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Background: Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity., Methods: KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50-1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41., Findings: From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50-1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4-30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission., Interpretation: Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing., Funding: Kura Oncology., Competing Interests: Declaration of interests ESW declares honoraria for educational talks from Aptitude, Astellas, Bioascend, CEA, CCO, Curio Sciences, Dava Oncology, Medscape, MD Education, OncLive, PER, Peerview, RTP, and Pfizer; participation on Data Safety Monitoring Committees and research grant committees for AbbVie and Gilead; advisory board participation for Abbvie, Astellas, Blueprint, Bristol Myers Squibb, Daiichi Sankyo, Gilead, GlaxoSmithKline, Immunogen, Janssen, Jazz, Kite, Novartis, NuProbe, PharmaEssentia, Pfizer, Qiagen, Rigel, Schrodinger, Sumitomo, Syndax, and Takeda; other financial and non-financial interests with UptoDate; and medical writing support for this work from Kura Oncology. GCI declares research funding to their institution from Astex, Cullinan Oncology, Kura Oncology, Merck, Novartis, and Syndax Pharmaceuticals; consultancy fees from AbbVie, Kura Oncology, Novartis, and Syndax Pharmaceuticals; support for attending meetings and travel from Kura Oncology; steering committee role with Kura Oncology and Novartis; receipt of material for sample analysis from NuProbe; and medical writing support for this work from Kura Oncology. HPE declares a leadership role with AbbVie (Chair, Independent Review Committee for VIALE A and VIALE C), Bristol Myers Squibb (Chair, AML Registry Steering Committee), and Glycomimetics (Scientific Steering Committee); speakers bureau for AbbVie, Bristol Myers Squibb, Incyte, Jazz, Novartis, and Servier; contracted research from AbbVie, ALX Oncology, Amgen, Aptose, Ascentage, Daiichi Sankyo, Forma, Gilead, Glycomimetics, Immunogen, Jazz, Kura Oncology, MacroGenics, Novartis, PTC, and Sumitomo Pharma; consultancy fees from AbbVie, Astellas, Bristol Myers Squibb, Daiichi Sankyo, Glycomimetics, Incyte, Jazz, Kura Oncology, Novartis, Pfizer, Servier, Stemline, and Sumitomo Pharma; and medical writing support for this work from Kura Oncology. JKA declares a leadership role with the American Society of Hematology (guidelines panel), National Comprehensive Cancer Network (acute myeloid leukaemia panel vice-chair), and National Cancer Institute (co-chair on Leukemia Steering Committee); honoraria from Astellas, HMP Education, MD Education, and VJ HemOnc; advisory board role with AbbVie, Aptitude Health, Astellas, BlueBird Bio, Curio, Daiichi Sankyo, Dark Blue Therapeutics, Gilead, Kura Oncology, Kymera, Rigel, Stemline Therapeutics, Syros, and Treadwell Therapeutics; meeting attendance and travel expenses from Astellas, Daiichi Sankyo, HMP Education, MD Education, and VJ HemOnc; medical writing support for this work from Kura Oncology; and participation on a Data Safety Committee for Glycomimetics. PM declares consultancy fees from Kura Oncology and Syndax Pharmaceuticals and medical writing support for this work from Kura Oncology. SDB declares honoraria from Astellas, Bristol Myers Squibb, Menarini, and Servier; consultancy fees from AbbVie, Bristol Myers Squibb, Forma, Remix, Rigel, and Servier; travel expenses from Janssen, Pfizer, Rigel, and Servier; and medical writing support for this work from Kura Oncology. RBW declares clinical trial support from Kura Oncology and medical writing support for this work from Kura Oncology. KP declares honoraria from Merck (investigator meeting lecture); advisory board role with AbbVie, Incyte, PharmaEssentia, Protagonist, and Sobi; and medical writing support for this work from Kura Oncology. MRS declares research funding to institution from ALX Oncology, Astex, Incyte, Takeda, and TG Therapeutics; consultancy fees from AbbVie, Bristol Myers Squibb, CTI BioPharma, Forma, Geron, GlaxoSmithKline, Karyopharm, Rigel, Ryvu, Taiho, and Treadwell; stock or stock options in Empath Bioscience, Karyopharm, and Ryvu; and medical writing support for this work from Kura Oncology. MVS declares research grant to their institution from AbbVie, Astellas, Celgene, Kura Oncology, and MRKR Therapeutics; travel expenses from Dava Oncology; and medical writing support for this work from Kura Oncology. MK declares consultancy fees from AbbVie, CTI Biopharma, Incyte, and Protagonist; advisory board role with CTI BioPharma, Incyte, Kura Oncology, and Morphosys; travel expenses from Protagonist; and medical writing support for this work from Kura Oncology. MRB declares research funding to their institution from AbbVie, Ascentage, Astellas, Gilead, Kura Oncology, and Takeda and medical writing support for this work from Kura Oncology. JMF declares leadership role with National Cancer Institute Leukemia Steering Committee and the National Heart, Lung, and Blood Institute national Myelodysplastic Syndrome Study Steering Committee; stock or stock options with Aurinia; honoraria from AmerisourceBergen/IntrinsiQ Specialty Solutions, Aptitude Health, and MJH LifeSciences; consultancy fees from Autolus, Bristol Myers Squibb, Remix, and Syndax; grants to institution for clinical trial support from Actinium, Astellas, Celgene, Chordia, Kura Oncology, Novartis, Pfizer, Roivant, Sellas, and Servier; and medical writing support for this work from Kura Oncology. GS declares contracts through their institution from AbbVie, Actinium, Actuate, Agios, Arog, Astellas, AlloVir, Amgen, Aptevo, AltruBio, AVM Bio, Bristol Myers Squibb/Celgene; BioMea, Biopath, Biosight, Cellularity, Celator, Constellation, Cogent, Cellectis, Cullinan, Daiichi Sankyo, Deciphera, Delta-Fly, Fate, Forma, FujiFilm, Gamida, Genentech-Roche, Rigel Glycomimetics, Geron, Gilead, Incyte, Janssen, Jazz, Karyopharm, Kite/Gilead, Kronos Bio, Kura Oncology, Immunogene, ImmuneOnc, Loxo, Marker, Mateon, Novartis, Onconova, Ono-UK, Orca, Pfizer, PrECOG, Regimmune, Samus, Sangamo, Sellas, Stemline, Syros, Takeda, Tolero, and Trovagene; consultancy fees from Bristol Myers Squibb, Curios, Daiichi, and Novartis; speakers bureau role for AbbVie, Agios, Amgen, Astellas, Blueprint Medicine, Bristol Myers Squibb, Celgene, Karyopharm, GlaxoSmithKline, Kite (Gilead), Jazz, Rigel, Seattle genetics, and Stemline; board or advisory committee membership for Agios, Autolus, AVM Biotech, Bristol Myers Squibb, Gamida, Gilead, GlaxoSmithKline, Incyte, Novartis, Orca, Rigel, and Stemline; board of trustees membership for Leukemia Lymphoma Society Los Angeles; secretary or treasurer membership for the American Society of Hematology Research Collaborative Board of Directors; and holds stock with Amgen, Bristol Myers Squibb, and Janssen/Johnson & Johnson. LA declares research funding to institution from AbbVie, Bristol Myers Squibb, Jazz Pharmaceuticals, and Novartis; consultancy fees from AbbVie, Jazz Pharmaceuticals, and Novartis; and medical writing support for this work from Kura Oncology. ER declares consulting fees from Astellas and Laboratories Delbert; honoraria from AbbVie, Astellas, Eurocept, and Jazz Pharmaceuticals; support for attending meetings and travel from AbbVie, Gilead, and Jazz Pharmaceuticals; and medical writing support for this work from Kura Oncology. MMP declares research funding to institution from Epigenetix, Kura Oncology, Polaris, Solutherapeutics, and Stem Line Pharma; medical writing support for this work from Kura Oncology; and Data Safety Monitoring Boards with CTI Biopharma. CP declares honoraria from AbbVie, Amgen, Astellas, Blueprint, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Incyte, Janssen, Jazz Pharmaceuticals, Laboratories Delbert, Menarini-Stemline, Novartis, Paladin Labs, Pfizer, and Servier; travel expenses from AbbVie, Amgen and Pfizer; medical writing support for this work from Kura Oncology; and Data Safety Monitoring Board or advisory board membership for AbbVie, Amgen, Astellas, Blueprint, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Incyte, Janssen, Jazz Pharmaceuticals, Laboratories Delbert, Paladin Labs, and Pfizer. JG declares research support to institution, consultancy fees, royalties, patents, and stock with Kura Oncology, and medical writing support for this work from Kura Oncology. TC declares research support to institution and royalties from, and patents and owns stock with Kura Oncology; and medical writing support for this work from Kura Oncology. BC, JR, BML, MH, PP, and OS declare medical writing support for this work from Kura Oncology. KN declares employment with Kura Oncology; received stock options from Kura Oncology; and medical writing support for this work from Kura Oncology. AM declares employment with Kura Oncology; owns stock with Kura Oncology; patents and patent applications with Kura Oncology; and medical writing support for this work from Kura Oncology. JMA declares employment and stock or stock options with and travel expenses from Kura Oncology, and medical writing support for this work from Kura Oncology. MT declares employment with Kura Oncology; stock and restricted stock units with Kura Oncology; reimbursement for conference fees, hotels and travel expenses from Kura Oncology; and medical writing support for this work from Kura Oncology. HSS declares employment, patents and patent applications, and owns stock with, Kura Oncology, and medical writing support for this work from Kura Oncology. DC declares employment with Kura Oncology; stock or stock options with Kura Oncology; and medical writing support for this work from Kura Oncology. ML declares employment, patents and patent applications, stock or stock options, support for attending meetings and travel, and other financial or non-financial interests with Kura Oncology; and medical writing support for this work from Kura Oncology. SD declares employment, patents and patent applications, stock or stock options, and other financial or non-financial interests with Kura Oncology; and medical writing support for this work from Kura Oncology. ATF declares consultancy fees from AbbVie, Amgen, Astellas, AstraZeneca, Autolus, Bristol Myers Squibb/Celgene, Daiichi Sankyo, EnClear, Forma, Genentech, Gilead, Immunogen, Ipsen, Kite, Mablytics, Menarini, Novartis, Orum, Pfizer, PureTech, Remix, Rigel, Servier, and Takeda; clinical trial support from AbbVie, Bristol Myers Squibb, and Servier; and medical writing support for this work from Kura Oncology. CB declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

We report on the outcomes of 53 patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia secondary to MDS, autografted in first complete remission. Five (9.4%) died from the procedure whereas hematological reconstitution occurred in all the remaining patients. Forty patients (75%) relapsed, with 87.5% of the relapses occurring within 2 years of the autologous transplant. With a median follow-up of 6.2 years, the median actuarial disease-free survival and overall survival were 8 and 17 months after autograft, respectively. Karyotype was the only prognostic factor for disease-free and overall survival. The eight survivors (15%), including two patients with unfavorable or intermediate karyotype, remained in first complete remission 50+ to 119+ months after transplantation and are probably cured.

Since leukemic cells primed by exposure to fludarabine exhibit enhanced accumulation of cytarabine triphosphate (the cytotoxic nucleotide of cytarabine), especially with continuous cytarabine (AraC) infusion, a phase II trial was designed to explore the feasibility and efficacy of a combination chemotherapy associating fludarabine, mitoxantrone (MXN), and high-dose cytarabine (continuous infusion) for high-risk P glycoprotein (PGP)-negative myelodysplastic syndromes (MDS) (FAM protocol). The outcomes of FAM-treated patients were compared with those of 32 PGP-negative MDS patients fulfilling identical inclusion and response criteria treated with MXN+AraC (1 g/m(2)/12 h d(1-5), MA protocol). A total of 29 patients (median age 55 years) were included in the FAM group. Six (21%) died from the procedure, and 16 (55%) achieved complete remission (CR). Of these, nine received consolidation chemotherapy, five were autografted and two were allografted in first CR. Abnormal karyotype was the only factor associated with poor survival. The overall median follow-up was 10.9 months. There was no significant difference between FAM and MA protocols with respect to CR rate, treatment-related mortality, duration of leukopenia, neutropenia, autologous stem cell transplantation feasibility, relapse-free survival, or overall survival. The duration of thrombocytopenia was significantly longer in the FAM protocol. In conclusion, the present results suggest that the combination therapy of fludarabine, MXN, and high-dose AraC does not improve CR rate, survival, or disease-free survival in high-risk MDS.