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Background: Olutasidenib is a potent, selective, oral, small molecule inhibitor of mutant IDH1 (mIDH1) which induced durable remissions in high-risk, relapsed/refractory (R/R) mIDH1 AML patients in a phase 1/2 trial. We present a pooled analysis from multiple cohorts of the phase 1/2 trial of patients with R/R AML who received combination olutasidenib and azacitidine therapy., Methods: Adult patients with mIDH1 R132 AML received 150 mg olutasidenib twice daily plus standard-of-care azacitidine (OLU + AZA) and were evaluated for response and safety., Results: Sixty-seven patients with R/R mIDH1 R132 AML received combination OLU + AZA. Median age was 66 years (range 28-82) and 54% were male. Most patients (83%) had 2 + prior regimens, including a hypomethylating agent in 40%, IDH1 inhibitor therapy in 31% (olutasidenib in 24%), and hematopoietic stem cell transplant in 10%. Cytogenetic risk was intermediate in 72%, poor in 18% and unknown in 10%. CR/CRh was achieved in 21/67 (31%; 95% CI 21-44) patients, with a median duration of 14.7 months (95% CI 4.6-not reached). CR was achieved in 18/67 (27%; 95% CI 17-39) patients, with median duration of 20.3 months (95% CI 3.7-not reached). Overall response (partial remission or better) was achieved in 34/67 (51%; 95% CI 38-63) patients. Median overall survival was 12.9 months (95% CI 18.7-19.3). In a subset analysis excluding patients who had prior OLU exposure (N = 51), CR/CRh was achieved in 19/51 (37%; 95% CI 24-52) patients, CR was achieved in 16/51 (31%; 95% CI 19-46), and overall response was achieved in 30/51 (59%; 95% CI 44-72). In patients who achieved CR/CRh and were transfusion-dependent at baseline, transfusion independence (RBC and platelets) was achieved in 64% (7/11) and 57% (4/7) of patients, respectively. The most common Grade 3 or 4 adverse events (> 20% patients) were decreased platelet count (37%), red blood cell count (25%), and neutrophil count (24%). Six patients (9%) experienced differentiation syndrome. Four (6%) discontinued treatment due to an adverse event., Conclusions: Olutasidenib plus azacitidine induced high response rates and durable remissions with a tolerable side effect profile in patients with R/R AML with diverse treatment histories. The results represent another therapeutic option for patients with mIDH1 AML who may benefit from a targeted therapy., Trial Registration: NCT02719574., Competing Interests: Declarations. Ethics approval and consent to participate: The study was performed in accordance with the Declaration of Helsinki and in compliance with good clinical practice guidelines and applicable laws. The protocol was approved by the institutional review boards or ethics committee at study sites. Written informed consent was obtained before study entry from each patient or from the patient’s legally authorized representative if the patient was unable to provide consent. Consent for publication: Not applicable. Competing interests: JEC has received research funding for his current or former institution from, and is a consultant to, Astellas, Amphivena, BMS, Novartis, Pfizer, Takeda, Daiichi, Jazz Pharmaceuticals, Merus, and Forma Therapeutics; and is a consultant to Rigel, BiolineRx, Biopath, Sun Pharma, and Tern. GJR has served as a consultant for Agios, Amgen, Amphivena, Astex, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Onconova, Pfizer, Roche, and Sunesis; received research funding from AbbVie, BMS, Teva and Karyopharm; is an advisory board member or consultant for Novartis, AbbVie, BeiGene, BerGenBio, Arcellx, Jazz Pharmaceuticals, Syros, BMS, Genentech, ImmunoGen, AstraZeneca, Kura, Ryvu, Magenta, and Qihan Zentalis; has provided research support to Janssen. MRB received research funding from Abbvie, Ascnetage Pharma, Forma Therapeutics, Kite/Gilead, Kura Oncology, and Takeda. BAJ served in a consultancy/advisory role for AbbVie, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Gilead, GlycoMimetics, Kymera, Kura, Rigel, Schrodinger, Servier, Syndax and Treadwell, on a protocol steering committee for GlycoMimetics, on a data monitoring committee for Gilead, received travel reimbursement from AbbVie and Rigel, research funding to institution from AbbVie, Amgen, Aptose, AROG, Biomea, Bristol Myers Squibb, Celgene, Daiichi Sankyo, F. Hoffmann‑La Roche, Forma, Forty‑Seven, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune‑Onc, Incyte, Jazz, Kymera, Loxo, Pfizer, Pharmacyclics, Sigma Tau, and Treadwell. GJS has received advisory board and/or speaker program honoraria from Agios, Stemline, GSK, AVM Biotech, Orca, Novartis, BMS, Rigel, Incyte, Gilead, Gamida, Autolus, Abbvie, Seattle Genetics, Jazz Pharmaceuticals, Kite (Gilead), Karyopharm, BMS/Celgene, Blueprint Medicine, Astellas, and Amgen; has received consultant fees from BMS, Curios, Daichi-Sankyo, and Novartis; and holds stock or stock options in Amgen, Janssen, and BMS. KY was a consultant for Bristol Myers Squibb/Celgene, F. Hoffmann-La Roche, GSK, Jazz Pharmaceuticals, Novartis, Pfizer, Shattuck Labs, Taiho Oncology, and Takeda; received research funding from Astex Pharmaceuticals, Forma Therapeutics, F. Hoffmann-La Roche, Forma Therapeutics, Genentech, Geron Corporation, Gilead Sciences, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Novartis, and Treadwell Therapeutics; and received honoraria from AbbVie, TaiHo, and Novartis. PBF received unrelated research funding from Novartis. JY received research funding from Pfizer, Puretech, and Janssen. ESW served as advisory/consulting for Abbvie, Blueprint, Daiichi Sankyo, Immunogen, Kite, Kura, Novartis, Qiagen, Rigel, Ryvu, Schrodinger, Servier, Stemline, Syndax, Takeda; speaking roles for Pfizer, Astellas, Dava (all with my own slides); served on DSMC for Gilead and Abbvie; and is section editor for UpToDate. WGB has no competing interests to declare. AM served on DSMC for Foghorn Therapeutics, Daiichi Saynko, advisory for BMS, Abbvie, Novartis, treadwell therapeutics, and is senior medical director for beat aml study for the leukemia and lymphoma society. HT and AS are employees and shareholders of Rigel Pharmaceuticals, Inc. SDB has received honoraria from AbbVie, Astellas Pharma, Bristol Myers Squibb, Jazz Pharmaceuticals, and Servier; has acted as a consultant or advisor to Bristol Myers Squibb, GlaxoSmithKline, Servier, and Syndax; has participated in speakers' bureau for AbbVie, Astellas Pharma, Bristol Myers Squibb, Jazz Pharmaceuticals, and Servier; has received research funding to his institution from Auron Therapeutics and Forma Therapeutics; and has received travel, accommodations, or expenses from AbbVie and Servier. PM has served as a consultant and has received research funding from Servier and Bristol Myers Squibb. AC received support for research/honoraria for advisory boards and meetings from Abbvie and Pfizer; received honoraria for advisory board and meetings from Menarini Stemline, Jazz Pharmaceutical and Servier. JMW has received research funding from and was a board/advisory committee member for Takeda; has received research funding from Immune System Key Ltd; and is a consultant or board/advisory committee member for Genentech, Rafael Pharma, Reven Pharma, Celgene/Bristol-Myers Squib (BMS), Servier, Rigel, Aptose, Astellas, and Daiichi-Sankyo. BAJ served in a consultancy/advisory role for AbbVie, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Gilead, GlycoMimetics, Kymera, Kura, Rigel, Schrodinger, Servier, Syndax and Treadwell, on a protocol steering committee for GlycoMimetics, on a data monitoring committee for Gilead, received travel reimbursement from AbbVie and Rigel, research funding to institution from AbbVie, Amgen, Aptose, AROG, Biomea, Bristol Myers Squibb, Celgene, Daiichi Sankyo, F. Hoffmann‑La Roche, Forma, Forty‑Seven, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune‑Onc, Incyte, Jazz, Kymera, Loxo, Pfizer, Pharmacyclics, Sigma Tau, and Treadwell. GJS has received advisory board and/or speaker program honoraria from Agios, Stemline, GSK, AVM Biotech, Orca, Novartis, BMS, Rigel, Incyte, Gilead, Gamida, Autolus, Abbvie, Seattle Genetics, Jazz Pharmaceuticals, Kite (Gilead), Karyopharm, BMS/Celgene, Blueprint Medicine, Astellas, and Amgen; has received consultant fees from BMS, Curios, Daichi-Sankyo, and Novartis; and holds stock or stock options in Amgen, Janssen, and BMS. KY was a consultant for Bristol Myers Squibb/Celgene, F. Hoffmann-La Roche, GSK, Jazz Pharmaceuticals, Novartis, Pfizer, Shattuck Labs, Taiho Oncology, and Takeda; received research funding from Astex Pharmaceuticals, Forma Therapeutics, F. Hoffmann-La Roche, Forma Therapeutics, Genentech, Geron Corporation, Gilead Sciences, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Novartis, and Treadwell Therapeutics; and received honoraria from AbbVie, TaiHo, and Novartis. PBF received unrelated research funding from Novartis. JY received research funding from Pfizer, Puretech, and Janssen. ESW served as advisory/consulting for Abbvie, Blueprint, Daiichi Sankyo, Immunogen, Kite, Kura, Novartis, Qiagen, Rigel, Ryvu, Schrodinger, Servier, Stemline, Syndax, Takeda; speaking roles for Pfizer, Astellas, Dava (all with my own slides); served on DSMC for Gilead and Abbvie; and is section editor for UpToDate. WGB has no competing interests to declare. AM served on DSMC for Foghorn Therapeutics, Daiichi Saynko, advisory for BMS, Abbvie, Novartis, treadwell therapeutics, and is senior medical director for Beat AML study for the Leukemia and Lymphoma Society. HT and AS are employees and shareholders of Rigel Pharmaceuticals, Inc. SDB has received honoraria from AbbVie, Astellas Pharma, Bristol Myers Squibb, Jazz Pharmaceuticals, and Servier; has acted as a consultant or advisor to Bristol Myers Squibb, GlaxoSmithKline, Servier, and Syndax; has participated in speakers' bureau for AbbVie, Astellas Pharma, Bristol Myers Squibb, Jazz Pharmaceuticals, and Servier; has received research funding to his institution from Auron Therapeutics and Forma Therapeutics; and has received travel, accommodations, or expenses from AbbVie and Servier. PM has served as a consultant and has received research funding from Servier and Bristol Myers Squibb. AC received support for research/honoraria for advisory boards and meetings from Abbvie and Pfizer; received honoraria for advisory board and meetings from Menarini Stemline, Jazz Pharmaceutical and Servier. JMW has received research funding from and was a board/advisory committee member for Takeda; has received research funding from Immune System Key Ltd; and is a consultant or board/advisory committee member for Genentech, Rafael Pharma, Reven Pharma, Celgene/Bristol-Myers Squib (BMS), Servier, Rigel, Aptose, Astellas, and Daiichi-Sankyo., (© 2025. The Author(s).)

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.

Background: Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aims for phase 1 of this phase 1/2 study were to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of olutasidenib, as monotherapy or in combination with azacitidine, in patients with acute myeloid leukaemia or myelodysplastic syndrome, harbouring mutant IDH1., Methods: In this phase 1/2, multicentre, open-label clinical trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia or intermediate, high, or very high risk myelodysplastic syndrome harbouring mutant IDH1 at 18 study sites in the USA, Australia, France, and Spain. Other key eligibility criteria included Eastern Cooperative Oncology Group performance status 0-2 with adequate liver and renal function. The primary outcomes were dose-limiting toxicities and the maximum tolerated dose, maximum evaluated dose, and the recommended phase 2 dose of olutasidenib. Olutasidenib was administered orally in doses of 150 mg once daily, 150 mg twice per day, and 300 mg once daily. Azacitidine (75 mg/m 2 ) was administered subcutaneously or intravenously daily for 7 days on, 21 days off. The study was ongoing at the data cutoff (Oct 2, 2019) and is registered with ClinicalTrials.gov, NCT02719574., Findings: Patients were enrolled between Aug 8, 2016, and Nov 14, 2018. 78 patients received olutasidenib as monotherapy (n=32) or in combination with azacitidine (n=46). The median follow-up was 8·3 months (IQR 3·1-13·3) for monotherapy and 10·1 months (4·2-15·3) for combination therapy. 16 (50%) of 32 patients in the monotherapy group and 24 (52%) of 46 patients in the combination therapy group were women. Most patients were White (26 [81%] for monotherapy and 31 [67%] for combination therapy). No dose-limiting toxicities were reported in the dose-escalation cohorts and 150 mg twice per day was declared the recommended phase 2 dose on the basis of safety, pharmacokinetics and pharmacodynamics, and clinical activity. The most common (≥20%) grade 3-4 treatment-emergent adverse events with monotherapy were thrombocytopenia (nine [28%] of 32 patients), febrile neutropenia (seven [22%] of 32), and anaemia (seven [22%] of 32); and with combination therapy were thrombocytopenia (19 [41%] of 46), febrile neutropenia (13 [28%] of 46), neutropenia (13 [28%] of 46), and anaemia (nine [20%] of 46). 11 (34%) of 32 patients in the monotherapy group and nine (20%) of 46 patients in the combination therapy group died (most commonly from disease progression [three (9%) of 32 and four (9%) of 46]). No deaths were considered study-drug related. For patients with relapsed or refractory acute myeloid leukaemia, 41% (95% CI 21-64; nine of 22) receiving monotherapy and 46% (27-67; 12 of 26) receiving combination therapy had an overall response. For treatment-naive patients with acute myeloid leukaemia, 25% (1-81; one of four) receiving monotherapy and 77% (46-95; ten of 13) receiving combination therapy had an overall response., Interpretation: Olutasidenib, with or without azacitidine, was well tolerated and showed meaningful clinical activity in patients with IDH1-mutated acute myeloid leukaemia. The results of this phase 1 study provide rationale for the continued evaluation of olutasidenib in multiple patient populations with myeloid malignancies., Funding: Forma Therapeutics., Competing Interests: Declaration of interests JMW has received research funding from and was a board/advisory committee member for Takeda; has received research funding from Immune System Key Ltd and Takeda; and was a board/advisory committee member for Genentech, Rafael Pharma, Reven Pharma, and Celgene/Bristol-Myers Squib (BMS). MRB has received research funding for her institution from AbbVie, Forma Therapeutics, Kite, Kura, and Takeda. JY has received research funding from Seattle Genetics, Janssen, AROG, Loxo Oncology, and Agios. TP is a consultant to Curios and Daiichi; and has received research funding, is a consultant to, and has recently become an employee of BMS. SL is a consultant to AstraZeneca, BMS, Helsinn, Innate Pharma, and PIN Pharma, and has recently become an employee of Janssen Research and Development. GJS has received research funding, honoraria, is on the speakers’ bureau for, and is a board/advisory committee member for Agios, Gamida, Gilead, and Incyte; has received research funding, honoraria, is on the speakers’ bureau for, holds stock in, and is a board/advisory committee member for Amgen and BMS; has received research funding, honoraria, and is a board/advisory committee member for Novartis, Ono Pharma, and AVM Biotech; has received honoraria, is on the speakers’ bureau for, and is a board/advisory committee member for GlaxoSmithKline (GSK); has received research funding and holds stock in Janssen/Johnson & Johnson; has received research funding and is on the speakers’ bureau for AbbVie, Astellas, Celgene, Karyopharm, and Stemline; has received honoraria and is a board/advisory committee member for AstraZeneca; and has received research funding from Actinium, Actuate, Ambit, Cellectis, Cyclacel, Constellation, Daiichi-Sankyo, Deciphera, DeltaFly, Forma Therapeutics, FujiFilm, Genentech/Roche, Geron, Glycomimetics, Kura Oncology, Mateon, Medimmune, Millennium; Onconova, Pfizer, PrECOG, RegImmune, Sangamo, Samus, Sellas, Tolero, and Trovagene. SND has no conflicts to disclose. AP has received honoraria from and is a consultant to AbbVie; is a consultant to Gilead; and has received honoraria from Astellas, Agios, Pfizer, and Jazz Pharmaceuticals. PM has received research funding from, is a consultant to, and is on the speakers’ bureau for BMS; and is a consultant to Forma Therapeutics, Syndax, and Kura Oncology. ESW is a consultant to and a board/advisory committee member for AbbVie and Gilead; is a consultant to, and is on the speakers’ bureau for Astellas, Pfizer, and Stemline; is a board/advisory committee member for Rafael Pharmaceuticals; is a consultant to Amgen, BMS, GSK, Janssen, Jazz Pharmaceuticals, Kite, Mana Therapeutics, Novartis, PharmaEssentia; and is on the speakers’ bureau for Kura Oncology and Dava Oncology. KPS has received research funding and honoraria from, is a consultant to, and is on the speakers’ bureau of Jazz Pharmaceuticals; has received honoraria from, is a consultant to, and is on the speakers’ bureau for Novartis; has received honoraria from and is on the speakers’ bureau for Incyte; and has received research funding from Rafael, Glycomimetics, and Celgene. AHW has received research funding, honoraria, is a consultant to, is on the speakers’ bureau for, and is a board/advisory committee member for Astellas; has received research funding, honoraria, is on the speakers’ bureau for, and is a board/advisory committee member for AbbVie/Genentech, Amgen, Celgene/BMS, and Novartis; has received research funding, honoraria, is a consultant to, is a board/advisory committee member for Servier and Syndax; has received honoraria, is a consultant to, and is a board/advisory committee member for Janssen and Gilead; has received honoraria, and is a board/advisory committee member for MacroGenetics and Pfizer; has received research funding and honoraria from, and is a board/advisory committee member for AstraZeneca; has received research funding from Astex; and is an employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to venetoclax. SDB has received honoraria and research funding from Forma Therapeutics, has received honoraria, research funding, and is a consultant to Agios; has received honoraria, is a consultant to, and is on the speakers’ bureau for Celgene; has received honoraria and is a consult to Astellas, Daiichi Sankyo, Syros, AbbVie, Bayer, and Janssen; has received honoraria from Seattle Genetics; and is a consultant to Pierre Fabre, Novartis, Pfizer, and Servier. MA is a consultant to and a board/advisory committee member for BMS-Celgene and Novartis; and is a consultant to Astellas, Jazz Pharmaceuticals, and Pfizer. WD is a consultant to Janssen, BMS, and BeiGene. APS has received honoraria from AbbVie, Novartis, and Amgen; and is a board/advisory committee member for Pfizer. CR has received research funding from MaaT Pharma; has received honoraria from Incyte and Janssen; has received honoraria and has membership on an entity's board of directors or advisory committee for MacroGenics, Pfizer, and Takeda; has received honoraria, research funding, and has membership on an entity's board of directors or advisory committee for Amgen, Astellas, BMS/Celgene and Roche; and has received honoraria, research funding, is a consultant to, and has membership on an entity's board of directors or advisory committee for AbbVie, Daiichi Sankyo, Jazz Pharmaceuticals, and Novartis. BAJ has received research funding to his institution, is a consultant to, and is a board/advisory committee member for AbbVie, BMS, Genentech/Roche, Jazz Pharmaceuticals, Pfizer, and Treadwell; has received research funding to his institution, is a consultant to, and is a data monitoring committee member for Gilead; has received research funding to his institution, is a consultant to, and is a protocol steering committee member for GlycoMimetics; is a consultant to and a board/advisory committee member for Servier, Takeda, and Tolero; has received travel reimbursement from AbbVie; has received research funding to his institution from 47, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffman-La-Roche, Forma Therapeutics, Hanmi, Immune-Onc, Incyte, Loxo Oncology, LP Therapeutics, Pharmacyclics, and Sigma Tau. PBF has received research funding from Forma Therapeutics, Astex Pharmaceuticals, and Incyte. CM has received honoraria from Astellas, BMS, and Celgene. PK, JS, SF, SMG, and JB are employees of and hold stock in Forma Therapeutic. PH was an employee of and holds stock in Forma Therapeutics; and is an employee of and holds stock in Kymera Therapeutics. HM was an employee of and holds stock in Forma Therapeutics. JEC has received research funding for his institution from, and is a consultant to BMS, Novartis, Pfizer, Takeda, Daiichi, Jazz Pharmaceuticals, Merus, and Forma Therapeutics; has received research funding for his institution from Astellas and Amphivena; and is a consultant to BiolineRx and Bioptah. All authors had access to and had the opportunity to review the study data and are responsible for data analysis and interpretation. All authors participated in writing of the report (including original draft, review, and editing). All authors attest to study completeness, and accuracy of the data and data analysis. JMW and JEC participated in analysis of the data, and directly accessed and verified the underlying data reported in the manuscript. JMW had final responsibility for the decision to submit for publication., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Clonal evolution in myelodysplastic syndrome (MDS) can result in clinical progression and secondary acute myeloid leukemia (sAML). To dissect changes in clonal architecture associated with this progression, we performed single-cell genotyping of paired MDS and sAML samples from 18 patients. Analysis of single-cell genotypes revealed patient-specific clonal evolution and enabled the assessment of single-cell mutational cooccurrence. We discovered that changes in clonal architecture proceed via distinct patterns, classified as static or dynamic, with dynamic clonal architectures having a more proliferative phenotype by blast count fold change. Proteogenomic analysis of a subset of patients confirmed that pathogenic mutations were primarily confined to primitive and mature myeloid cells, though we also identify rare but present mutations in lymphocyte subsets. Single-cell transcriptomic analysis of paired sample sets further identified gene sets and signaling pathways involved in two cases of progression. Together, these data define serial changes in the MDS clonal landscape with clinical and therapeutic implications., Significance: Precise clonal trajectories in MDS progression are made possible by single-cell genomic sequencing. Here we use this technology to uncover the patterns of clonal architecture and clonal evolution that drive the transformation to secondary AML. We further define the phenotypic and transcriptional changes of disease progression at the single-cell level. See related article by Menssen et al., p. 330 (31). See related commentary by Romine and van Galen, p. 270. This article is highlighted in the In This Issue feature, p. 265., (©2022 American Association for Cancer Research.)

Mutations in isocitrate dehydrogenase 2 (IDH2) have been noted to impact cellular differentiation in addition to DNA and histone methylation. However, little is known about the impact of IDH2 mutations on intracellular signaling. Using an isogenic cell line model, we investigated both differentiation and signaling responses in IDH2 mutant cells and show augmented responses to inflammatory immune ligands. Using phospho-specific flow and mass cytometry, we demonstrate IDH2 mutant cells were significantly more sensitive to IL-1β at multiple downstream readouts. Further, bulk RNA sequencing confirmed increases in cytokine-related signaling pathways and NF-κB target genes. Single-cell RNA sequencing of unstimulated and stimulated cells confirmed altered IL-1β transcriptional responses in the IDH2 mutant cells. Targeted inhibition of the IKK complex reduced IL-1β responses and induced cell death in primary IDH-mutated leukemia samples. Together, these results confirm altered IL-1β signaling in IDH2 mutant cells and identify this pathway as a potential therapeutic target., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: All-trans retinoic acid (ATRA), a derivate of vitamin A, has been successfully used as a therapy to induce differentiation in M3 acute promyelocytic leukemia (APML), and has led to marked improvement in outcomes. Previously, attempts to use ATRA in non-APML in the clinic, however, have been underwhelming, likely due to persistent signaling through other oncogenic drivers. Dysregulated JAK/STAT signaling is known to drive several hematologic malignancies, and targeting JAK1 and JAK2 with the JAK1/JAK2 inhibitor ruxolitinib has led to improvement in survival in primary myelofibrosis and alleviation of vasomotor symptoms and splenomegaly in polycythemia vera and myelofibrosis., Objective: While dose-dependent anemia and thrombocytopenia limit the use of JAK2 inhibition, selectively targeting JAK1 has been explored as a means to suppress inflammation and STAT-associated pathologies related to neoplastogenesis. The objective of this study is to employ JAK1 inhibition (JAK1i) in the presence of ATRA as a potential therapy in non-M3 acute myeloid leukemia (AML)., Methods: Efficacy of JAK1i using INCB52793 was assessed by changes in cell cycle and apoptosis in treated AML cell lines. Transcriptomic and proteomic analysis evaluated effects of JAK1i. Synergy between JAK1i+ ATRA was assessed in cell lines in vitro while efficacy in vivo was assessed by tumor reduction in MV-4-11 cell line-derived xenografts., Results: Here we describe novel synergistic activity between JAK1i inhibition and ATRA in non-M3 leukemia. Transcriptomic and proteomic analysis confirmed structural and functional changes related to maturation while in vivo combinatory studies revealed significant decreases in leukemic expansion., Conclusions: JAK1i+ ATRA lead to decreases in cell cycle followed by myeloid differentiation and cell death in human leukemias. These findings highlight potential uses of ATRA-based differentiation therapy of non-M3 human leukemia., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

For patients with high risk myeloid disease, allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy. Unfortunately, many of these patients relapse after HCT and have a limited survival. The recent approval of venetoclax, an orally bioavailable BCL-2 inhibitor, resulted in significant responses in treatment naïve acute myeloid leukemia (AML), and off-label use in the relapsed/refractory setting is increasing. We report the outcomes of 21 patients who underwent allogeneic HCT for myeloid disease, relapsed with AML, and were treated with venetoclax. Several patients had poor risk features including antecedent hematologic malignancy (6/21), complex karyotype (6/21), and TP53 mutations (5/21). The median age was 64.5 years and time from HCT to relapse was 5.7 months (range: 0.9 to 44.9 months). Of the 19 patients who were assessed for response, there were meaningful treatment responses seen in eight patients: five CR, three CRi, zero PR, for an ORR of 42.1%. Treatment effect was seen in six additional patients, including four in the morphologic leukemia-free state. Nine patients maintained their response for ≥3 months and eight were receiving therapy at data cut. Post-HCT AML relapse has an exceedingly poor outcome, and venetoclax-based therapy is a potent therapy option that should be studied prospectively in this setting., (© 2020 Wiley Periodicals LLC.)

Acute myeloid leukemia (AML) is a systemic, heterogeneous hematologic malignancy with poor overall survival. While some malignancies have seen improvements in clinical outcomes with immunotherapy, success of these agents in AML remains elusive. Despite limited progress, stem cell transplantation and donor lymphocyte infusions show that modulation of the immune system can improve overall survival of AML patients. Understanding the causes of immune evasion and disease progression will identify potential immune-mediated targets in AML. This review explores immunosuppressive mechanisms that alter T-cell-mediated immunity in AML.

The National Comprehensive Cancer Network (NCCN) defines the following types of acute myeloid leukemia (AML) as favorable-risk: acute promyelocytic leukemia with t(15;17) (APL); AML with core-binding factor (CBF) rearrangements, including t(8;21) and inv(16) or t(16;16) without mutations in KIT (CBF-KIT wt ); and AML with normal cytogenetics and mutations in NPM1 (NPM1 mut ); or biallelic mutations in CEBPA (CEBPA mut/mut ), without FLT3-ITD. Although these AMLs are categorized as favorable risk by NCCN, clinical experience suggests that there are differences in clinical outcome amongst these cytogenetically and molecularly distinct leukemias. This study compared clinical and genotypic characteristics of 60 patients with favorable-risk AML, excluding APL, and demonstrated significant differences between them. Patients with NPM1 mut AML were significantly older than those in the other groups. Targeted next-generation sequencing on DNA from peripheral blood or bone marrow revealed significantly more mutations in NPM1 mut AML than the other favorable-risk diseases, especially in genes related to DNA splicing and methylation. CEBPA mut/mut AMLs exhibited more mutations in transcription-related genes. Patients with NPM1 mut AML and CEBPA mut/mut AML show significantly reduced overall survival in comparison with CBF-KIT wt AML. These findings emphasize that favorable-risk AML patients have divergent outcomes and that differences in clinical and genotypic characteristics should be considered in their evaluation and management., (Copyright © 2018. Published by Elsevier Ltd.)