete neutrophil recovery; CRp, CR with incomplete platelet recovery; R/R, relapsed/refractory; SD, stable disease; PD, progressive disease; *post-transplant sample Figure 1. VAF analysis using FoundationOne® Heme NGS assay in 4 AML patients with IDH1-MC treated with AG-120. / Figure subscript: Y-axis is mIDH1 VAF, x-axis is days on treatment. Text indicates investigator-assessed clinical response. CR, complete remission; CRi, CR with incomplete neutrophil recovery; CRp, CR with incomplete platelet recovery; R/R, relapsed/refractory; SD, stable disease; PD, progressive disease; *post-transplant sample Disclosures DiNardo: Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. de Botton:Novartis: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Servier: Consultancy; Pierre Fabre: Consultancy. Stein:Agios: Other: advisory board; Celgene: Other: advisory board; Novartis: Other: advisory board. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Pollyea:Alexion: Other: advisory board; Pfizer: Other: advisory board, Research Funding; Ariad: Other: advisory board; Glycomimetics: Other: DSMB member; Celgene: Other: advisory board, Research Funding. Fathi:Bexalata: Other: Advisory Board participation; Agios Pharmaceuticals: Other: Advisory Board participation; Seattle Genetics: Consultancy, Other: Advisory Board participation, Research Funding; Merck: Other: Advisory Board participation; Celgene: Consultancy, Research Funding. Altman:Syros: Honoraria; BMS: Honoraria; Janssen Pharmaceuticals: Honoraria; Novartis: Honoraria. Flinn:Janssen: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Gilead Sciences: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership. Foran:novartis: Honoraria; Millennium Pharmaceuticals, Inc.: Research Funding; karyopharm: Honoraria; medscape: Honoraria; pfizer: Honoraria; boehringer ingelheim: Research Funding; agios: Research Funding; Cellerant: Research Funding. Pigneux:Sunesis: Consultancy, Honoraria; Agios: Consultancy, Honoraria. Kantarjian:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. Liu:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Attar:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Sacolick:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yen:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Hurov:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Choe:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Wu:Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Stone:Amgen: Consultancy; Sunesis Pharmaceuticals: Consultancy; Pfizer: Consultancy; Roche: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Celator: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Xenetic Biosciences: Consultancy.

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.