75 results on '"Uy, Geoffrey L."'
Search Results
2. Gilteritinib as Post-Transplant Maintenance for AML With Internal Tandem Duplication Mutation of FLT3 .
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Levis MJ, Hamadani M, Logan B, Jones RJ, Singh AK, Litzow M, Wingard JR, Papadopoulos EB, Perl AE, Soiffer RJ, Ustun C, Ueda Oshima M, Uy GL, Waller EK, Vasu S, Solh M, Mishra A, Muffly L, Kim HJ, Mikesch JH, Najima Y, Onozawa M, Thomson K, Nagler A, Wei AH, Marcucci G, Geller NL, Hasabou N, Delgado D, Rosales M, Hill J, Gill SC, Nuthethi R, King D, Wittsack H, Mendizabal A, Devine SM, Horowitz MM, and Chen YB
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- Humans, Male, Female, Middle Aged, Adult, Aged, Tandem Repeat Sequences, Young Adult, Neoplasm, Residual, Protein Kinase Inhibitors therapeutic use, Maintenance Chemotherapy, Gene Duplication, fms-Like Tyrosine Kinase 3 genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute therapy, Leukemia, Myeloid, Acute mortality, Pyrazines therapeutic use, Aniline Compounds therapeutic use, Hematopoietic Stem Cell Transplantation, Mutation
- Abstract
Purpose: Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD ) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit., Methods: Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS., Results: Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575)., Conclusion: Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.
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- 2024
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3. Identifying long-term survivors and those at higher or lower risk of relapse among patients with cytogenetically normal acute myeloid leukemia using a high-dimensional mixture cure model.
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Archer KJ, Fu H, Mrózek K, Nicolet D, Mims AS, Uy GL, Stock W, Byrd JC, Hiddemann W, Braess J, Spiekermann K, Metzeler KH, Herold T, and Eisfeld AK
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- Humans, Middle Aged, Adult, Male, Female, Cancer Survivors, Recurrence, Young Adult, Prognosis, Survivors, Leukemia, Myeloid, Acute genetics
- Abstract
Patients with cytogenetically normal acute myeloid leukemia (CN-AML) may harbor prognostically relevant gene mutations and thus be categorized into one of the three 2022 European LeukemiaNet (ELN) genetic-risk groups. Nevertheless, there remains heterogeneity with respect to relapse-free survival (RFS) within these genetic-risk groups. Our training set included 306 adults on Alliance for Clinical Trials in Oncology studies with de novo CN-AML aged < 60 years who achieved a complete remission and for whom centrally reviewed cytogenetics, RNA-sequencing, and gene mutation data from diagnostic samples were available (Alliance trial A152010). To overcome deficiencies of the Cox proportional hazards model when long-term survivors are present, we developed a penalized semi-parametric mixture cure model (MCM) to predict RFS where RNA-sequencing data comprised the predictor space. To validate model performance, we employed an independent test set from the German Acute Myeloid Leukemia Cooperative Group (AMLCG) consisting of 40 de novo CN-AML patients aged < 60 years who achieved a complete remission and had RNA-sequencing of their pre-treatment sample. For the training set, there was a significant non-zero cure fraction (p = 0.019) with 28.5% of patients estimated to be cured. Our MCM included 112 genes associated with cure, or long-term RFS, and 87 genes associated with latency, or shorter-term time-to-relapse. The area under the curve and C-statistic were respectively, 0.947 and 0.783 for our training set and 0.837 and 0.718 for our test set. We identified a novel, prognostically relevant molecular signature in CN-AML, which allows identification of patient subgroups independent of 2022 ELN genetic-risk groups.Trial registration Data from companion studies CALGB 8461, 9665 and 20202 (trials registered at www.clinicaltrials.gov as, respectively, NCT00048958, NCT00899223, and NCT00900224) were obtained from Alliance for Clinical Trials in Oncology under data sharing study A152010. Data from the AMLCG 2008 trial was registered at www.clinicaltrials.gov as NCT01382147., (© 2024. The Author(s).)
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- 2024
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4. Targeting hematologic malignancies by inhibiting E-selectin: A sweet spot for AML therapy?
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Uy GL, DeAngelo DJ, Lozier JN, Fisher DM, Jonas BA, Magnani JL, Becker PS, Lazarus HM, and Winkler IG
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- Humans, Bone Marrow pathology, E-Selectin antagonists & inhibitors, E-Selectin metabolism, Endothelial Cells metabolism, Hematologic Neoplasms drug therapy, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology
- Abstract
E-selectin, a cytoadhesive glycoprotein, is expressed on venular endothelial cells and mediates leukocyte localization to inflamed endothelium, the first step in inflammatory cell extravasation into tissue. Constitutive marrow endothelial E-selectin expression also supports bone marrow hematopoiesis via NF-κB-mediated signaling. Correspondingly, E-selectin interaction with E-selectin ligand (sialyl Lewis
x ) on acute myeloid leukemia (AML) cells leads to chemotherapy resistance in vivo. Uproleselan (GMI-1271) is a carbohydrate analog of sialyl Lewisx that blocks E-selectin binding. A Phase 2 trial of MEC chemotherapy combined with uproleselan for relapsed/refractory AML showed a median overall survival of 8.8 months and low (2%) rates of severe oral mucositis. Clinical trials seek to confirm activity in AML and mitigation of neutrophil-mediated adverse events (mucositis and diarrhea) after intensive chemotherapy. In this review we summarize E-selectin biology and the rationale for uproleselan in combination with other therapies for hematologic malignancies. We also describe uproleselan pharmacology and ongoing clinical trials., Competing Interests: Declaration of competing interest Geoffrey L. Uy: Advisory Board, Jazz Pharmaceuticals. Daniel J. DeAngelo: Consultancy for Amgen, Autolos, Agios, Blueprint, FortySeven, Gilead, Incyte, Jazz Pharmaceuticals, Novartis, Pfizer, Servier and Takeda. Research funding from Abbvie, GlycoMimetics, Novartis, and Blueprint Pharmaceuticals. Data Safety Monitoring Boards for Daiichi-Sankyo, Fibrogen, Mt. Sinai Myeloproliferative Neoplasms Consortium. Jay N. Lozier: Employment and equity position in GlycoMimetics, Inc. Dennis M Fisher: Consultancy for GlycoMimetics, Inc. Brian A Jonas: Consultant/advisor for AbbVie, BMS, Daiichi Sankyo, Genentech, Gilead, GlycoMimetics, Kymera, Pfizer, Rigel, Servier, and Takeda; protocol steering committee for GlycoMimetics; data monitoring committee for Gilead; travel reimbursement/support from Rigel; institutional research funding from AbbVie, Amgen, Aptose, AROG, BMS, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma, Forty-Seven, Genentech/Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, and Treadwell. John L. Magnani: Employment, consultancy, and equity positions in GlycoMimetics, Inc., and Glycotech, Inc. Pamela S. Becker: Research funding from Glycomimetics, Notable Labs, Pfizer and GPCR. Medical Advisor to Accordant Health Services. Hillard M. Lazarus: Consultancy for Actinium Pharmaceuticals, CSL Behring, GlycoMimetics Inc., Jazz Pharmaceuticals, Partner Therapeutics, Pluristem Therapeutics Inc., and Seattle Genetics. Equity position in Partner Therapeutics. Speakers' bureau for AstraZeneca and Bristol-Myers Squibb. Data Safety Monitoring Board for BioSight and Bristol-Myers Squibb. Ingrid G. Winkler: Patents and royalties on GlycoMimetics, Inc. compounds. The authors thank Drew Provan for excellent graphic design and rendering of figures, Ed Rock and Kerry Woodford for careful review of the manuscript, Scott Brittain for help generating Supplemental Figs. 1 and 2, and Shanti Rodriguez for help in preparation of the manuscript., (Copyright © 2024 GlycoMimetics, Inc. Published by Elsevier Ltd.. All rights reserved.)- Published
- 2024
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5. Determining treatment tolerance and fitness for intensive chemotherapy in older adults with AML: a call to action.
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Bhatt VR, Uy GL, and Klepin HD
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- Humans, Aged, Prospective Studies, Comorbidity, Cognition, Quality of Life, Leukemia, Myeloid, Acute therapy
- Abstract
Abstract: Determining fitness for intensive chemotherapy in an older adult with acute myeloid leukemia (AML) is an unanswered age-old question. Geriatric assessment captures any variation in multidimensional health, which can influence treatment tolerance. A prospective study is necessary to validate fitness criteria, determine whether geriatric assessment-based fitness performs superiorly to other criteria, and what components of geriatric assessment are associated with treatment tolerance. A validation study should enroll diverse patients from both academic and community centers and patients receiving intensive and lower-intensity chemotherapy. Geriatric assessment should include at minimum measures of comorbidity burden, cognition, physical function, and emotional health, which in previous smaller studies have shown to be associated with mortality in AML. These assessments should be completed before or within a few days of initiation of chemotherapy to reduce the influence of chemotherapy on the assessment results. Treatment tolerance has been measured by rates of toxicities in patients with solid malignancies; however, during the initial treatment of AML, rates of toxicities are very high regardless of treatment intensity. Early mortality, frequently used in previous studies, can provide a highly consequential and easily identifiable measure of treatment tolerance. The key end point to assess treatment tolerance, thus, should include early mortality. Other end points may include decline in function and quality of life and treatment modifications or cessation due to toxicities. Validating fitness criteria can guide treatment selection and supportive care interventions and are crucial to guide fitness-based trial eligibility, inform the interpretation of trial results, and facilitate drug labeling., (© 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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6. Clinical evaluation of complete remission (CR) with partial hematologic recovery (CRh) in acute myeloid leukemia: a report of 7235 patients from seven cohorts.
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Appelbaum JS, Wei AH, Mandrekar SJ, Tiong IS, Chua CC, Teh TC, Fong CY, Ting SB, Weber D, Benner A, Hill H, Saadati M, Yin J, Stone RM, Garcia-Manero G, Erba HP, Uy GL, Marcucci G, Larson RA, Thomas A, Freeman SD, Almuina NM, Döhner K, Thomas I, Russel NH, Döhner H, Othus M, Estey EH, and Walter RB
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- Humans, Remission Induction, Pathologic Complete Response, Antineoplastic Combined Chemotherapy Protocols, Leukemia, Myeloid, Acute drug therapy
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- 2024
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7. A randomized phase III study of standard versus high-dose cytarabine with or without vorinostat for AML.
- Author
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Garcia-Manero G, Podoltsev NA, Othus M, Pagel JM, Radich JP, Fang M, Rizzieri DA, Marcucci G, Strickland SA, Litzow MR, Savoie ML, Medeiros BC, Sekeres MA, Lin TL, Uy GL, Powell BL, Kolitz JE, Larson RA, Stone RM, Claxton D, Essell J, Luger SM, Mohan SR, Moseley A, Appelbaum FR, and Erba HP
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- Humans, Vorinostat therapeutic use, Daunorubicin, Idarubicin therapeutic use, Remission Induction, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cytarabine, Leukemia, Myeloid, Acute
- Abstract
Prior experience indicated that use of higher doses of cytarabine during induction for acute myeloid leukemia (AML) with a histone deacetylase inhibitor resulted in high response rates. S1203 was a randomized multicenter trial for previously untreated patients aged 18-60 with AML which compared daunorubicin and cytarabine (DA), idarubicin with higher dose cytarabine (IA) and IA with vorinostat (IA + V). The primary endpoint was event free survival (EFS). 738 patients were randomized: 261 to each DA and IA arms and 216 to the IA + V arm. 96, 456, and 150 patients had favorable-, intermediate-, and unfavorable-risk cytogenetics, respectively. 152 were NPM1 and 158 FLT3 mutated. The overall remission rate was 77.5% including 62.5% CR and 15.0% CRi. No differences in remission, EFS, or overall survival were observed among the 3 arms except for the favorable cytogenetics subset who had improved outcomes with DA and postremission high dose cytarabine. A trend towards increased toxicity was observed with the IA and IA + V arms. The use of higher dose cytarabine during induction therapy in younger patients with AML, with or without vorinostat, does not result in improved outcomes. (Funded by the US National Institutes of Health and others, ClinicalTrials.gov number, NCT01802333.)., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)
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- 2024
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8. Sex-associated differences in frequencies and prognostic impact of recurrent genetic alterations in adult acute myeloid leukemia (Alliance, AMLCG).
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Ozga M, Nicolet D, Mrózek K, Yilmaz AS, Kohlschmidt J, Larkin KT, Blachly JS, Oakes CC, Buss J, Walker CJ, Orwick S, Jurinovic V, Rothenberg-Thurley M, Dufour A, Schneider S, Sauerland MC, Görlich D, Krug U, Berdel WE, Woermann BJ, Hiddemann W, Braess J, Subklewe M, Spiekermann K, Carroll AJ, Blum WG, Powell BL, Kolitz JE, Moore JO, Mayer RJ, Larson RA, Uy GL, Stock W, Metzeler KH, Grimes HL, Byrd JC, Salomonis N, Herold T, Mims AS, and Eisfeld AK
- Subjects
- Adult, Humans, Male, Female, Prognosis, Nucleophosmin, Mutation, fms-Like Tyrosine Kinase 3 genetics, Sex Characteristics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute drug therapy
- Abstract
Clinical outcome of patients with acute myeloid leukemia (AML) is associated with demographic and genetic features. Although the associations of acquired genetic alterations with patients' sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling, cytogenetic and outcome analyses in 1726 adults with AML (749 female and 977 male) treated on frontline Alliance for Clinical Trials in Oncology protocols. A validation cohort comprised 465 women and 489 men treated on frontline protocols of the German AML Cooperative Group. Compared with men, women more often had normal karyotype, FLT3-ITD, DNMT3A, NPM1 and WT1 mutations and less often complex karyotype, ASXL1, SRSF2, U2AF1, RUNX1, or KIT mutations. More women were in the 2022 European LeukemiaNet intermediate-risk group and more men in adverse-risk group. We found sex differences in co-occurring mutation patterns and prognostic impact of select genetic alterations. The mutation-associated splicing events and gene-expression profiles also differed between sexes. In patients aged <60 years, SF3B1 mutations were male-specific adverse outcome prognosticators. We conclude that sex differences in AML-associated genetic alterations and mutation-specific differential splicing events highlight the importance of patients' sex in analyses of AML biology and prognostication., (© 2023. The Author(s).)
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- 2024
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9. Standardising acute myeloid leukaemia classification systems: a perspective from a panel of international experts.
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Shallis RM, Daver N, Altman JK, Komrokji RS, Pollyea DA, Badar T, Bewersdorf JP, Bhatt VR, de Botton S, de la Fuente Burguera A, Carraway HE, Desai P, Dillon R, Duployez N, El Chaer F, Fathi AT, Freeman SD, Gojo I, Grunwald MR, Jonas BA, Konopleva M, Lin TL, Mannis GN, Mascarenhas J, Michaelis LC, Mims AS, Montesinos P, Pozdnyakova O, Pratz KW, Schuh AC, Sekeres MA, Smith CC, Stahl M, Subklewe M, Uy GL, Voso MT, Walter RB, Wang ES, Zeidner JF, Žučenka A, and Zeidan AM
- Subjects
- Humans, Leukemia, Myeloid, Acute diagnosis
- Abstract
The existence of two acute myeloid leukaemia classification systems-one put forth by WHO and one by the International Consensus Classification in 2022-is concerning. Although both systems appropriately move towards genomic disease definitions and reduced emphasis on blast enumeration, there are consequential disagreements between the two systems on what constitutes a diagnosis of acute myeloid leukaemia. This fundamental problem threatens the ability of heath-care providers to diagnose acute myeloid leukaemia, communicate with patients and other health-care providers, and deliver appropriate and consistent management strategies for patients with the condition. Clinical trial eligibility, standardised response assessments, and eventual drug development and regulatory pathways might also be negatively affected by the discrepancies. In this Viewpoint, we review the merits and limitations of both classification systems and illustrate how the coexistence, as well as application of both systems is an undue challenge to patients, clinicians, hematopathologists, sponsors of research, and regulators. Lastly, we emphasise the urgency and propose a roadmap, by which the two divergent classification systems can be harmonised., Competing Interests: Declaration of interests RMS has served in a consulting or advisory role for Bristol Myers Squibb, Curio Science, Gilead Sciences, and Sciences, Servier, and Rigel. ND 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. ND has served in a consulting or advisory role for Daiichi-Sankyo, Bristol Myers Squibb, Arog, Pfizer, Novartis, Jazz Pharmaceuticals, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. JKA has received institutional research funding from AbbVie, Agios, ALX Oncology, Amgen, Amphivena, Aprea AB, Aptose Biosciences, Astellas Pharma, BioSight, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Cyclacel, Fujifilm, Immunogen, Kartos Therapeutics, Kura Oncology, Loxo, Pfizer, and Telios; has served in a consulting or advisory role for AbbVie, Astellas Pharma, BioSight, Bluebird Bio, Curio, Gilead, Kura Oncology, Kymera, Stemline Therapeutics, and Syros; and has served on a data monitoring committee for GlycoMimetics. DAP has served as a consultant or advisor for AbbVie, Novartis, Karyopharm, Syndax, Jazz, Syros, Bristol Myers Squibb, BeiGene, Bergen Bio, Arcellx, Genentech, Immunogen, AstraZeneca, Kura, Ryvu, Magenta, Qihan, Zentalis, Medivir, Hibercell, Link, Daiichi Sankyo, Schrodinger, Aptevo, Rigel, Sumitomo, Adicet, Gilead, and Oncoverity; he has received research funding from AbbVie, Karyopharm, Teva, and Bristol Myers Squibb. TB has served as a consultant or advisor for Pfizer and Takeda. VRB reports participating in safety monitoring committee for protagonist. VRB receives consulting fees from Imugene, research funding from AbbVie, Pfizer, Incyte, Jazz Pharmaceuticals, and National Marrow Donor Program, and provided drug from Chimerix for a trial. AdlFB received research funding from Janssen-Cilag, Novartis, BTG Pharmaceuticals, and AbbVie; has served on advisory boards for Abbvie, Astellas, Bristol Meyers Squibb, Curis, Daiichi Sankyo, Incyte, Immunogen, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, and Servier. AdlFB has received speakers' fees from Abbvie, Astellas, Celgene-BMS, Daiichi Sankyo, Incyte, Janssen Cilag, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, and Servier. HEC received research funding from Celgene and has served as a consultant or advisor for Bristol Myers Squibb, Jazz Pharmaceuticals, Novartis, Daiichi, Genentech and Stemline. She has received speakers fees from Jazz, Novartis, BMS and Stemline; she has been on Data Safety Monitoring Board Committees for AbbVie, ASTEX, Syndax, and Takeda. FEC has received institutional research funding from Celgene, Bristol Myers Squib, Amgen, Fibrogen, Sumitomo Pharma Oncology, and AbbVie, and is a consultant for the Association of Community Cancer Centers. ATF has received research funding from Celgene, AbbVie, and Servier, and has served in a consulting or advisory role for Genentech, Celgene, Foghorn, Kite, Morphosys, AbbVie, Takeda, Ipsen, Forma, Amgen, Novartis, Astellas, Immunogen, Mablytics, EnClear, Orum, PureTech, Pfizer, Daiichi Sankyo, Minovia, Rigel, and Servier. IG has received research funding from Merck, Amgen, Gilead, Incyte, and Genentech, and has served as a consultant and advisor for Immunogen, Bristol Meyer Squibb, Amgen, ClearView, Curio, and Nkarta. MRG has stock ownership in Medtronic, received research support from Incyte and Jannsen, and received consulting fees from AbbVie, Amgen, Astellas, Blueprint Medicines, Bristol Myers Squibb, Cardinal Health, CTI BioPharma, Daiichi Sankyo, Gamida Cell, Genentech, Gilead, GSK, Sierra Oncology, Incyte, Invitae, Jazz, Karius, Novartis, Ono Pharmaceutical, Pfizer, Pharmacosmos, Premier, Servier, and Stemline Therapeutics. BAJ has served as a consultant and advisor for AbbVie, Bristol Meyers Squibb, Daiichi Sankyo, Genentech, Gilead, GlycoMimetics, Jazz, Kymera, Pfizer, Rigel, Servier, and Takeda; was on the protocol steering committee for GlycoMimetics, data monitoring committee for Gilead; and received travel reimbursement and [ support from AbbVie and Rigel; BAJ received institutional research funding from AbbVie, Amgen, Aptose, AROG, Bristol Meyers Squibb, Celgene, Daiichi Sankyo, F Hoffmann-La Roche, Forma, Forty Seven, Genentech, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, and Treadwell. GNM has received research funding from Bristol Meyers Squibb, Celgene, Glycomimetics, Forty Seven, Jazz, Astex, Syndax, Immune Onc, and Immunogen; has served as a consultant and advisor for AbbVie, Agios, Macrogenics and Pfizer, and has served on a scientific advisory committee for Abbvie, Agios, Astellas, Bristol Myers Squibb, Forty Seven, Genentech, and Stemline. JM has received institutional research funding from Incyte, Novartis, Bristol Meyers Squibb, CTI Bio, Geron, AbbVie, Kartos, and PharmaEssentia, and has received consulting fees from Bristol Meyers Squibb Incyte, Novartis, Roche, CTI Bio, Geron, Kartos, GSK, MorphoSys, PharmaEssentia, Imago, and Galecto. LCM has received institutional research funding from Jazz Pharmaceuticals, has served in a consulting or advisory role for AbbVie, Curio Science, Celgene Corp, Sierra Oncology, and Nkarta; has received honoraria from the American Society of Hematology, the American Board of Internal Medicine, and the Society of Hematologic Oncology; received royalties from Wintrobe's Publishing; and has served as an expert witness for Incyte Corporation. ASM has served in a consulting or advisory role for AbbVie, Servier, Syndax Pharmaceuticals, Bristol Meyers Squibb, Astellas, Rigel, Zentalis, and Ryvu Therapeutics; has served on a data monitoring safety committee for Jazz Pharmaceuticals, Daiichi Sankyo, and Foghorn Therapeutics; and has served as a medical monitor for the Leukemia and Lymphoma Society Beat AML Study. OP has served in a consulting or advisory role for Scopio Labs, Sysmex America, and F Hoffman-La Roche. KWP Research funding from AbbVie, Agios, Daiichi Sankyo, Millennium; was an advisory board member for AbbVie, Astellas, AstraZeneca, Boston BioMedical, Bristol Myers Squibb, Celgene, Novartis, Roche, Jazz Pharmaceuticals, and Servier. MAS has served on advisory boards for Bristol Meyers Squibb, Novartis, Kurome, and Gilead. CCS has received research funding from AbbVie, Bristol Myers Squibb, Erasca, Revolution Medicines, and Zentalis, and has served on a board of advisory committee for Astellas Pharma, Daichi Sanyko, and Genentech. MSt served on the advisory board for Novartis, Kymera, Sierra Oncology, GSK, and Rigel; consulted for Boston Consulting and Dedham group and participated in GME activity for Novartis, Curis Oncology, Haymarket Media and Clinical care options. MSu receives industry research support from Amgen, Bristol Myers Squibb, Gilead, Janssen, Miltenyi Biotec, Morphosys, Novartis, Roche, Seattle Genetics, and Takeda; serves as a consultant and advisor to AvenCell, CDR-Life, Ichnos Sciences, Incyte Biosciences, Janssen, Molecular Partners, and Takeda; and serves on the speakers' bureau at Amgen, AstraZeneca, Bristol Meyers Squibb, Gilead, GSK, Janssen, Novartis, Pfizer, Roche, and Takeda. GLU served in a consulting role for Novartis and Jazz. MTV received compensation for being a speakers from AbbVie, Bristol Myers Squibb, Astellas, Jazz, Novartis, and Servier; has served in a consulting or advisory role for Jazz and Syros Pharmaceuticals. RBW received laboratory research grants and clinical trial support from Amgen, Aptevo, Celgene, ImmunoGen, Janssen, Jazz Pharmaceuticals, Kura, MacroGenics, and Pfizer; has ownership interests in Amphivena; and served in a consulting role to AbbVie, Adicet, Amphivena, BerGenBio, Bristol Myers Squibb, GlaxoSmithKline, ImmunoGen, Kura, and Orum. ESW has served in a consulting and advisory role for AbbVie, Astellas, Bristol Meyers Squibb, Daiichi Sankyo, Genentech, Gilead, GlaxoSmithKline, Janssen, Jazz, Kite, Kura, Novartis, NuProbe, Pfizer, Rigel, Sellas, and Sumitomo Pharma; has received speaking fees from AbbVie, Astellas, Dava Oncology, Kura Oncology, Novartis, and Pfizer; has served on a data monitoring committee for Abbvie and Gilead; and has served on a research committee for Gilead. JFZ has received honoraria from AbbVie, Bristol Myers Squibb, Daiichi Sankyo, Genentech, Gilead, Immunogen, Servier, and Shattuck Labs; has served as a consultant for AbbVie, Foghorn, Gilead and Servier; and has received research funding from AbbVie, Arog, Astex, Gilead, Jazz, Merck, Shattuck Labs, Stemline, Sumitomo Dainippon Pharma, and Takeda. AZ has served in a consulting or advisory role for AbbVie, Astellas, Jannsen, Novartis, and Pfizer, and received honoraria from AbbVie, Astellas, Jannsen, Novartis, and Takeda. AMZ has served in a consulting or advisory role for AbbVie, Acceleron, Agios, Amgen, Aprea, Astellas, AstraZeneca, BeyondSpring, Boehringer Ingelheim, Cardiff Oncology, Bristol Meyers Squibb, Daiichi Sankyo, Epizyme, Genentech, Gilead, Kura, Incyte, Ionis, Loxo Oncology, Janssen, Novartis; served on clinical trial committees for AbbVie, BioCryst, Bristol Meyers Squibb, Geron, Gilead, Kura, Loxo Oncology, Novartis; has received research funding from AbbVie, Acceleron, ADC Therapeutics, Amgen, Aprea, Astex, Boehringer Ingelheim, Cardiff Oncology, Bristol Meyers Squibb, Incyte, Jasper, Jazz, Novartis, and Pfizer. JPB, RSK, SdB, PD, RD, ND, SDF, MK, TLL, PM, and ACS declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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10. Association of social deprivation with survival in younger adult patients with AML: an Alliance study.
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Rebechi M, Kohlschmidt J, Mrózek K, Nicolet D, Mims AS, Blachly JS, Orwick S, Larkin KT, Oakes CC, Hantel A, Carroll AJ, Blum WG, Powell BL, Uy GL, Stone RM, Larson RA, Byrd JC, Paskett ED, Plascak JJ, and Eisfeld AK
- Subjects
- Humans, Adult, Disease-Free Survival, Remission Induction, Social Deprivation, Leukemia, Myeloid, Acute therapy
- Published
- 2023
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11. Outcomes of Older Adults With AML Treated in Community Versus Academic Centers: An Analysis of Alliance Trials.
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Bhatt VR, Ulrich AM, Uy GL, Stone RM, Stock W, Ojelabi MO, Yin J, Kohlschmidt J, Eisfeld AK, Baer MR, Chow S, Klepin H, Le-Rademacher J, and Jatoi A
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- Aged, Humans, Middle Aged, Logistic Models, Proportional Hazards Models, Clinical Trials, Phase III as Topic, Leukemia, Myeloid, Acute drug therapy
- Abstract
Purpose: Clinical trials are important for managing older patients with AML. We investigated differences in outcomes of older patients with AML on the basis of whether patients participated in intensive chemotherapy trials at community versus academic cancer centers., Methods: We used data from the Alliance for Clinical Trials in Oncology phase III trials that enrolled patients age ≥ 60 years with newly diagnosed AML between 1998 and 2002 in the Cancer and Leukemia Group B (CALGB) 9720 trial and between 2004 and 2006 in the CALGB 10201 trial. Centers funded by the NCI Community Oncology Research Program were identified as community cancer centers; others were designated as academic cancer centers. Logistic regression models and Cox proportional hazards models were used to compare 1-month mortality and overall survival (OS) by center type., Results: Seventeen percent of the 1,170 patients were enrolled in clinical trials in community cancer centers. The study results demonstrated comparable rates of grade ≥3 adverse events (97% v 93%), 1-month mortality (19.1% v 16.1%), and OS (43.9% v 35.7% at 1 year) between community versus academic cancer centers, respectively. After adjusting for covariates, 1-month mortality (odds ratio, 1.40; 95% CI, 0.92 to 2.12; P = .11) and OS (hazard ratio, 1.04; 95% CI, 0.88 to 1.22; P = .67) were not statistically different among patients treated in community versus academic cancer centers., Conclusion: An older patient population, who have complex health care needs, can be successfully treated on intensive chemotherapy trials in select community cancer centers with outcomes comparable with that achieved at academic cancer centers.
- Published
- 2023
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12. Outcome prediction by the 2022 European LeukemiaNet genetic-risk classification for adults with acute myeloid leukemia: an Alliance study.
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Mrózek K, Kohlschmidt J, Blachly JS, Nicolet D, Carroll AJ, Archer KJ, Mims AS, Larkin KT, Orwick S, Oakes CC, Kolitz JE, Powell BL, Blum WG, Marcucci G, Baer MR, Uy GL, Stock W, Byrd JC, and Eisfeld AK
- Subjects
- Adult, Humans, Prognosis, Treatment Outcome, Risk Factors, Mutation, fms-Like Tyrosine Kinase 3 genetics, Nucleophosmin, Leukemia, Myeloid, Acute therapy
- Abstract
Recently, the European LeukemiaNet (ELN) revised its genetic-risk classification of acute myeloid leukemia (AML). We categorized 1637 adults with AML treated with cytarabine/anthracycline regimens according to the 2022 and 2017 ELN classifications. Compared with the 2017 ELN classification, 2022 favorable group decreased from 40% to 35% and adverse group increased from 37% to 41% of patients. The 2022 genetic-risk groups seemed to accurately reflect treatment outcomes in all patients and patients aged <60 years, but in patients aged ≥60 years, relapse rates, disease-free (DFS) and overall (OS) survival were not significantly different between intermediate and adverse groups. In younger African-American patients, DFS and OS did not differ between intermediate-risk and adverse-risk patients nor did DFS between favorable and intermediate groups. In Hispanic patients, DFS and OS did not differ between favorable and intermediate groups. Outcome prediction abilities of 2022 and 2017 ELN classifications were similar. Among favorable-risk patients, myelodysplasia-related mutations did not affect patients with CEBPA
bZIP mutations or core-binding factor AML, but changed risk assignment of NPM1-mutated/FLT3-ITD-negative patients to intermediate. NPM1-mutated patients with adverse-risk cytogenetic abnormalities were closer prognostically to the intermediate than adverse group. Our analyses both confirm and challenge prognostic significance of some of the newly added markers., (© 2023. The Author(s).)- Published
- 2023
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13. A randomized phase II/III study of 'novel therapeutics' versus azacitidine in newly diagnosed patients with acute myeloid leukemia (AML), high-risk myelodysplastic syndrome (MDS), or chronic myelomonocytic leukemia (CMML), age 60 or older: a report of the comparison of azacitidine and nivolumab to azacitidine: SWOG S1612.
- Author
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Assouline S, Michaelis LC, Othus M, Hay AE, Walter RB, Jacoby MA, Schroeder MA, Uy GL, Law LY, Cheema F, Sweet KL, Asch AS, Liu JJ, Moseley AB, Maher T, Kingsbury LL, Fang M, Radich J, Little RF, and Erba HP
- Subjects
- Humans, Middle Aged, Azacitidine adverse effects, Nivolumab therapeutic use, Leukemia, Myelomonocytic, Chronic diagnosis, Leukemia, Myelomonocytic, Chronic drug therapy, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes drug therapy, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute chemically induced
- Published
- 2023
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14. Transplant outcomes after CPX-351 vs 7 + 3 in older adults with newly diagnosed high-risk and/or secondary AML.
- Author
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Uy GL, Newell LF, Lin TL, Goldberg SL, Wieduwilt MJ, Ryan RJ, Faderl S, and Lancet JE
- Subjects
- Aged, Humans, Cytarabine, Daunorubicin, Leukemia, Myeloid, Acute therapy, Neoplasms, Second Primary
- Published
- 2022
- Full Text
- View/download PDF
15. Decitabine salvage for TP53 -mutated, relapsed/refractory acute myeloid leukemia after cytotoxic induction therapy.
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Ferraro F, Gruszczynska A, Ruzinova MB, Miller CA, Percival ME, Uy GL, Pusic I, Jacoby MA, Christopher MJ, Kim MY, Westervelt P, Cashen AF, Schroeder MA, DiPersio JF, Abboud CN, Wartman LD, Gao F, Link DC, Ley TJ, and Welch JS
- Subjects
- Antineoplastic Combined Chemotherapy Protocols, Decitabine therapeutic use, Humans, Induction Chemotherapy, Remission Induction, Salvage Therapy, Treatment Outcome, Tumor Suppressor Protein p53 genetics, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Published
- 2022
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- View/download PDF
16. Clinical and molecular relevance of genetic variants in the non-coding transcriptome of patients with cytogenetically normal acute myeloid leukemia.
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Papaioannou D, Ozer HG, Nicolet D, Urs AP, Herold T, Mrózek K, Batcha AMN, Metzeler KH, Yilmaz AS, Volinia S, Bill M, Kohlschmidt J, Pietrzak M, Walker CJ, Carroll AJ, Braess J, Powell BL, Eisfeld AK, Uy GL, Wang ES, Kolitz JE, Stone RM, Hiddemann W, Byrd JC, Bloomfield CD, and Garzon R
- Subjects
- Adult, Cytosine, Humans, Middle Aged, Mutation, Prognosis, Thymidine, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, RNA, Long Noncoding genetics, Transcriptome
- Abstract
Expression levels of long non-coding RNA (lncRNA) have been shown to associate with clinical outcome of patients with cytogenetically normal acute myeloid leukemia (CN-AML). However, the frequency and clinical significance of genetic variants in the nucleotide sequences of lncRNA in AML patients is unknown. Herein, we analyzed total RNA sequencing data of 377 younger adults (aged <60 years) with CN-AML, who were comprehensively characterized with regard to clinical outcome. We used available genomic databases and stringent filters to annotate genetic variants unequivocally located in the non-coding transcriptome of AML patients. We detected 981 variants, which are recurrently present in lncRNA that are expressed in leukemic blasts. Among these variants, we identified a cytosine-to-thymidine variant in the lncRNA RP5-1074L1.4 and a cytosine-to-thymidine variant in the lncRNA SNHG15, which independently associated with longer survival of CN-AML patients. The presence of the SNHG15 cytosine-to-thymidine variant was also found to associate with better outcome in an independent dataset of CN-AML patients, despite differences in treatment protocols and RNA sequencing techniques. In order to gain biological insights, we cloned and overexpressed both wild-type and variant versions of the SNHG15 lncRNA. In keeping with its negative prognostic impact, overexpression of the wild-type SNHG15 associated with higher proliferation rate of leukemic blasts when compared with the cytosine-to-thymidine variant. We conclude that recurrent genetic variants of lncRNA that are expressed in the leukemic blasts of CN-AML patients have prognostic and potential biological significance.
- Published
- 2022
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17. Contemporary Approach to Acute Myeloid Leukemia Therapy in 2022.
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Roloff GW, Odenike O, Bajel A, Wei AH, Foley N, and Uy GL
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Humans, Remission Induction, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy
- Abstract
Recent advances in acute myeloid leukemia biology and drug development have transformed the therapeutic landscape for patients diagnosed with this disease. By harnessing insights from the study of the molecular pathogenesis of the disease, the acute myeloid leukemia treatment armamentarium now extends beyond conventional cytotoxic agents to include targeted therapies, and immunotherapeutics, with multiple novel modalities under investigation. During the past 5 years, recent drug approvals have also focused attention on disease scenarios and patient populations for whom newer therapies might be deployed. In this review, we highlight select acute myeloid leukemia therapies in the frontline setting through the lens of both disease and patient-related factors. Particular emphasis is placed on the assessment of patient fitness, as contemporary acute myeloid leukemia therapy decisions largely hinge on the determination of whether intensive chemotherapy is suitable for a patient. Additionally, we detail scenarios and areas of controversy wherein disease biology may inspire a reframing of traditional intensive treatment philosophies, regardless of patient fitness. Lastly, we provide an overview of emerging agents that are being investigated in the relapsed/refractory setting.
- Published
- 2022
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18. A phase I study of the fully human, fragment crystallizable-engineered, anti-CD-33 monoclonal antibody BI 836858 in patients with previously-treated acute myeloid leukemia.
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Vasu S, Altman JK, Uy GL, Tallman MS, Gojo I, Lozanski G, Burkard U, Osswald A, James P, Rüter B, and Blum W
- Subjects
- Antibodies, Monoclonal, Humanized, Humans, Immunoglobulin Fc Fragments, Antibodies, Monoclonal therapeutic use, Leukemia, Myeloid, Acute therapy
- Published
- 2022
- Full Text
- View/download PDF
19. Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy.
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Berrien-Elliott MM, Becker-Hapak M, Cashen AF, Jacobs M, Wong P, Foster M, McClain E, Desai S, Pence P, Cooley S, Brunstein C, Gao F, Abboud CN, Uy GL, Westervelt P, Jacoby MA, Pusic I, Stockerl-Goldstein KE, Schroeder MA, DiPersio JF, Soon-Shiong P, Miller JS, and Fehniger TA
- Subjects
- Allogeneic Cells immunology, Female, Humans, Interleukin-15 immunology, Killer Cells, Natural immunology, Male, Antineoplastic Agents administration & dosage, CD8-Positive T-Lymphocytes immunology, Hematopoietic Stem Cell Transplantation, Immunotherapy, Adoptive, Interleukin-15 administration & dosage, Killer Cells, Natural transplantation, Leukemia, Myeloid, Acute immunology, Leukemia, Myeloid, Acute therapy, Recombinant Fusion Proteins administration & dosage
- Abstract
Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793., (© 2022 by The American Society of Hematology.)
- Published
- 2022
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20. Hematopoietic cell transplantation donor-derived memory-like NK cells functionally persist after transfer into patients with leukemia.
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Berrien-Elliott MM, Foltz JA, Russler-Germain DA, Neal CC, Tran J, Gang M, Wong P, Fisk B, Cubitt CC, Marin ND, Zhou AY, Jacobs MT, Foster M, Schappe T, McClain E, Kersting-Schadek S, Desai S, Pence P, Becker-Hapak M, Eisele J, Mosior M, Marsala L, Griffith OL, Griffith M, Khan SM, Spencer DH, DiPersio JF, Romee R, Uy GL, Abboud CN, Ghobadi A, Westervelt P, Stockerl-Goldstein K, Schroeder MA, Wan F, Lie WR, Soon-Shiong P, Petti AA, Cashen AF, and Fehniger TA
- Subjects
- Humans, Immunity, Innate, Interleukin-15, Killer Cells, Natural, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute therapy
- Abstract
Natural killer (NK) cells are innate lymphoid cells that eliminate cancer cells, produce cytokines, and are being investigated as a nascent cellular immunotherapy. Impaired NK cell function, expansion, and persistence remain key challenges for optimal clinical translation. One promising strategy to overcome these challenges is cytokine-induced memory-like (ML) differentiation, whereby NK cells acquire enhanced antitumor function after stimulation with interleukin-12 (IL-12), IL-15, and IL-18. Here, reduced-intensity conditioning (RIC) for HLA -haploidentical hematopoietic cell transplantation (HCT) was augmented with same-donor ML NK cells on day +7 and 3 weeks of N-803 (IL-15 superagonist) to treat patients with relapsed/refractory acute myeloid leukemia (AML) in a clinical trial (NCT02782546). In 15 patients, donor ML NK cells were well tolerated, and 87% of patients achieved a composite complete response at day +28, which corresponded with clearing high-risk mutations, including TP53 variants. NK cells were the major blood lymphocytes for 2 months after HCT with 1104-fold expansion (over 1 to 2 weeks). Phenotypic and transcriptional analyses identified donor ML NK cells as distinct from conventional NK cells and showed that ML NK cells persisted for over 2 months. ML NK cells expressed CD16, CD57, and high granzyme B and perforin, along with a unique transcription factor profile. ML NK cells differentiated in patients had enhanced ex vivo function compared to conventional NK cells from both patients and healthy donors. Overall, same-donor ML NK cell therapy with 3 weeks of N-803 support safely augmented RIC haplo-HCT for AML.
- Published
- 2022
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21. Turning AML targets inside out.
- Author
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Uy GL
- Subjects
- Biomechanical Phenomena, Humans, Gait, Leukemia, Myeloid, Acute genetics
- Published
- 2021
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22. Immunosuppression and outcomes in adult patients with de novo acute myeloid leukemia with normal karyotypes.
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Ferraro F, Miller CA, Christensen KA, Helton NM, O'Laughlin M, Fronick CC, Fulton RS, Kohlschmidt J, Eisfeld AK, Bloomfield CD, Ramakrishnan SM, Day RB, Wartman LD, Uy GL, Welch JS, Christopher MJ, Heath SE, Baty JD, Schuelke MJ, Payton JE, Spencer DH, Rettig MP, Link DC, Walter MJ, Westervelt P, DiPersio JF, and Ley TJ
- Subjects
- Adult, CD4-Positive T-Lymphocytes immunology, Female, Humans, Immune Tolerance immunology, Karyotype, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Prognosis, Recurrence, Remission Induction, Risk Factors, Sequence Analysis, RNA methods, Th1 Cells immunology, Transcriptome genetics, Treatment Outcome, Immune Tolerance genetics, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute immunology
- Abstract
Acute myeloid leukemia (AML) patients rarely have long first remissions (LFRs; >5 y) after standard-of-care chemotherapy, unless classified as favorable risk at presentation. Identification of the mechanisms responsible for long vs. more typical, standard remissions may help to define prognostic determinants for chemotherapy responses. Using exome sequencing, RNA-sequencing, and functional immunologic studies, we characterized 28 normal karyotype (NK)-AML patients with >5 y first remissions after chemotherapy (LFRs) and compared them to a well-matched group of 31 NK-AML patients who relapsed within 2 y (standard first remissions [SFRs]). Our combined analyses indicated that genetic-risk profiling at presentation (as defined by European LeukemiaNet [ELN] 2017 criteria) was not sufficient to explain the outcomes of many SFR cases. Single-cell RNA-sequencing studies of 15 AML samples showed that SFR AML cells differentially expressed many genes associated with immune suppression. The bone marrow of SFR cases had significantly fewer CD4
+ Th1 cells; these T cells expressed an exhaustion signature and were resistant to activation by T cell receptor stimulation in the presence of autologous AML cells. T cell activation could be restored by removing the AML cells or blocking the inhibitory major histocompatibility complex class II receptor, LAG3. Most LFR cases did not display these features, suggesting that their AML cells were not as immunosuppressive. These findings were confirmed and extended in an independent set of 50 AML cases representing all ELN 2017 risk groups. AML cell-mediated suppression of CD4+ T cell activation at presentation is strongly associated with unfavorable outcomes in AML patients treated with standard chemotherapy., Competing Interests: The authors declare no competing interest.- Published
- 2021
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23. Combination of dociparstat sodium (DSTAT), a CXCL12/CXCR4 inhibitor, with azacitidine for the treatment of hypomethylating agent refractory AML and MDS.
- Author
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Huselton E, Rettig MP, Campbell K, Cashen AF, DiPersio JF, Gao F, Jacoby MA, Pusic I, Romee R, Schroeder MA, Uy GL, Marcus S, and Westervelt P
- Subjects
- Aged, Aged, 80 and over, Anticoagulants therapeutic use, Antimetabolites, Antineoplastic therapeutic use, Biomarkers, Tumor, Chemokine CXCL12 antagonists & inhibitors, Drug Therapy, Combination, Female, Follow-Up Studies, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Myelodysplastic Syndromes genetics, Myelodysplastic Syndromes pathology, Pilot Projects, Prognosis, Receptors, CXCR4 antagonists & inhibitors, Survival Rate, Azacitidine therapeutic use, DNA Methylation, Drug Resistance, Neoplasm drug effects, Gene Expression Regulation, Neoplastic drug effects, Heparin therapeutic use, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes drug therapy
- Abstract
Leukemia stem cells utilize cell adhesion molecules like CXCR4/CXCL12 to home to bone marrow stromal niches where they are maintained in a dormant, protected state. Dociparstat sodium (DSTAT, CX-01) is a low anticoagulant heparin with multiple mechanisms of action, including inhibition of the CXCR4/CXCL12 axis, blocking HMGB1, and binding platelet factor 4 (PF-4). We conducted a pilot study adding DSTAT to azacitidine for patients with AML or MDS unresponsive to or relapsed after prior hypomethylating agent therapy, hypothesizing that DSTAT may improve response rates. Twenty patients were enrolled, with a median of 2 prior lines of therapy and 6 cycles of prior hypomethylating agents. Among fifteen patients evaluable for response, there was 1 complete remission, and 3 marrow complete remissions, for a response rate of 27 % among evaluable patients (20 % overall). Hematologic improvement was observed in 5 additional patients. The median overall survival for all enrolled patients was 205 days (95 % CI 119-302). While cytopenias and infections were common, these were not out of proportion to what would be expected in this population of patients undergoing treatment with azacitidine alone. In summary, this trial demonstrated the feasibility of combining DSTAT with azacitidine, with several responses observed, suggesting this combination warrants further study., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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24. Outcomes of patients with IDH1-mutant relapsed or refractory acute myeloid leukemia receiving ivosidenib who proceeded to hematopoietic stem cell transplant.
- Author
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DiNardo CD, Stein EM, Pigneux A, Altman JK, Collins R, Erba HP, Watts JM, Uy GL, Winkler T, Wang H, Choe S, Liu H, Wu B, Kapsalis SM, Roboz GJ, and de Botton S
- Subjects
- Adult, Aged, Combined Modality Therapy, Female, Follow-Up Studies, Glycine therapeutic use, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Neoplasm Recurrence, Local therapy, Prognosis, Survival Rate, Antineoplastic Agents therapeutic use, Drug Resistance, Neoplasm, Glycine analogs & derivatives, Hematopoietic Stem Cell Transplantation mortality, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute mortality, Mutation, Neoplasm Recurrence, Local mortality, Pyridines therapeutic use
- Published
- 2021
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25. Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of CPX-351 versus 7 + 3 in older adults with newly diagnosed high-risk/secondary AML.
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Cortes JE, Lin TL, Uy GL, Ryan RJ, Faderl S, and Lancet JE
- Subjects
- Age Factors, Aged, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Female, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute epidemiology, Male, Middle Aged, Neoplasms, Second Primary diagnosis, Neoplasms, Second Primary drug therapy, Neoplasms, Second Primary epidemiology, Quality of Life, Survival Analysis, Antineoplastic Agents therapeutic use, Cytarabine therapeutic use, Daunorubicin therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Background: CPX-351 (United States: Vyxeos
® ; Europe: Vyxeos® Liposomal), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, is approved by the US FDA and the EMA for the treatment of adults with newly diagnosed therapy-related acute myeloid leukemia or acute myeloid leukemia with myelodysplasia-related changes. In a pivotal phase 3 study that evaluated 309 patients aged 60 to 75 years with newly diagnosed high-risk/secondary acute myeloid leukemia, CPX-351 significantly improved median overall survival versus conventional 7 + 3 chemotherapy (cytarabine continuous infusion for 7 days plus daunorubicin for 3 days), with a comparable safety profile. A Quality-adjusted Time Without Symptoms of disease or Toxicity (Q-TWiST) analysis of the phase 3 study was performed to compare survival quality between patients receiving CPX-351 versus conventional 7 + 3 after 5 years of follow-up., Methods: Patients were randomized 1:1 between December 20, 2012 and November 11, 2014 to receive induction with CPX-351 or 7 + 3. Survival time for each patient was partitioned into 3 health states: TOX (time with any grade 3 or 4 toxicity or prior to remission), TWiST (time in remission without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Within each treatment arm, Q-TWiST was calculated by adding the mean time spent in each health state weighted by its respective quality-of-life, represented by health utility. The relative Q-TWiST gain, calculated as the difference in Q-TWiST between treatment arms divided by the mean survival of the 7 + 3 control arm, was determined in order to evaluate results in the context of other Q-TWiST analyses., Results: The relative Q-TWiST gain with CPX-351 versus 7 + 3 was 53.6% in the base case scenario and 39.8% among responding patients. Across various sensitivity analyses, the relative Q-TWiST gains for CPX-351 ranged from 48.0 to 57.6%, remaining well above the standard clinically important difference threshold of 15% for oncology., Conclusions: This post hoc analysis demonstrates that CPX-351 improved quality-adjusted survival, further supporting the clinical benefit in patients with newly diagnosed high-risk/secondary acute myeloid leukemia. Trial registration This trial was registered on September 28, 2012 at www.clinicaltrials.gov as NCT01696084 ( https://clinicaltrials.gov/ct2/show/NCT01696084 ) and is complete., (© 2021. The Author(s).)- Published
- 2021
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26. CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial.
- Author
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Lancet JE, Uy GL, Newell LF, Lin TL, Ritchie EK, Stuart RK, Strickland SA, Hogge D, Solomon SR, Bixby DL, Kolitz JE, Schiller GJ, Wieduwilt MJ, Ryan DH, Faderl S, and Cortes JE
- Subjects
- Aged, Cytarabine administration & dosage, Daunorubicin administration & dosage, Drug Administration Schedule, Female, Follow-Up Studies, Hematopoietic Stem Cell Transplantation, Humans, Infusions, Intravenous, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Neoplasms, Second Primary, Proportional Hazards Models, Treatment Outcome, Cytarabine therapeutic use, Daunorubicin therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Background: Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results., Methods: This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60-75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m
2 administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m2 per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m2 on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m2 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov, NCT01696084, and is complete., Findings: Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60·91 months (IQR 60·06-62·98) in the CPX-351 group and 59·93 months (59·73-60·50) in the 7+3 group, median overall survival was 9·33 months (95% CI 6·37-11·86) with CPX-351 and 5·95 months (4·99-7·75) with 7+3 (HR 0·70, 95% CI 0·55-0·91). 5-year overall survival was 18% (95% CI 12-25%) in the CPX-351 group and 8% (4-13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment., Interpretation: After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia., Funding: Jazz Pharmaceuticals., Competing Interests: Declaration of interests JEL has received consulting fees from AbbVie, BerGenBio/DAVA Oncology, Celgene/Bristol Myers Squibb, Daiichi Sankyo, ElevateBio Management, Millennium Pharma/Takeda, and Novartis. GLU has received consulting fees from AbbVie, Agios, GlaxoSmithKline, Jazz Pharmaceuticals, and Novartis, and received honoraria from Astellas Pharma. TLL has received institutional research funding from AbbVie, Aptevo, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech/Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Mateon Therapeutics, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero Pharmaceuticals, and Trovagene. EKR has served as a consultant for Celgene, Incyte, Novartis, and Pfizer; served on speakers bureaus for Ariad Pharmaceuticals, Celgene, Incyte, and Novartis; received research funding from Astellas Pharma, Bristol Myers Squibb, Novartis, NS Pharma, and Pfizer; and received travel support from Celgene and Novartis. RKS has served as a consultant for Sunesis Pharmaceuticals; received honoraria from Sunesis Pharmaceuticals; received research funding from Agios, Astellas Pharma, Bayer AG, Incyte, Jazz Pharmaceuticals, Ono Pharmaceuticals, and Sunesis Pharmaceuticals; and received travel support from Sunesis Pharmaceuticals. SAS has served as a consultant for AbbVie, ArcherDx, Astellas Pharma, Genentech, Incyte, Jazz Pharmaceuticals, Kite Pharma, Kura Oncology, and Novartis; and received research funding from Sunesis Pharmaceuticals. JEK participated in advisory boards for Amgen, Magellan, and Pfizer, and has served on the editorial board for UpToDate. GJS has received research funding from AbbVie, Agios, Actinium, Amgen, Ariad Pharmaceuticals, Astellas Pharma, Bristol Myers Squibb, Constellation, Cyclacel, Daiichi Sankyo, Deciphera, Delta-Fly, Forma, Fujifilm, Gamida, Genentech/Roche, Geron, Incyte, Jazz Pharmaceuticals, Karyopharm, Kite Pharma, Mateon, MedImmune, Novartis, Onconova, Pfizer, Regimmune, Samus, Sangamo, Tolero, and Trovagene; received consulting fees from Agios, Amgen, AstraZeneca, Incyte, Novartis, and Ono Pharma; served on speakers bureaus for Agios, Amgen, Celgene, Gilead Sciences, Incyte, Sanofi, and Stemline; provided expert testimony for Kaiser Permanente; and holds stock ownership and options in Amgen, Bristol Myers Squibb, Johnson & Johnson, and Pfizer. MJW has received research funding from Amgen, Leadiant, Merck, and Shire; participated in advisory committees for Daiichi Sankyo; and holds stock ownership in Reata Pharmaceuticals. DHR holds stock ownership in AbbVie and patents and royalties with the University of Rochester. SF is an employee of and holds stock ownership and options in Jazz Pharmaceuticals. JEC has received consulting fees from Astellas Pharma, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, and Pfizer; and research funding (to his institution) from Arog, Astellas Pharma, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, and Pfizer. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)- Published
- 2021
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27. BL-8040 CXCR4 antagonist is safe and demonstrates antileukemic activity in combination with cytarabine for the treatment of relapsed/refractory acute myelogenous leukemia: An open-label safety and efficacy phase 2a study.
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Borthakur G, Ofran Y, Tallman MS, Foran J, Uy GL, DiPersio JF, Showel MM, Shimoni A, Nagler A, Rowe JM, Altman JK, Abraham M, Peled A, Shaw S, Bohana-Kashtan O, Sorani E, Pereg Y, Foley-Comer A, Oberkovitz G, Lustig TM, Glicko-Kabir I, Aharon A, Vainstein-Haras A, Kadosh SE, Samara E, Al-Rawi AN, Pemmaraju N, Bueso-Ramos C, Cortes JE, and Andreeff M
- Subjects
- Adult, Aged, Antineoplastic Combined Chemotherapy Protocols adverse effects, Bone Marrow Cells drug effects, Drug Administration Schedule, Drug Resistance, Neoplasm, Female, Hematopoietic Stem Cell Mobilization, Humans, Leukemia, Myeloid, Acute blood, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Peptides adverse effects, Peptides pharmacokinetics, Recurrence, Remission Induction, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Cytarabine administration & dosage, Leukemia, Myeloid, Acute drug therapy, Peptides administration & dosage, Receptors, CXCR4 antagonists & inhibitors
- Abstract
Background: CXCR4 mediates the retention and survival of acute myelogenous leukemia blasts in bone marrow and contributes to their resistance to chemotherapy. The authors evaluated a combination of the high-affinity CXCR4 antagonist BL-8040 with high-dose cytarabine (HiDAC) chemotherapy in a phase 2a study of patients with relapsed and refractory AML., Methods: Forty-two patients received treatment with BL-8040 monotherapy for 2 days followed by a combination of BL-8040 with HiDAC for 5 days. Six escalating BL-8040 dose levels were investigated (0.5, 0.75, 1.0, 1.25, 1.5, and 2.0 mg/kg), and 1.5 mg/kg was selected as the dose for the expansion phase (n = 23)., Results: BL-8040 in combination with HiDAC was safe and well tolerated at all dose levels. Clinical response was observed with BL-8040 doses ≥1.0 mg/kg. The composite response rate (complete remissions plus complete remissions with incomplete hematologic recovery of platelets or neutrophils) was 29% (12 of 42) in all patients and 39% (9 of 23) in the 1.5-mg/kg phase. The median overall survival was 8.4 months for all patients, 10.8 months in the 1.5-mg/kg phase, and 21.8 months for responding patients in the 1.5-mg/kg cohort. Two days of BL-8040 monotherapy triggered the mobilization of blasts into peripheral blood, with significantly higher mean fold-changes in responders versus nonresponders. This was accompanied by a decrease in bone marrow blasts., Conclusions: The current results demonstrate the efficacy of CXCR4 targeting with BL-8040 and support continued clinical development in acute myelogenous leukemia., (© 2020 American Cancer Society.)
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- 2021
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28. Older adults with newly diagnosed high-risk/secondary AML who achieved remission with CPX-351: phase 3 post hoc analyses.
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Lin TL, Rizzieri DA, Ryan DH, Schiller GJ, Kolitz JE, Uy GL, Hogge DE, Solomon SR, Wieduwilt MJ, Ryan RJ, Faderl S, Cortes JE, and Lancet JE
- Subjects
- Aged, Cytarabine, Daunorubicin, Humans, Middle Aged, Leukemia, Myeloid, Acute drug therapy, Myelodysplastic Syndromes
- Abstract
CPX-351, a dual-drug liposomal encapsulation of daunorubicin/cytarabine in a synergistic 1:5 molar ratio, is approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). In a pivotal phase 3 study, patients aged 60 to 75 years with newly diagnosed, high-risk/secondary AML were randomized to receive CPX-351 or conventional 7+3 chemotherapy. In the primary endpoint analysis, CPX-351 demonstrated significantly prolonged median overall survival (OS) vs 7+3. These exploratory post hoc subgroup analyses evaluated the impact of achieving complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CRi) with CPX-351 (73/153 [48%]) vs conventional 7+3 (52/56 [33%]) on outcomes. CPX-351 improved median OS vs 7+3 in patients who achieved CR or CRi (25.43 vs 10.41 months; hazard ratio = 0.49; 95% confidence interval, 0.31, 0.77). Improved median OS was seen across AML subtypes (t-AML, AML-MRC), age subgroups (60 to 69 vs 70 to 75 years), patients with prior hypomethylating agent exposure, and patients who did not undergo transplantation. Patients who achieved CR or CRi with CPX-351 also had a higher rate of transplantation, a longer median OS landmarked from the date of transplantation (not reached vs 11.65 months; hazard ratio = 0.43; 95% confidence interval, 0.21, 0.89), and a safety profile that was consistent with the known safety profile of 7+3. These results suggest deeper remissions may be achieved with CPX-351, leading to improved OS. This study was registered at www.clinicaltrials.gov as #NCT01696084., (© 2021 by The American Society of Hematology.)
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- 2021
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29. Genome Sequencing as an Alternative to Cytogenetic Analysis in Myeloid Cancers.
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Duncavage EJ, Schroeder MC, O'Laughlin M, Wilson R, MacMillan S, Bohannon A, Kruchowski S, Garza J, Du F, Hughes AEO, Robinson J, Hughes E, Heath SE, Baty JD, Neidich J, Christopher MJ, Jacoby MA, Uy GL, Fulton RS, Miller CA, Payton JE, Link DC, Walter MJ, Westervelt P, DiPersio JF, Ley TJ, and Spencer DH
- Subjects
- Feasibility Studies, Female, Humans, Male, Middle Aged, Proportional Hazards Models, Survival Analysis, Cytogenetic Analysis, Leukemia, Myeloid, Acute genetics, Myelodysplastic Syndromes genetics, Whole Genome Sequencing methods
- Abstract
Background: Genomic analysis is essential for risk stratification in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Whole-genome sequencing is a potential replacement for conventional cytogenetic and sequencing approaches, but its accuracy, feasibility, and clinical utility have not been demonstrated., Methods: We used a streamlined whole-genome sequencing approach to obtain genomic profiles for 263 patients with myeloid cancers, including 235 patients who had undergone successful cytogenetic analysis. We adapted sample preparation, sequencing, and analysis to detect mutations for risk stratification using existing European Leukemia Network (ELN) guidelines and to minimize turnaround time. We analyzed the performance of whole-genome sequencing by comparing our results with findings from cytogenetic analysis and targeted sequencing., Results: Whole-genome sequencing detected all 40 recurrent translocations and 91 copy-number alterations that had been identified by cytogenetic analysis. In addition, we identified new clinically reportable genomic events in 40 of 235 patients (17.0%). Prospective sequencing of samples obtained from 117 consecutive patients was performed in a median of 5 days and provided new genetic information in 29 patients (24.8%), which changed the risk category for 19 patients (16.2%). Standard AML risk groups, as defined by sequencing results instead of cytogenetic analysis, correlated with clinical outcomes. Whole-genome sequencing was also used to stratify patients who had inconclusive results by cytogenetic analysis into risk groups in which clinical outcomes were measurably different., Conclusions: In our study, we found that whole-genome sequencing provided rapid and accurate genomic profiling in patients with AML or MDS. Such sequencing also provided a greater diagnostic yield than conventional cytogenetic analysis and more efficient risk stratification on the basis of standard risk categories. (Funded by the Siteman Cancer Research Fund and others.)., (Copyright © 2021 Massachusetts Medical Society.)
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- 2021
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30. Gene expression signature predicts relapse in adult patients with cytogenetically normal acute myeloid leukemia.
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Walker CJ, Mrózek K, Ozer HG, Nicolet D, Kohlschmidt J, Papaioannou D, Genutis LK, Bill M, Powell BL, Uy GL, Kolitz JE, Carroll AJ, Stone RM, Garzon R, Byrd JC, Eisfeld AK, de la Chapelle A, and Bloomfield CD
- Subjects
- Adult, Humans, Nuclear Proteins genetics, Nucleophosmin, Prognosis, Recurrence, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Transcriptome
- Abstract
Although ∼80% of adult patients with cytogenetically normal acute myeloid leukemia (CN-AML) achieve a complete remission (CR), more than half of them relapse. Better identification of patients who are likely to relapse can help to inform clinical decisions. We performed RNA sequencing on pretreatment samples from 268 adults with de novo CN-AML who were younger than 60 years of age and achieved a CR after induction treatment with standard "7+3" chemotherapy. After filtering for genes whose expressions were associated with gene mutations known to impact outcome (ie, CEBPA, NPM1, and FLT3-internal tandem duplication [FLT3-ITD]), we identified a 10-gene signature that was strongly predictive of patient relapse (area under the receiver operating characteristics curve [AUC], 0.81). The signature consisted of 7 coding genes (GAS6, PSD3, PLCB4, DEXI, JMY, NRP1, C10orf55) and 3 long noncoding RNAs. In multivariable analysis, the 10-gene signature was strongly associated with relapse (P < .001), after adjustment for the FLT3-ITD, CEBPA, and NPM1 mutational status. Validation of the expression signature in an independent patient set from The Cancer Genome Atlas showed the signature's strong predictive value, with AUC = 0.78. Implementation of the 10-gene signature into clinical prognostic stratification could be useful for identifying patients who are likely to relapse., (© 2021 by The American Society of Hematology.)
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- 2021
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31. Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.
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Uy GL, Aldoss I, Foster MC, Sayre PH, Wieduwilt MJ, Advani AS, Godwin JE, Arellano ML, Sweet KL, Emadi A, Ravandi F, Erba HP, Byrne M, Michaelis L, Topp MS, Vey N, Ciceri F, Carrabba MG, Paolini S, Huls GA, Jongen-Lavrencic M, Wermke M, Chevallier P, Gyan E, Récher C, Stiff PJ, Pettit KM, Löwenberg B, Church SE, Anderson E, Vadakekolathu J, Santaguida M, Rettig MP, Muth J, Curtis T, Fehr E, Guo K, Zhao J, Bakkacha O, Jacobs K, Tran K, Kaminker P, Kostova M, Bonvini E, Walter RB, Davidson-Moncada JK, Rutella S, and DiPersio JF
- Subjects
- Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytokine Release Syndrome chemically induced, Cytokine Release Syndrome drug therapy, Dose-Response Relationship, Immunologic, Drug Administration Schedule, Drug Resistance, Neoplasm, Female, Follow-Up Studies, Hematopoiesis drug effects, Humans, Leukemia, Myeloid, Acute drug therapy, Male, Maximum Tolerated Dose, Middle Aged, Nausea chemically induced, Protein Interaction Maps, Survival Rate, Antineoplastic Agents, Immunological therapeutic use, Immunotherapy, Leukemia, Myeloid, Acute therapy, Salvage Therapy
- Abstract
Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956., (© 2021 by The American Society of Hematology.)
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- 2021
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32. Impact of a 40-Gene Targeted Panel Test on Physician Decision Making for Patients With Acute Myeloid Leukemia.
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Barnell EK, Newcomer KF, Skidmore ZL, Krysiak K, Anderson SR, Wartman LD, Oh ST, Welch JS, Stockerl-Goldstein KE, Vij R, Cashen AF, Pusic I, Westervelt P, Abboud CN, Ghobadi A, Uy GL, Schroeder MA, Dipersio JF, Politi MC, Spencer DH, Duncavage EJ, Ley TJ, Griffith M, Jacoby MA, and Griffith OL
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Young Adult, Clinical Decision-Making, Genetic Testing methods, Leukemia, Myeloid, Acute genetics
- Abstract
Purpose: Physicians treating hematologic malignancies increasingly order targeted sequencing panels to interrogate recurrently mutated genes. The precise impact of these panels on clinical decision making is not well understood., Methods: Here, we report our institutional experience with a targeted 40-gene panel (MyeloSeq) that is used to generate a report for both genetic variants and variant allele frequencies for the treating physician (the limit of mutation detection is approximately one AML cell in 50)., Results: In total, 346 sequencing reports were generated for 325 patients with suspected hematologic malignancies over an 8-month period (August 2018 to April 2019). To determine the influence of genomic data on clinical care for patients with acute myeloid leukemia (AML), we analyzed 122 consecutive reports from 109 patients diagnosed with AML and surveyed the treating physicians with a standardized questionnaire. The panel was ordered most commonly at diagnosis (61.5%), but was also used to assess response to therapy (22.9%) and to detect suspected relapse (15.6%). The panel was ordered at multiple timepoints during the disease course for 11% of patients. Physicians self-reported that 50 of 114 sequencing reports (44%) influenced clinical care decisions in 44 individual patients. Influences were often nuanced and extended beyond identifying actionable genetic variants with US Food and Drug Administration-approved drugs., Conclusion: This study provides insights into how physicians are currently using multigene panels capable of detecting relatively rare AML cells. The most influential way to integrate these tools into clinical practice will be to perform prospective clinical trials that assess patient outcomes in response to genomically driven interventions., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Erica K. BarnellEmployment: Geneoscopy Stock and Other Ownership Interests: Geneoscopy Patents, Royalties, Other Intellectual Property: Inventor of intellectual property in start-up company (Geneoscopy) Travel, Accommodations, Expenses: GeneoscopyKenneth F. NewcomerEmployment: Geneoscopy (I) Stock and Other Ownership Interests: Geneoscopy (I) Patents, Royalties, Other Intellectual Property: Inventor of intellectual property owned by Geneoscopy (I)Zachary L. SkidmoreStock and Other Ownership Interests: Aim Immunotech, Catalyst PharmaceuticalsKilannin KrysiakConsulting or Advisory Role: Gerson Lehrman GroupLukas D. WartmanConsulting or Advisory Role: Novartis, IncyteStephen T. OhConsulting or Advisory Role: Incyte, Novartis, Blueprint Medicines, Celgene, Kartos, CTI BioPharma Corp, PharmaEssentia, Disc Medicine, Constellation Pharmaceuticals Research Funding: Incyte (Inst), Gilead Sciences (Inst), CTI BioPharma Corp (Inst), Kartos (Inst), Celgene (Inst), Sierra Oncology (Inst), Blueprint Medicines (Inst), Constellation Pharmaceuticals (Inst)John S. WelchConsulting or Advisory Role: Archer Biosciences, Agios Research Funding: Janssen Oncology (Inst), Notable Labs (Inst)Keith E. Stockerl-GoldsteinStock and Other Ownership Interests: Abbott Laboratories, AbbVie Consulting or Advisory Role: Celgene Research Funding: GlaxoSmithKline, Takeda, BiolineRx, Janssen Other Relationship: CellerantRavi VijConsulting or Advisory Role: Bristol Myers Squibb, Celgene, Janssen, Sanofi, Karyopharm Therapeutics, Takeda, Genentech, AbbVie, Oncopeptides Research Funding: Takeda, Celgene, Bristol Myers Squibb Travel, Accommodations, Expenses: Celgene, Bristol Myers Squibb, Sanofi, Janssen, DAVAOncology, Karyopharm Therapeutics, Amgen, Takeda, AbbVieAmanda F. CashenConsulting or Advisory Role: Agios Speakers' Bureau: Novartis, CelgeneIskra PusicConsulting or Advisory Role: Kadmon, Incyte, SyndaxCamille N. AbboudStock and Other Ownership Interests: AbbVie (I), Abbott Laboratories (I), Gilead Sciences (I), Bristol Myers Squibb (I), Johnson & Johnson (I) Honoraria: Cardinal Health, Dova Pharmaceuticals, NkartaTherapeutics, Archer Biosciences Research Funding: Actinium Pharmaceuticals, Selvita (Inst), AlloVir (Inst), Forty-Seven (Inst)Armin GhobadiHonoraria: Kite Pharma Consulting or Advisory Role: Kite Pharma, Celgene, Amgen, Wugen Speakers' Bureau: Kite Pharma, AmgenGeoffrey L. UyConsulting or Advisory Role: Astellas Pharma, Genentech, Jazz PharmaceuticalsMark A. SchroederConsulting or Advisory Role: Astellas Pharma, Dova Pharmaceuticals, Flatiron Health, GlaxoSmithKline, Incyte, Partners Therapeutics, Partners Therapeutics, Pfizer Speakers' Bureau: AbbVie, Merck, TakedaJohn F. DiPersioStock and Other Ownership Interests: Magenta Therapeutics, Wugen Honoraria: Incyte Consulting or Advisory Role: Cellworks, Rivervest, Magenta Therapeutics, Incyte Research Funding: Amphivena Therapeutics (Inst), Macrogenics (Inst), Incyte (Inst), Wugen (Inst), BiolineRx (Inst), Maxcyte (Inst), Bigelow Aerospace (Inst) Patents, Royalties, Other Intellectual Property: Patents: CD7 and CD2 knockout for CART to CD7 and CDL; Duvelisib for treatment of cytokine release syndrome; NT-17 to enhance CART survival; Novel WU mobilizing compounds (Inst); Selection of IMPDH mutant stem cells; IFNγ, upregulate MHCII for relapsed AML; Dextran-based molecules to detect CAR-T cells; Combining integrin inhibitor with chemokine binders, 016131; JAK and calcineurin inhibition, solid organ transplant; VLA4, gro-b; Triple combination–CXCR2, VLA-4, gro-b; Targeting IFNR/CSCR3 in GvHD; WU/SLU compounds VLA4 and CXCR2 (Inst) Travel, Accommodations, Expenses: Incyte, Macrogenics, Magenta TherapeuticsMary C. PolitiResearch Funding: MerckDavid H. SpencerConsulting or Advisory Role: Wugen Research Funding: IlluminaEric J. DuncavageStock and Other Ownership Interests: P&V Licensing Consulting or Advisory Role: Cofactor Genomics, Bristol Myers Squibb, Eli Lilly Open Payments Link: https://openpaymentsdata.cms.gov/physician/317379Timothy J. LeyResearch Funding: Rigel Patents, Royalties, Other Intellectual Property: Licenses for monoclonal antibodies and recombinant granzymesMeagan A. JacobyHonoraria: Takeda Research Funding: Geron (Inst), AbbVie (Inst), Jazz Pharmaceuticals (Inst), Aprea AB (Inst), Amphivena (Inst), Janssen (Inst) No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)
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- 2021
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33. Phase 1 dose escalation trial of volasertib in combination with decitabine in patients with acute myeloid leukemia.
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Cortes J, Podoltsev N, Kantarjian H, Borthakur G, Zeidan AM, Stahl M, Taube T, Fagan N, Rajeswari S, and Uy GL
- Subjects
- Aged, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Decitabine adverse effects, Decitabine pharmacokinetics, Dose-Response Relationship, Drug, Febrile Neutropenia chemically induced, Feeding and Eating Disorders chemically induced, Female, Humans, Leukemia, Myeloid, Acute pathology, Male, Molecular Targeted Therapy, Pteridines adverse effects, Pteridines pharmacokinetics, Treatment Outcome, Polo-Like Kinase 1, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Cell Cycle Proteins physiology, Decitabine administration & dosage, Gene Expression, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Protein Serine-Threonine Kinases physiology, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins metabolism, Proto-Oncogene Proteins physiology, Pteridines administration & dosage
- Abstract
Polo-like kinase 1 (PLK1) regulates mitotic checkpoints and cell division. PLK1 overexpression is reported in numerous cancers, including acute myeloid leukemia (AML), and is associated with poor prognosis. Volasertib is a selective, potent cell-cycle kinase inhibitor that targets PLK to induce mitotic arrest and apoptosis. This phase 1 trial investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-leukemic activity of volasertib in combination with decitabine in AML patients aged ≥ 65 years. Thirteen patients were treated with escalating volasertib doses (3 + 3 design; 300 mg, 350 mg, and 400 mg) plus standard-dose decitabine. Dose-limiting toxicity was reported in one patient in cycle 1; the MTD of volasertib in combination with decitabine was determined as 400 mg. The most common treatment-emergent adverse events were febrile neutropenia, pneumonia, and decreased appetite. Objective response rate was 23%. The combination was well tolerated, and the adverse event profile was in line with previous findings.
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- 2021
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34. Multidimensional Analyses of Donor Memory-Like NK Cells Reveal New Associations with Response after Adoptive Immunotherapy for Leukemia.
- Author
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Berrien-Elliott MM, Cashen AF, Cubitt CC, Neal CC, Wong P, Wagner JA, Foster M, Schappe T, Desai S, McClain E, Becker-Hapak M, Foltz JA, Cooper ML, Jaeger N, Srivatsan SN, Gao F, Romee R, Abboud CN, Uy GL, Westervelt P, Jacoby MA, Pusic I, Stockerl-Goldstein KE, Schroeder MA, DiPersio J, and Fehniger TA
- Subjects
- Humans, Leukemia, Myeloid, Acute pathology, Immunotherapy, Adoptive methods, Killer Cells, Natural metabolism, Leukemia, Myeloid, Acute genetics
- Abstract
Natural killer (NK) cells are an emerging cancer cellular therapy and potent mediators of antitumor immunity. Cytokine-induced memory-like (ML) NK cellular therapy is safe and induces remissions in patients with acute myeloid leukemia (AML). However, the dynamic changes in phenotype that occur after NK-cell transfer that affect patient outcomes remain unclear. Here, we report comprehensive multidimensional correlates from ML NK cell-treated patients with AML using mass cytometry. These data identify a unique in vivo differentiated ML NK-cell phenotype distinct from conventional NK cells. Moreover, the inhibitory receptor NKG2A is a dominant, transcriptionally induced checkpoint important for ML, but not conventional NK-cell responses to cancer. The frequency of CD8α
+ donor NK cells is negatively associated with AML patient outcomes after ML NK therapy. Thus, elucidating the multidimensional dynamics of donor ML NK cells in vivo revealed critical factors important for clinical response, and new avenues to enhance NK-cell therapeutics. SIGNIFICANCE: Mass cytometry reveals an in vivo memory-like NK-cell phenotype, where NKG2A is a dominant checkpoint, and CD8α is associated with treatment failure after ML NK-cell therapy. These findings identify multiple avenues for optimizing ML NK-cell immunotherapy for cancer and define mechanisms important for ML NK-cell function. This article is highlighted in the In This Issue feature, p. 1775 ., (©2020 American Association for Cancer Research.)- Published
- 2020
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35. CD123 bi-specific antibodies in development in AML: What do we know so far?
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Slade MJ and Uy GL
- Subjects
- Humans, Interleukin-3 Receptor alpha Subunit immunology, Leukemia, Myeloid, Acute immunology, Neoplasm Proteins immunology, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Antibodies, Bispecific therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Immunoconjugates therapeutic use, Interleukin-3 Receptor alpha Subunit antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Neoplasm Proteins antagonists & inhibitors
- Abstract
Bispecific antibodies are synthetic molecules designed to simultaneously bind two separate antigens. Given the recent success of blinatumomab in the treatment of acute lymphoblastic leukemia, there is growing interest in the use of bispecific antibodies as T-cell redirecting antibody for the treatment of cancer. In acute myeloid leukemia (AML), CD123 (also known as the interleukin receptor 3 alpha subunit) has emerged as a promising therapeutic target for bispecific antibodies. Prior attempts to target CD123 with unconjugated antibodies and antibody-drug conjugates have been mixed. However, available data from CD123-directed bispecific antibodies currently in clinical trials have been encouraging. In this review, we discuss the biology of CD123 and prior attempts to target this cell surface marker as part of anti-leukemic therapy. We then summarize and discuss the five CD123-directed bispecific antibodies currently in clinical trials for treatment of AML and provide practical insights regarding the use of these agents., (Copyright © 2020. Published by Elsevier Ltd.)
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- 2020
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36. Phase 1 study of the MDM2 antagonist RO6839921 in patients with acute myeloid leukemia.
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Uy GL, Assouline S, Young AM, Blotner S, Higgins B, Chen LC, and Yee K
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Female, Humans, Infusions, Intravenous, Leukemia, Myeloid, Acute blood, Leukemia, Myeloid, Acute metabolism, Male, Maximum Tolerated Dose, Middle Aged, Prodrugs adverse effects, Prodrugs pharmacokinetics, Proto-Oncogene Proteins c-mdm2 blood, Pyrrolidines adverse effects, Pyrrolidines blood, Pyrrolidines metabolism, Pyrrolidines pharmacokinetics, Young Adult, para-Aminobenzoates adverse effects, para-Aminobenzoates blood, para-Aminobenzoates metabolism, para-Aminobenzoates pharmacokinetics, Antineoplastic Agents administration & dosage, Leukemia, Myeloid, Acute drug therapy, Prodrugs administration & dosage, Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors, Pyrrolidines administration & dosage, para-Aminobenzoates administration & dosage
- Abstract
In acute myeloid leukemia (AML), TP53 mutations and dysregulation of wild-type p53 is common and supports an MDM2 antagonist as a therapy. RO6839921 is an inactive pegylated prodrug of the oral MDM2 antagonist idasanutlin (active principle [AP]) that allows for IV administration. This phase 1 monotherapy study evaluated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with AML. Primary objectives identified dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD). Secondary objectives assessed pharmacokinetic, pharmacodynamic, and antileukemic activity. A total of 26 patients received 120-300 mg AP of idasanutlin. The MTD was 200 mg, with DLTs at 250 (2/8 patients) and 300 mg (2/5). Treatment-related adverse events in >20% of patients were diarrhea, nausea, vomiting, decreased appetite, and fatigue. Six deaths (23.1%) occurred, all unrelated to treatment. Pharmacokinetics showed rapid and near-complete conversion of the prodrug to AP and dose-proportional exposure across doses. Variability ranged from 30%-47% (22%-54% for idasanutlin). TP53 was 21 (87.5%) wild-type and 3 mutant (12.5%). The composite response rate (complete remission [CR], CR with incomplete hematologic recovery/morphological leukemia-free state [CRi/MLFS], or CR without platelet recovery [CRp]) was 7.7%. Antileukemic activity (CR, CRi/MLFS, partial response, hematologic improvement/stable disease) was observed in 11 patients (disease control rate, 42%): 10/11 were TP53 wild-type; 1 had no sample. p53 activation was demonstrated by MIC-1 induction and was associated with AP exposure. There was not sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development of RO6839921. NCT02098967.
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- 2020
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37. Selinexor combined with cladribine, cytarabine, and filgrastim in relapsed or refractory acute myeloid leukemia.
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Abboud R, Chendamarai E, Rettig MP, Trinkaus KM, Riedell PA, Abboud CN, Ghobadi A, Pusic I, Stockerl-Goldstein K, Schroeder MA, Vij R, Westervelt P, DiPersio JF, and Uy GL
- Subjects
- Adult, Aged, Animals, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cytarabine therapeutic use, Female, Filgrastim therapeutic use, Humans, Hydrazines, Male, Mice, Inbred C57BL, Middle Aged, Remission Induction, Treatment Outcome, Triazoles, Young Adult, Cladribine therapeutic use, Leukemia, Myeloid, Acute drug therapy
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- 2020
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38. Reduced intensity conditioning for acute myeloid leukemia using melphalan- vs busulfan-based regimens: a CIBMTR report.
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Zhou Z, Nath R, Cerny J, Wang HL, Zhang MJ, Abdel-Azim H, Agrawal V, Ahmed G, Al-Homsi AS, Aljurf M, Alkhateeb HB, Assal A, Bacher U, Bajel A, Bashir Q, Battiwalla M, Bhatt VR, Byrne M, Cahn JY, Cairo M, Choe H, Copelan E, Cutler C, Damlaj MB, DeFilipp Z, De Lima M, Diaz MA, Farhadfar N, Foran J, Freytes CO, Gerds AT, Gergis U, Grunwald MR, Gul Z, Hamadani M, Hashmi S, Hertzberg M, Hildebrandt GC, Hossain N, Inamoto Y, Isola L, Jain T, Kamble RT, Khan MW, Kharfan-Dabaja MA, Kebriaei P, Kekre N, Khera N, Lazarus HM, Liesveld JL, Litzow M, Liu H, Marks DI, Martino R, Mathews V, Mishra A, Murthy HS, Nagler A, Nakamura R, Nathan S, Nishihori T, Olin R, Olsson RF, Palmisiano N, Patel SS, Patnaik MM, Pawarode A, Perales MA, Politikos I, Popat U, Rizzieri D, Sandmaier BM, Savani BN, Seo S, Shah NN, Uy GL, Valcárcel D, Verdonck LF, Waller EK, Wang Y, Weisdorf D, Wirk B, Wong E, Yared JA, and Saber W
- Subjects
- Adult, Busulfan, Humans, Melphalan, Transplantation Conditioning, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy
- Abstract
There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.
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- 2020
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39. Rapid Donor Identification Improves Survival in High-Risk First-Remission Patients With Acute Myeloid Leukemia.
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Pagel JM, Othus M, Garcia-Manero G, Fang M, Radich JP, Rizzieri DA, Marcucci G, Strickland SA, Litzow MR, Savoie ML, Spellman SR, Confer DL, Chell JW, Brown M, Medeiros BC, Sekeres MA, Lin TL, Uy GL, Powell BL, Bayer RL, Larson RA, Stone RM, Claxton D, Essell J, Luger SM, Mohan SR, Moseley A, Erba HP, and Appelbaum FR
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- Adult, Humans, Middle Aged, Prospective Studies, Remission Induction, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy
- Abstract
Purpose: Patients with acute myeloid leukemia with high-risk cytogenetics in first complete remission (CR1) achieve better outcomes if they undergo allogeneic hematopoietic cell transplantation (HCT) compared with consolidation chemotherapy alone. However, only approximately 40% of such patients typically proceed to HCT., Methods: We used a prospective organized approach to rapidly identify donors to improve the allogeneic HCT rate in adults with high-risk acute myeloid leukemia in CR1. Newly diagnosed patients had cytogenetics obtained at enrollment, and those with high-risk cytogenetics underwent expedited HLA typing and were encouraged to be referred for consultation with a transplantation team with the goal of conducting an allogeneic HCT in CR1., Results: Of 738 eligible patients (median age, 49 years; range, 18-60 years of age), 159 (22%) had high-risk cytogenetics and 107 of these patients (67%) achieved CR1. Seventy (65%) of the high-risk patients underwent transplantation in CR1 ( P < .001 compared with the historical rate of 40%). Median time to HCT from CR1 was 77 days (range, 20-356 days). In landmark analysis, overall survival (OS) among patients who underwent transplantation was significantly better compared with that of patients who did not undergo transplantation (2-year OS, 48% v 35%, respectively [ P = .031]). Median relapse-free survival after transplantation in the high-risk cohort who underwent transplantation in CR1 (n = 70) was 11.5 months (range, 4-47 months), and median OS after transplantation was 14 months (range, 4-44 months)., Conclusion: Early cytogenetic testing with an organized effort to identify a suitable allogeneic HCT donor led to a CR1 transplantation rate of 65% in the high-risk group, which, in turn, led to an improvement in OS when compared with the OS of patients who did not undergo transplantation.
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- 2020
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40. Combination of dasatinib with chemotherapy in previously untreated core binding factor acute myeloid leukemia: CALGB 10801.
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Marcucci G, Geyer S, Laumann K, Zhao W, Bucci D, Uy GL, Blum W, Eisfeld AK, Pardee TS, Wang ES, Stock W, Kolitz JE, Kohlschmidt J, Mrózek K, Bloomfield CD, Stone RM, and Larson RA
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- Adult, Aged, Cytarabine, Dasatinib therapeutic use, Daunorubicin, Humans, Remission Induction, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Acute myeloid leukemia (AML) with either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) is referred to as core binding factor (CBF) AML. Although categorized as favorable risk, long-term survival for these patients is only ∼50% to 60%. Mutated (mut) or overexpressed KIT, a gene encoding a receptor tyrosine kinase, has been found almost exclusively in CBF AML and may increase the risk of disease relapse. We tested the safety and clinical activity of dasatinib, a multi-kinase inhibitor, in combination with chemotherapy. Sixty-one adult patients with AML and CBF fusion transcripts (RUNX1/RUNX1T1 or CBFB/MYH11) were enrolled on Cancer and Leukemia Group B (CALGB) 10801. Patients received cytarabine/daunorubicin induction on days 1 to 7 and oral dasatinib 100 mg/d on days 8 to 21. Upon achieving complete remission, patients received consolidation with high-dose cytarabine followed by dasatinib 100 mg/d on days 6 to 26 for 4 courses, followed by dasatinib 100 mg/d for 12 months. Fifteen (25%) patients were older (aged ≥60 years); 67% were CBFB/MYH11-positive, and 19% harbored KITmut. There were no unexpected or dose-limiting toxicities. Fifty-five (90%) patients achieved complete remission. With a median follow-up of 45 months, only 16% have relapsed. The 3-year disease-free survival and overall survival rates were 75% and 77% (79% and 85% for younger patients [aged <60 years], and 60% and 51% for older patients). Patients with KITmut had comparable outcome to those with wild-type KIT (3-year rates: disease-free survival, 67% vs 75%; overall survival, 73% vs 76%), thereby raising the question of whether dasatinib may overcome the negative impact of these genetic lesions. CALGB 10801 was registered at www.clinicaltrials.gov as #NCT01238211., (© 2020 by The American Society of Hematology.)
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- 2020
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41. Ivosidenib induces deep durable remissions in patients with newly diagnosed IDH1-mutant acute myeloid leukemia.
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Roboz GJ, DiNardo CD, Stein EM, de Botton S, Mims AS, Prince GT, Altman JK, Arellano ML, Donnellan W, Erba HP, Mannis GN, Pollyea DA, Stein AS, Uy GL, Watts JM, Fathi AT, Kantarjian HM, Tallman MS, Choe S, Dai D, Fan B, Wang H, Zhang V, Yen KE, Kapsalis SM, Hickman D, Liu H, Agresta SV, Wu B, Attar EC, and Stone RM
- Subjects
- Aged, Aged, 80 and over, Blood Transfusion, Female, Glycine adverse effects, Glycine therapeutic use, Humans, Leukemia, Myeloid, Acute genetics, Male, Middle Aged, Pyridines adverse effects, Remission Induction, Survival Analysis, Translational Research, Biomedical, Treatment Outcome, Glycine analogs & derivatives, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Mutation genetics, Pyridines therapeutic use
- Abstract
Ivosidenib (AG-120) is an oral, targeted agent that suppresses production of the oncometabolite 2-hydroxyglutarate via inhibition of the mutant isocitrate dehydrogenase 1 (IDH1; mIDH1) enzyme. From a phase 1 study of 258 patients with IDH1-mutant hematologic malignancies, we report results for 34 patients with newly diagnosed acute myeloid leukemia (AML) ineligible for standard therapy who received 500 mg ivosidenib daily. Median age was 76.5 years, 26 patients (76%) had secondary AML, and 16 (47%) had received ≥1 hypomethylating agent for an antecedent hematologic disorder. The most common all-grade adverse events were diarrhea (n = 18; 53%), fatigue (n = 16; 47%), nausea (n = 13; 38%), and decreased appetite (n = 12; 35%). Differentiation syndrome was reported in 6 patients (18%) (grade ≥3 in 3 [9%]) and did not require treatment discontinuation. Complete remission (CR) plus CR with partial hematologic recovery (CRh) rate was 42.4% (95% confidence interval [CI], 25.5% to 60.8%); CR 30.3% (95% CI, 15.6% to 48.7%). Median durations of CR+CRh and CR were not reached, with 95% CI lower bounds of 4.6 and 4.2 months, respectively; 61.5% and 77.8% of patients remained in remission at 1 year. With median follow-up of 23.5 months (range, 0.6-40.9 months), median overall survival was 12.6 months (95% CI, 4.5-25.7). Of 21 transfusion-dependent patients (63.6%) at baseline, 9 (42.9%) became transfusion independent. IDH1 mutation clearance was seen in 9/14 patients achieving CR+CRh (5/10 CR; 4/4 CRh). Ivosidenib monotherapy was well-tolerated and induced durable remissions and transfusion independence in patients with newly diagnosed AML. This trial was registered at www.clinicaltrials.gov as #NCT02074839., (© 2020 by The American Society of Hematology.)
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- 2020
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42. Clinical and functional significance of circular RNAs in cytogenetically normal AML.
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Papaioannou D, Volinia S, Nicolet D, Świerniak M, Petri A, Mrózek K, Bill M, Pepe F, Walker CJ, Walker AE, Carroll AJ, Kohlschmidt J, Eisfeld AK, Powell BL, Uy GL, Kolitz JE, Wang ES, Kauppinen S, Dorrance A, Stone RM, Byrd JC, Bloomfield CD, and Garzon R
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- Adolescent, Adult, Female, Humans, Male, Middle Aged, Prognosis, Young Adult, Cytogenetics methods, Leukemia, Myeloid, Acute genetics, RNA, Circular metabolism
- Abstract
Circular RNAs (circRNAs) are noncoding RNA molecules that display a perturbed arrangement of exons, called backsplicing. To examine the prognostic and biologic significance of circRNA expression in cytogenetically normal acute myeloid leukemia (CN-AML), we conducted whole-transcriptome profiling in 365 younger adults (age 18-60 years) with CN-AML. We applied a novel pipeline, called Massive Scan for circRNA, to identify and quantify circRNA expression. We validated the high sensitivity and specificity of our pipeline by performing RNase R treatment and RNA sequencing in samples of AML patients and cell lines. Unsupervised clustering analyses identified 3 distinct circRNA expression-based clusters with different frequencies of clinical and molecular features. After dividing our cohort into training and validation data sets, we identified 4 circRNAs (circCFLAR, circKLHL8, circSMC1A, and circFCHO2) that were prognostic in both data sets; high expression of each prognostic circRNA was associated with longer disease-free, overall, and event-free survival. In multivariable analyses, high circKLHL8 and high circFCHO2 expression were independently associated with better clinical outcome of CN-AML patients, after adjusting for other covariates. To examine the biologic relevance of circRNA expression, we performed knockdown screening experiments in a subset of prognostic and gene mutation-related candidate circRNAs. We identified circFBXW7, but not its linear messenger RNA, as a regulator of the proliferative capacity of AML blasts. In summary, our findings underscore the molecular associations, prognostic significance, and functional relevance of circRNA expression in CN-AML., (© 2020 by The American Society of Hematology.)
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- 2020
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43. Geriatric assessment among older adults receiving intensive therapy for acute myeloid leukemia: Report of CALGB 361006 (Alliance).
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Klepin HD, Ritchie E, Major-Elechi B, Le-Rademacher J, Seisler D, Storrick L, Sanford BL, Marcucci G, Zhao W, Geyer SA, Ballman KV, Powell BL, Baer MR, Stock W, Cohen HJ, Stone RM, Larson RA, and Uy GL
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- Activities of Daily Living, Aged, Humans, Mental Health, Surveys and Questionnaires, Geriatric Assessment, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Objective: To demonstrate feasibility of performing geriatric assessment (GA) in the National Clinical Trials Network (NCTN) and to explore the utility of GA to characterize treatment tolerance., Materials and Methods: We conducted a multisite companion study (CALGB 361006) to CALGB 11001, a phase 2 trial of adults ≥60 years old with newly diagnosed FLT3- mutated AML, testing the efficacy of adding sorafenib to intensive chemotherapy. On 361006, a GA was administered prior to induction and prior to post-remission therapy. The GA is divided into items requiring administration by a health care professional (HCP) and patient self-administered questionnaires. Feasibility outcomes were recruitment rate, time to GA completion, difficulty with GA administration, percent of patients requiring assistance, and satisfaction. Change in GA measures pre- and post-induction were compared using Wilcoxon signed rank test and McNemar's tests., Results: The recruitment rate was 80% (N = 43, median age 68 years). Median completion time of the GA was 30 min; (10 and 21 min for HCP and patients, respectively). HCP reported no difficulty completing assessments (100%). Most patients completed questionnaires without assistance (77%), and were satisfied with the length (89%). Self-reported physical function, mental health, social activity and nutritional parameters worsened after induction., Conclusion: GA is feasible to administer in the setting of intensive induction for older adults with AML in the NCTN and provides evidence of the impact of induction therapy on physical and emotional health., (Copyright © 2019. Published by Elsevier Ltd.)
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- 2020
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44. Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia.
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Walker CJ, Kohlschmidt J, Eisfeld AK, Mrózek K, Liyanarachchi S, Song C, Nicolet D, Blachly JS, Bill M, Papaioannou D, Oakes CC, Giacopelli B, Genutis LK, Maharry SE, Orwick S, Archer KJ, Powell BL, Kolitz JE, Uy GL, Wang ES, Carroll AJ, Stone RM, Byrd JC, de la Chapelle A, and Bloomfield CD
- Subjects
- Adolescent, Adult, Aged, Cytogenetics methods, Disease-Free Survival, Female, Humans, Leukemia, Myeloid, Acute epidemiology, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Mutation, Nuclear Proteins genetics, Uniparental Disomy pathology, Young Adult, Leukemia, Myeloid, Acute genetics, Loss of Heterozygosity genetics, Prognosis, Uniparental Disomy genetics
- Abstract
Purpose: Uniparental disomy (UPD) is a way cancer cells duplicate a mutated gene, causing loss of heterozygosity (LOH). Patients with cytogenetically normal acute myeloid leukemia (CN-AML) do not have microscopically detectable chromosome abnormalities, but can harbor UPDs. We examined the prognostic significance of UPDs and frequency of LOH in patients with CN-AML. Experimental Design: We examined the frequency and prognostic significance of UPDs in a set of 425 adult patients with de novo CN-AML who were previously sequenced for 81 genes typically mutated in cancer. Associations of UPDs with outcome were analyzed in the 315 patients with CN-AML younger than 60 years., Results: We detected 127 UPDs in 109 patients. Most UPDs were large and typically encompassed all or most of the affected chromosome arm. The most common UPDs occurred on chromosome arms 13q (7.5% of patients), 6p (2.8%), and 11p (2.8%). Many UPDs significantly cooccurred with mutations in genes they encompassed, including 13q UPD with FLT3 -internal tandem duplication ( FLT3 -ITD; P < 0.001), and 11p UPD with WT1 mutations ( P = 0.02). Among patients younger than 60 years, UPD of 11p was associated with longer overall survival (OS) and 13q UPD with shorter disease-free survival (DFS) and OS. In multivariable models that accounted for known prognostic markers, including FLT3 -ITD and WT1 mutations, UPD of 13q maintained association with shorter DFS, and UPD of 11p maintained association with longer OS., Conclusions: LOH mediated by UPD is a recurrent feature of CN-AML. Detection of UPDs of 13q and 11p might be useful for genetic risk stratification of patients with CN-AML., (©2019 American Association for Cancer Research.)
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- 2019
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45. Allogeneic hematopoietic cell transplantation compared to chemotherapy consolidation in older acute myeloid leukemia (AML) patients 60-75 years in first complete remission (CR1): an alliance (A151509), SWOG, ECOG-ACRIN, and CIBMTR study.
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Ustun C, Le-Rademacher J, Wang HL, Othus M, Sun Z, Major B, Zhang MJ, Storrick E, Lafky JM, Chow S, Mrózek K, Attar EC, Nand S, Bloomfield CD, Cripe LD, Tallman MS, Appelbaum F, Larson RA, Marcucci G, Roboz GJ, Uy GL, Stone RM, Jatoi A, Shea TC, de Lima M, Foran JM, Sandmaier BM, Litzow MR, Erba HP, Hurria A, Weisdorf DJ, and Artz AS
- Subjects
- Aged, Disease-Free Survival, Female, Humans, Male, Middle Aged, Multivariate Analysis, Remission Induction, Retrospective Studies, Risk Factors, Transplantation, Homologous, Treatment Outcome, United States, Antineoplastic Agents therapeutic use, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute therapy
- Abstract
The preferred post-remission therapy for older patients with acute myeloid leukemia (AML) in first complete remission (CR1) remains uncertain. In this retrospective, multicenter study, we compared the outcomes for older AML patients (age 60-77 years) receiving allogeneic hematopoietic cell transplantation (alloHCT) (n = 431) with those treated on prospective National Clinical Trials Network induction and nontransplantation chemotherapy (CT) consolidation trials (n = 211). AlloHCT patients were younger (median age: 64.2 versus 67.9 years, p < 0.001), but more frequently had high-risk AML (high WBC, secondary AML, and unfavorable cytogenetics). Overall survival (OS) was worse in alloHCT during the first 9 months after CR1 (HR = 1.52, p = 0.02), but was significantly better thereafter (HR = 0.53, p < 0.0001) relative to CT. Treatment-related mortality (TRM) following HCT was worse in the first 9 months (HR = 2.8, 95% CI: 1.5-5.2, p = 0.0009), while post-HCT relapse was significantly less frequent beyond 9 months (HR = 0.42, 95% CI: 0.29-0.61, p < 0.0001). Despite higher early TRM, alloHCT recipients had superior long-term OS [29% (24-34%) versus CT 13.8% (9-21%) at 5 years]. Although this is a retrospective analysis with potential biases, it indicates that alloHCT led to heightened early risks from TRM, yet reduced relapse and superior long-term survival relative to CT in older AML patients in CR1.
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- 2019
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46. CCGG deletion (rs201074739) in CD33 results in premature termination codon and complete loss of CD33 expression: another key variant with potential impact on response to CD33-directed agents.
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Papageorgiou I, Loken MR, Brodersen LE, Gbadamosi M, Uy GL, Meshinchi S, and Lamba JK
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- Aged, Antineoplastic Agents therapeutic use, Biopsy, Bone Marrow pathology, Codon, Nonsense, Codon, Terminator genetics, DNA Mutational Analysis, Female, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Sequence Deletion, Sialic Acid Binding Ig-like Lectin 3 analysis, Sialic Acid Binding Ig-like Lectin 3 antagonists & inhibitors, Sialic Acid Binding Ig-like Lectin 3 metabolism, Antineoplastic Agents pharmacology, Drug Resistance, Neoplasm genetics, Leukemia, Myeloid, Acute therapy, Neoplasm Recurrence, Local therapy, Sialic Acid Binding Ig-like Lectin 3 genetics
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- 2019
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47. Complex karyotype in de novo acute myeloid leukemia: typical and atypical subtypes differ molecularly and clinically.
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Mrózek K, Eisfeld AK, Kohlschmidt J, Carroll AJ, Walker CJ, Nicolet D, Blachly JS, Bill M, Papaioannou D, Wang ES, Uy GL, Kolitz JE, Powell BL, Blum W, Stone RM, Byrd JC, and Bloomfield CD
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Female, Follow-Up Studies, Gene Expression Regulation, Neoplastic, Humans, Male, Middle Aged, Nucleophosmin, Prognosis, Survival Rate, Young Adult, Biomarkers, Tumor genetics, Chromosome Aberrations, Chromosomes, Human genetics, Karyotyping methods, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Mutation
- Abstract
Complex karyotype (CK) with ≥ 3 abnormalities is detected in 10-12% of patients with acute myeloid leukemia (AML) and associated with poor prognosis. The most common unbalanced abnormalities found in CK result in loss of material from the 5q, 7q, and/or 17p chromosome arms. The presence of 5q, 7q, and/or 17p abnormalities denotes typical CK and their absence denotes atypical CK. Since molecular features of CK-AML are not well characterized, we investigated mutational status of 81 leukemia/cancer-associated genes in 160 clinically well-characterized patients. They included 136 patients with ≥ 3 exclusively unbalanced chromosome abnormalities, 96 of whom had a typical CK and 40 atypical CK, and 24 patients with ≥ 1 balanced abnormality in addition to ≥ 2 unbalanced ones. Patients with atypical CK-AML differed from those with typical CK-AML: they carried TP53 mutations less often (P < 0.001) and more often PHF6 (P = 0.008), FLT3-TKD (P = 0.02), MED12 (P = 0.02), and NPM1 (P = 0.02) mutations. They were younger (P = 0.007), had higher WBC (P = 0.001) and percentages of marrow (P < 0.001) and blood (P = 0.006) blasts, higher complete remission rates (P = 0.02), and longer overall survival (P < 0.001), thus indicating that atypical and typical CK-AMLs constitute distinct disease subtypes. We also identified smaller patient subsets within both typical and atypical CK-AML that differed molecularly and clinically.
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- 2019
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48. Evaluation of event-free survival as a robust end point in untreated acute myeloid leukemia (Alliance A151614).
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Yin J, LaPlant B, Uy GL, Marcucci G, Blum W, Larson RA, Stone RM, and Mandrekar SJ
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Allografts, Anthracyclines administration & dosage, Cytarabine administration & dosage, Disease-Free Survival, Female, Humans, Induction Chemotherapy, Male, Middle Aged, Survival Rate, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute therapy
- Abstract
Event-free survival (EFS) is controversial as an end point for speeding approvals in newly diagnosed acute myeloid leukemia (AML). We aimed to examine the robustness of EFS, specifically timing of complete remission (CR) in defining induction failure and impact of hematopoietic cell transplantation (HCT). The study included 1884 untreated AML patients enrolled across 5 trials conducted through Alliance for Clinical Trials in Oncology using anthracycline and cytarabine induction chemotherapy. EFS was defined as time from randomization/registration to induction failure, relapse, or death. Three definitions of induction failure were evaluated: failure to achieve CR by 60 days after randomization/registration, failure to achieve CR by the end of all protocol-defined induction courses, and failure to achieve CR by the end of all protocol-defined treatment. We considered either censoring or no censoring at time of non-protocol-mandated HCT. Although relapse and death are firm end points, the determination of induction failure was not consistent across studies. There was minimal impact of censoring at HCT on EFS estimates; however, median EFS estimates differed considerably based on the timing of CR in defining induction failure, with the magnitude of difference being large enough in most cases to lead to incorrect conclusions about efficacy in a single-arm trial, if the trial definition was not consistent with the definition used for the historical control. Timing of CR should be carefully examined in the historical control data used to guide the design of single-arm trials using EFS as the primary end point. Trials were registered at www.clinicaltrials.gov as #NCT00085124, #NCT00416598, # NCT00651261, #NCT01238211, and #NCT01253070., (© 2019 by The American Society of Hematology.)
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- 2019
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49. Choosing induction chemotherapy in therapy-related acute myeloid leukemia.
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Shea LK and Uy GL
- Subjects
- Humans, Leukemia, Myeloid, Acute chemically induced, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Mutation, Neoplasms, Second Primary genetics, Neoplasms, Second Primary metabolism, Cytarabine therapeutic use, Daunorubicin therapeutic use, Enzyme Inhibitors therapeutic use, Induction Chemotherapy methods, Leukemia, Myeloid, Acute drug therapy, Neoplasms, Second Primary drug therapy
- Abstract
Patients with AML that develops after cytotoxic therapy (tAML) have overall inferior outcomes relative to de novo AML due to both patient-related factors and the intrinsic biology of the disease. Treatment of patients with tAML is challenging. The key initial clinical decision is whether a patient is a candidate for or likely to benefit from intensive induction chemotherapy, a determination which we argue should not be predicated on chronologic age alone. For those determined likely to tolerate intensive induction chemotherapy, CPX-351 is likely superior to conventional induction with cytarabine and daunorubicin. For those deemed inappropriate for intensive induction, hypomethylating agents have the strongest evidence base in elderly adults with AML, and are an attractive option in tAML. This is particularly true in patients with TP53 mutations who are less likely to respond to conventional induction chemotherapy. Exciting options on the therapeutic horizon for tAML include combination therapies incorporating BCL2 inhibitors, Hedgehog pathway inhibitors, and isocitrate dehydrogenase inhibitors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
50. Bispecific Antibodies for the Treatment of Acute Myeloid Leukemia.
- Author
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Guy DG and Uy GL
- Subjects
- Humans, Leukemia, Myeloid, Acute pathology, Antibodies, Bispecific metabolism, Leukemia, Myeloid, Acute therapy
- Abstract
Purpose of Review: Bispecific antibodies combine antigen recognition sites from two or more antibodies into a single construct allowing simultaneous binding to multiple targets. Bispecific antibodies exist which can redirect immune effector cells against acute myeloid leukemia (AML) targets. This review will highlight the progress to date and the challenges in developing bispecific antibodies for the treatment of AML., Recent Findings: Currently, a number of bispecific antibody formats including bispecific T cell engagers, dual affinity retargeting proteins, and tandem diabodies are in clinical development for AML. These antibodies target antigens present on AML blasts, including CD33, and the low affinity IL3 receptor, CD123. T cell redirecting bispecific antibodies in early phase clinical trials for AML include AG330, flotetuzumab, JNJ-63709178, and AMV564. Bispecific antibodies represent a promising immunotherapeutic approach for the treatment of cancer. The results of ongoing studies in AML will elucidate the potential for these agents in AML.
- Published
- 2018
- Full Text
- View/download PDF
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