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Background: Advanced phase Philadelphia chromosome-positive myeloid disease-consisting of chronic myeloid leukaemia in the myeloid blast phase and in the accelerated phase, and Philadelphia chromosome-positive acute myeloid leukaemia-is associated with poor outcomes. Although previous studies have suggested the benefit of chemotherapy and BCR::ABL1 tyrosine kinase inhibitor combinations, the optimal regimen is uncertain and prospective studies for this rare group of diseases are scant. Preclinical and retrospective clinical data suggest possible synergy between the BCL-2 inhibitor venetoclax and BCR::ABL1 tyrosine kinase inhibitors. We therefore aimed to design a study to evaluate the safety and activity of a novel combination of decitabine, venetoclax, and the third-generation BCR::ABL1 tyrosine kinase inhibitor ponatinib in advanced phase Philadelphia chromosome-positive myeloid diseases., Methods: For this phase 2 study, patients aged 18 years or older with previously untreated or relapsed or refractory myeloid chronic myeloid leukaemia-blast phase, chronic myeloid leukaemia-accelerated phase, or advanced phase Philadelphia chromosome-positive acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-3 were eligible. Patients were eligible regardless of the number of previous lines of therapy received or previous receipt of ponatinib. Cycle 1 (induction) consisted of a 7-day lead-in of ponatinib 45 mg orally daily (days 1-7), followed by combination therapy with decitabine 20 mg/m 2 intravenously on days 8-12, venetoclax orally daily with ramp-up to a maximum dose of 400 mg on days 8-28, and ponatinib 45 mg orally daily on days 8-28. Cycles 2-24 consisted of decitabine 20 mg/m 2 intravenously on days 1-5, venetoclax orally 400 mg on days 1-21, and ponatinib orally daily on days 1-28. Response-based dosing of ponatinib was implemented in consolidation cycles, with reduction to 30 mg daily in patients who reached complete remission or complete remission with an incomplete haematological recovery and a reduction to 15 mg daily in patients with undetectable BCR::ABL1 transcripts. The primary endpoint was the composite rate of complete remission or complete remission with incomplete haematological recovery in the intention-to-treat population. Safety was assessed in the intention-to-treat population. This trial was registered with ClinicalTrials.gov (NCT04188405) and is still ongoing., Results: Between July 12, 2020, and July 8, 2023, 20 patients were treated (14 with chronic myeloid leukaemia-blast phase, four with chronic myeloid leukaemia-accelerated phase, and two with advanced phase Philadelphia chromosome-positive acute myeloid leukaemia). The median age was 43 years (IQR 32-58); 13 (65%) patients were male and seven (35%) were female; and 12 (60%) were White, three (15%) were Hispanic, four (20%) were Black, and one (5%) was Asian. 12 (60%) patients had received 2 or more previous BCR::ABL1 tyrosine kinase inhibitors, and 14 (70%) patients had at least one high-risk additional chromosomal abnormality or complex karyotype. The median duration of follow-up was 21·2 months (IQR 14·1-24·2). The complete remission or complete remission with an incomplete haematological recovery rate was 50% (10 of 20 patients); complete remission in one [5%] patient and complete remission with incomplete haematological recovery in nine [45%]). An additional six (30%) patients had a morphologic leukaemia-free state. The most common grade 3-4 non-haematological adverse events were febrile neutropenia in eight (40%) patients, infection in six (30%), and alanine or aspartate transaminase elevation in five (25%). Eight (40%) patients had at least one cardiovascular event of any grade. There were three on-study deaths, none of which was considered related to the study treatment and all from infections in the setting of refractory leukaemia., Interpretation: The combination of decitabine, venetoclax, and ponatinib is safe and shows promising activity in patients with advanced phase chronic myeloid leukaemia, including those with multiple previous therapies or high-risk disease features. Further studies evaluating chemotherapy and venetoclax-based combination strategies using newer-generation BCR::ABL1 tyrosine kinase inhibitors are warranted., Funding: Takeda Oncology, the National Institutes of Health, and the National Cancer Institute Cancer Center., Competing Interests: Declaration of interests NJS has received consulting fees from Pfizer, GlaxoSmithKline, NKARTA, Autolus, and Sanofi; research funding from Takeda Oncology, Astellas Pharma, Xencor, Stemline Therapeutics, and NextCure; and honoraria from Adaptive Biotechnologies, Novartis, Amgen, Takeda Oncology, Pfizer, Astellas Pharma, Sanofi, and BeiGene. EJ has received consulting fees and research funding from AbbVie, Adaptive Biotechnologies, Amgen, Ascentage, ASTX Pharmaceuticals, AstraZeneca, Autolus, BMS, Genenenctech, Hikma, Kite, Novartis, Pfizer, Takeda Oncology, and Jazz. HA has received consulting fees from Molecular Partners; research funding from Genentech, GlaxoSmithKline, and EBD-300; and honoraria from Illumina. MK has received consulting fees from AbbVie, AstraZeneca, Auxenion, Bakx, Boehringer, Dark Blue Therapeutics, F Hoffman-La Roche, Genentech, Gilead, Janssen, Legend, MEI Pharma, Redona, Sanofi, Sellas, Stemline, and Vincerx; research funding from AbbVie, Allogene, AstraZeneca, Genentech, Gilead, ImmunoGen, MEI Pharma, Precision, Rafael, Sanofi, and Stemline; honoraria from AbbVie, Baxk Therapeutics, Genentech, and Stemline Therapeutics; stock options in Reata Pharamceuticals; and holds patents with Novartis, Eli Lilly, and Reata Pharmaceutical. HK has received research funding from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, and Novartis and honoraria from AbbVie, Amgen, Ascentage, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Shenzhen Target Rx, Stemline, and Takeda Oncology. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Patients with acute myeloid leukaemia have high rates of relapse, especially if they are unable to complete standard consolidation strategies or allogeneic haematopoietic stem-cell transplantation (HSCT). The phase 3 QUAZAR AML-001 study showed an overall survival benefit with oral azacitidine maintenance. The BCL2 inhibitor venetoclax is highly active in acute myeloid leukaemia and synergistic with azacitidine. We aimed to evaluate the efficacy and safety of low dose azacitidine plus venetoclax as maintenance therapy in acute myeloid leukaemia., Methods: We performed a single-centre, single-arm, phase 2 study at the University of Texas MD Anderson Cancer Center in the USA. Eligible patients were adults (aged ≥18 years) with a WHO 2016 diagnosis of acute myeloid leukaemia in complete remission or complete remission with incomplete blood count recovery following intensive or low-intensity induction and not immediately eligible for HSCT. Eastern Cooperative Oncology Group performance status had to be 3 or less. Patients were assigned to maintenance therapy with azacitidine 50 mg/m 2 intravenously or subcutaneously for 5 days and venetoclax 400 mg orally for 7 days or 14 days. The primary outcome was relapse-free survival. The study was closed early due to slow accrual. All patients were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04062266)., Findings: Between Sept 26, 2019, and Oct 26, 2022, 35 patients were enrolled, of whom 25 (71%) were assigned to cohort 1 following intensive induction and ten (29%) to cohort 2 following low-intensity induction. Of 35 patients, 18 (51%) were male and 17 (49%) were female. The median age was 55 years (IQR 41-62). The median number of cycles given was 9 (IQR 2-22) and median follow-up time was 23·3 months (IQR 9·0-30·0). The median relapse-free survival was not reached (95% CI 20·2 to not calculable) in the full cohort, not reached (29·1 to not calculable) in cohort 1, and 30·3 months (16·5 to not calculable) in cohort 2. The 2-year relapse-free survival was 65% (95% CI 50-85) in the full cohort, 71% (53-94) in cohort 1, and 52% (27-100) in cohort 2. The most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (n=6), lung infection (n=4), leukopenia (n=4), and neutropenia (n=3). No deaths occurred during maintenance therapy., Interpretation: Low dose azacitidine plus venetoclax is a feasible maintenance strategy in acute myeloid leukaemia following intensive and low-intensity induction., Funding: University of Texas MD Anderson Cancer Center, MDS/AML Moon Shot, Genentech., Competing Interests: Declaration of interests HK declares grants from AbbVie, Amgen, Ascentage, Bristol Myers Squibb, Daiichi-Sankyo, Immunogen, Jazz, and Novartis, and payment or honoraria from AbbVie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Ipsen Biopharmaceuticals, KAHR Medical, Labcorp, Novartis, Pfizer, Shenzhen Target Rx, Stemline, and Takeda. NP declares licenses from Karger publishers and consulting fees or is an advisory board member for Abbvie, Aplastic Anemia & MDS International Foundation, Aptitude Health, Astellas Pharma, Blueprint Medicines, Bristol Myers Squibb, CancerNet, CareDx, Celgene, Cimeio Therapeutics AG, ClearView Healthcare Partners, CTI BioPharma, Curio Science, Dava Oncology, EUSA Pharma, Harborside Press, Imedex, Immunogen, Intellisphere, Karyopharm, Magdalen Medical Publishing, Medscape, Menarini Group, Morphosys, Neopharm, Novartis, OncLive, Pacylex, Patient Power, PeerView Institute for Medical Education, Pharma Essentia, and Physician Education Resource, and has board of director's role for Dan's House of Hope. KC declares research funding from Amgen and consulting fees from Abbvie. PB declares research funding from Incyte, Bristol Myers Squibb, CTI (Sobi), Morphosys, Kartos, Ionis, Disc, Janssen, Geron, Telios, Sumitomo, Karyopharm, Cogent, and Blueprint, consulting fees from Incyte, Bristol Myers Squibb, GlaxoSmithKline, CTI (Sobi), Abbvie, Morphosys, Sumitomo, Karyopharm, Ionis, Pharma Essentia, Morphic, Jubilant, Blueprint, Novartis, and Cogent, and payment or honoraria from GlaxoSmithKline, Sumitomo, Pharma Essentia, Incyte, and CTI (Sobi). EJ declares grants from AbbVie, Adaptive Biotechnologies, Amgen, Pfizer, and Takeda, and consulting fees from AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Genentech, Incyte, Novartis, Pfizer, and Takeda. CDD declares grants from AbbVie, Astex, ImmuneOnc, Bristol Myers Squibb, Cleave, Foghorn, Loxo, Rigel, and Servier, consulting fees from Amgen, AbbVie, Astellas, Bristol Myers Squibb, Genmab, GlaxoSmithKline, Gilead, Jazz, Shrodinger, Servier, and Stemline, payment or honoraria from AbbVie, Astellas, Bristol Myers Squibb, Jazz, and Servier, travel support from Servier, and participation on data safety board for Genmab. GI declares grants from Celgene, Kura Oncology, Syndax, Merck, Cullinan, and Novartis, and consulting fees from Novartis, Kura Oncology, and Nuprobe. NS declares research funding from Takeda Oncology, Astellas Pharma, Xencor, Stemline Therapeutics, and NextCure, consulting fees from Pfizer, GlaxoSmithKline, NKARTA, Autolus, and Sanofi, and payment or honoraria from Adaptive Biotechnologies, Novartis, Amgen, Takeda Oncology, Pfizer, Astellas Pharma, Sanofi, and BeiGene. ND declares grants from Daiichi–Sankyo, Bristol Myers Squibb, Pfizer, Gilead, Servier, Genentech, Astellas, AbbVie, ImmunoGen, Amgen, Trillium, Hanmi, Trovagene, FATE Therapeutics, Novimmune, Glycomimetics, and KITE, and consulting fees from Daiichi–Sankyo, Bristol Myers Squibb, Pfizer, Gilead, Servier, Genentech, Astellas, AbbVie, ImmunoGen, Amgen, Trillium, Arog, Novartis, Jazz, Celgene, Syndax, Shattuck Labs, Agios, KITE, and Stemline/Menarini. GG-M declares grants from Astex, Novartis, AbbVie, Genentech, Aprea, Curis, and Gilead, consulting fees from Astex, Acceleron, and Bristol Myers Squibb, and payment or honoraria from Astex, Acceleron, AbbVie, Gilead, Curis, Genentech, and Bristol Myers Squibb. FR declares clinical trial support from Astex and Taiho Oncology and payment or honoraria from Taiho Oncology. TK declares grants from Bristol Myers Squibb, AbbVie, Amgen, Ascentage Pharma Group, Astellas Pharma, DrenBio, Astex, AstraZeneca, Bristol Myers Squibb, Celgene, Incyte, Cellenkos, Cyclacel, Delta-Fly Pharma, Genentech, Genfleet, Glycomimetics, Iterion, Janssen, Jazz Pharmaceuticals, Pfizer, Pulmotect, Regeneron, and SELLAS, consulting fees from AbbVie, Agios, Daiichi Sankyo, Genentech, Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, PinotBio, Pulmotect, Sanofi-Aventis, and Servier, and payment or honoraria from AbbVie, Agios, Daiichi Sankyo, DAVA Oncology, Delta-Fly, DrenBio, Genentech, Genfleet, Genzyme, Jazz Pharmaceuticals, Liberum, Novartis, Pfizer, Rigel, Sanofi-Aventis, SELLAS, and Servier. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Pivekimab sunirine (IMGN632) is a first-in-class antibody-drug conjugate comprising a high-affinity CD123 antibody, cleavable linker, and novel indolinobenzodiazepine pseudodimer payload. CD123 is overexpressed in several haematological malignancies, including acute myeloid leukaemia. We present clinical data on pivekimab sunirine in relapsed or refractory acute myeloid leukaemia., Methods: This first-in-human, phase 1/2 dose-escalation and dose-expansion study enrolled participants aged 18 years or older at nine hospitals in France, Italy, Spain, and the USA with CD123+ haematological malignancies (Eastern Cooperative Oncology Group performance status of 0-1); participants reported here were in a cohort of participants with acute myeloid leukaemia who were refractory to or had relapsed on one or more previous treatments for acute myeloid leukaemia. The 3 + 3 dose-escalation phase evaluated two dosing schedules: schedule A (once every 3 weeks, on day 1 of a 3-week cycle) and fractionated schedule B (days 1, 4, and 8 of a 3-week cycle). The dose-expansion phase evaluated two cohorts: one cohort given 0·045 mg/kg of bodyweight (schedule A) and one cohort given 0·090 mg/kg of bodyweight (schedule A). The primary endpoints were the maximum tolerated dose and the recommended phase 2 dose. Antileukaemia activity (overall response and a composite complete remission assessment) was a secondary endpoint. The study is ongoing and registered with ClinicalTrials.gov, NCT03386513., Findings: Between Dec 29, 2017, and May 27, 2020, 91 participants were enrolled (schedule A, n=68; schedule B, n=23). 30 (44%) of schedule A participants were female and 38 (56%) were male; 60 (88%) were White, six (9%) were Black or African American, and two (3%) were other races. Pivekimab sunirine at doses of 0·015 mg/kg to 0·450 mg/kg in schedule A was administered in six escalating doses with no maximum tolerated dose defined; three dose-limiting toxicities were observed (reversible veno-occlusive disease; 0·180 mg/kg, n=1 and 0·450 mg/kg, n=1; and neutropenia; 0·300 mg/kg, n=1). Schedule B was not pursued further on the basis of comparative safety and antileukaemia findings with schedule A. The recommended phase 2 dose was selected as 0·045 mg/kg once every 3 weeks. At the recommended phase 2 dose (n=29), the most common grade 3 or worse treatment-related adverse events were febrile neutropenia (three [10%]), infusion-related reactions (two [7%]), and anaemia (two [7%]). Treatment-related serious adverse events occurring in 5% or more of participants treated at the recommended phase 2 dose were febrile neutropenia (two [7%]) and infusion-related reactions (two [7%]). Among 68 participants who received schedule A, one death (1%) was considered to be treatment-related (cause unknown; 0·300 mg/kg cohort). At the recommended phase 2 dose, the overall response rate was 21% (95% CI 8-40; six of 29) and the composite complete remission rate was 17% (95% CI 6-36; five of 29)., Interpretation: Pivekimab sunirine showed single-agent activity across multiple doses, with a recommended phase 2 dose of 0·045 mg/kg once every 3 weeks. These findings led to a phase 1b/2 study of pivekimab sunirine plus azacitidine and venetoclax in patients with CD123-positive acute myeloid leukaemia., Funding: ImmunoGen., Competing Interests: Declaration of interests NGD reports consultancy for Agios, Astellas, KITE, AbbVie, Gilead, Jazz, Daiichi Sankyo, BMS, ImmunoGen, Syndax, Novartis, Shattuck Labs, Trillium, Genentech, Stemline/Menarini, Celgene, Amgen, Pfizer, Servier, and Arog; and research funding from Astellas, Trovagene, FATE Therapeutics, Novimmune, KITE, Hanmi Pharm, AbbVie, Gilead, Daiichi Sankyo, BMS, ImmunoGen, Glycomimetics, Trillium, Genentech, Amgen, Pfizer, and Servier. PM reports consultancy for Daiichi Sankyo and Celgene; membership on an entity's Board of Directors or advisory committees for Daiichi Sankyo, AbbVie, Celgene, Novartis, Karyopharm, Incyte, Janssen, Pfizer, and Teva; research support from Daiichi Sankyo, Celgene, Novartis, Karyopharm, Janssen, Pfizer, and Teva; being on a speaker's bureau for Daiichi Sankyo, Celgene, Novartis, Incyte, Janssen, Pfizer and Teva; and research funding from Novartis, Janssen, Pfizer, and Teva. DJD reports research funding from AbbVie, Glycomimetics, and Novartis; and consultancy for Novartis, Amgen, Blueprint, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Pfizer, Servier, and Takeda. ESW reports being on an advisory board or consulting for AbbVie, BMS, CTI Biopharma, Daiichi Sankyo, Genentech, GSK, Johnson & Johnson, Kite, Kura, Novartis, Rigel, Sellas, and Sumitomo Pharma; a speaker role for Astellas, Kura, and Pfizer; being on a data monitoring committee for AbbVie and Gilead; and being on a research committee for Gilead. NPa reports being on an advisory board for CTI Biopharma and Cambium Oncology; consultancy for CTI Biopharma; and research funding from Gilead, ONO Pharma, and AbbVie. ET reports consultancy for AbbVie, Janssen, and Jazz Pharmaceuticals; and being on an advisory board for AbbVie, Janssen, and Jazz Pharmaceuticals. KLS reports consultancy for Bristol Myers Squibb, Gilead, Jazz Arog, Pfizer, BerGenBio, Astellas, Novartis, Curis, Mablytics, Daiichi Sankyo, and Nkarta; and research funding from Jazz and Incyte. NPe reports consultancy for MustangBio, AbbVie, Celgene, Stemline Therapeutics, Novartis, and Incyte; research funding from MustangBio, Samus, AbbVie, Cellectis, Stemline Therapeutics, Novartis, Plexxikon, Daiichi-Sankyo, SagerStrong, Affymetrix, and Incyte; and honoraria from AbbVie, Celgene, and Stemline Therapeutics. AAL received research funding from AbbVie and Stemline Therapeutics; and consulting fees from Cimeio Therapeutics, IDRx, Jnana Therapeutics, N-of-One, and Qiagen. JET reports research funding from Bristol Myers Squibb and Novartis. MYK reports research funding from Allogene, Daiichi, Gilead, ImmunoGen, MEI Pharma, Precision Biosciences, Sanofi, Ablynx, Genentech, Cellectis, AbbVie, Stemline Therapeutics, Forty-Seven, and AstraZeneca; consultancy for Gilead, MEI Pharma, Sanofi, Janssen, Vincerx, Genentech, AbbVie, Stemline Therapeutics, and AstraZeneca; honoraria from BAKX Therapeutics, Genentech, AbbVie, and Stemline Therapeutics; and equity ownership, patents & royalties from Reata Pharmaceuticals. CMS, KW, GB, YD, KEM, and PAZ-M are employees of ImmunoGen. HMK reports honoraria from Pfizer, Takeda, Amphista, Amgen, Ascentage, Astellas, Agios, Biologix, Curis, Ipsen Biopharmaceuticals, KAHR, Medical LabCorp, Shenzhen Target, Stemline, Novartis, and AbbVie; and research funding from Jazz Pharma, BMS, Amgen, Ascentage, Agios, ImmunoGen, Cyclacel, Daiichi-Sankyo, Novartis, and AbbVie. LT-M declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

AML with chromosomal alterations involving 3q26 overexpresses the transcription factor (TF) EVI1, associated with therapy refractoriness and inferior overall survival in AML. Consistent with a CRISPR screen highlighting BRD4 dependency, treatment with BET inhibitor (BETi) repressed EVI1, LEF1, c-Myc, c-Myb, CDK4/6, and MCL1, and induced apoptosis of AML cells with 3q26 lesions. Tegavivint (TV, BC-2059), known to disrupt the binding of nuclear β-catenin and TCF7L2/LEF1 with TBL1, also inhibited co-localization of EVI1 with TBL1 and dose-dependently induced apoptosis in AML cell lines and patient-derived (PD) AML cells with 3q26.2 lesions. TV treatment repressed EVI1, attenuated enhancer activity at ERG, TCF7L2, GATA2 and MECOM loci, abolished interactions between MYC enhancers, repressing AML stemness while upregulating mRNA gene-sets of interferon/inflammatory response, TGF-β signaling and apoptosis-regulation. Co-treatment with TV and BETi or venetoclax induced synergistic in vitro lethality and reduced AML burden, improving survival of NSG mice harboring xenografts of AML with 3q26.2 lesions., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Abstract: Hypomethylating agents (HMAs) and venetoclax (Ven) represent the standard of care for patients with acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy. However, the European LeukemiaNet (ELN) risk classifications have been validated for patients treated with intensive therapy. In this study, we validate a recently proposed new molecular prognostic risk signature (mPRS) for patients with AML treated with HMAs and Ven. This classification allocated patients to favorable, intermediate (N/KRAS or FLT3-internal tandem duplication mutations), and lower (TP53 mutations) benefit groups. We retrospectively analyzed 159 patients treated with HMA and Ven. The mPRS classification allocated 74 (47%), 31 (19%), and 54 (34%) patients to the higher, intermediate, and lower-benefit groups, respectively. The overall response rate was 71% (86%, 54%, and 59% in the higher, intermediate, and lower-benefit groups, respectively). The median overall survival (OS) and event-free survival (EFS) times were 30 and 19 months, respectively, in the higher-benefit group; 12 and 8 months in the intermediate-benefit group; and 5 and 4 months in the lower-benefit group (P < .001). The C-index for OS and EFS was higher when stratifying patients according to mPRS classification than with the ELN 2022 classification. The 2-year cumulative incidence of relapse was 35%, 70%, and 60% in the higher, intermediate, and lower-benefit groups, respectively (P = .005). The mPRS classification accurately segregated groups of patients with AML treated with HMA plus Ven. In these patients, N/KRAS and TP53 mutations appear to negatively affect outcomes; therefore, new treatment approaches are warranted., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Abstract: CD123, a subunit of the interleukin-3 receptor, is expressed on ∼80% of acute myeloid leukemias (AMLs). Tagraxofusp (TAG), recombinant interleukin-3 fused to a truncated diphtheria toxin payload, is a first-in-class drug targeting CD123 approved for treatment of blastic plasmacytoid dendritic cell neoplasm. We previously found that AMLs with acquired resistance to TAG were re-sensitized by the DNA hypomethylating agent azacitidine (AZA) and that TAG-exposed cells became more dependent on the antiapoptotic molecule BCL-2. Here, we report a phase 1b study in 56 adults with CD123-positive AML or high-risk myelodysplastic syndrome (MDS), first combining TAG with AZA in AML/MDS, and subsequently TAG, AZA, and the BCL-2 inhibitor venetoclax (VEN) in AML. Adverse events with 3-day TAG dosing were as expected, without indication of increased toxicity of TAG or AZA+/-VEN in combination. The recommended phase 2 dose of TAG was 12 μg/kg/day for 3 days, with 7-day AZA +/- 21-day VEN. In an expansion cohort of 26 patients (median age 71) with previously untreated European LeukemiaNet adverse-risk AML (50% TP53 mutated), triplet TAG-AZA-VEN induced response in 69% (n=18/26; 39% complete remission [CR], 19% complete remission with incomplete count recovery [CRi], 12% morphologic leukemia-free state [MLFS]). Among 13 patients with TP53 mutations, 7/13 (54%) achieved CR/CRi/MLFS (CR = 4, CRi = 2, MLFS = 1). Twelve of 17 (71%) tested responders had no flow measurable residual disease. Median overall survival and progression-free survival were 14 months (95% CI, 9.5-NA) and 8.5 months (95% CI, 5.1-NA), respectively. In summary, TAG-AZA-VEN shows encouraging safety and activity in high-risk AML, including TP53-mutated disease, supporting further clinical development of TAG combinations. The study was registered on ClinicalTrials.gov as #NCT03113643., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Polycythemia vera (PV) belongs to the BCR-ABL1-negative myeloproliferative neoplasms and is characterized by activating mutations in JAK2 and clinically presents with erythrocytosis, variable degrees of systemic and vasomotor symptoms, and an increased risk of both thromboembolic events and progression to myelofibrosis and acute myeloid leukemia (AML). Treatment selection is based on a patient's age and a history of thrombosis in patients with low-risk PV treated with therapeutic phlebotomy and aspirin alone, whereas cytoreductive therapy with either hydroxyurea or interferon alfa (IFN-α) is added for high-risk disease. However, other disease features such as significant disease-related symptoms and splenomegaly, concurrent thrombocytosis and leukocytosis, or intolerance of phlebotomy can constitute an indication for cytoreductive therapy in patients with otherwise low-risk disease. Additionally, recent studies demonstrating the safety and efficacy (ie, reduction in phlebotomy requirements and molecular responses) of ropegylated IFN-α2b support its use for patients with low-risk PV. Additionally, emerging data suggest that early treatment is associated with higher rates of molecular responses, which might eventually enable time-limited therapy. Nonetheless, longer follow-up is needed to assess whether molecular responses associate with clinically meaningful outcome measures such as thrombosis and progression to myelofibrosis or AML. In this article, we provide an overview of the current and evolving treatment landscape of PV and outline our vision for a patient-centered, phlebotomy-free, treatment approach using time-limited, disease-modifying treatment modalities early in the disease course, which could ultimately affect the natural history of the disease., (© 2023 by The American Society of Hematology.)

Mutations in splicing factor (SF) genes SRSF2, U2AF1, SF3B1, and ZRSR2 are now considered adverse risk in the European LeukemiaNet 2022 acute myeloid leukemia (AML) risk stratification. The prognostic impact of SF mutations in AML has been predominantly derived from younger patients treated with intensive (INT) therapy. We evaluated 994 patients with newly diagnosed AML, including 266 (27%) with a SFmut. Median age was 67 years overall, with patients with SFmut being older at 72 years. SRSF2 (n = 140, 53%) was the most common SFmut. In patients treated with INT, median relapse-free survival (RFS) (9.6 vs 21.4 months, P = .04) and overall survival (OS) (15.9 vs 26.7 months, P = .06) were shorter for patients with SFmut than without SFwt, however this significance abrogated when evaluating patients who received venetoclax with INT therapy (RFS 15.4 vs 20.3 months, P = .36; OS 19.6 vs 30.7 months, P = .98). In patients treated with LI, median RFS (9.3 vs 7.7 months, P = .35) and OS (12.3 vs 8.5 months, P = .14) were similar for patients with and without SFmut , and outcomes improved in all groups with venetoclax. On multivariate analysis, SFmut did not affect hazards of relapse and death for INT arm but reduced both these hazards in LI arm. In a large AML data set with >60% of patients receiving venetoclax with LI/INT therapy, SFmut had no independent negative prognostic impact. Newer prognostic models that consider LI therapy and use of venetoclax among other factors are warranted., (© 2023 by The American Society of Hematology.)

Chronic myelomonocytic leukaemia (CMML) is a haematological disorder with high risk of transformation to acute myeloid leukaemia (AML). To characterize the phenotypic and genomic patterns of CMML progression, we evaluated a cohort of 189 patients with AML evolving from CMML. We found that transformation occurs through distinct trajectories characterized by genomic profiles and clonal evolution: monocytic (Mo-AML, 53%), immature myeloid (My-AML, 43%) or erythroid (Ery-AML, 2%). Mo-AML, characterized by expansion of monoblasts and promonocytes (low CD34, CD117 expression; high CD14, CD33, CD56 and CD64 expression), were defined by SRSF2, TET2 and RAS pathway mutation co-dominance and were more likely to evolve from SRSF2-TET2 co-mutant CMML through emergence/expansion of RAS pathway mutant clones. Conversely, My-AML, characterized by expansion of immature myeloid blasts (high frequency of CD34, CD38, CD117; low frequency of CD14, CD64 and CD56 expression) were less likely to exhibit SRSF2-TET2 co-mutations or RAS pathway mutations and had higher frequency of CEBPA mutations. Ery-AML was defined by complex karyotypes and TP53 mutations. A trend towards improved OS and EFS with hypomethylating agent-venetoclax combination was observed in My-AML, but not Mo-AML. These findings define distinct progression of CMML and set the basis for future studies evaluating the role of phenotype-specific therapeutics., (© 2023 British Society for Haematology and John Wiley & Sons Ltd.)

Purpose: Treatment outcomes in patients with relapsed/refractory (R/R) myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remains dismal. On the basis of both extensive preclinical data and emerging clinical data, treatment with bromodomain and extra-terminal domain inhibitors (BETi) is a potential approach for patients with high-risk myeloid malignancies., Patients and Methods: We conducted a phase I trial to study the safety and efficacy of PLX51107 (BETi) and azacitidine combination therapy in patients with R/R AML and high-risk (HR) MDS and studied mechanisms of resistance to the combination therapy., Results: Thirty-seven patients with HR R/R MDS (n = 4) and R/R AML (n = 33) were treated. Sixteen patients (43%) had MECOM gene rearrangement and 7 other patients had TP53 mutation. Median prior number of therapies was three (range 1-9); 97% had received prior hypomethylating agent and 84% prior venetoclax. Overall response rate was 8/37 (22%): complete remission with incomplete platelet recovery (n = 1); morphologic leukemia-free state (n = 2); hematologic improvement (n = 5). The most common nonhematologic toxicities were febrile neutropenia and pneumonia in 12 (32%) patients each; 6 patients (17%) had severe hyperbilirubinemia. RNA-sequencing analysis of mononuclear cells harvested on treatment (day 3) versus pretreatment showed significant changes in mRNA expressions in responders: downregulation of MYC, BCL2, IL7R, and CDK6 and upregulation of HEXIM1, CD93, DCXR, and CDKN1A. Immunoblot analyses confirmed reduction in protein levels of c-Myc, CDK6, BCL2, and BCL-xL, and induction of BRD4 and HEXIM1 protein levels in responders., Conclusions: In a heavily pretreated patient cohort with R/R MDS and AML, PLX51107+ azacitidine was well-tolerated and resulted in modest clinical benefit., (©2023 American Association for Cancer Research.)

The addition of cladribine, or sorafenib to standard chemotherapy have each demonstrated improved survival in patients with newly-diagnosed acute myeloid leukemia (AML). We studied the combination of cladribine, idarubicin, and intermediate-dose cytarabine (CLIA) in patients ≤65 years of age with newly diagnosed AML, fit to receive intensive therapy. Cladribine (5 mg/m2) IV was administered on days (D)1-5, cytarabine (1 g/m2) on D1-5, and idarubicin (10 mg/m2) on D1-3. Sorafenib was added to the CLIA backbone for patients with FLT3-ITD mutated AML. 80 patients were enrolled: 65 with newly diagnosed AML and 15 with AML arising from previously treated MDS (ts-AML). The median age was 55 years (range, 21-65). CR + CRi was 83% (54/65) and 27% in the untreated and ts-AML cohorts, respectively; 74% and 75% of responding patients, respectively, had undetectable measurable residual disease (MRD). Among patients with FLT3-ITD mutated AML receiving CLIA+sorafenib, the CR + CRi rate was 95%, with 81% negative for MRD. With a median follow-up of 76 months, the 2- and 4-year OS of 57% and 50% compared to 20%, and 13% for ts-AML, respectively. Patients treated with CLIA+sorafenib had 2- and 5-year OS rates of 63% and 59%, respectively. The most common Grade ≥3 adverse events were infection/fever, elevated bilirubin, rash, and nausea. CLIA was safe and effective in young, fit patients with newly diagnosed AML with inferior outcomes among patients with ts-AML. The addition of sorafenib to CLIA in FLT3-ITD mutated AML resulted in high rates of durable remission and excellent long-term survival., (© 2023 Wiley Periodicals LLC.)

BCL-XL and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-XL/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-XL and BCL-2 to the von Hippel-Lindau (VHL) E3 ligase, leading to BCLX L/BCL-2 ubiquitination and degradation selectively in cells expressing VHL. Because platelets lack VHL expression, 753B spares on-target platelet toxicity caused by the first-generation dual BCL-XL/BCL-2 inhibitor navitoclax (ABT-263). Here, we report pre-clinical single-agent activity of 753B against different leukemia subsets. 753B effectively reduced cell viability and induced dose-dependent degradation of BCL-XL and BCL-2 in a subset of hematopoietic cell lines, acute myeloid leukemia (AML) primary samples, and in vivo patient-derived xenograft AML models. We further demonstrated the senolytic activity of 753B, which enhanced the efficacy of chemotherapy by targeting chemotherapy-induced cellular senescence. These results provide a pre-clinical rationale for the utility of 753B in AML therapy, and suggest that 753B could produce an added therapeutic benefit by overcoming cellular senescence-induced chemoresistance when combined with chemotherapy.

TP 53-mutant acute myeloid leukemia (AML) remains the ultimate therapeutic challenge. Epichaperomes, formed in malignant cells, consist of heat shock protein 90 (HSP90) and associated proteins that support the maturation, activity, and stability of oncogenic kinases and transcription factors including mutant p53. High-throughput drug screening identified HSP90 inhibitors as top hits in isogenic TP53-wild-type (WT) and -mutant AML cells. We detected epichaperomes in AML cells and stem/progenitor cells with TP53 mutations but not in healthy bone marrow (BM) cells. Hence, we investigated the therapeutic potential of specifically targeting epichaperomes with PU-H71 in TP53-mutant AML based on its preferred binding to HSP90 within epichaperomes. PU-H71 effectively suppressed cell intrinsic stress responses and killed AML cells, primarily by inducing apoptosis; targeted TP53-mutant stem/progenitor cells; and prolonged survival of TP53-mutant AML xenograft and patient-derived xenograft models, but it had minimal effects on healthy human BM CD34+ cells or on murine hematopoiesis. PU-H71 decreased MCL-1 and multiple signal proteins, increased proapoptotic Bcl-2-like protein 11 levels, and synergized with BCL-2 inhibitor venetoclax in TP53-mutant AML. Notably, PU-H71 effectively killed TP53-WT and -mutant cells in isogenic TP53-WT/TP53-R248W Molm13 cell mixtures, whereas MDM2 or BCL-2 inhibition only reduced TP53-WT but favored the outgrowth of TP53-mutant cells. Venetoclax enhanced the killing of both TP53-WT and -mutant cells by PU-H71 in a xenograft model. Our data suggest that epichaperome function is essential for TP53-mutant AML growth and survival and that its inhibition targets mutant AML and stem/progenitor cells, enhances venetoclax activity, and prevents the outgrowth of venetoclax-resistant TP53-mutant AML clones. These concepts warrant clinical evaluation., (© 2023 by The American Society of Hematology.)

Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) has a very poor prognosis. Determinants of clinical outcomes and optimal treatment remain uncertain. We retrospectively reviewed 108 cases of AML with inv(3)/t(3;3) and evaluated clinicopathological characteristics and clinical outcomes: 53 newly diagnosed (ND) AML and 55 relapsed/refractory (R/R) AML. Median age was 55 years. White blood cell (WBC) count ≥20x109/L and platelet count ≥140x109/L was observed in 25% and 32% of ND patients, respectively. Anomalies involving chromosome 7 were identified in 56% of patients. The most frequently mutated genes were SF3B1, PTPN11, NRAS, KRAS and ASXL1. In ND patients, the composite complete remission (CRc) rate was 46% overall; 46% with high-intensity treatments and 47% with lowintensity treatments. The 30-day mortality was 14% and 0%, with high- and low-intensity treatment, respectively. In R/R patients, the CRc rate was 14%. Venetoclax based-regimens were associated with a CRc rate of 33%. The 3-year overall survival (OS) was 8.8% and 7.1% in ND and R/R patients, respectively. The 3-year cumulative incidence of relapse was 81.7% overall. Older age, high WBC, high peripheral blast count, secondary AML and KRAS, ASXL1, DNMT3A mutations were associated with worse OS in univariable analyses. The 5-year OS rates were 44% and 6% with or without hematopoietic stem cell transplantation in CR1, respectively. AML with inv(3)/t(3;3) is associated with low CR rates, very high risk of relapse and dismal long-term survival. Intensive chemotherapy and hy pomethylating agents provide similar rates of remission and patients achieving CR benefit from hematopoietic stem cell transplantation in first CR.

In TP53 wild-type acute myeloid leukemia (AML), inhibition of MDM2 can enhance p53 protein expression and potentiate leukemic cell apoptosis. MDM2 inhibitor (MDM2i) monotherapy in AML has shown modest responses in clinical trials but combining options of MDM2i with other potent AML-directed agents like cytarabine and venetoclax could improve its efficacy. We conducted a phase I clinical trial (NCT03634228) to study the safety and efficacy of milademetan (an MDM2i) with low-dose cytarabine (LDAC)±venetoclax in adult patients with relapsed refractory (R/R) or newly diagnosed (ND; unfit) TP53 wild-type AML and performed comprehensive CyTOF analyses to interrogate multiple signaling pathways, the p53-MDM2 axis and the interplay between pro/anti-apoptotic molecules to identify factors that determine response and resistance to therapy. Sixteen patients (14 R/R, 2 N/D treated secondary AML) at a median age of 70 years (range, 23-80 years) were treated in this trial. Two patients (13%) achieved an overall response (complete remission with incomplete hematological recovery). Median cycles on trial were 1 (range 1-7) and at a median follow-up of 11 months, no patients remained on active therapy. Gastrointestinal toxicity was significant and dose-limiting (50% of patients ≥ grade 3). Single-cell proteomic analysis of the leukemia compartment revealed therapy-induced proteomic alterations and potential mechanisms of adaptive response to the MDM2i combination. The response was associated with immune cell abundance and induced the proteomic profiles of leukemia cells to disrupt survival pathways and significantly reduced MCL1 and YTHDF2 to potentiate leukemic cell death. The combination of milademetan, LDAC±venetoclax led to only modest responses with recognizable gastrointestinal toxicity. Treatment-induced reduction of MCL1 and YTHDF2 in an immune-rich milieu correlate with treatment response., (© 2023. The Author(s).)

Mutations in Nucleophosmin 1 (NPM1) are associated with a favorable prognosis in newly diagnosed acute myeloid leukemia (AML), however, their prognostic impact in relapsed/refractory (R/R) settings are unknown. In a retrospective analysis, we identified 206 patients (12%) with mutated NPM1 (NPM1c) and compared their outcomes to 1516 patients (88%) with NPM1 wild-type (NPM1wt). NPM1c was associated with higher rates of complete remission or complete remission with incomplete count recovery compared with NPM1wt following each line of salvage therapy (first salvage, 56% vs 37%; P < .0001; second salvage, 33% vs 22%; P = .02; third salvage, 24% vs 14%; P = .02). However, NPM1 mutations had no impact on relapse-free survival (RFS) and overall survival (OS) with each salvage therapy with a median OS following salvage 1, 2 or 3 therapies in NPM1c vs NPM1wt of 7.8 vs 6.0; 5.3 vs 4.1; and 3.5 vs 3.6 months, respectively. Notably, the addition of venetoclax to salvage regimens in patients with NPM1c improved RFS and OS (median RFS, 15.8 vs 4.6 months; P = .05; median OS, 14.7 vs 5.9 months; P = .02). In conclusion, NPM1 mutational status has a minimal impact on prognosis in relapsed or refractory AML; therefore, novel treatment strategies are required to improve outcomes in this entity., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

This study aimed to identify a recommended phase II dose and evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and preliminary clinical activity of JNJ-63709178, a CD123/CD3 dual-targeting antibody, in patients with relapsed or refractory acute myeloid leukemia. Intravenous (i.v.) and subcutaneous (s.c.) administration of JNJ-63709178 were evaluated. The i.v. infusions were administered once every 2 weeks (cohorts 1-5 [n = 17]) or twice weekly (cohorts 6-11 [n = 36]). A twice-weekly s.c. dosing regimen with step-up dosing was also studied (s.c. cohorts 1-2 [n = 9]). Treatment-emergent adverse events (TEAEs) greater than or equal to grade 3 were observed in 11 (65%) patients in cohorts 1-5 and 33 (92%) patients in cohorts 6-11. At the highest i.v. dose (4.8 μg/kg), 5 (71%) patients discontinued treatment due to TEAEs. For s.c. administration (n = 9), eight (89%) patients experienced TEAEs greater than or equal to grade 3 and injection site reactions (≤ grade 3) emerged in all patients. At 4.8 μg/kg (i.v. and s.c.), the mean maximum serum concentrations were 30.3 and 3.59 ng/ml, respectively. Increases in multiple cytokines were observed following i.v. and s.c. administrations, and step-up dosing strategies did not mitigate cytokine production or improve the safety profile and led to limited duration of treatment. Minimal clinical activity was observed across all cohorts. The i.v. and s.c. dosing of JNJ-63709178 was associated with suboptimal drug exposure, unfavorable safety profiles, limited clinical activity, and inability to identify a recommended phase II dose., (© 2022 Janssen Research and Development, LLC and The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Patients with higher risk chronic myelomonocytic leukemia (CMML) have limited therapeutic options beyond hydroxyurea and hypomethylating agents (HMAs). Regimens based on a backbone of cladribine (CLAD), low-dose cytarabine (LDAC), and an HMA are effective low-intensity therapies for acute myeloid leukemia (AML)., Methods: The authors conducted a retrospective chart review to evaluate the efficacy of CLAD/LDAC/HMA in CMML and secondary acute myeloid leukemia (sAML) arising from CMML. Responses were evaluated according to the 2006 International Working Group criteria for CMML and the 2017 European LeukemiaNet criteria for AML. The overall survival (OS), leukemia-free survival (LFS), and duration of response were evaluated with the Kaplan-Meier method. Patients were stratified on the basis of prior HMA exposure., Results: The authors identified 21 patients with CMML (eight with HMA-naive CMML and 13 with HMA-failure CMML) and 33 patients with sAML (11 with HMA-naive sAML and 22 with HMA-failure sAML) treated with CLAD/LDAC/HMA-based regimens. The CMML cohort was enriched for high-risk features (proliferative type, elevated blasts, and RAS/MAPK mutations). The overall response rate was 33% in CMML (50% in HMA-naive CMML and 23% in HMA-failure CMML) and 48% in sAML (82% in HMA-naive sAML and 32% in HMA-failure sAML). The median OS was 14.4, 8.8, 42.9, and 2.9 months for HMA-naive CMML, HMA-failure CMML, HMA-naive sAML, and HMA-failure sAML, respectively. The median LFS was 14.4 and 3.9 months for HMA-naive CMML and HMA-failure CMML, respectively., Conclusions: CLAD/LDAC/HMA-based regimens are effective in a subset of patients with higher risk CMML and sAML arising from CMML who have not previously experienced HMA failure. These findings must be confirmed in prospective studies., (© 2022 American Cancer Society.)

Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Splenomegaly is a hallmark of myelofibrosis, a debilitating haematological malignancy for which the only curative option is allogeneic haematopoietic cell transplantation (HCT). Considerable splenic enlargement might be associated with a higher risk of delayed engraftment and graft failure, increased non-relapse mortality, and worse overall survival after HCT as compared with patients without significantly enlarged splenomegaly. Currently, there are no standardised guidelines to assist transplantation physicians in deciding optimal management of splenomegaly before HCT. Therefore, the aim of this Position Paper is to offer a shared position statement on this issue. An international group of haematologists, transplantation physicians, gastroenterologists, surgeons, radiotherapists, and radiologists with experience in the treatment of myelofibrosis contributed to this Position Paper. The key issues addressed by this group included the assessment, prevalence, and clinical significance of splenomegaly, and the need for a therapeutic intervention before HCT for the control of splenomegaly. Specific scenarios, including splanchnic vein thrombosis and COVID-19, are also discussed. All patients with myelofibrosis must have their spleen size assessed before allogeneic HCT. Myelofibrosis patients with splenomegaly measuring 5 cm and larger, particularly when exceeding 15 cm below the left costal margin, or with splenomegaly-related symptoms, could benefit from treatment with the aim of reducing the spleen size before HCT. In the absence of, or loss of, response, patients with increasing spleen size should be evaluated for second-line options, depending on availability, patient fitness, and centre experience. Splanchnic vein thrombosis is not an absolute contraindication for HCT, but a multidisciplinary approach is warranted. Finally, prevention and treatment of COVID-19 should adhere to standard recommendations for immunocompromised patients., Competing Interests: Declaration of interests CH received grants from Novartis and Constellation Pharmaceutical; consulting fees from Keros, Galecto, AOP, and Roche; payment for presentations from Novartis, Celgene, CTI BioPharma, AbbVie, Jansen, Constellation Pharmaceuticals, Galecto, CTI BioPharma, Roche, Geron, Promedior, AbbVie, and AOP Pharma; support for attending meetings from Novartis; participated on advisory boards for Galecto and Keros; and held leadership or fiduciary roles in European Hematology Association, British Society for Haematology, Myeloproliferative Neoplasms Voice, and Blood Cancer UK. NK received research grants from Novartis; consulting fees from Novartis; payments or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Novartis and Neovii; support for attending meetings and travel from Neovii; participated on a data safety monitoring board or advisory board for Hovon and Novartis; and held leadership or fiduciary roles in other boards, societies, committees or advocacy groups, paid or unpaid, for the European Society for Blood and Marrow Transplantation, German Society for Stem Cell Transplantation and Cellular Therapy, and the German Registry for Stem Cell Transplantation. RM received funding from Celgene, Incyte, AbbVie, Samus, Genotech, Promedior, CTI, Constellation, Mays Cancer Center, and P30 Cancer Center; support grants from National Cancer Institute (grant number CA054174); and consulting fees from Novartis, Sierra Onc, LaJolla, Pharma, and Constellation. NPe received support from the National Institutes of Health, National Cancer Institute (award number P30 CA016672); grants from Affymetrix, US Department of Defence, and SagerStrong foundation; royalties from Karger Publishers; consulting fees from Pacylex Pharmaceuticals, ImmunoGen, Bristol-Myers Squibb, Blueprint Medicines, Clearview Healthcare Partners, Astellas Pharma US, and Protagonist Therapeutics; honoraria from Incyte, Novartis, LFB Biotechnologies, Stemline Therapeutics, Celgene, AbbVie, MustangBio, Roche Diagnostics, Blueprint Medicines, DAVA Oncology, Springer Science + Business Media, Aptitude Health, and CareDx; support for attending meetings from Stemline Therapeutics, Celgene, MustangBio, DAVA oncology, AbbVie; participated on a data safety monitoring board and advisory board for ASCO Leukemia Advisory Panel; held leadership or fiduciary role in other boards, societies, committees or advocacy groups, paid or unpaid for by American Society of Hematology Communications Committee, Dan's House of Hope, and HemOnc Times/Oncology Times; and received equipment, materials, drugs, medical writing support, gifts, or other services from Novartis, Stemline Therapeutics, Samus Therapeutics, AbbVie, CEllectis, Affymetrix, Daiichi Sankyo, and Plexxikon. UP received research funding from Bayer, Novartis, AbbVie, and Incyte. AMV participated in advisory boards for Novartis; and provided consulting services for Novartis. IY-A received honoraria from Novartis. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Activating mutations in RAS have been reported in about 10-15% of patients with AML; previous studies have not identified a prognostic significance. However, RAS mutations have emerged as a potential resistance mechanism to treatment with inhibitors of FLT3, IDH, and BCL2. We aimed to determine the characteristics and outcomes of patients with RAS-mutated (RAS-mut) AML across therapy subsets of 1410 patients newly diagnosed (ND AML). RAS-mut was observed in 273 (20%) patients. Overall, patients with RAS-mut AML had an estimated 3-year survival rate of 38% vs. 28% in those with RAS wild type (RAS-wt), p = .01. Among patients with RAS-mut, favorable karyotype and concomitant NPM1 mutations were associated with a higher CR/CRi rate, OR 23.2 (95% CI: 2.7-192.7; p < .001) and OR 2.8 (95% CI: 1.1-6.9; p = .02), respectively, while secondary and treated secondary (ts)-AML were associated with low response rates, OR 0.34 (95% CI: 0.1-0.9; p = .04) and OR 0.22 (95% CI: 0.09-0.5; p = .001), respectively. Intensive chemotherapy was associated with high response rates OR 5.9 (95% CI: 2.9-12.2; p < .001). Better median OS was observed among those with favorable karyotype, HR 0.28 (95% CI: 0.1-0.6; p = .002), and those treated with intensive chemotherapy, HR 0.42 (95% CI: 0.2-0.6 p < .001). Conversely, ts- AML and co-occurrence of mutations in TP53 were associated with poor median OS; HR 2.3 (95% CI: 1.4-3.9; p = .001) and HR 1.7 (95% CI: 0.9-3.1; p = .06), respectively. The addition of venetoclax was associated with a non-significant improvement in CR/CRi and OS., (© 2022 Wiley Periodicals LLC.)

Purpose: The combination of venetoclax and 5-azacitidine (5-AZA) for older or unfit patients with acute myeloid leukemia (AML) improves remission rates and survival compared with 5-AZA alone. We hypothesized that the addition of venetoclax to cladribine (CLAD)/low-dose araC (low-dose cytarabine [LDAC]) alternating with 5-AZA backbone may further improve outcomes for older patients with newly diagnosed AML., Methods: This is a phase II study investigating the combination of venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA in older (≥ 60 years) or unfit patients with newly diagnosed AML. The primary objective was composite complete response (CR) rate (CR plus CR with incomplete blood count recovery); secondary end points were overall survival, disease-free survival (DFS), overall response rate, and toxicity., Results: A total of 60 patients were treated; median age was 68 years (range, 57-84 years). By European LeukemiaNet, 23%, 33%, and 43% were favorable, intermediate, and adverse risk, respectively. Fifty-six of 60 evaluable patients responded (composite CR: 93%) and 84% were negative for measurable residual disease. There was one death (2%) within 4 weeks. With a median follow-up of 22.1 months, the median overall survival and DFS have not yet been reached. The most frequent grade 3/4 nonhematologic adverse events were febrile neutropenia (n = 33) and pneumonia (n = 14). One patient developed grade 4 tumor lysis syndrome., Conclusion: Venetoclax and CLAD/LDAC alternating with venetoclax and 5-AZA is an effective regimen among older or unfit patients with newly diagnosed AML. The rates of overall survival and DFS are encouraging. Further study of this non-anthracycline-containing backbone in younger patients, unfit for intensive chemotherapy, as well as comparisons to standard frontline therapies is warranted.

Fludarabine, cytarabine, GCSF (FLAG)-based induction/consolidation results in high remission rates in core binding factor (CBF) acute myelogenous leukemia. We treated 174 consecutive patients with newly diagnosed CBF-AML in a prospective clinical trial of FLAG-based induction/consolidation in combination with gemtuzumab ozogamicin (FLAG-GO; N = 65) or in combination with idarubicin (FLAG-IDA; N = 109). The 5 year RFS in the FLAG-GO cohort was significantly better than the FLAG-IDA cohort, 78% versus 59%, respectively (p-value = .02). In multivariate analysis for RFS, age (p = .0001), FLAG-GO regimen (p = .04), 4 log reduction in CBF-related fusion transcript by quantitative polymerase chain reaction (qPCR) in bone marrow samples at end of consolidation therapy (p = .03), and additional cytogenetic abnormalities (p = .03) were significant variables. Lower age (p = .0001) and 3 log or more transcript reduction at end of induction (p = .04) were significant variables predicting for better overall survival (OS), while there was strong trend for better OS with FLAG-GO (p = .06) regimen. FLAG-GO regimen was superior in optimal disease specific fusion transcript reduction at end of induction (p = .002), mid-consolidation (p < .01), and end of consolidation (p < .001) therapy. Induction/consolidation with FLAG-GO regimen results in better clinical outcomes in newly diagnosed patients with CBF-AML compared to FLAG-IDA and achieves deeper molecular clearance by qPCR assessment of the fusion transcripts., (© 2022 Wiley Periodicals LLC.)

Abstract: Targeted therapy in oncology brings with it the promise to maximize cancer cell cytotoxicity with minimal off-target effects. Antibody-drug conjugates (ADCs), an important group of such targeted agents, consist of a monoclonal antibody conjugated to a potent cytotoxic drug. In the field of leukemia, ADCs form an important component of therapeutic arsenal through the use of gemtuzumab ozogamicin in acute myeloid leukemia and inotuzumab ozogamicin (InO) in B-cell acute lymphoblastic leukemia, 2 approved agents. A recombinant fusion protein, tagraxofusp, which function similar to ADC, has gained approval for therapy in blastic plasmacytic dendritic cell neoplasm. The use of such agents as monotherapy or as part of a combination therapy has led to improved response rates and outcomes in certain specific disease subtypes and has led to further studies to identify novel cellular targets and improved delivery of cytotoxic agents using ADC. In this review, we will discuss about ADCs in myeloid leukemia and understand their development and current use in the field., Competing Interests: Conflicts of Interest and Source of Funding: N.P.: leadership: ASH and ASCO; honoraria: Incyte, Novartis, LFB Biotechnologies, Stemline Therapeutics, Celgene, AbbVie, MustangBio, Roche Molecular Diagnostics, Blueprint Medicines, DAVA Pharmaceuticals, Springer, Aptitude Health, NeoPharm, and CareDX; consulting or advisory role: Blueprint Medicines, Pacylex, Immunogen, Bristol Myers Squibb, ClearView Healthcare Partners, Astellas Pharma, Protagonist Therapeutics, Triptych Health Partners, and CTI BioPharma Corp; research funding: Novartis, Stemline Therapeutics, Samus Therapeutics, AbbVie, Cellectis, Affymetrix/Thermo Fisher Scientific, Daiichi Sankyo, Plexxikon, and MustangBio; travel, accommodations, expenses: Stemline Therapeutics, Celgene, AbbVie, DAVA Oncology and MustangBio; uncompensated relationships: Dan's House of Hope and Oncology Times. N.G.D.: consulting or advisory role: Celgene, Agios, Jazz Pharmaceuticals, Pfizer, AbbVie, Astellas Pharma, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Amgen, Immunogen, Genentech, Servier, Syndax, Trillium Therapeutics, Gilead Sciences, Arog, and Shattuck Labs; research funding: Bristol Myers Squibb, Pfizer, Immunogen, Genentech, AbbVie, Astellas Pharma, Sevier, Daiichi Sankyo, Gilead Sciences, Amgen, Trillium Therapeutics, Hanmi, Trovagene, FATE Therapeutics, Novimmune, and GlycoMimetics. For J.S., none were declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) mutations occur frequently in newly diagnosed (ND) acute myeloid leukemia (AML) often with co-occurring NPM1 mutations, which may influence treatment outcomes. Detailed analysis of IDH-mutated AML treated with venetoclax and influence of co-occurring NPM1 mutations remains unclear. This retrospective single-center cohort study evaluated clinical and molecular demographics,response and survival, and impact of co-occurring NPM1 mutations in patients with IDH1 or IDH2-mutated AML. 556 patients with IDH1, IDH2, and/or NPM1 mutated AML were included. Patients with IDH1 mut AML (N = 119) were more likely to have older age, sAML, ELN-adverse risk disease, and adverse-risk cytogenetics compared to those with IDH2 mut (N = 229) or IDH wt /NPM1 mut AML (N = 208). In multivariate analysis, patients with IDH2 mut (HR 0.61 [95%CI: 0.43-0.88], p value: .007) or IDH wt /NPM1 mut (HR 0.65 [95% CI: 0.45-0.94], p value: .024) AML had a decreased risk of death versus IDH1 mut AML. Venetoclax-based lower-intensity regimens partially abrogated the detrimental effect of IDH1 mut with similar OS observed between IDH1 mut /NPM1 wt , IDH2 mut /NPM1 wt , and IDH wt /NPM1 mut AML. With regards to the influence of IDH mut /NPM1 mut cases, IC improved survival in IDH2 mut /NPM1 mut versus IDH2 mut /NPM1 wt AML (HR: 0.54 [95% CI: 0.2644-1.082], p value: .077), while venetoclax-based therapy improved survival in IDH1 mut /NPM1 mut versus IDH1 mut /NPM1 wt AML (HR: 0.094 [95% CI: 0.01-0.74], p value: .0056). Differing outcomes were observed in IDH1 mut versus IDH2 mut or NPM1 mut AML which were influenced by co-occurring NPM1 mutations and partially abrogated with venetoclax-based therapy. Given the differing biology and survival in IDH1 mut AML, investigations incorporating molecularly targeted therapies such as IDH inhibitors remain warranted in this subgroup., (© 2022 Wiley Periodicals LLC.)

We conducted a phase Ib/II multi-arm, parallel cohort study to simultaneously evaluate various immunotherapeutic agents and combinations in relapsed/refractory acute myeloid leukemia (AML). Overall, 50 patients were enrolled into one of 6 arms: (A) single agent PF-04518600 (OX40 agonist monoclonal antibody), (B) azacitidine + venetoclax + gemtuzumab ozogamicin (GO), (C) azacitidine + avelumab (anti-PD-L1 monoclonal antibody) + GO, (D) azacitidine + venetoclax + avelumab, (E) azacitidine + avelumab + PF-04518600, and (F) glasdegib + GO. Among all regimens evaluated, azacitidine + venetoclax + GO appeared most promising. In this arm, the CR/CRi rates among venetoclax-naïve and prior venetoclax-exposed patients were 50% and 22%, respectively, and the 1-year OS rate was 31%. This study shows the feasibility of a conducting a multi-arm trial to efficiently and simultaneously evaluate novel therapies in AML, a needed strategy in light of the plethora of emerging therapies. This trial was registered at www.clinicaltrials.gov as NCT03390296.

Multi-agent induction chemotherapy (IC) improves response rates in younger patients with acute myeloid leukemia (AML); however, relapse remains the principal cause of treatment failure. Improved induction regimens are needed. A prospective single-center phase Ib/II study evaluating fludarabine, cytarabine, G-CSF, and idarubicin combined with venetoclax (FLAG-IDA + VEN) in patients with newly diagnosed (ND) or relapsed/refractory AML. The primary efficacy endpoint was assessment of overall activity (overall response rate [ORR]: complete remission [CR] + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery [CRi] + morphologic leukemia free state + partial response). Secondary objectives included additional assessments of efficacy, overall survival (OS), and event-free survival (EFS). Results of the expanded ND cohort with additional follow-up are reported. Forty-five patients (median age: 44 years [range 20-65]) enrolled. ORR was 98% (N = 44/45; 95% credible interval 89.9%-99.7%). Eighty-nine percent (N = 40/45) of patients attained a composite CR (CRc + CRh + CRi) including 93% (N = 37/40) who were measurable residual disease (MRD) negative. Twenty-seven (60%) patients transitioned to allogeneic stem cell transplant (alloHSCT). Common non-hematologic adverse events included febrile neutropenia (44%; N = 20), pneumonia (22%, N = 10), bacteremia (18%, N = 8), and skin/soft tissue infections (44%, N = 20). After a median follow-up of 20 months, median EFS and OS were not reached. Estimated 24-month EFS and OS were 64% and 76%, respectively. FLAG-IDA + VEN is an active regimen in ND-AML capable of producing high MRD-negative remission rates and enabling transition to alloHSCT when appropriate in most patients. Toxicities were as expected with IC and were manageable. Estimated 24-month survival appears favorable compared to historical IC benchmarks., (© 2022 Wiley Periodicals LLC.)

Newly diagnosed acute myeloid leukemia is often deemed a medical emergency, requiring urgent treatment. This is in contradiction with the need for accurate cytogenetic and molecular data, which is not immediately available, to select optimal therapy. We hypothesized that cytoreduction with hydroxyurea or cytarabine would enable urgent disease control and provide a bridge to clinical trial enrollment. We analyzed three prospective frontline clinical trials that allowed the use of cytoreduction before treatment initiation. Among 274 patients with a median age of 62 (range, 18-89), there was no significant difference in short- and long-term outcome and safety among patients who did (CytoRed) or did not receive (NoCytoRed) cytoreduction. The overall response rate in CytoRed group was 91%, compared with 86% in NoCytoRed group (p = .264). The 30- and 60-day mortality rates were 2% and 7% in CytoRed group, compared with 2% (p = .978) and 6% (p = .652) in NoCytoRed group, respectively. There was no significant difference in overall survival (OS) between in CytoRed group compared with NoCytoRed group (Hazard ratio 0.97, 95% CI 0.70-1.37, p = .879). Results were unchanged after stratification by age (< or ≥65 years) or after multivariate analyses for OS. Our data suggests that urgent cytoreduction using hydroxyurea or cytarabine is a feasible and safe approach to facilitate acquisition of complete diagnostic information prior to treatment initiation on a clinical trial., (© 2022 Wiley Periodicals LLC.)

In older/unfit newly diagnosed patients with FLT3 mutated acute myeloid leukemia (AML), lower intensity chemotherapy (LIC) in combination with either a FLT3 inhibitor or with venetoclax results in poor overall survival (median 8 to 12.5 months). We performed a retrospective analysis of 87 newly diagnosed FLT3 mutated AML patients treated on triplet (LIC + FLT3 inhibitor + Venetoclax, [N = 27]) and doublet (LIC + FLT3 inhibitor, [N = 60]) regimens at our institution. Data were collected from prospective clinical trials in 75% (N = 65) and 25% (N = 22) who received the same treatment regimens outside of a clinical trial. Triplet therapy was associated with significantly higher rates of complete remission (CR) (67% versus 32%, P = 0.002), CR/CRi (93% versus 70%, P = 0.02), FLT3-PCR negativity (96% versus 54%, P < 0.01), and flow-cytometry negativity (83% versus 38%, P < 0.01) than doublets. At the end of the first cycle, the median time to ANC > 0.5 (40 versus 21 days, P = 0.15) and platelet > 50 K (29 versus 25 days, P = 0.6) among responders was numerically longer with triplets, but 60-day mortality was similar (7% v 10%). With a median follow-up of 24 months (median 12 months for triplet arm, and 63 months for doublet arm), patients receiving a triplet regimen had a longer median overall survival (not reached versus 9.5 months, P < 0.01). LIC combined with FLT3 inhibitor and venetoclax (triplet) may be an effective frontline regimen for older/unfit FLT3 mutated AML that should be further validated prospectively., (© 2022. The Author(s).)

Background: Posttherapy measurable residual disease (MRD) positivity in core binding factor acute myeloid leukemia (CBF-AML) is associated with shorter relapse-free survival (RFS). Elimination of MRD measured via quantitative reverse transcription polymerase chain reaction (qRTPCR) for disease specific transcripts can potentially lead to better outcomes in CBF-AML., Methods: We prospectively monitored the MRD using qRTPCR and flow cytometry on bone marrow samples in patients with newly diagnosed CBF-AML who received decitabine (DAC) maintenance therapy after fludarabine/cytarabine/G-CSF (FLAG)-based induction/consolidation regimen. Negative qRTPCR (CMR) was defined as fusion transcript <0.01%., Results: Thirty-one patients with CBF-AML including 14 with t(8;21) and 17 with inv(16) received parenteral DAC as maintenance therapy. Fifteen patients (48.3%) had completed FLAG-based induction/consolidation but with positive MRD (0.35%, range = 0.01%-0.91%) (Group 1). Sixteen patients (51.7%) could not complete recommended consolidations with FLAG-based regimen (due to older age or complications) and were switched to DAC maintenance (Group 2). In Group 2, eight patients (50%) had undetectable MRD (Group 2A) (all had qRTPCR ≤ 0.01%) and the other eight patients (50%) had residual fusion product by qRTPCR (0.1%, range = 0.02%-0.36%) (Group 2B) prior to starting DAC. Amongst the 23 patients who had a PCR ≥ 0.01% before maintenance therapy (Groups 1 and 2B), 12 patients (52%) attained a CMR as their best response (responders). The median pre-DAC qRTPCR amongst responders were 0.03% compared to 0.14% in nonresponders (p = .002). The median estimated molecular RFS amongst responders were 93.9 months. At a median follow-up of 59.3 months (13.2-106 months) from DAC initiation, 16 patients (51.6%) had to be initiated on a second line of therapy (40%, 25%, and 100% patients, respectively, in Groups1, 2A, and 2B). The median estimated time to new treatment between responders was 112.4 versus 5.8 months in nonresponders (hazard ratio = 0.16, 95% confidence interval = 0.04-0.54); however, there were no difference in overall survival between these groups (p = .37)., Conclusion: DAC is an effective maintenance therapy for CBF-AML patients with persistent fusion transcript at a low level after FLAG-based regimen. Attainment of CMR with DAC maintenance can lead to long-term remission in patients who have persistent MRD positive after FLAG-based regimen or are unable to receive the full course of consolidation therapy., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Venetoclax combined with intensive chemotherapy has been shown to be safe with promising activity in fit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to compare the activity of venetoclax plus intensive chemotherapy with intensive chemotherapy alone., Methods: This was a post-hoc propensity score matched analysis of prospective clinical trials (NCT03214562, NCT02115295, and NCT01289457) in patients at The University of Texas MD Anderson Cancer Center, Texas, USA between March 29, 2010, and June 15, 2021. Eligible patients were aged 18 years and older, and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and were treated within trials incorporating purine analogues with an anthracycline and cytarabine either with venetoclax plus intensive chemotherapy or with intensive chemotherapy alone. Patients in the venetoclax plus intensive chemotherapy cohort were matched with patients in the intensive chemotherapy cohort. Morphological response and measurable residual disease (MRD) was assessed using bone marrow aspiration and biopsy and eight-colour multiparameter flow cytometry. The primary objectives were rate of MRD negative composite complete response and cumulative incidence of transition to allogeneic haematopoietic stem-cell transplantation (HSCT). All patients who had response within two treatment cycles (induction and re-induction) were included in the analyses. Secondary objectives included assessment of event-free and overall survival., Findings: The propensity matched cohort included 279 patients (median age 49 years [IQR 39-57]; 131 [47%] were men and 148 [53%] were women); 85 in the venetoclax plus intensive chemotherapy cohort and 194 in the intensive chemotherapy cohort. After a median follow up of 30 months (95% CI 26-36), 64 (86%) of 74 patients in the venetoclax plus intensive chemotherapy cohort had an MRD-negative composite complete response rate compared with 86 [61%] of 140 patients in the intensive chemotherapy cohort (odd ratio 3·2 [95% CI 1·5-6·7]; p=0·0028). The overall cumulative incidence of allogeneic HSCT in responding patients was higher with venetoclax plus intensive chemotherapy than intensive chemotherapy (79% [95% CI 67-88] vs 57% [49-65]; hazard ratio [HR] 1·52 [95% CI 1·11-2·08]; p=0·012). Venetoclax plus intensive chemotherapy improved event-free survival (median not reached [NR; 95% CI NR-NR] vs 14·3 months [10·7-33·5]; HR 0·57 [95% CI 0·34-0·95]; p=0·030), but overall survival did not significantly differ between the two cohorts (median NR [95% CI 24-NR] vs 32 months [19-NR]; HR 0·63 [95% CI 0·35-1·1], p=0·13)., Interpretations: Venetoclax combined with intensive induction chemotherapy induced deep MRD-negative remissions, allowing transition to allogeneic HSCT in first remission, and improvement in event-free survival. These results highlight the incremental benefit of venetoclax added to intensive induction chemotherapy across European LeukemiaNet risk groups, and serve as a benchmark to inform enrolment on future confirmatory prospective clinical trials., Funding: None., Competing Interests: Declaration of interests GB reports consultancy fees from Protagonist Therapeutics, research funding from Ryvu, membership on an entity's Board of Directors or advisory committees from Takeda, research funding from Astex, membership on an entity's Board of Directors or advisory committees from ArgenX, current employment by University of Texas MD Anderson Cancer Center, consultancy and membership on an entity's Board of Directors or advisory committees from Novartis, and consultancy from GSK. MY reports research funding from Daiichi-Sankyo and Pfizer. NP reports consultancy from DAVA Oncology, LFB Biotechnologies, MustangBio, Stemline Therapeutics, Affymetrix, Roche Diagnostics, Blueprint Medicines, Clearview Healthcare Partners, Novartis Pharmaceuticals, Celgene Corporation, Incyte, Protagonist Therapeutics, Abbvie Pharmaceuticals, Aptitude Health, Bristol-Myers Squibb, ImmunoGen, Pacylex Pharmaceuticals, and CareDx; membership on the Board of Directors or advisory committees of ASCO Leukemia Advisory Panel, Dan's House of Hope, Stemline Therapeutics, Abbvie Pharmaceuticals, ASH Communications Committee, and HemOnc Times/Oncology Times; and grants or contracts from Sager Strong Foundation, MustangBio, Daiichi Sankyo, Springer Science + Business Media, Stemline Therapeutics, Samus, Novartis Pharmaceuticals, Abbvie Pharmaceuticals, Plexxicon, and Cellectis S.A. ADR; research funding from Cellectis S.A. ADR, Daiichi Sankyo, Affymetrix, Samus, Novartis Pharmaceuticals, Abbvie Pharmaceuticals, Plexxicon, and Stemline Therapeutics; and research support from Novartis Pharmaceuticals. UP reports research funding from Bayer, Abbvie, Novartis, and Incyte. ES reports honoraria from Magenta, Novartis, and Bayer HealthCare Pharmaceuticals; consultancy from Navan, Axio, Adaptimmune, Magenta, and Novartis; and patents and royalties from Affimed and Takeda. CDD reports membership on an entity's Board of Directors or advisory committees from GlaxoSmithKline and Notable Labs; current stock options in a privately-held company in Notable Labs, honoraria from ImmuneOnc, Bristol Myers Squibb, Agios/Servier, Takeda, Novartis, Foghorn, Celgene a Bristol Myers Squibb company, and Forma; research funding from ImmuneOnc, and Bristol Myers Squibb, AbbVie, Agios/Servier, Foghorn, Celgene a Bristol Myers Squibb company, and Forma; and consultancy for AbbVie and Agios/Servier. TMK reports consultancy from Abbvie, Sanofi-Aventis, Liberum, Jazz, Genentech, Daiichi Sankyo, Novartis, Pfizer, and Aglos; grant or research support from Abbvie, Genentech, Bristol Myers Squibb, and Amgen; speaker's bureau fees from Cure, and research support from Genfleet, Cellonkos, Astellas, AstraZeneca, Ascentage, and Pulmotech. ND reports consultancy for Novartis, Trovagene, Abbvie, Genentech, Amgen, Pfizer, Bristol Myers Squibb, Astellas, Daiichi Sankyo, Sevier, ImmunoGen, Gilead Sciences, Trillium, Dava Oncology (Arog), Celgene, Syndax, Shattuck Labs, Agios, Kite Pharmaceuticals, SOBI, STAR Therapeutics, and Jazz Pharmaceuticals; member of the Data Monitoring Committee for Jazz Pharmaceuticals; research funding from Trovagene, Genentech, FATE Therapeutics, Hanmi, Amgen, Pfizer, Bristol Myers Squibb, Novimmune, Astellas, Daiichi Sankyo, Sevier, ImmunoGen, Glycomimetics, Gilead Sciences, Trillium, Karyopharm, Newave, and Abbvie. NJS reports consultancy for Takeda Oncology, Jazz Pharmaceuticals, NGMBio, AstraZeneca, and Amgen; research funding from Takeda Oncology and Astellas; honoraria from Amgen, and Novartis. MK reports grant support from Agios, Rafael Pharmaceuticals, Cellectis, Ascentage, AstraZeneca, Sanofi, Ablynx, Genentech, Forty Seven, AbbVie, F Hoffmann-La Roche, and Calithera; research funding from Agios, Rafael Pharmaceuticals, KisoJi, Eli Lilly, Ascentage, AstraZeneca, Sanofi, Ablynx, Genentech, Forty Seven, AbbVie, Stemline Therapeutics, and Calithera; intellectual property rights from Eli Lilly, Novartis, and Reata Pharmaceuticals; current stock options in Reata Pharmaceuticals; pending research funding from Novartis; consultancy for Genentech, F Hoffmann-La Roche, and AbbVie; honoraria from Genentech, F Hoffmann-La Roche, and AbbVie. FR reports honoraria from Astex, Taiho, Bristol Myers Squibb, Xencor, Agios, AstraZeneca, Novartis, AbbVie, Celgene, Jazz, Syros Pharmaceuticals, and Amgen; research funding from Astex, Taiho, Bristol Myers Squibb, Xencor, Agios, Prelude, AbbVie, Celgene, Jazz, Syros Pharmaceuticals, and Amgen; membership on the Board of Directors or advisory committees of Bristol Myers Squibb and Celgene; consultancy for Syros Pharmaceuticals. KT reports consultancy for Novartis, Celgene/BMS, GSK, and Symbio Pharmaceuticals; and membership on Symbio Pharmaceuticals’ Board of Directors or advisory committee. SL reports current equity in publicly-traded Abbvie; honoraria from Curio Sciences and Peerview; and consultancy for Gerson Lehrman Group, Guidepoint, and Qualworld. KS reports consultancy for Novartis; research funding from Novartis; membership on the Board of Directors or advisory committees of Pfizer and Daiichi-Sankyo. HK reports honoraria from AbbVie, Ipsen Pharmaceuticals, AstraZeneca, KAHR Medical, Aptitude Health, Pfizer, Astellas Health, Novartis, NOVA Research, Precision Biosciences, Taiho Pharmaceutical Canada, and Amgen; research funding from AbbVie, Immunogen, BMS, Jazz Pharmaceuticals, Ascentage, Daiichi-Sankyo, Pfizer, Novartis, and Amgen. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Mutations in fms-like tyrosine kinase 3 (FLT3) gene are common genomic alterations in acute myeloid leukemia (AML). FLT3 internal tandem duplication mutations (FLT3-ITD) have consistently been shown to be adversely prognostic, particularly those with high allelic ratio (AR). Current AML treatment strategies, including high dose cytarabine, purine analogs, FLT3 inhibitors (FLT3i), and with or without allogeneic stem cell transplant (SCT) have been shown to improve the outcomes in patients with FLT3 mutations. We analyzed a consecutive cohort of newly diagnosed patients with AML treated at a large academic medical center from January 2012 to January 2020. A total of 1576 patients with a new diagnosis of AML were reviewed. Among these, 1438 (91%) had molecular testing for FLT3 mutations and 21% (304/1438) had an FLT3 mutation, including 17% with an FLT3-ITD mutation. We show that FLT3-ITD high AR with NPM1 wild-type have significantly improved survival compared with other European LeukemiaNet (ELN) adverse risk disease. In multivariable cox proportional hazards model of patients receiving intensive or low-intensity induction regimens, FLT3 mutations did not have prognostic significance. The use of allogeneic SCT in CR1 for patients with FLT3 mutations appears to improve survival, particularly in those with ELN adverse risk disease. Overall, this data highlights the changing prognostic impact of FLT3 mutations in a contemporary era with appropriate use of induction therapy combined with targeted agents and allogenic SCT., (© 2022 Wiley Periodicals LLC.)

Introduction: RAS pathway mutations are common mechanisms of resistance to acute myeloid leukemia (AML) therapies. Trametinib, an oral MEK inhibitor, has been shown to have single-agent activity in relapsed/refractory AML and preclinical synergy with venetoclax., Methods: We conducted a single-center, open-label, phase 2 trial of the combination of azacitidine, venetoclax, and trametinib in patients with relapsed or refractory AML harboring a RAS pathway-activating mutation., Results: Sixteen patients were treated. The patients were heavily pretreated with a median number of 4 prior therapies; 13 (81%) had received a prior hypomethylating agent (HMA) with venetoclax, and 8 (50%) had undergone prior stem cell transplant. Four patients (25%) responded (CR, n = 1; CRi, n = 1; MLFS, n = 2). Two of the 3 patients (67%) who had not previously received HMA plus venetoclax responded; in contrast, only 2 of the 13 patients (15%) who had previously received HMA plus venetoclax responded. The median OS was 2.4 months, and the 6-month OS rate was 31%. Related grade 3-4 adverse events occurred in 50% of patients, and 50% of patients required a dose adjustment of trametinib., Conclusions: The combination of azacitidine, venetoclax, and trametinib had only modest activity in patients with relapsed/refractory AML, with a response rate that was similar to previous reports of trametinib monotherapy. Substantial toxicity was observed with this combination. Given the established role of RAS pathway mutations in mediating resistance to AML therapies, future studies of better tolerated, more active inhibitors of this pathway are still needed., (© 2022 S. Karger AG, Basel.)

Plasmacytoid dendritic cells (pDCs) serve as immunoregulatory antigen-presenting cells that play a role in various inflammatory, viral, and malignant conditions. Malignant proliferation of pDCs is implicated in the pathogenesis of certain hematologic cancers, specifically blastic plasmacytoid dendritic cell neoplasm (BPDCN) and acute myelogenous leukemia with clonal expansion of pDC (pDC-AML). In recent years, BPDCN and pDC-AML have been successfully treated with targeted therapy of pDC-specific surface marker, CD123. However, relapsed and refractory BPDCN remains an elusive cancer, with limited therapeutic options. CD303 is another specific surface marker of human pDCs, centrally involved in antigen presentation and immune tolerance. Monoclonal antibodies directed against CD303 have been studied in preclinical models and have achieved disease control in patients with cutaneous lupus erythematosus. We performed a comprehensive review of benign and malignant disorders in which CD303 have been studied, as there may be a potential future CD303-directed therapy for many of these conditions.

Myeloid sarcoma (MS) in the setting of concomitant medullary AML is relatively well described, while much less is known about patients presenting with MS with <20% bone marrow blasts. We conducted a retrospective analysis of 56 patients with MS with <20% marrow blasts seen at MD Anderson between 2005 and 2020. The prevalence of MS without medullary AML was 1.4% among all newly diagnosed AML patients. The majority (75%) of patients had a single known anatomic site involved, with the skin (34%) being the most frequent. The most common histologic subtype was monocytic, and 11% of patients had a known history of an antecedent hematologic disorder. The majority of patients (70%) received frontline intensive chemotherapy induction, with 75% of those evaluable attaining complete or partial responses. The median overall survival (OS) and event-free survival (EFS) were 3.41 and 3.07 years, respectively. Patients with bone marrow blasts of ≥5% or medullary relapse had inferior outcomes, while age (>60 years) was not associated with outcomes. There was a suggestion that patients with isolated leukemia cutis may have had better outcomes compared to patients with other organ involvement, but this did not reach statistical significance. Most patients who had cytogenetic analysis had a diploid karyotype within their MS and bone marrow . RAS pathway mutations were enriched in MS at diagnosis, and at time of medullary relapse. Our study provides a large dataset summarizing the clinical and molecular analysis of patients with MS with <20% BM blasts and suggests that monitoring for medullary leukemia is important for early detection of relapse.

Background: Relapsed/refractory (R/R) acute myeloid leukemia (AML) has poor outcomes. Although lower-intensity venetoclax-containing regimens are standard for older/unfit patients with newly diagnosed AML, it is unknown how such regimens compare with intensive chemotherapy (IC) for R/R AML., Methods: Outcomes of R/R AML treated with 10-day decitabine and venetoclax (DEC10-VEN) were compared with IC-based regimens including idarubicin with cytarabine, with or without cladribine, clofarabine, or fludarabine, with or without additional agents. Propensity scores derived from patient baseline characteristics were used to match DEC10-VEN and IC patients to minimize bias., Results: Sixty-five patients in the DEC10-VEN cohort were matched to 130 IC recipients. The median ages for the DEC10-VEN and IC groups were 64 and 58 years, respectively, and baseline characteristics were balanced between the 2 cohorts. DEC10-VEN conferred significantly higher responses compared with IC including higher overall response rate (60% vs 36%; odds ratio [OR], 3.28; P < .001), complete remission with incomplete hematologic recovery (CRi, 19% vs 6%; OR, 3.56; P = .012), minimal residual disease negativity by flow cytometry (28% vs 13%; OR, 2.48; P = .017), and lower rates of refractory disease. DEC10-VEN led to significantly longer median event-free survival compared with IC (5.7 vs 1.5 months; hazard ratio [HR], 0.46; 95% CI, 0.30-0.70; P < .001), as well as median overall survival (OS; 6.8 vs 4.7 months; HR, 0.56; 95% CI, 0.37-0.86; P = .008). DEC10-VEN was independently associated with improved OS compared with IC in multivariate analysis. Exploratory analysis for OS in 27 subgroups showed that DEC10-VEN was comparable with IC as salvage therapy for R/R AML., Conclusion: DEC10-VEN represents an appropriate salvage therapy and may offer better responses and survival compared with IC in adults with R/R AML., (© 2021 American Cancer Society.)

Although clonal hematopoiesis (CH) can precede the development of acute myeloid leukemia (AML), it can also persist after achieving remission. Long-term clonal dynamics and clinical implications of persistent CH are not well understood. Here, we studied the prevalence, dynamics, and clinical implications of postremission CH in 164 AML patients who attained complete remission after induction chemotherapies. Postremission CH was identified in 79 (48%) patients. Postremission CH persisted long term in 91% of the trackable patients despite treatment with various types of consolidation and maintenance therapies. Postremission CH was eradicated in 20 out of 21 (95%) patients who underwent allogeneic stem cell transplant. Although patients with postremission CH as a group had comparable hematopoiesis with those without it, patients with persistent TET2 mutations showed significant neutropenia long term. Postremission CH had little impact on relapse risk, nonrelapse mortality, and incidence of atherosclerotic cardiovascular disease, although the clinical impact of post-CR CH was heterogeneous among different mutations. These data suggest that although residual clonal hematopoietic stem cells are generally resistant to consolidation and maintenance therapies, they retain the ability to maintain normal hematopoiesis and have little impact on clinical outcomes. Larger study is needed to dissect the gene-specific heterogeneity., (© 2021 by The American Society of Hematology.)

Following the observation of interleukin 3 receptor α chain (IL-3Rα; CD123) upregulation on leukemia stem cells (LSCs) almost two decades ago, targeted treatment via CD123-diptheria toxin conjugates has now been tested in patients with diverse myeloid malignancies. Targeted eradication of LSCs could result in effective treatments for many challenging diseases initiated by these cells. Consequently, considerable effort has been directed toward targeting CD123 as a potential strategy for treating patients with hematologic malignancies in which CD123 is overexpressed. However, these therapies have had limited success so far, highlighting the need for suitable criteria to identify patients who could benefit from them. Given the diversity in CD123 expression across different hematologic malignancies, understanding CD123 expression patterns and the functional pathogenetic significance is crucial. Here, we review the methodologies available for CD123 assessment and discuss the biological and clinical characteristics of patients for whom CD123-targeting therapies may have a clinical impact.

Background: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. In preclinical models of AML, inhibition of the PD-1/PD-L1 axis demonstrated antileukemic activity. Avelumab is an anti-PD-L1 immune checkpoint inhibitor (ICI) approved in multiple solid tumors. The authors conducted a phase 1b/2 clinical trial to assess the safety and efficacy of azacitidine with avelumab in patients with R/R AML., Methods: Patients aged ≥18 years who had R/R AML received azacitidine 75 mg/m 2 on days 1 through 7 and avelumab on days 1 and 14 of 28-day cycles., Results: Nineteen patients were treated. The median age was 66 years (range, 22-83 years), 100% had European LeukemiaNet 2017 adverse-risk disease, and 63% had prior exposure to a hypomethylating agent. Avelumab was dosed at 3 mg/kg for the first 7 patients and at 10 mg/kg for the subsequent 12 patients. The most common grade ≥3 treatment-related adverse events were neutropenia and anemia in 2 patients each. Two patients experienced immune-related adverse events of grade 2 and grade 3 pneumonitis, respectively. The overall complete remission rate was 10.5%, and both were complete remission with residual thrombocytopenia. The median overall survival was 4.8 months. Bone marrow blasts were analyzed for immune-related markers by mass cytometry and demonstrated significantly higher expression of PD-L2 compared with PD-L1 both pretherapy and at all time points during therapy, with increasing PD-L2 expression on therapy., Conclusions: Although the combination of azacitidine and avelumab was well tolerated, clinical activity was limited. High expression of PD-L2 on bone marrow blasts may be an important mechanism of resistance to anti-PD-L1 therapy in AML., Lay Summary: This report describes the results of a phase 1b/2 study of azacitidine with the anti-PD-L1 immune checkpoint inhibitor avelumab for patients with relapsed/refractory acute myeloid leukemia (AML). The clinical activity of the combination therapy was modest, with an overall response rate of 10.5%. However, mass cytometry analysis revealed significantly higher expression of PD-L2 compared with PD-L1 on AML blasts from all patients who were analyzed at all time points. These data suggest a novel potential role for PD-L2 as a means of AML immune escape., (© 2021 American Cancer Society.)

Background: Venetoclax (VEN) in combination with a hypomethylating agent (HMA) has become the standard of care for patients aged >75 years and for those not eligible for intensive chemotherapy who have newly diagnosed acute myeloid leukemia (AML). The benefit of VEN-based therapy in patients who have newly diagnosed AML with mutations in the TP53 gene (TP53 mut ) over standard therapy is undefined., Methods: In this single-institutional, retrospective analysis, the authors assessed the clinical outcomes of 238 patients with newly diagnosed TP53 mut AML and compared the clinical characteristics, response to different therapies, and outcomes of those who received VEN-based (n = 58) and non-VEN-based (n = 180) regimens., Results: Patients who received VEN-based regimens were older (aged >65 years: 81% vs 65%; P = .02) and had higher response rates (complete remission, 43% vs 32%; P = .06) than those who received non-VEN-based regimens. Compared with patients who received non-VEN-based regimens, no difference in overall survival (median, 6.6 vs 5.7 months; P = .4) or relapse-free survival (median, 4.7 vs 3.5 months; P = .43) was observed in those who received VEN-based regimens, regardless of age or intensity of treatment., Conclusions: The addition of VEN to standard treatment regimens did not improve outcomes in younger or older patients who had TP53 mut AML. These data highlight the need for novel therapies beyond VEN to improve the outcome of patients with TP53 mut AML., (© 2021 American Cancer Society.)

Purpose: Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving frontline therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refractory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic options. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML., Materials and Methods: The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-escalation algorithm for identification of maximum tolerated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML., Results: Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events occurring in ≥ 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a composite CR. Measurable residual disease-negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improvement in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML., Conclusion: Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep remissions and a high rate of transition to successful transplantation., Competing Interests: Courtney D. DiNardoLeadership: Notable LabsStock and Other Ownership Interests: Notable LabsHonoraria: Agios, Celgene, AbbVie, Jazz Pharmaceuticals, Daiichi Sankyo, Novartis, TakedaConsulting or Advisory Role: Celgene, Agios, AbbVieResearch Funding: AbbVie, Agios, Celgene, Daiichi Sankyo Koichi TakahashiHonoraria: Celgene, Novartis, GlaxoSmithKline, SymBio Pharmaceuticals, DAVA PharmaceuticalsConsulting or Advisory Role: SymBio Pharmaceuticals, Novartis, GlaxoSmithKline, CelgeneResearch Funding: Onconova TherapeuticsTravel, Accommodations, Expenses: SymBio Pharmaceuticals, Celgene, GlaxoSmithKline, DAVA Pharmaceuticals Sanam LoghaviStock and Other Ownership Interests: AbbVie, PureTechHonoraria: Curio ScienceConsulting or Advisory Role: Seattle Genetics, Gerson Lehrman Group, Guidepoint GlobalTravel, Accommodations, Expenses: Curio Science Tapan KadiaConsulting or Advisory Role: Novartis, Jazz Pharmaceuticals, Pfizer, AbbVie/Genentech, AgiosResearch Funding: Bristol Myers Squibb, Celgene, Sanofi, Amgen, BiolineRx, Incyte, Genentech/AbbVie, Pfizer, Jazz Pharmaceuticals, AstraZeneca, Astellas Pharma, Ascentage Pharma, Genfleet, Cyclacel Naval DaverHonoraria: BMS, Jazz Pharmaceuticals, Novartis, Incyte, Otsuka, Immunogen, Pfizer, Astellas Pharma, AbbVieConsulting or Advisory Role: Celgene, Agios, Jazz Pharmaceuticals, Pfizer, AbbVie, Astellas Pharma, Daiichi Sankyo, Novartis, Bristol Myers Squibb, Otsuka, Incyte, Karyopharm Therapeutics, Sunesis Pharmaceuticals, Amgen, Immunogen, Genentech, Servier, Syndax, Trillium TherapeuticsResearch Funding: Bristol Myers Squibb, Pfizer, Immunogen, Genentech, Nohla Therapeutics, AbbVie, Astellas Pharma, Servier, Daiichi Sankyo, Novartis, Karyopharm Therapeutics, Incyte, Sunesis Pharmaceuticals, Sobi Nicholas J. ShortHonoraria: AmgenConsulting or Advisory Role: AstraZenecaResearch Funding: Takeda, Astellas Pharma Koji SasakiHonoraria: OtsukaConsulting or Advisory Role: Novartis, Pfizer, TakedaResearch Funding: NovartisTravel, Accommodations, Expenses: Otsuka Sa WangConsulting or Advisory Role: Boston Biomedical, GlaxoSmithKline, Blueprint Medicines, CapricoResearch Funding: GlaxoSmithKline, Autolus Ltd, Genmab Gautam BorthakurConsulting or Advisory Role: Argenx, PTC Therapeutics, BiolineRx, BioTheryX, Nkarta, Treadwell Therapeutics, Novartis, Catamaran Bio, TakedaResearch Funding: Incyte, GlaxoSmithKline, Cyclacel, BiolineRx, MedImmune, Lilly, Oncoceutics, Ryvu Therapeutics, Janssen Scientific Affairs, Bristol Myers Squibb, AbbVie, Novartis, AstraZeneca, Mundipharma Research, PTC Therapeutics, BioTheryX, XBiotech, Arvinas, Astex Pharmaceuticals, TCR2 Therapeutics, Nkarta, Treadwell Therapeutics, Cellestia Biotech Ghayas IssaConsulting or Advisory Role: Novartis, Kura OncologyResearch Funding: Novartis, Syndax, Kura Oncology Abhishek MaitiResearch Funding: Celgene Yesid AlvaradoResearch Funding: Jazz Pharmaceuticals, FibroGen, Sun Pharma, BerGenBio, Daiichi Sankyo/Lilly, Astex Pharmaceuticals Naveen PemmarajuEmployment: MD Anderson Cancer CenterLeadership: ASH, ASCOHonoraria: Incyte, Novartis, LFB Biotechnologies, Stemline Therapeutics, Celgene, AbbVie, MustangBio, Roche Molecular Diagnostics, Blueprint Medicines, DAVA Pharmaceuticals, SpringerConsulting or Advisory Role: Blueprint Medicines, Pacylex, Immunogen, Bristol Myers SquibbResearch Funding: Novartis, Stemline Therapeutics, Samus Therapeutics, AbbVie, Cellectis, Affymetrix/Thermo Fisher Scientific, Daiichi Sankyo, PlexxikonTravel, Accommodations, Expenses: Stemline Therapeutics, Celgene, AbbVie, DAVA Oncology, MustangBioUncompensated Relationships: Dan's House of Hope, Oncology Times Guillermo BravoResearch Funding: IFM Therapeutics Musa YilmazResearch Funding: Daiichi Sankyo, Pfizer Nitin JainHonoraria: Pharmacyclics, ADC Therapeutics, Adaptive Biotechnologies, AbbVie/Genentech, Janssen, AstraZeneca/MedImmune, Servier, Precision Biosciences, BeiGene, TG Therapeutics, Cellectis, Bristol Myers Squibb/CelgeneConsulting or Advisory Role: Pharmacyclics, ADC Therapeutics, Adaptive Biotechnologies, AbbVie/Genentech, Janssen, AstraZeneca/MedImmune, Servier, Precision Biosciences, BeiGene, TG Therapeutics, Cellectis, Bristol Myers Squibb/CelgeneResearch Funding: Pfizer, Pharmacyclics, AbbVie, Genentech/Roche, Incyte, Infinity Pharmaceuticals, Bristol Myers Squibb, Seattle Genetics, Celgene, ADC Therapeutics, Servier, AstraZeneca/MedImmune, Cellectis, Adaptive Biotechnologies, Precision Biosciences, Aprea Therapeutics, Fate Therapeutics, Kite, a Gilead company Michael AndreefStock and Other Ownership Interests: Reata Pharmaceuticals, Aptose Biosciences, Eutropics, Senti Biosciences, Oncoceutics, OncolyzeConsulting or Advisory Role: Daiichi Sankyo, Jazz Pharmaceuticals, Celgene, Amgen, AstraZenecaResearch Funding: Daiichi Sankyo, Breast Cancer Research Foundation, United Therapeutics, Ono Pharmaceutical, Karyopharm Therapeutics, CPRIT, NIH/NCI, Amgen, AstraZenecaPatents, Royalties, Other Intellectual Property: Patent with ReataTravel, Accommodations, Expenses: Aptose Biosciences, Oncoceutics, Amgen, AstraZeneca Elias JabbourConsulting or Advisory Role: Pfizer, Takeda, Amgen, AbbVie, Bristol Myers Squibb, Incyte, Adaptive Biotechnologies, Astellas Pharma, GenentechResearch Funding: Pfizer, AbbVie, Amgen, Takeda, Adaptive Biotechnologies, Ascentage Pharma Group Guillermo Garcia-ManeroHonoraria: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Helssin, AbbVieConsulting or Advisory Role: Celgene, Astex Pharmaceuticals, Acceleron Pharma, Jazz Pharmaceuticals, Bristol Myers Squibb, Helsinn TherapeuticsResearch Funding: Celgene, Astex Pharmaceuticals, Amphivena, Helsinn Therapeutics, Novartis, AbbVie, Bristol Myers Squibb, Onconova Therapeutics, H3 Biomedicine, Merck Farhad RavandiHonoraria: Amgen, Pfizer, Astellas Pharma, Orsenix, Celgene, Agios, AbbVie/Genentech, AstraZeneca, Bristol Myers Squibb, Takeda, Jazz Pharmaceuticals, NovartisConsulting or Advisory Role: Amgen, Astellas Pharma, Orsenix, Celgene, Jazz Pharmaceuticals, Agios, AbbVie/Genentech, Bristol Myers Squibb, AstraZeneca, Taiho Oncology, Syros Pharmaceuticals, Certara IncResearch Funding: Bristol Myers Squibb, Amgen, Macrogenics, Xencor, Selvita, Cellerant Marina Y. KonoplevaHonoraria: AbbVie, Genentech, Roche, Amgen, Stemline Therapeutics, KisoJi BiotechnologyConsulting or Advisory Role: AbbVie, Genentech/Roche, Stemline Therapeutics, Amgen, Forty Seven, KisoJi Biotechnology, Roche, JanssenResearch Funding: AbbVie, Genentech, Roche, Lilly, Cellectis, Calithera Biosciences, Ablynx, Agios, Ascentage Pharma, AstraZeneca, SanofiPatents, Royalties, Other Intellectual Property: Novartis—Pending, Eli Lilly—Research Funding; Issued/Licensed, Reata Pharmaceutical—Research Funding (Issued, Licensed, Royalities) Hagop M. KantarjianHonoraria: AbbVie, Amgen, ARIAD, Bristol Myers Squibb, Immunogen, Orsenix, Pfizer, Agios, Takeda, Actinium PharmaceuticalsResearch Funding: Pfizer, Amgen, Bristol Myers Squibb, Novartis, ARIAD, Astex Pharmaceuticals, AbbVie, Agios, Cyclacel, Immunogen, Jazz PharmaceuticalsNo other potential conflicts of interest were reported.

Background: There are limited data on the clonal mechanisms underlying leukemogenesis, prognostic factors, and optimal therapy for atypical chronic myeloid leukemia (aCML)., Methods: The authors evaluated the clinicopathologic features, outcomes, and responses to therapy of 65 patients with aCML. The median age was 67 years (range, 46-89 years)., Results: The most frequently mutated genes included ASXL1 (83%), SRSF2 (68%), and SETBP1 (58%). Mutations in SETBP1, SRSF2, TET2, and GATA2 appeared at variant allele frequencies (VAFs) greater than 40%, whereas other RAS pathway mutations were more likely to appear at low VAFs. The acquisition of new, previously undetectable mutations at transformation was observed in 63% of the evaluable patients, with the most common involving signaling pathway mutations. Hypomethylating agents (HMAs) were associated with the highest response rates but with a short duration of response (median, 2.7 months). Therapy with ruxolitinib was not associated with clinically significant responses as a single agent or in combination with an HMA. Allogeneic stem cell transplantation was the only therapy associated with improved outcomes (hazard ratio, 0.144; 95% CI, 0.035-0.593; P = .007). Age, platelet counts, bone marrow blast percentages, and serum lactate dehydrogenase (LDH) levels were independent predictors of survival and were integrated in a multivariable model that allowed the prediction of 1- and 3-year survival., Conclusions: aCML is characterized by high frequencies of ASXL1, SRSF2, and SETBP1 mutations and is associated with a high risk of acute myeloid leukemia transformation. Response and survival outcomes with current therapies remain poor. The incorporation of age, platelet counts, bone marrow blast percentages, and LDH levels can allow survival prediction, and allogeneic stem cell transplantation should be considered for all eligible patients., (© 2021 American Cancer Society.)

The treatment of older patients with newly diagnosed acute myeloid leukemia (AML) using intensive chemotherapy is associated with treatment intolerance and poor survival. We evaluated two new lower-intensity regimens with clofarabine (n = 119) or cladribine (n = 129) combined with low-dose cytarabine (LDAC) alternating with decitabine. We reviewed response rates by subgroup and long term outcomes of 248 patients with newly diagnosed non core-binding-factor AML treated on two clinical trials investigating double nucleoside-analogue therapy (DNT) alternating with HMA from October, 2008 to April, 2018. Of 248 patients with a median age of 69 years (range, 49-85 years), 102 patients (41%) were ≥ 70 years, and 108 (44%) had adverse karyotype. Overall, 164 patients (66%) responded: 147 (59%) complete remission (CR) and 17 (7%) CR with incomplete count recovery (CRi). With a median follow up of 60 months, median relapse-free and overall survival (OS) were 10.8 and 12.5 months, respectively. The 2-year OS was 29%. Among patients with normal karyotype, the CR/CRi rate was 79% and the median OS 19.9 months. High response rates and OS were observed in patients with mutations in NPM1, FLT3, IDH2, and RUNX1. The 4- and 8-week mortality rates were 2% and 11%, respectively. The backbone of clofarabine or cladribine and LDAC alternating with decitabine was effective and safe for the treatment of older patients with newly diagnosed AML. Incorporating targeted therapies could extend the efficacy of this approach and provide more curative therapeutic options in this AML population., (© 2021 Wiley Periodicals LLC.)

Background: Addition of the BCL2 inhibitor venetoclax to lower intensity therapy has been shown to improve overall survival in older (aged 75 years or older) and unfit patients with newly diagnosed acute myeloid leukaemia. The aim of this study was to investigate the activity of venetoclax combined with intensive chemotherapy in patients aged 65 years or younger with acute myeloid leukaemia., Methods: This cohort study was done at the MD Anderson Cancer Center in the USA, as part of the single-centre, single arm, phase 2, CLIA trial. Here we report on the independent cohort investigating the safety and activity of venetoclax added to intensive chemotherapy (the CLIA regimen [cladribine, high-dose cytarabine, idarubicin]). Eligible patients were aged 18-65 years with a new diagnosis of acute myeloid leukaemia, mixed phenotype acute leukaemia, or high-risk myelodysplastic syndrome (≥10% blasts or International Prognostic Scoring System ≥2 [intermediate]), who received no previous potentially curative therapy for leukaemia. Patients received cladribine (5 mg/m 2 ) and cytarabine (1·5 g/m 2 for patients aged <60 years, 1 g/m 2 for patients aged ≥60 years) intravenously on days 1-5 and idarubicin (10 mg/m 2 ) intravenously on days 1-3. Consolidation was cladribine (5 mg/m 2 ) and cytarabine (1 g/m 2 for patients aged <60 years and 0·75 g/m 2 for patients aged ≥60 years) on days 1-3 and idarubicin (8 mg/m 2 ) on days 1-2. Venetoclax (400 mg) was given on days 2-8 with each course. Patients with a known FLT3-ITD or FLT3-TKD mutation received midostaurin or gilteritinib. The primary outcome was composite complete response (complete response plus complete response with incomplete blood count recovery). Secondary outcomes were overall response, duration of response, event-free survival, overall survival, and safety. This trial was registered with ClinicalTrials.gov, NCT02115295., Findings: Between Feb 25, 2019, and March 23, 2021, 77 patients were assessed for eligibility, 50 of whom were enrolled. Median age was 48 years (IQR 37-56). 47 (94% [95% CI 83-98]) patients had composite complete response, with the same proportion also having an overall response; two (4% [1-14]) patients did not respond, and one (2% [0-11]) patient died during induction. 37 (82% [95% CI 68-92]) of 45 patients had undetectable measurable residual disease (MRD). At a median follow-up of 13·5 months (IQR 6·4-19·5), the median duration of response, event-free survival, and overall survival were not reached. At 12 months, the estimated duration of response was 74% (95% CI 60-92), event-free survival was 68% (54-85), and overall survival was 85% (75-97). The most common adverse events of grade 3 or worse were febrile neutropenia (42 [84%] patients), infection (six [12%]), and alanine aminotransferase elevations (six [12%]). There was one death during induction in a patient treated with CLIA-venetoclax plus a FLT3 inhibitor. Two patients died of infectious complications while in complete response in consolidation cycles, both of whom had FLT3-mutated acute myeloid leukaemia and were receiving combined therapy with a FLT3 inhibitor. No deaths were deemed to be treatment related., Interpretation: Venetoclax added to CLIA was safe and active in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, producing high rates of durable MRD-negative remissions and encouraging event-free survival and overall survival., Funding: MD Anderson Cancer Center., Competing Interests: Declaration of interests TMK reports grants from Amgen, Ascentage, Astellas, AstraZeneca, BMS, Cellenkos, Pulmotech, Cyclacel, Glycomimetics, Incyte, and Genfleet; personal fees from Agios, Cure, Daichi Sankyo, Genzyme, Liberum, Novartis, and Sanofi-Aventis; and grants and personal fees from Abbvie, Genetech, Jazz Pharmaceuticals, and Pfizer. GB reports grants from Oncoceutics, Xbiotech USA, Arvina, Polaris, AstraZeneca, BMS, Cyclacel, GlaxoSmithKline, Janssen, Incyte, and AbbVie; personal fees from Argenx, PTC Therapeutics, BioTheryX, Nkarta, Treadwell Therapeutics, and Curio Science; and grants and personal fees from FTC Therapeutics, BioLine Rx, and Novartis. MY reports research support from Daiichi-Sankyo and Pfizer. CDD reports research support from Calithera, Cleave, Jazz, and Loxo; personal fees from Aprea, Cleave, Novartis, Takeda, and Notable Labs; and grants and personal fees from Abbvie, Agios, ImmuneOnc, Celgene/BMS, and Daiichi Sankyo. ND reports research support from NOHLA, Glycomimetics, Sobi, Hanmi, Forty Seven, Newave, Trovagene, Covance, FATE, and Novimmune; personal fees from Otsuka, Celgene, Incyte, Jazz Pharmaceuticals, Immunogen, Agios, Syndax, and Trillium; and grants and personal fees from Pfizer, BMS, Novartis, Daiichi-Sankyo, Karyopharm, Incyte, Abbvie, Genetech, Immunogen, Astellas, Servier, Gilead, Amgen, and Sunesis. NJ reports grants from Pfizer, Incyte, Aprea Therapeutics, Fate Therapeutics, and Kite; personal fees from Janssen, Beigene, and TG Therapeutics; and grants and personal fees from Pharmacyclics, AbbVie, Genentech, AstraZeneca, BMS, ADC Therapeutics, Cellectis, Adaptive Biotechnologies, Servier, and Precision Biosciences. NP reports grants from Affymetrix, SagerStrong Foundation, Samus Therapeutics, Cellectis, Daiichi Sankyo, and Plexxikon; personal fees from Pacylex Pharmaceuticals, ImmunoGen, BMS, Blueprint Medicines, Incyte, LFB Biotechnologies, Celgene, AbbVie, MustangBio, Roche Diagnostics, DAVA Oncology, Springer Science+Business Media; and grants and personal fees from AbbVie, Stemline Therapeutics, and Novartis. MK reports grants from Ablynx, Agios, Ascentage, AstraZeneca, Rafael Pharmaceutical, and Sanofi; personal fees from Reata Pharmaceutical and Janssen; and grants and personal fees from AbbVie, F Hoffman La-Roche, Stemline Therapeutics, Forty-Seven, and Genetech. In addition, MK has a patent US7795305B2 CDDO-compounds and combination therapies with royalties paid to Reata Pharmaceuticals, a patent combination therapy with a mutant IDH1 Inhibitor and a BCL2 licensed to Eli Lilly, and a patent 62/993166 combination of a MCL1 inhibitor and midostaurin, uses and pharmaceutical compositions thereof pending to Novartis. FR reports grants from AbbVie. HMK reports grants from Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz Pharmaceuticals, and Sanofi; personal fees from Actinium, Adaptive Biotechnologies, Apptitude Health, BioAscend, Daiichi-Sankyo, Delta Fly, Janssen Global, Novartis, Oxford Biomedical, and Takeda Oncology; and grants and personal fees from Abbvie, Amgen, and Pfizer. All other authors report no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation in acute myeloid leukemia (AML) is associated with poor prognosis. We hypothesized that quizartinib, a selective and potent FLT3 inhibitor, with azacitidine (AZA) or low-dose cytarabine (LDAC) might improve the outcomes in patients with FLT3-ITD-mutated AML. In this open-label phase I/II trial, patients of any age receiving first-salvage treatment for FLT3-ITD AML or age >60 years with untreated myelodysplastic syndrome or AML were treated with quizartinib plus AZA or LDAC. Seventy-three patients were treated (34 frontline, 39 first-salvage). Among previously untreated patients, composite response (CRc) was achieved in 13/15 (87%, 8 CR, 4 Cri, 1 CRp) treated with quizartinib/AZA and 14/19 (74%, 1 CR, 8 CRi, 5 CRp) in quizartinib/LDAC. The median OS was 19.2 months for quizartinib/AZA and 8.5 months for quizartinib/LDAC cohort; RFS was 10.5 and 6.4 months, respectively. Among previously treated patients, 16 (64%) achieved CRc in quizartinib/AZA and 4 (29%) in quizartinib/LDAC. The median OS for patients treated with quizartinib/AZA and quizartinib/LDAC was 12.8 vs. 4 months, respectively. QTc prolongation grade 3 occurred in only 1 patient in each cohort. Quizartinib-based combinations, particularly with AZA, appear effective in both frontline and first-salvage for patients with FLT3-ITD-mutated AML and are well tolerated.