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We conducted a phase 1 study evaluating 3 dose levels of quizartinib (30 mg, 40 mg or 60 mg) in combination with azacitidine for HMA-naïve or relapsed/refractory MDS or MDS/MPN with FLT3 or CBL mutations. Overall, 12 patients (HMA naïve: n=9, HMA failure: n=3) were enrolled; 7 (58 %) patients had FLT3 mutations and 5 (42 %) had CBL mutations. The maximum tolerated dose was not reached. Most common grade 3-4 treatment-emergent adverse events were thrombocytopenia (n=5, 42 %), anemia (n=4, 33 %), lung infection (n=2, 17 %), skin infection (n=2, 17 %), hyponatremia (n=2, 17 %) and sepsis (n=2, 17 %). The overall response rate was 83 % with median relapse-free and overall survivals of 15.1 months (95 % CI 0.0-38.4 months) and 17.5 months (95 % CI NC-NC), respectively. FLT3 mutation clearance was observed in 57 % (n=4) patients. These data suggest quizartinib is safe and shows encouraging activity in FLT3-mutated MDS and MDS/MPN. This study is registered at Clinicaltrials.gov as NCT04493138., Competing Interests: Declaration of Competing Interest GMB declares grant/research support from Takeda, Rigel and IFM Therapeutics. M.K. declares consulting and honoraria from AbbVie, Genentech, F. Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, and Kisoji; research funding and/or clinical trial support from AbbVie, Genentech, F. Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, and Astra Zeneca; and stock options/royalties from Reata Pharmaceutical. H.K. declares research support from AbbVie, Agios, Amgen, Ariad, Astex, BMS, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, and Pfizer, honoraria from AbbVie, Actinium, Agios, Amgen, Immunogen, Orsinex, Pfizer, and Takeda, and an advisory role with Actinium. G.G-M. declares support from and an advisory role with Celgene Corporation, Astex, and Amphivena, and grant/research support 15 from Helsinn, Novartis, AbbVie, Onconova, H3 Biomedicine, and Merck. S.L grant/research support from Amgen and Astellas and consulting and honoraria from Guidepoint, Qual World, Gerson Lehman Group, Caris, Blueprint Medicines Corporation, Daiichi Sankyo, Recordati, Abbvie, and Arima and owns Abbvie stocks. The rest of authors declare no competing financial interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Therapies beyond hypomethylating agents such as azacitidine are needed in high-risk myelodysplastic syndromes. Venetoclax is an orally bioavailable small molecule BCL-2 inhibitor that is synergistic with hypomethylating agents. We therefore aimed to evaluate the safety, tolerability, and preliminary activity of azacitidine combined with venetoclax for treatment-naive and relapsed or refractory high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia., Methods: We did a single centre, dose-escalation, dose-expansion, phase 1-2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). This Article details the phase 1 results. We enrolled patients (≥18 years) with treatment-naive or relapsed or refractory high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia and bone marrow blasts of more than 5%. No specific Eastern Cooperative Oncology Group status restriction was used. Patients were treated with intravenous or subcutaneous azacitidine (75 mg/m 2 ) for 5 days and oral venetoclax (100-400 mg) for 7-14 days. The primary outcome was safety and tolerability as well as determination of the maximum tolerated dose and recommended phase 2 dose of the azacitidine and venetoclax combination using a 3 + 3 study design. All patients who received one dose of study drug were included in the analyses. This study is registered with ClinicalTrials.gov, number NCT04160052. The phase 2 dose-expansion part of the trial is ongoing., Findings: Between Nov 12, 2019, and Dec 17, 2021, a total of 23 patients were enrolled in the phase 1 portion of this study (17 [74%] hypomethylating agent naive and six [26%] post-hypomethylating agent failure). 18 (78%) patients were male and five (22%) were female; 21 (91%) were white and two (9%) were Asian. Median follow-up was 13·2 months (IQR 6·8-18·3). The maximum tolerated dose was not reached and the recommended phase 2 dose was established as azacitidine 75 mg/m 2 for 5 days plus venetoclax 400 mg for 14 days. The most common grade 3-4 treatment-emergent adverse events were neutropenia (nine [39%] of 23), thrombocytopenia (nine [39%]), lung infection (seven [30%]), and febrile neutropenia (four [17%]). Three deaths due to sepsis, which were not deemed treatment-related, occurred on the study drugs. The overall response rate was 87% (95% CI 66-97; 20 of 23 patients)., Interpretation: Azacitidine with venetoclax is safe and shows encouraging activity in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia., Funding: MD Anderson Cancer Center., Competing Interests: Declaration of interests EJ declares research funding from Amgen, Pfizer, Abbvie, Adaptive Biotechnologies, Astex, and Ascentage; and consulting fees from Amgen, Pfizer, Abbvie, Takeda, Adaptive Biotechnologies, Astex, Ascentage, Genentech, Novartis, BMS, Jazz Pharmaceuticals, Hikma Pharmaceuticals, and Incyte. GM-B declares research funding from IFM Therapeutics, Rigel Pharmaceuticals, Jazz Pharmaceuticals, Daiichi Sankyo, Stemline Therapeutics, and Salarius Pharmaceuticals. TK reports research funding from Ascentage and Abbvie; and consulting fees from Abbvie. KT reports consulting fees from SymBio Pharmaceuticals, Novartis, Celgene/BMS, GSK, and Agios; and payment or honoraria from Otsuka Pharmaceutical, Mission Bio, and Illumina. NS reports research funding from Astellas Pharma, Stemline Therapeutics, Xencor, and Takeda Oncology; consulting fees from Pfizer and Jazz Pharmaceuticals; and payment or honoraria from Pfizer, Novartis, Astellas Pharma, and Amgen. MY reports research funding from Pfizer and Daiichi Sankyo. MA declares research funding from Daiichi Sankyo, Breast Cancer Research Foundation, AstraZeneca, Oxford Biomedical UK, Brooklyn ITX, SentiBio, Pinot Bio, and Syndax; participation on a data monitoring or advisory board with Cancer UK, Leukemia & Lymphoma Society, Aptose, German Research Council, NCI, CLL Foundation, Brooklyn ITX; and stock or stock options with Reata, Aptose, Eutropics, SentiBio, and Chimerix. HK declares research funding from Abbvie, Amgen, Ascentage, BMS, Daiichi Sankyo, Immunogen, Jazz Pharmaceuticals, Novartis; and payment or honoraria from Abbvie, Amgen, Amphista, Ascentage, Astellas, Biologix, Curis, Ipsen Biopharmaceuticals, KAHR Medical, Novartis, Pfizer, Precision Biosciences, Shenzhen Target Rx, and Takeda. GG-M declares research funding from Astex Pharmaceuticals, Novartis, Abbvie, BMS, Genentech, Aprea Therapeutics, Curis, Gilead Sciences; consulting fees from Astex Pharmaceuticals, Acceleron Pharma, and BMS; and payment or honoraria from Astex Pharmaceuticals, Acceleron Pharma, Abbvie, Novartis, Gilead Sciences, Curis, Genentech, and BMS. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.)

Background: Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations increase the risk of atherosclerotic heart disease. Comorbidities significantly impact the prognosis of patients with myelodysplastic syndromes (MDS). The objective of this study was to determine the association and impact of CHIP mutations with comorbidities in patients with MDS., Methods: This retrospective analysis of 566 consecutive patients with MDS was conducted at The University of Texas MD Anderson Cancer Center from August 2013 to December 2016. The 27-item Adult Comorbidity Evaluation (ACE-27) scale was used to assess the severity of comorbid conditions. Next-generation sequencing was used to detect the presence of CHIP mutations in bone marrow aspirates. Spearman correlations and logistic regression analyses were used to determine the association between mutations and comorbidities., Results: Mutations in the genes tet methylcytosine dioxygenase 2 (TET2), ASXL transcriptional regulator 1 (ASXL1), DNA methyltransferase 3α (DNMT3A), Janus kinase 2 (JAK2), and tumor protein 53 (TP53) were noted in 20%, 18%, 9%, 2%, and 21% of patients, respectively. Patients with DNMT3A and JAK2 mutations had higher likelihoods of a prior history of myocardial infarction (odds ratio, 2.62; P = .03) and veno-occlusive disease (odds ratio, 6.48; P = .02), respectively. TP53 mutation was associated with a prior history of malignancy. Patients with TET2 mutation had no association with any comorbidity. A prognostic model including the revised International Prognostic Scoring System classification, the ACE-27 score, and TP53 mutation status (the I-RAT model) predicted median overall survival., Conclusions: In patients with MDS, the presence of CHIP-associated mutations is associated with comorbidities. DNMT3A and JAK2 mutations were associated with higher likelihoods of prior myocardial infarction and thrombotic events. There was no association between comorbidity and TET2 mutation. Incorporating the revised International Prognostic Scoring System classification with the ACE-27 and TP53 mutation status improved outcome prediction in patients with MDS., (© 2019 American Cancer Society.)