47 results on '"Wei, Andrew"'
Search Results
2. Genetic Risk Stratification and Outcomes Among Treatment-Naive Patients With AML Treated With Venetoclax and Azacitidine.
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Döhner H, Pratz KW, DiNardo CD, Wei AH, Jonas BA, Pullarkat V, Thirman MJ, Récher C, Schuh AC, Babu S, Li X, Ku G, Liu Z, Sun Y, Potluri J, Dail M, Chyla B, and Pollyea DA
- Abstract
European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems were based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. Here, pooled analysis of patients in the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to 2017 and 2022 ELN risk classifications. A bioinformatic algorithm derived new molecular signatures differentiating venetoclax-azacitidine-treated patients based on median overall survival (OS). 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. When classified by ELN 2017 or 2022 prognostic criteria, most patients had adverse-risk AML (60.2% and 72.8% for venetoclax-azacitidine and 65.5% and 75.2% for placebo-azacitidine, respectively). While outcomes with venetoclax-azacitidine were improved across all ELN risk groups compared with placebo-azacitidine, ELN classification systems poorly discriminated venetoclax-azacitidine outcomes. By applying a bioinformatic algorithm, new molecular signatures were derived differentiating OS outcomes with venetoclax-azacitidine; the mutational status of TP53, FLT3-ITD, NRAS, and KRAS categorized patients into higher-, intermediate-, and lower-benefit groups (52%, 25%, and 23% of patients, respectively), each associated with a distinct median OS (26.5 months [95% CI, 20.2 to 32.7], 12.1 months [95% CI, 7.3 to 15.2], and 5.5 months [95% CI, 2.8 to 7.6], respectively). ELN prognostic classifiers do not provide clinically meaningful risk stratification of OS outcomes for patients with AML treated with venetoclax-azacitidine. TP53, FLT3-ITD, NRAS, and KRAS mutation status allows classification of these patients into three risk groups with distinct differences in median OS., (Copyright © 2024 American Society of Hematology.)
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- 2024
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3. Real-world Effectiveness of Azacitidine in Treatment-Naive Patients With Higher-risk Myelodysplastic Syndromes.
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Rajakumaraswamy N, Gandhi M, Wei AH, Sallman DA, Daver NG, Mo S, Iqbal S, Karalliyadda R, Chen M, Wang Y, and Vyas P
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- Humans, Antimetabolites, Antineoplastic pharmacology, Antimetabolites, Antineoplastic therapeutic use, Retrospective Studies, Mutation, Treatment Outcome, Azacitidine pharmacology, Azacitidine therapeutic use, Myelodysplastic Syndromes genetics
- Abstract
Introduction: Azacitidine (AZA) is an approved frontline therapy for higher-risk myelodysplastic syndromes (HR-MDS); however, poor survival denotes unmet needs to increase depth/duration of response (DOR)., Methods: This retrospective study with patient chart review evaluated AZA effectiveness in 382 treatment-naive patients with HR-MDS from a US electronic health record (EHR)-derived database. Responses were assessed using International Working Group (IWG) 2006 criteria; real-world equivalents were derived from EHRs. Primary endpoint was IWG 2006-based complete remission rate (CRR). Secondary endpoints were EHR-based CRR, IWG 2006- and EHR-based objective response rates (ORRs), duration of CR, DOR, progression-free survival, time-to-next-treatment, and overall survival (OS)., Results: Using IWG 2006 criteria, the CRR was 7.9% (n = 30); median duration of CR was 12.0 months (95% CI, 7.7-15.6). In poor cytogenetic risk (n = 101) and TP53 mutation (n = 46) subgroups, CRRs were 7.9% (n = 8) and 8.7% (n = 4), respectively. ORR was 62.8% (n = 240), including a hematologic improvement rate (HIR) of 46.9% (n = 179). Using EHR-based data, CRR was 3.7% (n = 14); median duration of CR was 13.5 months (95% CI, 4.5-21.5). ORR was 67.8% (n = 259), including an HIR of 29.3% (n = 112). Median follow-up was 12.9 months; median OS was 17.9 months (95% CI, 15.5-21.7)., Conclusions: Consistent with other studies, CRRs and median OS with AZA in treatment-naive patients with HR-MDS were low in this large, real-world cohort. Novel agents/combinations are urgently needed to improve these outcomes in HR-MDS., Competing Interests: Disclosure N.R., S.M., S.I., M.C., and R.K. are current equity holders at Gilead Sciences Inc. and were employed by Gilead Sciences Inc. at the time of this study. A.H.W. receives institutional research funding from Abbvie, Amgen, Astex, Astra Zeneca, BMS, Novartis, Servier, and Syndax; is an employee of the Walter and Eliza Hall Institute, and is eligible for a fraction of the royalty stream related to venetoclax; serves on speaker's bureaus for Abbvie, Astellas, BMS, and Novartis; and served on advisory boards for Abbvie, Agios, Amgen, Astellas, BMS, Gilead Sciences Inc., Janssen, Macrogenics, Novartis, Pfizer, Roche, and Servier. D.A.S. received consulting fees from AbbVie, Affimed, Gilead Sciences Inc., Incyte, Intellisphere, Molecular Partners, PGEN Therapeutics, Takeda, and Zentalis; served on advisory boards for AvenCell, Bluebird Bio, BMS, Intellia, Jasper Therapeutics, Kite, Magenta Therapeutics, Nkarta, Novartis, Shattuck Labs, Servier, Syndax, and Syros; and has financial or nonfinancial interests in Aprea, Jazz, and Moffit. M.G. served on advisory boards for GSK, Janssen, Karyopharm, Sanofi, and TG Therapeutics. N.G.D. receives institutional research funding from AbbVie, Amgen, Astellas, Bristol-Meyers Squibb, Daiichi-Sankyo, FATE Therapeutics, Genentech, Gilead Sciences Inc., Glycomimetics, Hanmi, ImmunoGen, Novimmune, Pfizer, Servier, Trillium, and Trovagene; and received consulting fees from AbbVie, Agios, Amgen, Arog, Astellas, Bristol-Meyers Squibb, Celgene, Daichii-Sankyo, Genentech, Gilead Sciences Inc., ImmunoGen, Jazz, Novartis, Pfizer, Servier, Shattuck Labs, Syndax, and Trillium. Y.W. has received support for the current study from Gilead Sciences Inc.; and is a current equity holder in McKesson. P.V. has received support for the current study from Gilead Sciences Inc. and Scimentum., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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4. Molecular MRD is strongly prognostic in patients with NPM1-mutated AML receiving venetoclax-based nonintensive therapy.
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Othman J, Tiong IS, O'Nions J, Dennis M, Mokretar K, Ivey A, Austin M, Latif AL, Amer M, Chan WY, Crawley C, Crolla F, Cross J, Dang R, Elliot J, Fong CY, Galli S, Gallipoli P, Hogan F, Kalkur P, Khan A, Krishnamurthy P, Laurie J, Loo S, Marshall S, Mehta P, Murthy V, Nagumantry S, Pillai S, Potter N, Sellar R, Taylor T, Zhao R, Russell NH, Wei AH, and Dillon R
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- Humans, Prognosis, Mutation, Cytarabine, Neoplasm, Residual genetics, Nucleophosmin, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Sulfonamides, Bridged Bicyclo Compounds, Heterocyclic
- Abstract
Abstract: Assessment of measurable residual disease (MRD) by quantitative reverse transcription polymerase chain reaction is strongly prognostic in patients with NPM1-mutated acute myeloid leukemia (AML) treated with intensive chemotherapy; however, there are no data regarding its utility in venetoclax-based nonintensive therapy, despite high efficacy in this genotype. We analyzed the prognostic impact of NPM1 MRD in an international real-world cohort of 76 previously untreated patients with NPM1-mutated AML who achieved complete remission (CR)/CR with incomplete hematological recovery following treatment with venetoclax and hypomethylating agents (HMAs) or low-dose cytarabine (LDAC). A total of 44 patients (58%) achieved bone marrow (BM) MRD negativity, and a further 14 (18%) achieved a reduction of ≥4 log10 from baseline as their best response, with no difference between HMAs and LDAC. The cumulative rates of BM MRD negativity by the end of cycles 2, 4, and 6 were 25%, 47%, and 50%, respectively. Patients achieving BM MRD negativity by the end of cycle 4 had 2-year overall of 84% compared with 46% if MRD was positive. On multivariable analyses, MRD negativity was the strongest prognostic factor. A total of 22 patients electively stopped therapy in BM MRD-negative remission after a median of 8 cycles, with 2-year treatment-free remission of 88%. In patients with NPM1-mutated AML attaining remission with venetoclax combination therapies, NPM1 MRD provides valuable prognostic information., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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5. Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML: a randomized, placebo-controlled study by the ALLG.
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Loo S, Roberts AW, Anstee NS, Kennedy GA, He S, Schwarer AP, Enjeti AK, D'Rozario J, Marlton P, Bilmon IA, Taper J, Cull G, Tiley C, Verner E, Hahn U, Hiwase DK, Iland HJ, Murphy N, Ramanathan S, Reynolds J, Ong DM, Tiong IS, Wall M, Murray M, Rawling T, Leadbetter J, Rowley L, Latimer M, Yuen S, Ting SB, Fong CY, Morris K, Bajel A, Seymour JF, Levis MJ, and Wei AH
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- Humans, Sorafenib, fms-Like Tyrosine Kinase 3 genetics, Retrospective Studies, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Sorafenib maintenance improves outcomes after hematopoietic cell transplant (HCT) for patients with FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients (aged 18-65 years) 2:1 to sorafenib vs placebo (days 4-10) combined with intensive induction: idarubicin 12 mg/m2 on days 1 to 3 plus either cytarabine 1.5 g/m2 twice daily on days 1, 3, 5, and 7 (18-55 years) or 100 mg/m2 on days 1 to 7 (56-65 years), followed by consolidation and maintenance therapy for 12 months (post-HCT excluded) in newly diagnosed patients with FLT3-ITD AML. Four patients were excluded in a modified intention-to-treat final analysis (3 not commencing therapy and 1 was FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery were high in both arms (sorafenib, 78%/9%; placebo, 70%/24%). With 49.1-months median follow-up, the primary end point of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.51-1.51; P = .61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR, 0.76; 95% CI, 0.42-1.39). For patients who received HCT in first remission, the 2-year OS rates were 84% and 67% in the sorafenib and placebo arms, respectively (HR, 0.45; 95% CI, 0.18-1.12; P = .08). In exploratory analyses, FLT3-ITD measurable residual disease (MRD) negative status (<0.001%) after induction was associated with improved 2-year OS (83% vs 60%; HR, 0.4; 95% CI, 0.17-0.93; P = .028). In conclusion, routine use of pretransplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study., (© 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.)
- Published
- 2023
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6. TP53 status and impact on AML prognosis within the ELN 2022 risk classification.
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Fleming S, Tsai XC, Morris R, Hou HA, and Wei AH
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- Humans, Mutation, Abnormal Karyotype, Prognosis, Tumor Suppressor Protein p53 genetics, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics
- Abstract
This study reports the following: (1) frequency of TP53 comutation within each component of the European LeukemiaNet 2022 acute myeloid leukemia risk classification, (2) relevance of TP53 mutated variant allelic fraction <10%, (3) prognostic impact of -7, -5/del(5q), -17/abn(17p), complex karyotype/monosomal karyotype, or myelodysplasia-related gene mutations with/without mutated TP53., (© 2023 by The American Society of Hematology.)
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- 2023
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7. Classification, risk stratification and response assessment in myelodysplastic syndromes/neoplasms (MDS): A state-of-the-art report on behalf of the International Consortium for MDS (icMDS).
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Stahl M, Bewersdorf JP, Xie Z, Porta MGD, Komrokji R, Xu ML, Abdel-Wahab O, Taylor J, Steensma DP, Starczynowski DT, Sekeres MA, Sanz G, Sallman DA, Roboz GJ, Platzbecker U, Patnaik MM, Padron E, Odenike O, Nimer SD, Nazha A, Majeti R, Loghavi S, Little RF, List AF, Kim TK, Hourigan CS, Hasserjian RP, Halene S, Griffiths EA, Gore SD, Greenberg P, Figueroa ME, Fenaux P, Efficace F, DeZern AE, Daver NG, Churpek JE, Carraway HE, Buckstein R, Brunner AM, Boultwood J, Borate U, Bejar R, Bennett JM, Wei AH, Santini V, Savona MR, and Zeidan AM
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- Humans, Risk Assessment, Quality of Life, Prognosis, Neoplasms, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes therapy
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The guidelines for classification, prognostication, and response assessment of myelodysplastic syndromes/neoplasms (MDS) have all recently been updated. In this report on behalf of the International Consortium for MDS (icMDS) we summarize these developments. We first critically examine the updated World Health Organization (WHO) classification and the International Consensus Classification (ICC) of MDS. We then compare traditional and molecularly based risk MDS risk assessment tools. Lastly, we discuss limitations of criteria in measuring therapeutic benefit and highlight how the International Working Group (IWG) 2018 and 2023 response criteria addressed these deficiencies and are endorsed by the icMDS. We also address the importance of patient centered care by discussing the value of quality-of-life assessment. We hope that the reader of this review will have a better understanding of how to classify MDS, predict clinical outcomes and evaluate therapeutic outcomes., Competing Interests: Declaration of Competing Interest Maximilian Stahl consulted for Curis Oncology and Boston Consulting; served on the advisory board for Novartis and Kymera, GSK, Rigel, Sierra Oncology; and participated in GME activity for Novartis, Curis Oncology, Haymarket Media and Clinical care options (CCO). Elizabeth A. Griffiths has received honoraria for advisory board membership from AbbVie, Alexion Pharmaceuticals, Apellis, Celgene/BMS, CTI Biopharma, Genentech, Novartis, Picnic Health, Takeda Oncology, Taiho Oncology. EAG has received research funding from Astex Pharmaceuticals, AstraZeneca Rare Disease, Alexion Pharmaceuticals, Apellis Pharmaceuticals, Blueprint Medicines, Genentech Inc., and honoraria for CME activities from Physicians Educational Resource, MediComWorldwide, American Society of Hematology, AAMDS International Foundation. Ravindra Majeti is on the Advisory Boards of Kodikaz Therapeutic Solutions, Syros Pharmaceuticals, TenSixteen Bio, Roche, and Cullgen Inc. and is an inventor on several patents related to CD47 cancer immunotherapy licensed to Gilead Sciences. R.M. receives research support from Gilead Sciences. Ravindra Majeti. is a co-founder and equity holder of Pheast Therapeutics, MyeloGene, and Orbital Therapeutics. Stephanie Halene consulted for Forma Therapeutics. Daniel T. Starczynowski is a consultant and received research funding from Kymera Therapeutics, Kurome Therapeutics, Captor Therapeutics, and Tolero Therapeutics. Daniel T. Starczynowski has equity in Kurome Therapeutics. Gail Roboz: Consultancy: Abbvie, Amgen, Argenx, Astra Zeneca, Bluebird Bio, Blueprint Medicines, Bristol-Myers Squibb, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses Pharma, GlaxoSmithKline, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Novartis, Pfizer, Rigel, Roche, Syndax, Takeda (IRC Chair), Telix Pharma Research support: Janssen. David A. Sallman served on the advisory board of Aprea, AvenCell, BlueBird Bio, BMS, Intellia, Kite, Novartis, Shattuck Labs, Servier, Syndax. David A. Sallman served as a consultant for AbbVie, Magenta, Molecular Partners AG, Takeda and on the speakers' bureau for BMS, Incyte, Servier; David A. Sallman received research funding from Aprea, Jazz. Mrinal Patnaik received research funding from Kura Oncology and StemLine Pharmaceuticals. Andrew Brunner received consulting or advisory board honoraria from Novartis, Acceleron, Agios, Abbvie, Takeda, Celgene/BMS, Keros Therapeutics, Taiho, Gilead. Andrew Brunner has research support from the NIH SPORE in Myeloid Malignancies, and from the Edward P. Evans Foundation. Tae Kon Kim received research funding from Nextcure and is a consultant for Agenus. Alan List is employed by and has equity in Precision BioSciences, and has served as a consultant for Halia Therapeutics, CTI Biopharma, Aileron. Naval Daver has received research funding from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol-Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. Guillermo Sanz received honoraria, advisory board membership or consultation fees from AbbVie, BMS, ExCellThera, Novartis, Roche, and Takeda and participated in sponsored speaker's bureau for BMS, Novartis, and Takeda. Mikkael A. Sekeres has served on advisory boards for BMS, Novartis, Kurome, and Gilead. Pierre Fenaux received research funding from BMS, Abbvie, Jazz Pharmaceuticals, Novartis, and Janssen. Pierre Fenaux had a consultancy with and received honoraria from BMS, Abbvie, Jazz Pharmaceuticals, and Novartis. Fabio Efficace had a consultancy or advisory role for AbbVie, Incyte, Janssen, and Syros, outside the submitted work. Omar Abdel-Wahab has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen, and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder; Omar Abdel-Wahab has received prior research funding from H3B Biomedicine and LOXO Oncology unrelated to the current manuscript. Andrew H.Wei has served on advisory boards for Novartis, Astra Zeneca, Astellas, Janssen, Jazz, Amgen, Roche, Pfizer, Abbvie, Servier, Gilead, BMS, Shoreline, Macrogenics, Novartis and Agios; receives research funding to the Institution from Novartis, Abbvie, Servier, Janssen, BMS, Syndax, Astex, Astra Zeneca, Amgen; serves on speaker's bureaus for Abbvie, Novartis, BMS, Servier, Astellas; Andrew H.Wei is an employee of the Walter and Eliza Hall Institute (WEHI). WEHI receives milestone and royalty payments related to the development of Venetoclax. Current and past employees of Walter and Eliza Hall Institute may be eligible for financial benefits related to these payments. Andrew H. Wei receives such a financial benefit. Amer M. Zeidan received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. AMZ participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. AMZ served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron and Celgene/BMS. The National Heart, Lung, and Blood Institute receives research funding for the laboratory of Dr. Hourigan from Sellas and from the Foundation of the NIH AML MRD Biomarkers Consortium. All other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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8. Current landscape of translational and clinical research in myelodysplastic syndromes/neoplasms (MDS): Proceedings from the 1 st International Workshop on MDS (iwMDS) Of the International Consortium for MDS (icMDS).
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Bewersdorf JP, Xie Z, Bejar R, Borate U, Boultwood J, Brunner AM, Buckstein R, Carraway HE, Churpek JE, Daver NG, Porta MGD, DeZern AE, Fenaux P, Figueroa ME, Gore SD, Griffiths EA, Halene S, Hasserjian RP, Hourigan CS, Kim TK, Komrokji R, Kuchroo VK, List AF, Loghavi S, Majeti R, Odenike O, Patnaik MM, Platzbecker U, Roboz GJ, Sallman DA, Santini V, Sanz G, Sekeres MA, Stahl M, Starczynowski DT, Steensma DP, Taylor J, Abdel-Wahab O, Xu ML, Savona MR, Wei AH, and Zeidan AM
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- Animals, Humans, Epigenomics, Cell- and Tissue-Based Therapy, Protein Processing, Post-Translational, Neoplasms, Myelodysplastic Syndromes etiology, Myelodysplastic Syndromes therapy
- Abstract
Biological events that contribute to the pathogenesis of myelodysplastic syndromes/neoplasms (MDS) are becoming increasingly characterized and are being translated into rationally designed therapeutic strategies. Herein, we provide updates from the first International Workshop on MDS (iwMDS) of the International Consortium for MDS (icMDS) detailing recent advances in understanding the genetic landscape of MDS, including germline predisposition, epigenetic and immune dysregulation, the complexities of clonal hematopoiesis progression to MDS, as well as novel animal models of the disease. Connected to this progress is the development of novel therapies targeting specific molecular alterations, the innate immune system, and immune checkpoint inhibitors. While some of these agents have entered clinical trials (e.g., splicing modulators, IRAK1/4 inhibitors, anti-CD47 and anti-TIM3 antibodies, and cellular therapies), none have been approved for MDS. Additional preclinical and clinical work is needed to develop a truly individualized approach to the care of MDS patients., Competing Interests: Declaration of Competing Interest Maximilian Stahl consulted for Curis Oncology and Boston Consulting; served on the advisory board for Novartis and Kymera; and participated in GME activity for Novartis, Curis Oncology, Haymarket Media and Clinical care options (CCO). Elizabeth A. Griffiths has received honoraria for advisory board membership from AbbVie, Alexion Pharmaceuticals, Apellis, Celgene/BMS, CTI Biopharma, Genentech, Novartis, Picnic Health, Takeda Oncology, Taiho Oncology. EAG has received research funding from Astex Pharmaceuticals, AstraZeneca Rare Disease, Alexion Pharmaceuticals, Apellis Pharmaceuticals, Blueprint Medicines, Genentech Inc., and honoraria for CME activities from Physicians Educational Resource, MediComWorldwide, American Society of Hematology, AAMDS International Foundation. Ravindra Majeti is on the Advisory Boards of Kodikaz Therapeutic Solutions, Syros Pharmaceuticals, TenSixteen Bio, Roche, and Cullgen Inc. and is an inventor on a number of patents related to CD47 cancer immunotherapy licensed to Gilead Sciences. R.M. receives research support from Gilead Sciences. Ravindra Majeti. is a co-founder and equity holder of Pheast Therapeutics, MyeloGene, and Orbital Therapeutics. Stephanie Halene consulted for Forma Therapeutics. Daniel T. Starczynowski is a consultant and received research funding from Kymera Therapeutics, Kurome Therapeutics, Captor Therapeutics, and Tolero Therapeutics. Daniel T. Starczynowski has equity in Kurome Therapeutics. David A. Sallman served on the advisory board of Aprea, AvenCell, BlueBird Bio, BMS, Intellia, Kite, Novartis, Shattuck Labs, Servier, Syndax. David A. Sallman served as a consultant for AbbVie, Magenta, Molecular Partners AG, Takeda and on the speakers' bureau for BMS, Incyte, Servier; David A. Sallman received research funding from Aprea, Jazz. Mrinal Patnaik received research funding from Kura Oncology and StemLine Pharmaceuticals. Andrew Brunner received consulting or advisory board honoraria from Novartis, Acceleron, Agios, Abbvie, Takeda, Celgene/BMS, Keros Therapeutics, Taiho, Gilead. Andrew Brunner has research support from the NIH SPORE in Myeloid Malignancies, and from the Edward P. Evans Foundation. Tae Kon Kim received research funding from Nextcure and is a consultant for Agenus. Alan List is employed by and has equity in Precision BioSciences, and has served as a consultant for Halia Therapeutics, CTI Biopharma, Aileron. Naval Daver has received research funding from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen and has served in a consulting or advisory role for Daiichi-Sankyo, Bristol-Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. Guillermo Sanz received honoraria, advisory board membership or consultation fees from AbbVie, BMS, ExCellThera, Novartis, Roche, and Takeda and participated in sponsored speaker's bureau for BMS, Novartis, and Takeda. Mikkael A. Sekeres has served on advisory boards for BMS, Novartis, Kurome, and Gilead. Pierre Fenaux received research funding from BMS, Abbvie, Jazz Pharmaceuticals, Novartis, and Janssen. Pierre Fenaux had a consultancy with and received honoraria from BMS, Abbvie, Jazz Pharmaceuticals, and Novartis. Omar Abdel-Wahab has served as a consultant for H3B Biomedicine, Foundation Medicine Inc., Merck, Prelude Therapeutics, and Janssen, and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder; Omar Abdel-Wahab has received prior research funding from H3B Biomedicine and LOXO Oncology unrelated to the current manuscript. Andrew H.Wei has served on advisory boards for Novartis, Astra Zeneca, Astellas, Janssen, Jazz, Amgen, Roche, Pfizer, Abbvie, Servier, Gilead, BMS, Shoreline, Macrogenics, Novartis and Agios; receives research funding to the Institution from Novartis, Abbvie, Servier, Janssen, BMS, Syndax, Astex, Astra Zeneca, Amgen; serves on speaker's bureaus for Abbvie, Novartis, BMS, Servier, Astellas; Andrew H.Wei is an employee of the Walter and Eliza Hall Institute (WEHI). WEHI receives milestone and royalty payments related to the development of Venetoclax. Current and past employees of Walter and Eliza Hall Institute may be eligible for financial benefits related to these payments. Andrew H.Wei receives such a financial benefit. Valeria Santini served in advisory boards from Abbvie, BMS, Geron, Gilead,Menarini, Novartis, Servier, Syros, ad received research support from BMS. Amer M. Zeidan received research funding (institutional) from Celgene/BMS, Abbvie, Astex, Pfizer, Medimmune/AstraZeneca, Boehringer-Ingelheim, Cardiff oncology, Incyte, Takeda, Novartis, Aprea, and ADC Therapeutics. AMZ participated in advisory boards, and/or had a consultancy with and received honoraria from AbbVie, Otsuka, Pfizer, Celgene/BMS, Jazz, Incyte, Agios, Boehringer-Ingelheim, Novartis, Acceleron, Astellas, Daiichi Sankyo, Cardinal Health, Taiho, Seattle Genetics, BeyondSpring, Cardiff Oncology, Takeda, Ionis, Amgen, Janssen, Epizyme, Syndax, Gilead, Kura, Chiesi, ALX Oncology, BioCryst, Notable, Orum, and Tyme. AMZ served on clinical trial committees for Novartis, Abbvie, Gilead, BioCryst, Abbvie, ALX Oncology, Geron and Celgene/BMS. The National Heart, Lung, and Blood Institute receives research funding for the laboratory of Dr. Hourigan from Sellas and from the Foundation of the NIH AML MRD Biomarkers Consortium. All other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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9. Acute myeloid leukaemia.
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DiNardo CD, Erba HP, Freeman SD, and Wei AH
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- Humans, Treatment Outcome, Prognosis, Risk Assessment, Neoplasm, Residual diagnosis, Neoplasm, Residual drug therapy, Neoplasm, Residual etiology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy
- Abstract
Progress in acute myeloid leukaemia treatment is occurring at an unprecedented pace. The past decade has witnessed an increasingly improved scientific understanding of the underlying biology of acute myeloid leukaemia, leading to enhanced prognostication tools and refined risk assessments, and most especially incorporating measurable residual disease (MRD) into longitudinal risk assessments. The classification of acute myeloid leukaemia has recently been updated by WHO and the International Consensus Classification (ICC). Recommendations for prognostic stratification, response assessment, and MRD determination have also been updated by the European LeukemiaNet. Treatment options have evolved substantially in the last 5 years for patients with newly diagnosed acute myeloid leukaemia, leading to improved outcomes in intensively treated patients and those more appropriate for non-intensive chemotherapy. More effective targeted treatment options in the relapsed setting are also available, further advancing the treatment armamentarium and improving patient outcomes., Competing Interests: Declaration of interests CDD received funding (to institution) from Abbvie, Astex, BMS, Cleave, Foghorn, ImmuneOnc, Loxo, and Servier; received consulting and honorarium fees from Abbvie, BMS, Genmab, Gilead, GSK, Jazz, Kura, Novartis, Servier, and Takeda; and was on the scientific advisory board of Notable Labs. HPE received funding (to institution) from AbbVie, ALX Oncology, Amgen, Ascentage, Daiichi Sankyo, Forma, Gilead, Glycomimetics, Immunogen, Jazz, MacroGenics, Novartis, PTC, and Sumitomo Pharma; received consulting fees from AbbVie, Agios, Astellas, BMS/Celgene, Daiichi Sankyo, Glycomimetics, Immunogen, Incyte, Jazz, Kura Oncology, MacroGenics, Novartis, Pfizer, Servier, Syros, Takeda, Trillium; was on the speaker's bureau for AbbVie, BMS, Incyte, Jazz, Novartis, and Servier. SDF received funding (to institution) from BMS and Jazz; received consulting and honorarium fees from Novartis, and was on the advisory board of Neogenomics and MPAAC. AHW acts on the advisory boards for Novartis, Astra Zeneca, Astellas, Janssen, Amgen, Roche, Pfizer, Abbvie, Servier, Gilead, BMS, Shoreline, Macrogenics and Agios; receives funding (to institution) from Novartis, Abbvie, Servier, Janssen, BMS, Syndax, Astex, Astra Zeneca, and Amgen; serves on the speaker's bureaus for Abbvie, Novartis, BMS, Servier, and Astellas; and is an employee of the Walter and Eliza Hall Institute (WEHI). WEHI receives milestone and royalty payments related to the development of venetoclax. Current and past employees of WEHI may be eligible for financial benefits related to these payments. AHW receives financial benefits from WEHI., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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10. Consensus proposal for revised International Working Group 2023 response criteria for higher-risk myelodysplastic syndromes.
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Zeidan AM, Platzbecker U, Bewersdorf JP, Stahl M, Adès L, Borate U, Bowen D, Buckstein R, Brunner A, Carraway HE, Daver N, Díez-Campelo M, de Witte T, DeZern AE, Efficace F, Garcia-Manero G, Garcia JS, Germing U, Giagounidis A, Griffiths EA, Hasserjian RP, Hellström-Lindberg E, Iastrebner M, Komrokji R, Kulasekararaj AG, Malcovati L, Miyazaki Y, Odenike O, Santini V, Sanz G, Scheinberg P, Stauder R, van de Loosdrecht AA, Wei AH, Sekeres MA, and Fenaux P
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- Humans, Treatment Outcome, Consensus, Outcome Assessment, Health Care, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes drug therapy, Hematology
- Abstract
Myelodysplastic syndromes/myelodysplastic neoplasms (MDS) are associated with variable clinical presentations and outcomes. The initial response criteria developed by the International Working Group (IWG) in 2000 have been used in clinical practice, clinical trials, regulatory reviews, and drug labels. Although the IWG criteria were revised in 2006 and 2018 (the latter focusing on lower-risk disease), limitations persist in their application to higher-risk MDS (HR-MDS) and their ability to fully capture the clinical benefits of novel investigational drugs or serve as valid surrogates for longer-term clinical end points (eg, overall survival). Further, issues related to the ambiguity and practicality of some criteria lead to variability in interpretation and interobserver inconsistency in reporting results from the same sets of data. Thus, we convened an international panel of 36 MDS experts and used an established modified Delphi process to develop consensus recommendations for updated response criteria that would be more reflective of patient-centered and clinically relevant outcomes in HR-MDS. Among others, the IWG 2023 criteria include changes in the hemoglobin threshold for complete remission (CR), the introduction of CR with limited count recovery and CR with partial hematologic recovery as provisional response criteria, the elimination of marrow CR, and specific recommendations for the standardization of time-to-event end points and the derivation and reporting of responses. The updated criteria should lead to a better correlation between patient-centered outcomes and clinical trial results in an era of multiple emerging new agents with novel mechanisms of action., (© 2023 by The American Society of Hematology.)
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- 2023
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11. Is BCL-xL the Achilles' heel of AEL and AMKL?
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Brown FC and Wei AH
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- Humans, Sulfonamides, Bridged Bicyclo Compounds, Heterocyclic, Leukemia, Myeloid, Acute
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- 2023
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12. TP53 mutation in therapy-related myeloid neoplasm defines a distinct molecular subtype.
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Hiwase D, Hahn C, Tran ENH, Chhetri R, Baranwal A, Al-Kali A, Sharplin K, Ladon D, Hollins R, Greipp P, Kutyna M, Alkhateeb H, Badar T, Wang P, Ross DM, Singhal D, Shanmuganathan N, Bardy P, Beligaswatte A, Yeung D, Litzow MR, Mangaonkar A, Giri P, Lee C, Yong A, Horvath N, Singhal N, Gowda R, Hogan W, Gangat N, Patnaik M, Begna K, Tiong IS, Wei A, Kumar S, Brown A, Scott H, Thomas D, Kok CH, Tefferi A, and Shah MV
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- Humans, Mutation, Tumor Suppressor Protein p53 genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Myeloproliferative Disorders genetics
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- 2023
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13. Acquired mutations in BAX confer resistance to BH3-mimetic therapy in acute myeloid leukemia.
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Moujalled DM, Brown FC, Chua CC, Dengler MA, Pomilio G, Anstee NS, Litalien V, Thompson E, Morley T, MacRaild S, Tiong IS, Morris R, Dun K, Zordan A, Shah J, Banquet S, Halilovic E, Morris E, Herold MJ, Lessene G, Adams JM, Huang DCS, Roberts AW, Blombery P, and Wei AH
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- Humans, Aged, bcl-2-Associated X Protein genetics, Cell Line, Tumor, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Apoptosis, Mutation, Proto-Oncogene Proteins c-bcl-2 genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Randomized trials in acute myeloid leukemia (AML) have demonstrated improved survival by the BCL-2 inhibitor venetoclax combined with azacitidine in older patients, and clinical trials are actively exploring the role of venetoclax in combination with intensive chemotherapy in fitter patients with AML. As most patients still develop recurrent disease, improved understanding of relapse mechanisms is needed. We find that 17% of patients relapsing after venetoclax-based therapy for AML have acquired inactivating missense or frameshift/nonsense mutations in the apoptosis effector gene BAX. In contrast, such variants were rare after genotoxic chemotherapy. BAX variants arose within either leukemic or preleukemic compartments, with multiple mutations observed in some patients. In vitro, AML cells with mutated BAX were competitively selected during prolonged exposure to BCL-2 antagonists. In model systems, AML cells rendered deficient for BAX, but not its close relative BAK, displayed resistance to BCL-2 targeting, whereas sensitivity to conventional chemotherapy was variable. Acquired mutations in BAX during venetoclax-based therapy represent a novel mechanism of resistance to BH3-mimetics and a potential barrier to the long-term efficacy of drugs targeting BCL-2 in AML., (© 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.)
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- 2023
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14. Azacitidine Monotherapy in Patients With Treatment-Naïve Higher-risk Myelodysplastic Syndrome: A Systematic Literature Review and Meta-analysis.
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Hasegawa K, Wei AH, Garcia-Manero G, Daver NG, Rajakumaraswamy N, Iqbal S, Chan RJ, Hu H, Tse P, Yan J, Zoratti MJ, Xie F, and Sallman DA
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- Humans, Antimetabolites, Antineoplastic adverse effects, Treatment Outcome, Remission Induction, Azacitidine adverse effects, Myelodysplastic Syndromes drug therapy
- Abstract
Background: The global incidence of myelodysplastic syndromes (MDS) has been estimated as 0.06 to 0.26/100,000. Since their introduction, hypomethylating agents have played a central role in the treatment of MDS, with heterogeneous real-world outcomes., Materials and Methods: We assessed and synthesized clinical outcomes of azacitidine (AZA) monotherapy in treatment-naïve patients with higher-risk MDS. A systematic literature review was conducted by searching MEDLINE, Embase, and CENTRAL to identify randomized clinical trials (RCTs) and observational studies, both prospective and retrospective, reporting complete remission (CR), partial remission (PR), overall survival (OS), duration of response (DOR), time-to-response (TTR), and myelosuppressive adverse events (AEs) for patients treated with AZA monotherapy. Noncomparative meta-analyses were used to summarize effects., Results: The search identified 3250 abstracts, of which 34 publications describing 16 studies (5 RCTs, 3 prospective, and 8 retrospective observational) were included. Across all studies, pooled CR was 16%; PR was 6%; Median OS was 16.4 months; median DOR was 10.1 months; median TTR was 4.6 months. Proportions of grade 3/4 anemia and thrombocytopenia AEs were 10% and 30%., Conclusions: The effectiveness and efficacy of AZA monotherapy-as measured by CR and median OS-was limited. These findings highlight a significant unmet medical need for effective treatments for patients with higher-risk MDS., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2023
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15. Revisiting coexisting chromosomal abnormalities in NPM1-mutated AML in light of the revised ELN 2022 classification.
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Angenendt L, Röllig C, Montesinos P, Ravandi F, Juliusson G, Récher C, Itzykson R, Ráčil Z, Wei AH, and Schliemann C
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- Humans, Nuclear Proteins genetics, Mutation, Prognosis, Chromosome Aberrations, Leukemia, Myeloid, Acute genetics
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- 2023
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16. Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial.
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de Botton S, Montesinos P, Schuh AC, Papayannidis C, Vyas P, Wei AH, Ommen H, Semochkin S, Kim HJ, Larson RA, Koprivnikar J, Frankfurt O, Thol F, Chromik J, Byrne J, Pigneux A, Thomas X, Salamero O, Vidriales MB, Doronin V, Döhner H, Fathi AT, Laille E, Yu X, Hasan M, Martin-Regueira P, and DiNardo CD
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- Aged, Humans, Cytarabine therapeutic use, Mutation, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
This open-label, randomized, phase 3 trial (NCT02577406) compared enasidenib, an oral IDH2 (isocitrate dehydrogenase 2) inhibitor, with conventional care regimens (CCRs) in patients aged ≥60 years with late-stage, mutant-IDH2 acute myeloid leukemia (AML) relapsed/refractory (R/R) to 2 or 3 prior AML-directed therapies. Patients were first preselected to a CCR (azacitidine, intermediate-dose cytarabine, low-dose cytarabine, or supportive care) and then randomized (1:1) to enasidenib 100 mg per day or CCR. The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), time to treatment failure (TTF), overall response rate (ORR), hematologic improvement (HI), and transfusion independence (TI). Overall, 319 patients were randomized to enasidenib (n = 158) or CCR (n = 161). The median age was 71 years, median (range) enasidenib exposure was 142 days (3 to 1270), and CCR was 36 days (1 to 1166). One enasidenib (0.6%) and 20 CCR (12%) patients received no randomized treatment, and 30% and 43%, respectively, received subsequent AML-directed therapies during follow-up. The median OS with enasidenib vs CCR was 6.5 vs 6.2 months (HR [hazard ratio], 0.86; P = .23); 1-year survival was 37.5% vs 26.1%. Enasidenib meaningfully improved EFS (median, 4.9 vs 2.6 months with CCR; HR, 0.68; P = .008), TTF (median, 4.9 vs 1.9 months; HR, 0.53; P < .001), ORR (40.5% vs 9.9%; P <.001), HI (42.4% vs 11.2%), and red blood cell (RBC)-TI (31.7% vs 9.3%). Enasidenib safety was consistent with prior reports. The primary study endpoint was not met, but OS was confounded by early dropout and subsequent AML-directed therapies. Enasidenib provided meaningful benefits in EFS, TTF, ORR, HI, and RBC-TI in this heavily pretreated older mutant-IDH2 R/R AML population., (© 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.)
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- 2023
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17. Long-term follow-up of VIALE-C in patients with untreated AML ineligible for intensive chemotherapy.
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Wei AH, Panayiotidis P, Montesinos P, Laribi K, Ivanov V, Kim I, Novak J, Champion R, Fiedler W, Pagoni M, Bergeron J, Ting SB, Hou JZ, Anagnostopoulos A, McDonald A, Murthy V, Yamauchi T, Wang J, Jiang Q, Sun Y, Chyla B, Mendes W, and DiNardo CD
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- Humans, Follow-Up Studies, Cytarabine, Antineoplastic Combined Chemotherapy Protocols, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute etiology
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- 2022
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18. Pretransplant FLT3-ITD MRD assessed by high-sensitivity PCR-NGS determines posttransplant clinical outcome.
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Loo S, Dillon R, Ivey A, Anstee NS, Othman J, Tiong IS, Potter N, Jovanovic J, Runglall M, Chong CC, Bajel A, Ritchie D, Gray K, Yeoh ZH, McBean M, Gilkes A, Thomas I, Johnson S, Russell NH, and Wei AH
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- Humans, fms-Like Tyrosine Kinase 3 genetics, Mutation, Neoplasm, Residual diagnosis, Neoplasm, Residual genetics, Polymerase Chain Reaction, Prognosis, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Hematopoietic Stem Cell Transplantation
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- 2022
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19. Prognostic impact of NPM1 and FLT3 mutations in patients with AML in first remission treated with oral azacitidine.
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Döhner H, Wei AH, Roboz GJ, Montesinos P, Thol FR, Ravandi F, Dombret H, Porkka K, Sandhu I, Skikne B, See WL, Ugidos M, Risueño A, Chan ET, Thakurta A, Beach CL, and Lopes de Menezes D
- Subjects
- Azacitidine therapeutic use, Humans, Mutation, Neoplasm, Residual, Nucleophosmin, Prognosis, Protein-Tyrosine Kinases genetics, Recurrence, Remission Induction, fms-Like Tyrosine Kinase 3 genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Nuclear Proteins genetics
- Abstract
The randomized, placebo-controlled, phase 3 QUAZAR AML-001 trial (ClinicalTrials.gov identifier: NCT01757535) evaluated oral azacitidine (Oral-AZA) in patients with acute myeloid leukemia (AML) in first remission after intensive chemotherapy (IC) who were not candidates for hematopoietic stem cell transplantation. Eligible patients were randomized 1:1 to Oral-AZA 300 mg or placebo for 14 days per 28-day cycle. We evaluated relapse-free survival (RFS) and overall survival (OS) in patient subgroups defined by NPM1 and FLT3 mutational status at AML diagnosis and whether survival outcomes in these subgroups were influenced by presence of post-IC measurable residual disease (MRD). Gene mutations at diagnosis were collected from patient case report forms; MRD was determined centrally by multiparameter flow cytometry. Overall, 469 of 472 randomized patients (99.4%) had available mutational data; 137 patients (29.2%) had NPM1 mutations (NPM1mut), 66 patients (14.1%) had FLT3 mutations (FLT3mut; with internal tandem duplications [ITD], tyrosine kinase domain mutations [TKDmut], or both), and 30 patients (6.4%) had NPM1mut and FLT3-ITD at diagnosis. Among patients with NPM1mut, OS and RFS were improved with Oral-AZA by 37% (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.41-0.98) and 45% (HR, 0.55; 95% CI, 0.35-0.84), respectively, vs placebo. Median OS was improved numerically with Oral-AZA among patients with NPM1mut whether without MRD (48.6 months vs 31.4 months with placebo) or with MRD (46.1 months vs 10.0 months with placebo) post-IC. Among patients with FLT3mut, Oral-AZA improved OS and RFS by 37% (HR, 0.63; 95% CI, 0.35-1.12) and 49% (HR, 0.51; 95% CI, 0.27-0.95), respectively, vs placebo. Median OS with Oral-AZA vs placebo was 28.2 months vs 16.2 months, respectively, for patients with FLT3mut and without MRD and 24.0 months vs 8.0 months for patients with FLT3mut and MRD. In multivariate analyses, Oral-AZA significantly improved survival independent of NPM1 or FLT3 mutational status, cytogenetic risk, or post-IC MRD status., (© 2022 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.)
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- 2022
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20. Diagnosis and management of AML in adults: 2022 recommendations from an international expert panel on behalf of the ELN.
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Döhner H, Wei AH, Appelbaum FR, Craddock C, DiNardo CD, Dombret H, Ebert BL, Fenaux P, Godley LA, Hasserjian RP, Larson RA, Levine RL, Miyazaki Y, Niederwieser D, Ossenkoppele G, Röllig C, Sierra J, Stein EM, Tallman MS, Tien HF, Wang J, Wierzbowska A, and Löwenberg B
- Subjects
- Adult, Humans, Mutation, Neoplasm, Residual diagnosis, Neoplasm, Residual drug therapy, Nucleophosmin, Prognosis, Proto-Oncogene Proteins c-bcl-2 genetics, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy
- Abstract
The 2010 and 2017 editions of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults are widely recognized among physicians and investigators. There have been major advances in our understanding of AML, including new knowledge about the molecular pathogenesis of AML, leading to an update of the disease classification, technological progress in genomic diagnostics and assessment of measurable residual disease, and the successful development of new therapeutic agents, such as FLT3, IDH1, IDH2, and BCL2 inhibitors. These advances have prompted this update that includes a revised ELN genetic risk classification, revised response criteria, and treatment recommendations., (© 2022 by The American Society of Hematology.)
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- 2022
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21. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data.
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Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, Wang SA, Bagg A, Barbui T, Branford S, Bueso-Ramos CE, Cortes JE, Dal Cin P, DiNardo CD, Dombret H, Duncavage EJ, Ebert BL, Estey EH, Facchetti F, Foucar K, Gangat N, Gianelli U, Godley LA, Gökbuget N, Gotlib J, Hellström-Lindberg E, Hobbs GS, Hoffman R, Jabbour EJ, Kiladjian JJ, Larson RA, Le Beau MM, Loh ML, Löwenberg B, Macintyre E, Malcovati L, Mullighan CG, Niemeyer C, Odenike OM, Ogawa S, Orfao A, Papaemmanuil E, Passamonti F, Porkka K, Pui CH, Radich JP, Reiter A, Rozman M, Rudelius M, Savona MR, Schiffer CA, Schmitt-Graeff A, Shimamura A, Sierra J, Stock WA, Stone RM, Tallman MS, Thiele J, Tien HF, Tzankov A, Vannucchi AM, Vyas P, Wei AH, Weinberg OK, Wierzbowska A, Cazzola M, Döhner H, and Tefferi A
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- Acute Disease, Consensus, Genomics, Humans, World Health Organization, Hematologic Neoplasms pathology, Leukemia diagnosis, Leukemia genetics, Leukemia pathology, Myeloproliferative Disorders diagnosis, Myeloproliferative Disorders genetics, Myeloproliferative Disorders pathology
- Abstract
The classification of myeloid neoplasms and acute leukemias was last updated in 2016 within a collaboration between the World Health Organization (WHO), the Society for Hematopathology, and the European Association for Haematopathology. This collaboration was primarily based on input from a clinical advisory committees (CACs) composed of pathologists, hematologists, oncologists, geneticists, and bioinformaticians from around the world. The recent advances in our understanding of the biology of hematologic malignancies, the experience with the use of the 2016 WHO classification in clinical practice, and the results of clinical trials have indicated the need for further revising and updating the classification. As a continuation of this CAC-based process, the authors, a group with expertise in the clinical, pathologic, and genetic aspects of these disorders, developed the International Consensus Classification (ICC) of myeloid neoplasms and acute leukemias. Using a multiparameter approach, the main objective of the consensus process was the definition of real disease entities, including the introduction of new entities and refined criteria for existing diagnostic categories, based on accumulated data. The ICC is aimed at facilitating diagnosis and prognostication of these neoplasms, improving treatment of affected patients, and allowing the design of innovative clinical trials.
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- 2022
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22. Oral azacitidine prolongs survival of patients with AML in remission independently of measurable residual disease status.
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Roboz GJ, Ravandi F, Wei AH, Dombret H, Thol F, Voso MT, Schuh AC, Porkka K, La Torre I, Skikne B, Zhong J, Beach CL, Risueño A, Menezes DL, Ossenkoppele G, and Döhner H
- Subjects
- Antimetabolites, Azacitidine therapeutic use, Humans, Neoplasm, Residual drug therapy, Prognosis, Recurrence, Remission Induction, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy
- Abstract
Measurable residual disease (MRD) in patients with acute myeloid leukemia (AML) in remission after intensive chemotherapy is predictive of early relapse and poor survival. Postremission maintenance therapy that prolongs MRD negativity or converts MRD+ patients to MRD- status may delay or prevent relapse and improve overall survival (OS). In the phase 3 QUAZAR AML-001 trial, oral azacitidine (oral-AZA; formerly CC-486), a hypomethylating agent, significantly prolonged OS and relapse-free survival (RFS) compared with placebo in patients aged ≥55 years with AML in first remission after intensive chemotherapy who were not candidates for hematopoietic stem cell transplantation. In this trial, MRD (≥0.1% leukemic cells in bone marrow) was assessed by multiparameter flow cytometry in serial samples collected at baseline and on day 1 of every 3 cycles. As expected, baseline MRD status was significantly associated with both OS and RFS. Multivariate analyses showed oral-AZA significantly improved OS and RFS vs placebo independent of baseline MRD status. Oral-AZA treatment also extended the duration of MRD negativity by 6 months vs placebo and resulted in a higher rate of conversion from MRD+ at baseline to MRD- during treatment: 37% vs 19%, respectively. In the oral-AZA arm, 24% of MRD responders achieved MRD negativity >6 months after treatment initiation. Although presence or absence of MRD was a strong prognostic indicator of OS and RFS, there were added survival benefits with oral-AZA maintenance therapy compared with placebo, independent of patients' MRD status at baseline. Registered at clinicaltrials.gov as #NCT01757535., (© 2022 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.)
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- 2022
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23. Oral Azacitidine (CC-486) for the Treatment of Myeloid Malignancies.
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Garcia-Manero G, Döhner H, Wei AH, La Torre I, Skikne B, Beach CL, and Santini V
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- Adult, Antimetabolites, Antineoplastic therapeutic use, Azacitidine pharmacology, Azacitidine therapeutic use, Clinical Trials, Phase III as Topic, Humans, Immunologic Factors therapeutic use, Randomized Controlled Trials as Topic, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute, Myelodysplastic Syndromes, Myeloproliferative Disorders drug therapy
- Abstract
Epigenetic dysregulation leads to aberrant DNA hypermethylation and is common in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). A large number of clinical trials in AML, MDS, and other hematologic malignancies have assessed hypomethylating agents (HMAs), used alone or in combination with other drugs, in the frontline, maintenance, relapsed/refractory, and peritransplant settings. Effective maintenance therapy has long been a goal for patients with AML in remission. Previous large, randomized clinical trials of maintenance with HMAs or other agents had not shown meaningful improvement in overall survival. Oral azacitidine (Oral-AZA [CC-486]) is approved in the United States, Canada, and European Union for treatment of adult patients with AML in first complete remission (CR) or CR with incomplete blood count recovery (CRi) following intensive induction chemotherapy who are ineligible for hematopoietic cell transplant. Regulatory approvals of Oral-AZA were based on outcomes from the randomized, phase III QUAZAR AML-001 trial, which showed a median overall survival advantage of 9.9 months with Oral-AZA versus placebo. Oral-AZA allows convenient extended AZA dosing for 14 days per 28-day treatment cycle, which is not feasible with injectable AZA. Focusing on AML and MDS, this report reviews the rationale for the use of orally bioavailable AZA and its potential use in all-oral combination therapy regimens; the unique pharmacokinetic and pharmacodynamic profile of Oral-AZA compared with injectable AZA; the clinical safety and efficacy of Oral-AZA maintenance therapy in patients with AML in first remission and for treatment of patients with active MDS; and ongoing Oral-AZA clinical trials., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2022
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24. Clonal hematopoiesis, myeloid disorders and BAX-mutated myelopoiesis in patients receiving venetoclax for CLL.
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Blombery P, Lew TE, Dengler MA, Thompson ER, Lin VS, Chen X, Nguyen T, Panigrahi A, Handunnetti SM, Carney DA, Westerman DA, Tam CS, Adams JM, Wei AH, Huang DCS, Seymour JF, Roberts AW, and Anderson MA
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Female, Humans, Male, Middle Aged, Vidarabine administration & dosage, Vidarabine adverse effects, Vidarabine analogs & derivatives, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Hematologic Neoplasms genetics, Hematologic Neoplasms metabolism, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell metabolism, Mutation, Myelopoiesis drug effects, Myeloproliferative Disorders genetics, Myeloproliferative Disorders metabolism, Neoplasms, Second Primary genetics, Neoplasms, Second Primary metabolism, Sulfonamides administration & dosage, Sulfonamides adverse effects, bcl-2-Associated X Protein antagonists & inhibitors, bcl-2-Associated X Protein genetics, bcl-2-Associated X Protein metabolism
- Abstract
The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment of CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (≥1 of neutropenia, thrombocytopenia, anemia) lasting ≥4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (t-MNs). t-MNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected the acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with t-MNs. Single-cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy., (© 2022 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.)
- Published
- 2022
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25. BCL2 and MCL1 inhibitors for hematologic malignancies.
- Author
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Roberts AW, Wei AH, and Huang DCS
- Subjects
- Animals, Antineoplastic Agents pharmacology, Apoptosis drug effects, Drug Discovery, Hematologic Neoplasms metabolism, Humans, Molecular Targeted Therapy, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Proto-Oncogene Proteins c-bcl-2 metabolism, Antineoplastic Agents therapeutic use, Hematologic Neoplasms drug therapy, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors
- Abstract
BCL2 and MCL1 are commonly expressed prosurvival (antiapoptotic) proteins in hematologic cancers and play important roles in their biology either through dysregulation or by virtue of intrinsic importance to the cell-of-origin of the malignancy. A new class of small-molecule anticancer drugs, BH3 mimetics, now enable specific targeting of these proteins in patients. BH3 mimetics act by inhibiting the prosurvival BCL2 proteins to enable the activation of BAX and BAK, apoptosis effectors that permeabilize the outer mitochondrial membrane, triggering apoptosis directly in many cells and sensitizing others to cell death when combined with other antineoplastic drugs. Venetoclax, a specific inhibitor of BCL2, is the first approved in class, demonstrating striking single agent activity in chronic lymphocytic leukemia and in other lymphoid neoplasms, as well as activity against acute myeloid leukemia (AML), especially when used in combination. Key insights from the venetoclax experience include that responses occur rapidly, with major activity as monotherapy proving to be the best indicator for success in combination regimens. This emphasizes the importance of adequate single-agent studies for drugs in this class. Furthermore, secondary resistance is common with long-term exposure and often mediated by genetic or adaptive changes in the apoptotic pathway, suggesting that BH3 mimetics are better suited to limited duration, rather than continuous, therapy. The success of venetoclax has inspired development of BH3 mimetics targeting MCL1. Despite promising preclinical activity against MYC-driven lymphomas, myeloma, and AML, their success may particularly depend on their tolerability profile given physiological roles for MCL1 in several nonhematologic tissues., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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26. Acute Myeloid Leukemia: Historical Perspective and Progress in Research and Therapy Over 5 Decades.
- Author
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Kantarjian HM, Short NJ, Fathi AT, Marcucci G, Ravandi F, Tallman M, Wang ES, and Wei AH
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Prognosis, Time Factors, Treatment Outcome, Leukemia, Myeloid, Acute therapy
- Abstract
With the Food and Drug Administration approval of 9 agents for different acute myeloid leukemia (AML) indications, the prognosis and management of AML is evolving rapidly. Herein, we review the important milestones in the history of AML research and therapy, discuss insights regarding prognostic assessment and prediction of treatment outcome, detail practical supportive care measures, and summarize the current treatment landscape and areas of evolving research., Competing Interests: Disclosure H.K. reports research grants and honoraria from AbbVie, Amgen, Ascentage, BMS, Daiichi-Sankyo, Immunogen, Jazz, Novartis, Pfizer, and Sanofi; and honoraria from Actinium (advisory board), Adaptive Biotechnologies, Aptitude Health, Bio Ascend, Delta Fly, Janssen Global, Oxford Biomedical, and Takeda Oncology. A.H.W. has served on advisory boards for Novartis, Janssen, Amgen, Roche, Pfizer, AbbVie, Servier, Celgene-BMS, MacroGenics, Agios, and Gilead; receives research funding to the institution from Novartis, AbbVie, Servier, Celgene-BMS, Astra Zeneca, and Amgen; serves on speakers bureaus for AbbVie, Novartis, and Celgene; and receives royalty payments from the Walter and Eliza Hall Institute of Medical Research related to venetoclax. M.S.T. has served on advisory boards for AbbVie, Daiichi-Sankyo, Orsenix, KAHR, Delta Fly Pharma, Jazz Pharma, Roche, BioSight, Novartis, Innate Pharmaceuticals, Kura, and Syros Pharmaceuticals; received research funding from AbbVie, Orsenix, BioSight, GlycoMimetics, Rafael Pharmaceuticals, and Amgen; and received royalty from UpToDate. N.J.S. has received consulting fees from Takeda Oncology and AstraZeneca, research funding from Takeda Oncology and Astellas Pharma Inc, and honoraria from Amgen. A.T.F. has provided consulting/advisory services for Agios, BMS/Celgene, Astellas, Seattle Genetics, AbbVie, Pfizer, Genentech, Kite, Amgen, Takeda, Kura, Blueprint, Trillium, Foghorn, Amphivena, NewLink Genetics, Trovagene, Novartis, and MorphoSys. He is receiving research support from Agios, Celgene/BMS, and AbbVie. G.M. has received honoraria from Agios, AbbVie, and Novartis; research support from Merck ESW; has served on advisory boards for AbbVie, Astellas, BMS/Celgene, Genentech, GlaxoSmithKline, Jazz, Kite Pharmaceuticals, Kura Oncology, Novartis, Pfizer, Stemline, and Takeda; provided consulting for Mana Therapeutics; served as a speaker for Stemline, Kura, Pfizer, and DAVA Oncology; and served on data safety monitoring committees for AbbVie and Rafael Pharmaceuticals., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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27. Fitness for intensive chemotherapy: a continuing conundrum.
- Author
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Wei AH
- Published
- 2021
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28. Intact TP-53 function is essential for sustaining durable responses to BH3-mimetic drugs in leukemias.
- Author
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Thijssen R, Diepstraten ST, Moujalled D, Chew E, Flensburg C, Shi MX, Dengler MA, Litalien V, MacRaild S, Chen M, Anstee NS, Reljić B, Gabriel SS, Djajawi TM, Riffkin CD, Aubrey BJ, Chang C, Tai L, Xu Z, Morley T, Pomilio G, Bruedigam C, Kallies A, Stroud DA, Bajel A, Kluck RM, Lane SW, Schoumacher M, Banquet S, Majewski IJ, Strasser A, Roberts AW, Huang DCS, Brown FC, Kelly GL, and Wei AH
- Subjects
- Animals, Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Apoptosis physiology, Apoptosis Regulatory Proteins physiology, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, CRISPR-Cas Systems, Cell Line, Tumor, DNA Damage, Genes, p53, Humans, Indolizines therapeutic use, Interleukin-2 Receptor alpha Subunit deficiency, Isoquinolines therapeutic use, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute therapy, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Morpholines therapeutic use, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Neoplasm Proteins antagonists & inhibitors, Oxidative Phosphorylation drug effects, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Sulfonamides administration & dosage, Sulfonamides therapeutic use, Tumor Suppressor Protein p53 deficiency, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, Apoptosis drug effects, Apoptosis Regulatory Proteins antagonists & inhibitors, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Indolizines pharmacology, Isoquinolines pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Myeloid, Acute drug therapy, Morpholines pharmacology, Neoplasm Proteins physiology, Peptide Fragments antagonists & inhibitors, Proto-Oncogene Proteins antagonists & inhibitors, Sulfonamides pharmacology, Tumor Suppressor Protein p53 physiology
- Abstract
Selective targeting of BCL-2 with the BH3-mimetic venetoclax has been a transformative treatment for patients with various leukemias. TP-53 controls apoptosis upstream of where BCL-2 and its prosurvival relatives, such as MCL-1, act. Therefore, targeting these prosurvival proteins could trigger apoptosis across diverse blood cancers, irrespective of TP53 mutation status. Indeed, targeting BCL-2 has produced clinically relevant responses in blood cancers with aberrant TP-53. However, in our study, TP53-mutated or -deficient myeloid and lymphoid leukemias outcompeted isogenic controls with intact TP-53, unless sufficient concentrations of BH3-mimetics targeting BCL-2 or MCL-1 were applied. Strikingly, tumor cells with TP-53 dysfunction escaped and thrived over time if inhibition of BCL-2 or MCL-1 was sublethal, in part because of an increased threshold for BAX/BAK activation in these cells. Our study revealed the key role of TP-53 in shaping long-term responses to BH3-mimetic drugs and reconciled the disparate pattern of initial clinical response to venetoclax, followed by subsequent treatment failure among patients with TP53-mutant chronic lymphocytic leukemia or acute myeloid leukemia. In contrast to BH3-mimetics targeting just BCL-2 or MCL-1 at doses that are individually sublethal, a combined BH3-mimetic approach targeting both prosurvival proteins enhanced lethality and durably suppressed the leukemia burden, regardless of TP53 mutation status. Our findings highlight the importance of using sufficiently lethal treatment strategies to maximize outcomes of patients with TP53-mutant disease. In addition, our findings caution against use of sublethal BH3-mimetic drug regimens that may enhance the risk of disease progression driven by emergent TP53-mutant clones., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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29. Taking aim at IDH in fitter patients with AML.
- Author
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Wei AH and Daver N
- Subjects
- Humans, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute genetics
- Published
- 2021
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30. Outcomes and health care utilization of older patients with acute myeloid leukemia.
- Author
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Sharplin K, Wee LYA, Singhal D, Edwards S, Danner S, Lewis I, Thomas D, Wei A, Yong ASM, and Hiwase DK
- Subjects
- Aged, Humans, Palliative Care, Patient Acceptance of Health Care, Retrospective Studies, Leukemia, Myeloid, Acute drug therapy, Terminal Care
- Abstract
Background: The incidence of acute myeloid leukemia (AML) in older patients is increasing, but practice guidelines balancing quality-of-life, time outside of hospital and overall survival (OS) are not established., Methods: We conducted a retrospective analysis comparing time outside hospital, OS and end-of-life care in AML patients ≥60 years treated with intensive chemotherapy (IC), hypomethylating agents (HMA) and best supportive care (BSC) in a tertiary hospital., Results: Of 201 patients diagnosed between 2005 and 2015, 54% received IC while 14% and 32% were treated with HMA and BSC respectively. Median OS was significantly higher in patients treated with IC and HMA compared with BSC (11.5 versus 16.2 versus 1.3 months; p < .0001). Median number of hospital admissions for the entire cohort was 3 (1-17) and patients spent <50% of their life after the diagnosis in the hospital setting. Compared to BSC, IC (HR 0.27, p < .0001) and HMA therapy (HR 0.16, p < .0001) were associated with the lower likelihood of spending at least 25% of survival time in hospital. Although 66% patients were referred to palliative care, the interval between referral to death was 24 (1-971) days and 46% patients died in the hospital., Conclusion: Older patients with AML, irrespective of treatment, require intensive health care resources, are more likely to die in hospital and less likely to use hospice services. Older AML patients treated with disease modifying therapy survive longer than those receiving BSC, and spend >50% of survival time outside the hospital. These data are informative for counselling older patients with AML., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2021
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31. Targeting MCL-1 in hematologic malignancies: Rationale and progress.
- Author
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Wei AH, Roberts AW, Spencer A, Rosenberg AS, Siegel D, Walter RB, Caenepeel S, Hughes P, McIver Z, Mezzi K, Morrow PK, and Stein A
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Gene Expression Regulation, Neoplastic drug effects, Hematologic Neoplasms drug therapy, Hematologic Neoplasms metabolism, Humans, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute metabolism, Molecular Targeted Therapy, Multiple Myeloma drug therapy, Multiple Myeloma metabolism, Myeloid Cell Leukemia Sequence 1 Protein analysis, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Signal Transduction drug effects, Up-Regulation drug effects, Antineoplastic Agents pharmacology, Hematologic Neoplasms genetics, Leukemia, Myeloid, Acute genetics, Multiple Myeloma genetics, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Myeloid Cell Leukemia Sequence 1 Protein genetics
- Abstract
Myeloid cell leukemia sequence 1 (MCL-1) is an antiapoptotic protein that plays a key role in promoting cell survival in multiple myeloma (MM), acute myeloid leukemia (AML), and non-Hodgkin lymphoma (NHL). Overexpression of MCL-1 is associated with treatment resistance and poor prognosis; thus, MCL-1 inhibitors are rational therapeutic options for malignancies depending on MCL-1. Several MCL-1 inhibitors have entered clinical trials, including AZD5991, S64315, AMG 176, and AMG 397. A key area of investigation is whether MCL-1 inhibitors will complement the activity of BCL-2 inhibitors, such as venetoclax, and synergistically enhance anti-tumor efficacy when given in combination with other anti-cancer drugs. Another important question is whether a safe therapeutic window can be found for this new class of inhibitors. In summary, inhibition of MCL-1 shows potential as a treatment for hematologic malignancies and clinical evaluation of MCL-1 inhibitors is currently underway., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2020
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32. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebo-controlled trial.
- Author
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Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi K, Kim I, Stevens DA, Fiedler W, Pagoni M, Samoilova O, Hu Y, Anagnostopoulos A, Bergeron J, Hou JZ, Murthy V, Yamauchi T, McDonald A, Chyla B, Gopalakrishnan S, Jiang Q, Mendes W, Hayslip J, and Panayiotidis P
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Mutation, Remission Induction, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Cytarabine administration & dosage, Leukemia, Myeloid, Acute drug therapy, Sulfonamides administration & dosage
- Abstract
Effective treatment options are limited for patients with acute myeloid leukemia (AML) who cannot tolerate intensive chemotherapy. Adults age ≥18 years with newly diagnosed AML ineligible for intensive chemotherapy were enrolled in this international phase 3 randomized double-blind placebo-controlled trial. Patients (N = 211) were randomized 2:1 to venetoclax (n = 143) or placebo (n = 68) in 28-day cycles, plus low-dose cytarabine (LDAC) on days 1 to 10. Primary end point was overall survival (OS); secondary end points included response rate, transfusion independence, and event-free survival. Median age was 76 years (range, 36-93 years), 38% had secondary AML, and 20% had received prior hypomethylating agent treatment. Planned primary analysis showed a 25% reduction in risk of death with venetoclax plus LDAC vs LDAC alone (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.52-1.07; P = .11), although not statistically significant; median OS was 7.2 vs 4.1 months, respectively. Unplanned analysis with additional 6-month follow-up demonstrated median OS of 8.4 months for the venetoclax arm (HR, 0.70; 95% CI, 0.50-0.98; P = .04). Complete remission (CR) plus CR with incomplete blood count recovery rates were 48% and 13% for venetoclax plus LDAC and LDAC alone, respectively. Key grade ≥3 adverse events (venetoclax vs LDAC alone) were febrile neutropenia (32% vs 29%), neutropenia (47% vs 16%), and thrombocytopenia (45% vs 37%). Venetoclax plus LDAC demonstrates clinically meaningful improvement in remission rate and OS vs LDAC alone, with a manageable safety profile. Results confirm venetoclax plus LDAC as an important frontline treatment for AML patients unfit for intensive chemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT03069352., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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33. Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia.
- Author
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Döhner K, Thiede C, Jahn N, Panina E, Gambietz A, Larson RA, Prior TW, Marcucci G, Jones D, Krauter J, Heuser M, Voso MT, Ottone T, Nomdedeu JF, Mandrekar SJ, Klisovic RB, Wei AH, Sierra J, Sanz MA, Brandwein JM, de Witte T, Jansen JH, Niederwieser D, Appelbaum FR, Medeiros BC, Tallman MS, Schlenk RF, Ganser A, Serve H, Ehninger G, Amadori S, Gathmann I, Benner A, Pallaud C, Stone RM, Döhner H, and Bloomfield CD
- Subjects
- Europe, Female, Genotype, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Multivariate Analysis, Nucleophosmin, Prognosis, Proportional Hazards Models, Risk Factors, Treatment Outcome, Gene Duplication, Genetic Predisposition to Disease, Leukemia, Myeloid, Acute genetics, Nuclear Proteins genetics, Tandem Repeat Sequences genetics, fms-Like Tyrosine Kinase 3 genetics
- Abstract
Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (≥0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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34. How I treat acute myeloid leukemia in the era of new drugs.
- Author
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DiNardo CD and Wei AH
- Subjects
- Adult, Aged, Aminopyridines therapeutic use, Aniline Compounds therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Cytarabine therapeutic use, Daunorubicin therapeutic use, Female, Glycine analogs & derivatives, Glycine therapeutic use, Humans, Isocitrate Dehydrogenase antagonists & inhibitors, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, Prognosis, Pyrazines therapeutic use, Pyridines therapeutic use, Sialic Acid Binding Ig-like Lectin 3 antagonists & inhibitors, Sialic Acid Binding Ig-like Lectin 3 genetics, Staurosporine analogs & derivatives, Staurosporine therapeutic use, Sulfonamides therapeutic use, Triazines therapeutic use, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, fms-Like Tyrosine Kinase 3 genetics, Antineoplastic Agents therapeutic use, Biomarkers, Tumor genetics, Leukemia, Myeloid, Acute drug therapy, Molecular Targeted Therapy, Mutation
- Abstract
The acute myeloid leukemia (AML) treatment landscape has changed substantially since 2017. New targeted drugs have emerged, including venetoclax to target B-cell lymphoma 2, midostaurin and gilteritinib to target FLT3, and ivosidenib and enasidenib to target mutant isocitrate dehydrogenase 1 and 2, respectively. Other additions include reapproval of gemtuzumab ozogomycin to target CD33, glasdegib to target the hedgehog pathway, and a liposomal formulation of daunorubicin and cytarabine (CPX-351). Genomically heterogeneous AML has a tendency to evolve, particularly under selective treatment pressure. For decades, treatment decisions have largely centered around chemotherapy drug intensity. Physicians now have access to an increasing number of drugs with novel mechanisms of action and distinctive side-effect profiles. Key issues faced by hematologists in this era of new drugs include (1) the timely identification of actionable mutations at diagnosis and at relapse; (2) deciding which drug to use among several therapeutic options; and (3) increasing awareness of how to anticipate, mitigate, and manage common complications associated with these new agents. This article will use 3 case presentations to discuss some of the new treatment challenges encountered in AML management, with the goal of providing practical guidance to aid the practicing physician., (© 2020 by The American Society of Hematology.)
- Published
- 2020
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35. Maintenance therapy for AML: are we there yet?
- Author
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Wei AH
- Subjects
- Aged, Humans, Maintenance Chemotherapy, Azacitidine, Leukemia, Myeloid, Acute
- Abstract
Competing Interests: Conflict-of-interest disclosure: The author is a medical advisor and receives honoraria and research funding from Celgene.
- Published
- 2019
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36. Clinicopathological aspects of therapy-related acute myeloid leukemia and myelodysplastic syndrome.
- Author
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Chua CC, Fleming S, and Wei AH
- Subjects
- Allografts, Humans, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes therapy, Neoplasms, Second Primary therapy
- Abstract
Therapy-related myeloid neoplasm (t-MN) is a rare but devastating consequence of chemotherapy and/or radiotherapy used for the treatment of solid cancers and various hematologic malignancies. Our current understanding of the etiology is that hematopoietic clones that are contemporaneous with the primary cancer and resistant to the cytotoxic exposure have the potential to undergo selective expansion and transformation to t-MN. Consequently, a large proportion of cases are associated with adverse risk factors, resulting in limited effective treatment options. Despite the emergence of some therapies with promising activity in t-MN, most effects are short-lived and allogeneic stem cell transplantation remains the only curative option for eligible patients. This review summarizes the current literature on t-AML and t-MDS, with the aim of providing practical recommendations on the clinical evaluation and management of these conditions., (Crown Copyright © 2019. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2019
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37. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia.
- Author
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DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, Frankfurt O, Konopleva M, Wei AH, Kantarjian HM, Xu T, Hong WJ, Chyla B, Potluri J, Pollyea DA, and Letai A
- Subjects
- Aged, Aged, 80 and over, Azacitidine administration & dosage, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Cohort Studies, Decitabine administration & dosage, Female, Follow-Up Studies, Humans, Leukemia, Myeloid, Acute pathology, Male, Maximum Tolerated Dose, Prognosis, Sulfonamides administration & dosage, Survival Rate, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m
2 , days 1-5, intravenously [IV]) or azacitidine (75 mg/m2 , days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773)., (© 2019 by The American Society of Hematology.)- Published
- 2019
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38. Time to repeal and replace response criteria for acute myeloid leukemia?
- Author
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Bloomfield CD, Estey E, Pleyer L, Schuh AC, Stein EM, Tallman MS, and Wei A
- Subjects
- Biomarkers, Tumor, Combined Modality Therapy, Humans, Leukemia, Myeloid, Acute mortality, Neoplasm, Residual diagnosis, Prognosis, Remission Induction, Treatment Outcome, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute therapy
- Abstract
The International Working Group (IWG) response criteria for acute myeloid leukemia, published in 2003, have remained the standard by which the efficacy of new drugs is measured in clinical trials. Over the last decade, concepts related to treatment response have been challenged by several factors; for example, the dissociation between early clinical response and survival outcome in older patients, the recognition that epigenetic and newer differentiating-agent therapies may produce delayed responses and also hematologic improvement/transfusion independence without a morphologic response, and evidence that remissions without minimal (or measurable) residual disease (MRD) may result in outcomes superior to those of morphologic remissions with persistent MRD. The evolving role of MRD status as a potential surrogate for predicting long-term survival has enhanced the clinical need to standardize and incorporate emerging technologies that enable deeper responses beyond those recognized by the IWG, and to pre-emptively identify patients at risk of early relapse. The potential for therapeutic interventions to erase MRD and alter the natural history represents an important and open research question. Reviewed here are some of the implications and challenges associated with establishing and incorporating new treatment response criteria, initially into clinical research, and eventually into real-world practice., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2018
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39. Midostaurin, enasidenib, CPX-351, gemtuzumab ozogamicin, and venetoclax bring new hope to AML.
- Author
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Wei AH and Tiong IS
- Subjects
- Aminoglycosides pharmacology, Aminopyridines pharmacology, Antibodies, Monoclonal, Humanized pharmacology, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Clinical Trials as Topic, Gemtuzumab, Humans, Isocitrate Dehydrogenase antagonists & inhibitors, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute mortality, Liposomes, Mutation, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Sialic Acid Binding Ig-like Lectin 3 antagonists & inhibitors, Staurosporine pharmacology, Staurosporine therapeutic use, Sulfonamides pharmacology, Treatment Outcome, Triazines pharmacology, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, fms-Like Tyrosine Kinase 3 genetics, Aminoglycosides therapeutic use, Aminopyridines therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Cytarabine administration & dosage, Daunorubicin administration & dosage, Leukemia, Myeloid, Acute drug therapy, Molecular Targeted Therapy, Staurosporine analogs & derivatives, Sulfonamides therapeutic use, Triazines therapeutic use
- Abstract
In 2017, 4 drugs received US Food and Drug Administration marketing approval for acute myeloid leukemia (AML) treatment: targeted therapies for mutant FLT3 and IDH2 , a liposomal cytarabine-daunorubicin formulation for therapy-related AML and AML with myelodysplasia-related changes, and resurgence of an antibody-drug conjugate designed to target CD33. Promising results also emerged for the BCL-2 inhibitor venetoclax combined with low-intensity therapy in older patients unfit for intensive chemotherapy. This quintet of new drugs is likely to reshape the therapeutic landscape of AML., (© 2017 by The American Society of Hematology.)
- Published
- 2017
- Full Text
- View/download PDF
40. Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population.
- Author
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Hein N, Cameron DP, Hannan KM, Nguyen NN, Fong CY, Sornkom J, Wall M, Pavy M, Cullinane C, Diesch J, Devlin JR, George AJ, Sanij E, Quin J, Poortinga G, Verbrugge I, Baker A, Drygin D, Harrison SJ, Rozario JD, Powell JA, Pitson SM, Zuber J, Johnstone RW, Dawson MA, Guthridge MA, Wei A, McArthur GA, Pearson RB, and Hannan RD
- Subjects
- Animals, Cell Division drug effects, Cell Division genetics, Cell Line, Tumor, Checkpoint Kinase 1 genetics, Checkpoint Kinase 1 metabolism, Checkpoint Kinase 2 genetics, Checkpoint Kinase 2 metabolism, G2 Phase drug effects, G2 Phase genetics, Humans, Leukemia, Myeloid, Acute epidemiology, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Mice, Mice, Inbred NOD, Mice, Mutant Strains, Neoplastic Stem Cells pathology, Pol1 Transcription Initiation Complex Proteins genetics, Pol1 Transcription Initiation Complex Proteins metabolism, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Benzothiazoles pharmacology, Leukemia, Myeloid, Acute drug therapy, Naphthyridines pharmacology, Neoplastic Stem Cells enzymology, Pol1 Transcription Initiation Complex Proteins antagonists & inhibitors, Transcription, Genetic drug effects
- Abstract
Despite the development of novel drugs, the prospects for many patients with acute myeloid leukemia (AML) remain dismal. This study reveals that the selective inhibitor of RNA polymerase I (Pol I) transcription, CX-5461, effectively treats aggressive AML, including mixed-lineage leukemia-driven AML, and outperforms standard chemotherapies. In addition to the previously characterized mechanism of action of CX-5461 (ie, the induction of p53-dependent apoptotic cell death), the inhibition of Pol I transcription also demonstrates potent efficacy in p53null AML in vivo. This significant survival advantage in both p53WT and p53null leukemic mice treated with CX-5461 is associated with activation of the checkpoint kinases 1/2, an aberrant G2/M cell-cycle progression and induction of myeloid differentiation of the leukemic blasts. The ability to target the leukemic-initiating cell population is thought to be essential for lasting therapeutic benefit. Most strikingly, the acute inhibition of Pol I transcription reduces both the leukemic granulocyte-macrophage progenitor and leukemia-initiating cell (LIC) populations, and suppresses their clonogenic capacity. This suggests that dysregulated Pol I transcription is essential for the maintenance of their leukemia-initiating potential. Together, these findings demonstrate the therapeutic utility of this new class of inhibitors to treat highly aggressive AML by targeting LICs., (© 2017 by The American Society of Hematology.)
- Published
- 2017
- Full Text
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41. Targeting sphingosine kinase 1 induces MCL1-dependent cell death in acute myeloid leukemia.
- Author
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Powell JA, Lewis AC, Zhu W, Toubia J, Pitman MR, Wallington-Beddoe CT, Moretti PA, Iarossi D, Samaraweera SE, Cummings N, Ramshaw HS, Thomas D, Wei AH, Lopez AF, D'Andrea RJ, Lewis ID, and Pitson SM
- Subjects
- Amino Acid Chloromethyl Ketones pharmacology, Amino Alcohols pharmacology, Animals, Bone Marrow Cells drug effects, Bone Marrow Cells metabolism, Bone Marrow Cells pathology, Caspase Inhibitors pharmacology, Caspases genetics, Caspases metabolism, Cell Death drug effects, Cell Line, Tumor, Female, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Lysophospholipids metabolism, Mice, Mice, Inbred NOD, Molecular Targeted Therapy, Myeloid Cell Leukemia Sequence 1 Protein genetics, Myeloid Cell Leukemia Sequence 1 Protein metabolism, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Phosphotransferases (Alcohol Group Acceptor) genetics, Phosphotransferases (Alcohol Group Acceptor) metabolism, Protein Kinase Inhibitors pharmacology, Quinolines pharmacology, Receptors, Lysosphingolipid genetics, Receptors, Lysosphingolipid metabolism, Signal Transduction, Sphingosine analogs & derivatives, Sphingosine metabolism, Survival Analysis, Xenograft Model Antitumor Assays, Gene Expression Regulation, Leukemic, Leukemia, Myeloid, Acute drug therapy, Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors, Phosphotransferases (Alcohol Group Acceptor) antagonists & inhibitors, Receptors, Lysosphingolipid antagonists & inhibitors
- Abstract
Acute myeloid leukemia (AML) is an aggressive malignancy where despite improvements in conventional chemotherapy and bone marrow transplantation, overall survival remains poor. Sphingosine kinase 1 (SPHK1) generates the bioactive lipid sphingosine 1-phosphate (S1P) and has established roles in tumor initiation, progression, and chemotherapy resistance in a wide range of cancers. The role and targeting of SPHK1 in primary AML, however, has not been previously investigated. Here we show that SPHK1 is overexpressed and constitutively activated in primary AML patient blasts but not in normal mononuclear cells. Subsequent targeting of SPHK1 induced caspase-dependent cell death in AML cell lines, primary AML patient blasts, and isolated AML patient leukemic progenitor/stem cells, with negligible effects on normal bone marrow CD34
+ progenitors from healthy donors. Furthermore, administration of SPHK1 inhibitors to orthotopic AML patient-derived xenografts reduced tumor burden and prolonged overall survival without affecting murine hematopoiesis. SPHK1 inhibition was associated with reduced survival signaling from S1P receptor 2, resulting in selective downregulation of the prosurvival protein MCL1. Subsequent analysis showed that the combination of BH3 mimetics with either SPHK1 inhibition or S1P receptor 2 antagonism triggered synergistic AML cell death. These results support the notion that SPHK1 is a bona fide therapeutic target for the treatment of AML., (© 2017 by The American Society of Hematology.)- Published
- 2017
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42. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel.
- Author
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Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, Dombret H, Ebert BL, Fenaux P, Larson RA, Levine RL, Lo-Coco F, Naoe T, Niederwieser D, Ossenkoppele GJ, Sanz M, Sierra J, Tallman MS, Tien HF, Wei AH, Löwenberg B, and Bloomfield CD
- Subjects
- Adult, Consensus, Drug Administration Schedule, Genetic Testing, Humans, Immunophenotyping, International Cooperation, Leukemia, Myeloid, Acute classification, Leukemia, Myeloid, Acute genetics, Neoplasm, Residual, Practice Guidelines as Topic, Risk Factors, Transplantation, Autologous, Treatment Outcome, Antineoplastic Agents therapeutic use, Disease Management, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute therapy
- Abstract
The first edition of the European LeukemiaNet (ELN) recommendations for diagnosis and management of acute myeloid leukemia (AML) in adults, published in 2010, has found broad acceptance by physicians and investigators caring for patients with AML. Recent advances, for example, in the discovery of the genomic landscape of the disease, in the development of assays for genetic testing and for detecting minimal residual disease (MRD), as well as in the development of novel antileukemic agents, prompted an international panel to provide updated evidence- and expert opinion-based recommendations. The recommendations include a revised version of the ELN genetic categories, a proposal for a response category based on MRD status, and criteria for progressive disease., (© 2017 by The American Society of Hematology.)
- Published
- 2017
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43. Tracking sentence comprehension: Test-retest reliability in people with aphasia and unimpaired adults.
- Author
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Mack JE, Wei AZ, Gutierrez S, and Thompson CK
- Abstract
Purpose: Visual-world eyetracking is increasingly used to investigate online language processing in normal and language impaired listeners. Tracking changes in eye movements over time also may be useful for indexing language recovery in those with language impairments. Therefore, it is critical to determine the test-retest reliability of results obtained using this method., Methods: Unimpaired young adults and people with aphasia took part in two eyetracking sessions spaced about one week apart. In each session, participants completed a sentence-picture matching task in which they listened to active and passive sentences (e.g., The [
N1+Aux woman was ] [V visiting/visited ] [NP/PP2 (by) the man ]) and selected between two pictures with reversed thematic roles. We used intraclass correlations (ICCs) to examine the test-retest reliability of response measures (accuracy, reaction time (RT)) and online eye movements (i.e., the likelihood of fixating the target picture in each region of the sentence) in each participant group., Results: In the unimpaired adults, accuracy was at ceiling (thus ICCs were not computed), with moderate ICCs for RT (i.e., 0.4 - 0.58) for passive sentences and low (<0.4) for actives. In individuals with aphasia, test-retest reliability was strong (0.590.75) for RT for both sentence types. Similarly, for the unimpaired listeners, reliability of eye movements was moderate for passive sentences (NP/PP2 region) and low in all regions for active sentences. But, for the aphasic participant group, eye movement reliability was excellent for passive sentences (in the first second after sentence end) and strong for active sentences (V and NP/PP2 regions)., Conclusion: Results indicated moderate-to-low reliability for unimpaired listeners; however, reliable eye movement patterns were detected for processes specific to passive sentences (e.g., thematic reanalysis). In contrast, individuals with aphasia exhibited strong and stable performance across sentence types in response measures and online eye movements. These findings indicate that visual-world eyetracking provides a reliable measure of online sentence comprehension, and thus may be useful for investigating sentence processing changes over time. - Published
- 2016
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44. Isavuconazole as salvage therapy for mucormycosis.
- Author
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Graves B, Morrissey CO, Wei A, Coutsouvelis J, Ellis S, Pham A, Gooi J, and Ananda-Rajah M
- Abstract
Mucormycosis carries a high mortality rate with few therapeutic options available. We describe a man with pulmonary/splenic mucormycosis complicating hypoplastic myelodysplastic syndrome on a background of chronic kidney disease, who achieved a complete response with salvage isavuconazole therapy following intolerance of consecutive courses of liposomal amphotericin and posaconazole therapy.
- Published
- 2016
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- View/download PDF
45. Inositol polyphosphate 4-phosphatase II (INPP4B) is associated with chemoresistance and poor outcome in AML.
- Author
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Rijal S, Fleming S, Cummings N, Rynkiewicz NK, Ooms LM, Nguyen NY, Teh TC, Avery S, McManus JF, Papenfuss AT, McLean C, Guthridge MA, Mitchell CA, and Wei AH
- Subjects
- Adolescent, Adult, Aged, Gene Expression Regulation, Leukemic, Genetic Association Studies, Humans, Leukemia, Myeloid, Acute mortality, Middle Aged, Phosphoric Monoester Hydrolases genetics, Polymorphism, Single Nucleotide, Prognosis, Retrospective Studies, Survival Analysis, Transcriptome, Treatment Outcome, Young Adult, Drug Resistance, Neoplasm genetics, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Phosphoric Monoester Hydrolases physiology
- Abstract
Phosphoinositide signaling regulates diverse cellular functions. Phosphoinositide-3 kinase (PI3K) generates PtdIns(3,4,5)P3 and PtdIns(3,4)P2, leading to the activation of proliferative and anti-apoptotic signaling pathways. Termination of phosphoinositide signaling requires hydrolysis of inositol ring phosphate groups through the actions of PtdIns(3,4,5)P3 3-phosphatase (PTEN), PtdIns(3,4,5)P3 5-phosphatases (eg, SHIP), and PtdIns(3,4)P2 4-phosphatases (eg, INPP4B). The biological relevance of most of these phosphoinositide phosphatases in acute myeloid leukemia (AML) remains poorly understood. Mass spectrometry-based gene expression profiling of 3-, 4- and 5-phosphatases in human AML revealed significant overexpression of INPP4B. Analysis of an expanded panel of 205 AML cases at diagnosis revealed INPP4B overexpression in association with reduced responses to chemotherapy, early relapse, and poor overall survival, independent of other risk factors. Ectopic overexpression of INPP4B conferred leukemic resistance to cytosine arabinoside (ara-C), daunorubicin, and etoposide. Expression of a phosphatase inert variant (INPP4B C842A) failed to abrogate resistance of AML cells to chemotherapy in vitro or in vivo. In contrast, targeted suppression of endogenously overexpressed INPP4B by RNA interference sensitized AML cell lines and primary AML to chemotherapy. These findings demonstrate a previously unsuspected and clinically relevant role for INPP4B gain of function as a mediator of chemoresistance and poor survival outcome in AML independent of its phosphoinositide phosphatase function., (© 2015 by The American Society of Hematology.)
- Published
- 2015
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46. Have all-trans retinoic acid and arsenic trioxide replaced all-trans retinoic acid and anthracyclines in APL as standard of care.
- Author
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Iland HJ, Wei A, and Seymour JF
- Subjects
- Adult, Age Factors, Aged, Anthracyclines administration & dosage, Anthracyclines pharmacology, Antineoplastic Agents therapeutic use, Arsenic Trioxide, Arsenicals administration & dosage, Arsenicals pharmacology, Arsenicals therapeutic use, Blood Coagulation Factors therapeutic use, Clinical Trials as Topic, Combined Modality Therapy, Cytarabine administration & dosage, Etoposide administration & dosage, Humans, Hydroxyurea therapeutic use, Idarubicin administration & dosage, Leukemia, Promyelocytic, Acute therapy, Maintenance Chemotherapy, Middle Aged, Mitoxantrone administration & dosage, Multicenter Studies as Topic, Oxides administration & dosage, Oxides pharmacology, Oxides therapeutic use, Platelet Transfusion, Practice Guidelines as Topic, Remission Induction, Risk Assessment, Thioguanine, Treatment Outcome, Tretinoin administration & dosage, Tretinoin pharmacology, Tretinoin therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Promyelocytic, Acute drug therapy
- Abstract
Until recently, the standard of care in the treatment of APL has involved the combination of all-trans retinoic acid with anthracycline-based chemotherapy during both induction and consolidation. Additionally, the intensity of consolidation chemotherapy has evolved according to a universally accepted relapse-risk stratification algorithm based on the white cell and platelet counts at presentation. That standard of care is being challenged by the increasing incorporation of arsenic trioxide into front-line treatment protocols, based on two complementary observations. The first is the undoubted anti-leukaemic activity of arsenic trioxide as shown in the relapsed and refractory setting, and in the initial management of low- and intermediate-risk patients. The second is an improved understanding of the action of both all-trans retinoic acid and arsenic trioxide in mediating APL cell eradication, with increasing recognition that PML-RARA fusion protein degradation rather than direct induction of terminal differentiation is the primary mechanism for their ability to eliminate leukaemia initiating cells. As a result, we believe the standard of care for initial therapy in APL is shifting towards an all-trans retinoic acid plus arsenic trioxide-based approach, with additional chemotherapy reserved for patients with high-risk disease., (Copyright © 2014 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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47. Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription.
- Author
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Thomas D, Powell JA, Vergez F, Segal DH, Nguyen NY, Baker A, Teh TC, Barry EF, Sarry JE, Lee EM, Nero TL, Jabbour AM, Pomilio G, Green BD, Manenti S, Glaser SP, Parker MW, Lopez AF, Ekert PG, Lock RB, Huang DC, Nilsson SK, Récher C, Wei AH, and Guthridge MA
- Subjects
- Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cells, Cultured, Gene Expression Regulation, Leukemic drug effects, HEK293 Cells, HL-60 Cells, Humans, Hydrazones therapeutic use, Leukemia, Myeloid, Acute pathology, Mice, Mice, Inbred NOD, Mice, Knockout, Mice, SCID, Myeloid Cell Leukemia Sequence 1 Protein, Protein Kinase Inhibitors pharmacology, Signal Transduction drug effects, Signal Transduction genetics, Sulfonamides therapeutic use, Transcription, Genetic drug effects, Xenograft Model Antitumor Assays, Cyclin-Dependent Kinase 9 antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Molecular Targeted Therapy methods, Phosphoinositide-3 Kinase Inhibitors, Protein Kinase Inhibitors therapeutic use, Proto-Oncogene Proteins c-bcl-2 genetics
- Abstract
Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples. We show that PIK-75 transiently blocks Cdk7/9, leading to transcriptional suppression of MCL-1, rapid loss of Mcl-1 protein, and alleviation of its inhibition of proapoptotic Bak. PIK-75 also targets the p110α isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss of Mcl-1 and Bcl-xL association with Bak leads to rapid apoptosis of AML cells. Concordantly, low Bak expression in AML confers resistance to PIK-75-mediated killing. On the other hand, the induction of apoptosis by PIK-75 did not require the expression of the BH3 proteins Bim, Bid, Bad, Noxa, or Puma. PIK-75 significantly reduced leukemia burden and increased the survival of mice engrafted with human AML without inducing overt toxicity. Future efforts to cotarget PI3K and Cdk9 with drugs such as PIK-75 in AML are warranted.
- Published
- 2013
- Full Text
- View/download PDF
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