121 results on '"Martinelli, Giovanni"'
Search Results
2. A practical algorithm for acute myeloid leukaemia diagnosis following the updated 2022 classifications.
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Della Porta MG, Martinelli G, Rambaldi A, Santoro A, and Voso MT
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- Humans, World Health Organization, fms-Like Tyrosine Kinase 3 genetics, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute classification, Leukemia, Myeloid, Acute therapy, Algorithms, Mutation
- Abstract
Disease classification of complex and heterogenous diseases, such as acute myeloid leukaemia (AML), is continuously updated to define diagnoses, appropriate treatments, and assist research and education. Recent availability of molecular profiling techniques further benefits the classification of AML. The World Health Organization (WHO) classification of haematolymphoid tumours and the International Consensus Classification of myeloid neoplasms and acute leukaemia from 2022 are two updated versions of the WHO 2016 classification. As a consequence, the European LeukemiaNet 2022 recommendations on the diagnosis and management of AML in adults have been also updated. The current review provides a practical interpretation of these guidelines to facilitate the diagnosis of AML and discusses genetic testing, disease genetic heterogeneity, and FLT3 mutations. We propose a practical algorithm for the speedy diagnosis of AML. Future classifications may need to incorporate gene mutation combinations to enable personalised treatment regimens in the management of patients with AML., Competing Interests: Declaration of Competing Interest Giovanni Martinelli received research support from Novartis, BMS, Amgen, Pfizer, AIRC, AIL, Genzyme, and Celgene; consulting fees from Novartis, BMS, Amgen, Pfizer, AIRC, AIL, Genzyme, Celgene, Ariad Pharma, and Roche; served as speaker bureau for Novartis, BMS, Amgen, Pfizer, AIRC, AIL, Genzyme, Celgene, Arida, and Glaxo; and received honoraria from Novartis, BMS, Amgen, Pfizer, AIRC, AIL, Genzyme, Celgene, Arida, and Glaxo. Alessandro Rambaldi received honoraria from Novartis, BMS, Sanofi, Abbvie, Amgen, Pfizer, Kite-Gilead, Jazz, Astellas, Incyte, and Omeros. Matteo Giovanni Della Porta, Maria Teresa Voso, and Alessandra Santoro declare no conflict of interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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3. Venetoclax and Cobimetinib in Relapsed/Refractory AML: A Phase 1b Trial.
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Konopleva MY, Dail M, Daver NG, Garcia JS, Jonas BA, Yee KWL, Kelly KR, Vey N, Assouline S, Roboz GJ, Paolini S, Pollyea DA, Tafuri A, Brandwein JM, Pigneux A, Powell BL, Fenaux P, Olin RL, Visani G, Martinelli G, Onishi M, Wang J, Huang W, Dunshee DR, Hamidi H, Ott MG, Hong WJ, and Andreeff M
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- Humans, Aged, Male, Female, Middle Aged, Aged, 80 and over, Treatment Outcome, Drug Resistance, Neoplasm drug effects, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Sulfonamides pharmacology, Sulfonamides therapeutic use, Sulfonamides administration & dosage, Azetidines therapeutic use, Azetidines pharmacology, Azetidines administration & dosage, Piperidines therapeutic use, Piperidines pharmacology, Leukemia, Myeloid, Acute drug therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Antineoplastic Combined Chemotherapy Protocols pharmacology, Antineoplastic Combined Chemotherapy Protocols adverse effects
- Abstract
Background: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies., Patients and Methods: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle., Results: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway., Conclusion: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations., Competing Interests: Disclosure MYK is a consultant for AbbVie, Inc., Genentech, Inc., and F. Hoffmann La-Roche; is an advisory board member for F. Hoffmann La-Roche; holds shares from Reata Pharmaceuticals; has received honoraria from Amgen, AbbVie, Inc., and Genentech, Inc.; and has received research funding from AbbVie, Inc., Genentech, Inc., Eli Lilly, Cellectis, Calithera, Stemline, Threshold, Flexus Biosciences, Novartis, Ablynx, and Agios. MD, MO, JW, WH, DD, and HH are employees of Genentech, Inc. and may hold Roche stock or stock options. NGD has received research funding from Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Inc., Astellas, Daiichi Sankyo, AbbVie, Inc., Hanmi, Trovagene, Fate Therapeutics, Amgen, Novimmune, GlycoMimetics, Trillium, Kite Pharma, Aptose, Shattuck Labs, KAHR, ArcellX, Sanofi, Sumitomo, and ImmunoGen; and has served in a consulting or advisory role for Daiichi Sankyo, Bristol-Myers Squibb, Arog Pharmaceuticals, Pfizer, Novartis, Jazz Pharmaceuticals, Celgene, AbbVie, Inc., Astellas, Genentech, Inc., Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck Labs, ArcellX, Kite Pharma, Sumitomo, Caribou Biosciences, Sanofi, Rigel, Aptose, KURA, GlycoMimetics, and Agios. JSG has received research funding (for trials) from AbbVie, Inc., Genentech, Inc., Pfizer, Prelude, and AstraZeneca; and has served on advisory boards for AbbVie, Inc., Astellas, Bristol-Myers Squibb and Servier. BAJ is a consultant/advisor for AbbVie, Inc., Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Inc., Gilead, GlycoMimetics, Jazz Pharmaceuticals, Kymera, Pfizer, Rigel, Servier, and Takeda; protocol steering committee for GlycoMimetics; data monitoring committee for Gilead; travel reimbursement/support from Rigel; and research funding to his institution from AbbVie, Inc., Amgen, Arog Pharmaceuticals, Aptose, BMS, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma Therapeutics, Forty-Seven, Genentech, Inc./Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz Pharmaceuticals, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, and Treadwell. KWLY is a consultant for Astex, Bristol-Myers Squibb/Celgene, F. Hoffmann-La Roche, Novartis, Otsuka, Paladin, Pfizer, Shattuck Labs, Taiho, and Takeda; has received honorarium from AbbVie, Inc. and Novartis; and has received research funding from Astex, Forma Therapeutics, F. Hoffmann-La Roche, Genentech, Inc., Geron, Janssen, Jazz Pharmaceuticals, MedImmune, Novartis, Onconova, and Tolero. KRK, NV, SP, AT, AP, PF, and GV declare no competing financial interests. SA reports non-financial support from Roche/Genentech, Inc. during the conduct of the study; and has received personal fees from Roche Canada, Pfizer, Bristol-Myers Squibb, Palladin, and Lundbeck outside of the submitted work. GJR consulted for AbbVie, Inc., Amgen, Argenx, AstraZeneca, Bluebird Bio, Blueprint Medicines, Bristol-Myers Squibb, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses Pharma, GlaxoSmithKline, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Novartis, Pfizer, Roche, Syndax, Takeda (IRC Chair), and Telix Pharma; and has received research funding from Janssen. DAP has received research funding from AbbVie, Inc. and has served as a consultant or advisory board member for AbbVie, Inc. and Genentech, Inc. JMB consulted for AbbVie, Inc., Bristol-Myers Squibb, Astex, Pfizer, Astellas, Taiho, and Jazz Pharmaceuticals. BLP has received research funding from Ambit Biosciences, Genentech, Inc., F. Hoffmann-La Roche, Jazz Pharmaceuticals, Novartis, Pfizer, and Cornerstone Pharmaceuticals; and is a consultant for Cornerstone Pharmaceuticals. RLO has received research support for trials from Astellas, Pfizer, Genentech, Inc., Daiichi Sankyo, and Cellectis; and consulted for AbbVie, Inc., Astellas, and Actinium. GM is a consultant for AbbVie, Inc., Celgene, Roche, Janssen, Astellas, Pfizer, and Incyte. W-JH is a former employee of Genentech, Inc. and may hold Roche stock; and is a current employee of Prelude Therapeutics. MGO is an employee of F. Hoffmann-La Roche and may hold stock or stock options. MA consulted for Amgen, AstraZeneca, Daiichi Sankyo, Syndax, GlycoMimetics, Oncoceutics, and Aptose; has received research funding from F. Hoffmann-La Roche, AstraZeneca, Amgen, Daiichi Sankyo, Jazz Pharmaceuticals, GlycoMimetics; and holds stock from Reata, Oncoceutics/Chimerix and Aptose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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4. Cusatuzumab plus azacitidine in newly diagnosed acute myeloid leukaemia ineligible for intensive chemotherapy (CULMINATE): part one of a randomised, phase 2, dose optimisation study.
- Author
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Pabst T, Papayannidis C, Demirkan F, Doronin V, Fogliatto LM, Guttke C, Gyan E, Hamad N, Herrera P, Hultberg A, Jacobs J, Johnson AJ, Langlois A, Ma X, Martinelli G, Arnan M, Müller R, Nottage K, Ofran Y, Özcan M, Samoilova O, Tolbert JA, Trudel GC, Xiu L, Vey N, and Wei AH
- Subjects
- Adult, Humans, Male, Female, Azacitidine adverse effects, Remission Induction, Drug Administration Schedule, Antibodies, Monoclonal therapeutic use, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute diagnosis
- Abstract
Background: Cusatuzumab, a high-affinity anti-CD70 antibody, has shown preliminary activity as a treatment for acute myeloid leukaemia when combined with azacitidine. We aimed to determine the optimum dose for future trials of cusatuzumab in combination with azacitidine in patients with previously untreated acute myeloid leukaemia who are not eligible for intensive chemotherapy., Methods: In this randomised, phase 2, open-label, dose-optimisation study we enrolled adult patients aged 18 years or older with newly diagnosed acute myeloid leukaemia not eligible for intensive chemotherapy, and with Eastern Cooperative Oncology Group scores of 0-2, from 40 hospitals and centres across seven countries. In part one of the trial, participants were randomly allocated 1:1 to 10 mg/kg or 20 mg/kg intravenous cusatuzumab on days 3 and 17, combined with subcutaneous or intravenous azacitidine 75 mg/m
2 on days 1-7 in 28-day cycles. The primary efficacy outcome was the rate of complete remission in the intention-to-treat group. The two dose cohorts were evaluated independently without between-cohort statistical comparison. Safety analyses were performed in all patients who received one dose of study drug. Part two of the trial was planned to be a single-arm expansion to evaluate cusatuzumab plus azacitidine at the cusatuzumab dose level selected in part one (primary hypothesis ≥35% rate of complete remission vs null hypothesis of 20%); however, changes in the acute myeloid leukaemia treatment landscape during this trial made it unlikely that enrolment to part two of the study would be clinically feasible, so the study stopped at the end of part one. The trial was registered at ClinicalTrials.gov, NCT04023526., Findings: 103 patients were enrolled between Aug 30, 2019, and Feb 25, 2020, and randomly assigned to either cusatuzumab 10 mg/kg (n=51) or 20 mg/kg (n=52). Median follow-up was 7·2 months (IQR 10·7 months). 57 of 103 (55%) patients were male and 46 (45%) patients were female, 78 (76%) were White, one (1%) was Asian, and 24 (23%) did not report their race. In the 10 mg/kg group, complete remission rate was 12% (six of 51 patients; 95% CI 6-23) and in the 20 mg/kg group was 27% (14 of 52; 17-40). Grade 3 or worse treatment-emergent adverse events (TEAEs) were similar between the cusatuzumab 10 mg/kg (n=51) and 20 mg/kg (n=51) cohorts and included thrombocytopenia (24 patients [47%] vs 29 [57%]), anaemia (24 [47%] vs 17 [33%]), and neutropenia (20 [39%] in both cohorts). Serious TEAEs were also similar in the two cohorts (44 [86%] vs 40 [78%]). Treatment-related TEAEs leading to death were reported in both groups (three patients [6%] in the 10 mg/kg group vs one patient [2%] in the 20 mg/kg group); the reported causes of death were pneumonia (n=2) and septic shock (n=2)., Interpretation: Although part one of this study was not designed to formally compare the two dose cohorts for efficacy, the totality of clinical data for cusatuzumab studies performed to date indicate that cusatuzumab 20 mg/kg plus azacitidine represents the optimal dose for further studies. A phase 1b study investigating the triple combination of cusatuzumab with venetoclax and azacitidine is underway (NCT04150887)., Funding: Janssen Research & Development and argenx., Competing Interests: Declaration of interests CG is an employee of Johnson & Johnson and has stock options. EG has received consulting fees and research funding from Novartis. AH is an employee of argenx which includes stock options and patents. AJJ is an employee and has stock options in Janssen. AL is an employee of Janssen R&D and has stock options in Johnson & Johnson. MA has received consulting fees from BMS-Celgene, Novartis, Astellas, Jazz Pharmaceuticals, and Pfizer; and is an advisory board member for BMS-Celgene and Novartis. KN is an employee of Janssen R&D; and has stock options in Johnson & Johnson. MÖ has received a research grant from Janssen; received grant funding or contracts from AbbVie, Bayer, Janssen, Acerta, Beddy's, Merck Sharp & Dohme, Roche, and Takeda; and has received meeting support from AbbVie, Jazz Pharmaceuticals, and Roche. GCT has stock options in Johnson & Johnson. NV has received honoraria payment from Amgen, argenx, BMS, Janssen, and Roche; and received meeting support from Novartis, Amgen, and BMS. AHW has received research funding from Novartis, AbbVie, Servier, BMS, Syndax, Astex, AstraZeneca, and Amgen; is an employee of Walter and Eliza Hall Institute of medical research which receives milestone and royalty payments related to venetoclax and is eligible for financial benefits associated with these payments; has received consulting fees from Shoreline, Servier, Novartis, and AbbVie; has served on speaker's bureaus for AbbVie, Novartis, BMS, and Astellas; and has served on advisory boards for Novartis, Astellas, Janssen, Amgen, Roche, Pfizer, AbbVie, Servier, Gilead, BMS, Macrogenics, and Agios. XM was an employee of Janssen at the time the study was completed. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)- Published
- 2023
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5. Personalizing precision medicine: Patients with AML perceptions about treatment decisions.
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Grauman Å, Kontro M, Haller K, Nier S, Aakko S, Lang K, Zingaretti C, Meggiolaro E, De Padova S, Marconi G, Martinelli G, Heckman CA, Simonetti G, Bullinger L, and Kihlbom U
- Subjects
- Humans, Decision Making, Precision Medicine, Patient Participation, Physician-Patient Relations, Qualitative Research, Leukemia, Myeloid, Acute therapy, Physicians
- Abstract
Background: This study aims to explore patients' with acute myeloid leukemia perceptions about precision medicine and their preferences for involvement in this new area of shared decision-making., Methods: Individual semi-structured interviews were conducted in Finland, Italy and Germany (n = 16). The study population included patients aged 24-79 years. Interviews were analyzed with thematic content analysis., Results: Patient's perceived lack of knowledge as a barrier for their involvement in decision-making. Treatment decisions were often made rapidly based on the patient's intuition and trust for the physician rather than on information, in situations that decrease the patient's decision capacity. The patients emphasized that they are in a desperate situation that makes them willing to accept treatment with low probabilities of being cured., Conclusions: The study raised important issues regarding patients' understanding of precision medicine and challenges concerning how to involve patients in medical decision-making. Although technical advances were viewed positively, the role of the physician as an expert and person-of-trust cannot be replaced., Practice Implications: Regardless of patients' preferences for involvement in decision-making, information plays a crucial role for patients' perceived involvement in their care. The concepts related to precision medicine are complex and will imply challenges to patient education., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2023
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6. Uncovering the expression of circPVT1 in the extracellular vesicles of acute myeloid leukemia patients.
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Ghetti M, Vannini I, Bochicchio MT, Azzali I, Ledda L, Marconi G, Melloni M, Fabbri F, Rondoni M, Chicchi R, Angeli D, Ghelli Luserna di Rorà A, Giannini B, Zacheo I, Biguzzi R, Lanza F, Martinelli G, and Simonetti G
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- Humans, RNA, Circular genetics, RNA, Circular metabolism, Hematopoietic Stem Cells metabolism, Cell Communication, Tumor Microenvironment genetics, Leukemia, Myeloid, Acute metabolism, Extracellular Vesicles metabolism
- Abstract
Extracellular vesicles (EVs) act as molecular mediators in the tumor microenvironment, by shuttling information contained within malignant cells and functioning as regulators of the immune system. Circular (circ)RNAs are characterized by a closed loop-like structure that makes them more stable in the extracellular milieu and suitable to be packaged inside EVs. circPVT1 (hsa_circ_0001821) showed an oncogenic role in several cancer types and immunosuppressive properties in myeloid and lymphoid cell subsets. In this study, we characterized EVs from acute myeloid leukemia (AML) patients in terms of size, concentrations, surface markers and circPVT1 cargo. We showed that circPVT1 is overexpressed by primary blast cells from newly-diagnosed AML patients compared with hematopoietic stem-progenitor cells and is released as cell-free RNA in the plasma. We isolated EVs from the plasma of AML patients and healthy subjects by size exclusion chromatography and characterized them by nanoparticle tracking analysis. EVs from patients' plasma are larger compared with those from healthy subjects and their surface profile is characterized by higher levels of the leukemic cell markers CD133, CD105, CD49e and other immune-related epitopes, with differences according to AML molecular profile. Moreover, digital PCR analysis revealed that circPVT1 is more abundant inside EVs from the plasma of AML patients compared with healthy subjects. Our findings provide new insights on the features and content of AML EVs and suggest a role of circPVT1 in the crosstalk between AML cells and the tumor microenvironment., Competing Interests: Declaration of Competing Interest The other authors declare that they have no competing interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2023
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7. The baseline comorbidity burden affects survival in elderly patients with acute myeloid leukemia receiving hypomethylating agents: Results from a multicentric clinical study.
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Marconi G, Candoni A, Di Nicola R, Sartor C, Parisi S, Abbenante M, Nanni J, Cristiano G, Zannoni L, Lazzarotto D, Giannini B, Baldazzi C, Bandini L, Ottaviani E, Testoni N, Bezzi CDG, Abd-Alatif R, Ciotti G, Fanin R, Martinelli G, Paolini S, Ricci P, Cavo M, Papayannidis C, and Curti A
- Subjects
- Humans, Aged, Retrospective Studies, Prognosis, Comorbidity, Frailty, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute epidemiology
- Abstract
Background: In older patients with acute myeloid leukemia (AML), the definition of fitness, prognosis, and risk of death represents an open question., Methods: In the present study, we tested the impact on survival of disease- and patient-related parameters in a large cohort of elderly AML patients homogeneously assigned to treatment with hypomethylating agents (HMAs)., Results: In 131 patients with a median age of 76 years, we confirmed that early response (<0.001) and biology-based risk classification (p = 0.003) can select patients with better-predicted survival. However, a full disease-oriented model had limitations in stratifying our patients, prompting us to investigate the impact of baseline comorbidities on overall survival basing on a comorbidity score. The albumin level (p = 0.001) and the presence of lung disease (p = 0.013) had a single-variable impact on prognosis. The baseline comorbidity burden was a powerful predictor of patients' frailty, correlating with increased incidence of adverse events, especially infections, and predicted overall survival (p < 0.001)., Conclusion: The comorbidity burden may contribute to impact prognosis in addition to disease biology. While the therapeutic armamentarium of elderly AML is improving, a comprehensive approach that combines AML biology with tailored interventions to patients' frailty is likely to fully exploit the anti-leukemia potential of novel drugs., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2023
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8. AVALON: The Italian cohort study on real-life efficacy of hypomethylating agents plus venetoclax in newly diagnosed or relapsed/refractory patients with acute myeloid leukemia.
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Todisco E, Papayannidis C, Fracchiolla N, Petracci E, Zingaretti C, Vetro C, Martelli MP, Zappasodi P, Di Renzo N, Gallo S, Audisio E, Griguolo D, Cerchione C, Selleri C, Mattei D, Bernardi M, Fumagalli M, Rizzuto G, Facchini L, Basilico CM, Manfra I, Borlenghi E, Cairoli R, Salutari P, Gottardi M, Molteni A, Martini V, Lunghi M, Fianchi L, Cilloni D, Lanza F, Abruzzese E, Cascavilla N, Rivellini F, Ferrara F, Maurillo L, Nanni J, Romano A, Cardinali V, Gigli F, Roncoroni E, Federico V, Marconi G, Volpi R, Sciumè M, Tarella C, Rossi G, and Martinelli G
- Subjects
- Humans, Aged, Cohort Studies, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Sulfonamides, Antineoplastic Combined Chemotherapy Protocols adverse effects, Leukemia, Myeloid, Acute
- Abstract
Background: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia., Methods: AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax + HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here., Results: In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60 days of therapy. Infections were confirmed as the most common nonhematologic adverse event., Conclusions: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax + HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax + HMA effectiveness and toxicities in real life., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)
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- 2023
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9. Outcomes in Patients with FLT3-Mutated Relapsed/ Refractory Acute Myelogenous Leukemia Who Underwent Transplantation in the Phase 3 ADMIRAL Trial of Gilteritinib versus Salvage Chemotherapy.
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Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Recher C, Yoon SS, Maeda Y, Hosono N, Onozawa M, Kato T, Kim HJ, Hasabou N, Nuthethi R, Tiu R, and Levis MJ
- Subjects
- Adult, Humans, Aniline Compounds therapeutic use, Aniline Compounds pharmacology, Recurrence, fms-Like Tyrosine Kinase 3 genetics, fms-Like Tyrosine Kinase 3 therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib improved the survival of patients with relapsed or refractory (R/R) FLT3-mutated acute myelogenous leukemia (AML) in the phase 3 ADMIRAL trial. In this study, we assessed survival and relapse rates of patients in the ADMIRAL trial who underwent hematopoietic stem cell transplantation (HSCT), as well as safety outcomes in patients who received post-transplantation gilteritinib maintenance therapy. ADMIRAL was a global phase 3 randomized controlled trial that enrolled adult patients with FLT3-mutated R/R AML. Patients with R/R AML who harbored FLT3 internal tandem duplication mutations in the juxtamembrane domain or D835/I836 point mutations in the tyrosine kinase domain were randomized (2:1) to gilteritinib (120 mg/day) or to preselected high- or low-intensity salvage chemotherapy (1 or 2 cycles). Patients in the gilteritinib arm who proceeded to HSCT could receive post-transplantation gilteritinib maintenance therapy if they were within 30 to 90 days post-transplantation and had achieved composite complete remission (CRc) with successful engraftment and no post-transplantation complications. Adverse events (AEs) during HSCT were recorded in the gilteritinib arm only. Survival outcomes and the cumulative incidence of relapse were assessed in patients who underwent HSCT during the trial. Treatment-emergent AEs were evaluated in patients who restarted gilteritinib as post-transplantation maintenance therapy. Patients in the gilteritinib arm underwent HSCT more frequently than those in the chemotherapy arm (26% [n = 64] versus 15% [n = 19]). For all transplantation recipients, 12- and 24-month overall survival (OS) rates were 68% and 47%, respectively. Despite a trend toward longer OS after pretransplantation CRc, post-transplantation survival was comparable in the 2 arms. Patients who resumed gilteritinib after HSCT had a low relapse rate after pretransplantation CRc (20%) or CR (0%). The most common AEs observed with post-transplantation gilteritinib therapy were increased alanine aminotransferase level (45%), pyrexia (43%), and diarrhea (40%); grade ≥3 AEs were related primarily to myelosuppression. The incidences of grade ≥III acute graft-versus-host disease and related mortality were low. Post-transplantation survival was similar across the 2 study arms in the ADMIRAL trial, but higher remission rates with gilteritinib facilitated receipt of HSCT. Gilteritinib as post-transplantation maintenance therapy had a stable safety and tolerability profile and was associated with low relapse rates. Taken together, these data support a preference for bridging therapy with gilteritinib over chemotherapy in transplantation-eligible patients., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2023
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10. Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial.
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Daver NG, Dail M, Garcia JS, Jonas BA, Yee KWL, Kelly KR, Vey N, Assouline S, Roboz GJ, Paolini S, Pollyea DA, Tafuri A, Brandwein JM, Pigneux A, Powell BL, Fenaux P, Olin RL, Visani G, Martinelli G, Onishi M, Wang J, Huang W, Green C, Ott MG, Hong WJ, Konopleva MY, and Andreeff M
- Subjects
- Humans, Core Binding Factor Alpha 2 Subunit, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Antineoplastic Agents therapeutic use
- Abstract
This phase 1b trial (NCT02670044) evaluated venetoclax-idasanutlin in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) ineligible for cytotoxic chemotherapy. Two-dimensional dose escalation (DE, n = 50) was performed for venetoclax daily with idasanutlin on days 1 to 5 in 28-day cycles, followed by dosing schedule optimization (n = 6) to evaluate reduced venetoclax schedules (21-/14-day dosing). Common adverse events (occurring in ≥40% of patients) included diarrhea (87.3% of patients), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%). During DE, across all doses, composite complete remission (CRc; CR + CR with incomplete blood count recovery + CR with incomplete platelet count recovery) rate was 26.0% and morphologic leukemia-free state (MLFS) rate was 12%. For anticipated recommended phase 2 doses (venetoclax 600 mg + idasanutlin 150 mg; venetoclax 600 mg + idasanutlin 200 mg), the combined CRc rate was 34.3% and the MLFS rate was 14.3%. Pretreatment IDH1/2 and RUNX1 mutations were associated with higher CRc rates (50.0% and 45.0%, respectively). CRc rate in patients with TP53 mutations was 20.0%, with responses noted among those with co-occurring IDH and RUNX1 mutations. In 12 out of 36 evaluable patients, 25 emergent TP53 mutations were observed; 22 were present at baseline with low TP53 variant allele frequency (median 0.0095% [range, 0.0006-0.4]). Venetoclax-idasanutlin showed manageable safety and encouraging efficacy in unfit patients with R/R AML. IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were preexisting. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations. This trial was registered at www.clinicaltrials.gov as #NCT02670044., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
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11. Biological therapy in elderly patients with acute myeloid leukemia.
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Ciotti G, Marconi G, Sperotto A, Giannini MB, Gottardi M, and Martinelli G
- Subjects
- Humans, Aged, Killer Cells, Natural, T-Lymphocytes, Tumor Microenvironment, Immunotherapy methods, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology
- Abstract
Introduction: The introduction of target molecules and immunological therapies is changing the treatment landscape of acute myeloid leukemia (AML)., Areas Covered: We recapitulate the biological therapies that can be employed in the treatment of elderly patients with AML. Alongside small molecules inhibitors that target specific gene mutations, antibodies, tumor microenvironment modulators, and cellular therapies are being developed for the cure of the disease. Here, we report the biological activities, the efficacy and toxicities of humanized antibodies and antibody-drug conjugates that targets surface antigens as CD33 (gemtuzumab ozogamicine) or CD123 (pivekimab sunirine). We further explore mechanisms and effectiveness of medications that modify the microenvironment, such as glasdegib, or that harness the immune system against leukemia, such as CD47 antibody magrolimab, PD1/PDL1 inhibitors pembrolizumab and nivolumab, TIM3 inhibitor sabatolimab, T-cell and NK-cell engagers. Cellular therapies are considered, even if a large trial is still pending for the feasibility of the approach. In this scenario, a brief overview of the mechanism of action of target agents is provided, particularly with respect to their biological mechanisms., Expert Opinion: Overall, this therapeutic armamentarium will constitute the basis for multimodal and personalized combinations that, in the idea of precision medicine, will enormously benefit elderly AML patients.
- Published
- 2023
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12. Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon.
- Author
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Ghelli Luserna di Rorà A, Jandoubi M, Martinelli G, and Simonetti G
- Subjects
- Humans, Animals, Mice, Transcription Factors metabolism, Acute Disease, Cell Cycle, Cell Division, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use, Cell Proliferation, Cell Line, Tumor, Apoptosis, DNA-Binding Proteins metabolism, Adaptor Proteins, Signal Transducing metabolism, Cell Cycle Proteins metabolism, Nuclear Proteins metabolism, Leukemia, Myeloid, Acute metabolism
- Abstract
Uncontrolled proliferative signals and cell cycle dysregulation due to genomic or functional alterations are important drivers of the expansion of undifferentiated blast cells in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cells. Therefore, they are largely studied as potential therapeutic targets in the field. We here present the most recent advancements in the evaluation of novel compounds targeting cell cycle proteins or oncogenic mechanisms, including those showing an antiproliferative effect in acute leukemia, independently of the identification of a specific target. Several new kinase inhibitors have been synthesized that showed effectiveness in a nanomolar to micromolar concentration range as inhibitors of FLT3 and its mutant forms, a highly attractive therapeutic target due to its driver role in a significant fraction of AML cases. Moreover, we introduce novel molecules functioning as microtubule-depolymerizing or P53-restoring agents, G-quadruplex-stabilizing molecules and CDK2, CHK1, PI3Kδ, STAT5, BRD4 and BRPF1 inhibitors. We here discuss their mechanisms of action, including the downstream intracellular changes induced by in vitro treatment, hematopoietic toxicity, in vivo bio-availability and efficacy in murine xenograft models. The promising activity profile demonstrated by some of these candidates deserves further development towards clinical investigation.
- Published
- 2023
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13. Idasanutlin plus cytarabine in relapsed or refractory acute myeloid leukemia: results of the MIRROS trial.
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Konopleva MY, Röllig C, Cavenagh J, Deeren D, Girshova L, Krauter J, Martinelli G, Montesinos P, Schäfer JA, Ottmann O, Petrini M, Pigneux A, Rambaldi A, Recher C, Rodriguez-Veiga R, Taussig D, Vey N, Yoon SS, Ott M, Muehlbauer S, Beckermann BM, Catalani O, Genevray M, Mundt K, Jamois C, Fenaux P, and Wei AH
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols adverse effects, Humans, Pyrrolidines, para-Aminobenzoates therapeutic use, Cytarabine, Leukemia, Myeloid, Acute
- Abstract
The phase 3 MIRROS (MDM2 antagonist Idasanutlin in Relapsed or Refractory acute myeloid leukemia [AML] for Overall Survival) trial (NCT02545283) evaluated the efficacy and safety of the small-molecule MDM2 antagonist idasanutlin plus cytarabine in patients with relapsed/refractory (R/R) AML. Adults (n = 447) with R/R AML whose disease relapsed or was refractory after ≤2 prior induction regimens as initial treatment or following salvage chemotherapy regimen, with Eastern Cooperative Oncology Group performance status ≤2 were enrolled regardless of TP53 mutation status and randomly assigned 2:1 to idasanutlin 300 mg or placebo orally twice daily plus cytarabine 1 g/m2 IV on days 1 to 5 of 28-day cycles. At primary analysis (cutoff, November 2019), 436 patients were enrolled, including 355 in the TP53 wild-type intention-to-treat (TP53WT-ITT) population. The primary endpoint, overall survival in the TP53WT-ITT population, was not met (median, 8.3 vs 9.1 months with idasanutlin-cytarabine vs placebo-cytarabine; stratified hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.81-1.45; P = .58). The complete remission (CR) rate, a key secondary endpoint, was 20.3% vs 17.1% (odds ratio [OR], 1.23; 95% CI, 0.70-2.18). The overall response rate (ORR) was 38.8% vs 22.0% (OR, 2.25; 95% CI, 1.36-3.72). Common any-grade adverse events (≥10% incidence in any arm) were diarrhea (87.0% vs 32.9%), febrile neutropenia (52.8% vs 49.3%), and nausea (52.5% vs 31.5%). In summary, despite improved ORR, adding idasanutlin to cytarabine did not improve overall survival or CR rates in patients with R/R AML., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
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14. Release of IFNγ by Acute Myeloid Leukemia Cells Remodels Bone Marrow Immune Microenvironment by Inducing Regulatory T Cells.
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Corradi G, Bassani B, Simonetti G, Sangaletti S, Vadakekolathu J, Fontana MC, Pazzaglia M, Gulino A, Tripodo C, Cristiano G, Bandini L, Ottaviani E, Ocadlikova D, Piccioli M, Martinelli G, Colombo MP, Rutella S, Cavo M, Ciciarello M, and Curti A
- Subjects
- Animals, Bone Marrow metabolism, Bone Marrow Cells, Interferon-gamma metabolism, Mice, T-Lymphocytes, Regulatory immunology, Tumor Microenvironment, Leukemia, Myeloid, Acute metabolism, Mesenchymal Stem Cells metabolism
- Abstract
Purpose: The stromal and immune bone marrow (BM) landscape is emerging as a crucial determinant for acute myeloid leukemia (AML). Regulatory T cells (Treg) are enriched in the AML microenvironment, but the underlying mechanisms are poorly elucidated. Here, we addressed the effect of IFNγ released by AML cells in BM Treg induction and its impact on AML prognosis., Experimental Design: BM aspirates from patients with AML were subdivided according to IFNG expression. Gene expression profiles in INFγhigh and IFNγlow samples were compared by microarray and NanoString analysis and used to compute a prognostic index. The IFNγ release effect on the BM microenvironment was investigated in mesenchymal stromal cell (MSC)/AML cell cocultures. In mice, AML cells silenced for ifng expression were injected intrabone., Results: IFNγhigh AML samples showed an upregulation of inflammatory genes, usually correlated with a good prognosis in cancer. In contrast, in patients with AML, high IFNG expression was associated with poor overall survival. Notably, IFNγ release by AML cells positively correlated with a higher BM suppressive Treg frequency. In coculture experiments, IFNγhigh AML cells modified MSC transcriptome by upregulating IFNγ-dependent genes related to Treg induction, including indoleamine 2,3-dioxygenase 1 (IDO1). IDO1 inhibitor abrogated the effect of IFNγ release by AML cells on MSC-derived Treg induction. In vivo, the genetic ablation of IFNγ production by AML cells reduced MSC IDO1 expression and Treg infiltration, hindering AML engraftment., Conclusions: IFNγ release by AML cells induces an immune-regulatory program in MSCs and remodels BM immunologic landscape toward Treg induction, contributing to an immunotolerant microenvironment. See related commentary by Ferrell and Kordasti, p. 2986., (©2022 American Association for Cancer Research.)
- Published
- 2022
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15. Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial.
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Perl AE, Larson RA, Podoltsev NA, Strickland S, Wang ES, Atallah E, Schiller GJ, Martinelli G, Neubauer A, Sierra J, Montesinos P, Récher C, Yoon SS, Hosono N, Onozawa M, Chiba S, Kim HJ, Hasabou N, Lu Q, Tiu R, and Levis MJ
- Subjects
- Follow-Up Studies, Humans, Mutation, Pyrazines, Recurrence, fms-Like Tyrosine Kinase 3 genetics, Aniline Compounds pharmacology, Aniline Compounds therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
The phase 3 ADMIRAL (NCT02421939; Study ID: 2215-CL-0301) trial showed superior overall survival in patients with relapsed/refractory FLT3-mutation-positive acute myeloid leukemia (AML) randomized 2:1 to receive the oral FMS-like tyrosine kinase 3 inhibitor gilteritinib vs those randomized to receive salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib in these patients with AML. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203 of 247 and 97 of 124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-treated patients remained on treatment. The median overall survival for the gilteritinib and SC arms was 9.3 and 5.6 months, respectively (hazard ratio, 0.665; 95% confidence interval [CI], 0.518, 0.853; two-sided P = .0013); 2-year estimated survival rates were 20.6% (95% CI, 15.8, 26.0) and 14.2% (95% CI, 8.3, 21.6). The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49 of 247 patients in the gilteritinib arm and 14 of 124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-treated patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (hematopoietic stem cell transplantation [HSCT]) and 16 restarted gilteritinib as post-HSCT maintenance therapy. The most common adverse events of interest during years 1 and 2 of gilteritinib therapy were increased liver transaminase levels; adverse event incidence decreased in year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival vs SC. This trial was registered at www.clinicaltrials.gov as #NCT02421939., (© 2022 by The American Society of Hematology.)
- Published
- 2022
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16. Clinical outcomes in patients with relapsed/refractory FLT3-mutated acute myeloid leukemia treated with gilteritinib who received prior midostaurin or sorafenib.
- Author
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Perl AE, Hosono N, Montesinos P, Podoltsev N, Martinelli G, Panoskaltsis N, Recher C, Smith CC, Levis MJ, Strickland S, Röllig C, Groß-Langenhoff M, Chou WC, Lee JH, Yokoyama H, Hasabou N, Lu Q, Tiu RV, and Altman JK
- Subjects
- Aniline Compounds, Humans, Mutation, Protein Kinase Inhibitors adverse effects, Pyrazines, Retrospective Studies, Sorafenib pharmacology, Sorafenib therapeutic use, Staurosporine analogs & derivatives, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, fms-Like Tyrosine Kinase 3 genetics
- Abstract
The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib is indicated for relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on its observed superior response and survival outcomes compared with salvage chemotherapy (SC). Frontline use of FLT3 tyrosine kinase inhibitors (TKIs) midostaurin and sorafenib may contribute to cross-resistance to single-agent gilteritinib in the R/R AML setting but has not been well characterized. To clarify the potential clinical impact of prior TKI use, we retrospectively compared clinical outcomes in patients with R/R FLT3-mutated AML in the CHRYSALIS and ADMIRAL trials who received prior midostaurin or sorafenib against those without prior FLT3 TKI exposure. Similarly high rates of composite complete remission (CRc) were observed in patients who received a FLT3 TKI before gilteritinib (CHRYSALIS, 42%; ADMIRAL, 52%) and those without prior FLT3 TKI therapy (CHRYSALIS, 43%; ADMIRAL, 55%). Among patients who received a prior FLT3 TKI in ADMIRAL, a higher CRc rate (52%) and trend toward longer median overall survival was observed in the gilteritinib arm versus the SC arm (CRc = 20%; overall survival, 5.1 months; HR = 0.602; 95% CI: 0.299, 1.210). Remission duration was shorter with prior FLT3 TKI exposure. These findings support gilteritinib for FLT3-mutated R/R AML after prior sorafenib or midostaurin., (© 2022. The Author(s).)
- Published
- 2022
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17. Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies.
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Padella A, Ghelli Luserna Di Rorà A, Marconi G, Ghetti M, Martinelli G, and Simonetti G
- Subjects
- Animals, Antineoplastic Agents pharmacology, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Molecular Targeted Therapy, Poly(ADP-ribose) Polymerase Inhibitors pharmacology, Poly(ADP-ribose) Polymerases genetics, Poly(ADP-ribose) Polymerases metabolism, Antineoplastic Agents therapeutic use, DNA Damage drug effects, Leukemia, Myeloid, Acute drug therapy, Poly(ADP-ribose) Polymerase Inhibitors therapeutic use
- Abstract
The members of the Poly(ADP-ribose) polymerase (PARP) superfamily are involved in several biological processes and, in particular, in the DNA damage response (DDR). The most studied members, PARP1, PARP2 and PARP3, act as sensors of DNA damages, in order to activate different intracellular repair pathways, including single-strand repair, homologous recombination, conventional and alternative non-homologous end joining. This review recapitulates the functional role of PARPs in the DDR pathways, also in relationship with the cell cycle phases, which drives our knowledge of the mechanisms of action of PARP inhibitors (PARPi), encompassing inhibition of single-strand breaks and base excision repair, PARP trapping and sensitization to antileukemia immune responses. Several studies have demonstrated a preclinical activity of the current available PARPi, olaparib, rucaparib, niraparib, veliparib and talazoparib, as single agent and/or in combination with cytotoxic, hypomethylating or targeted drugs in acute leukemia, thus encouraging the development of clinical trials. We here summarize the most recent preclinical and clinical findings and discuss the synthetic lethal interactions of PARPi in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Despite the low frequency of genomic alterations of PARP and other DDR-related genes in acute leukemia, selective vulnerabilities have been reported in several disease subgroups, along with a "BRCAness phenotype." AML carrying the RUNX1-RUNX1T1 or PML-RARA fusion genes or mutations in signaling genes (FLT3-ITD in combination with TET2 or TET2 and DNMT3A deficiency), cohesin complex members (STAG2), TP53 and BCOR as co-occurring lesions, IDH1/2 and ALL cases expressing the TCF3-HLF chimera or TET1 was highly sensitive to PARPi in preclinical studies. These data, along with the warning coming from the observation of cases of therapy-related myeloid malignancies among patients receiving PARPi for solid tumors treatment, indicate that PARPi represents a promising strategy in a personalized medicine setting. The characterization of the clonal and subclonal genetic background and of the DDR functionality is crucial to select acute leukemia patients that will likely benefit of PARPi-based therapeutic regimens., (© 2022. The Author(s).)
- Published
- 2022
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18. Genome-wide association study identifies susceptibility loci for acute myeloid leukemia.
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Lin WY, Fordham SE, Hungate E, Sunter NJ, Elstob C, Xu Y, Park C, Quante A, Strauch K, Gieger C, Skol A, Rahman T, Sucheston-Campbell L, Wang J, Hahn T, Clay-Gilmour AI, Jones GL, Marr HJ, Jackson GH, Menne T, Collin M, Ivey A, Hills RK, Burnett AK, Russell NH, Fitzgibbon J, Larson RA, Le Beau MM, Stock W, Heidenreich O, Alharbi A, Allsup DJ, Houlston RS, Norden J, Dickinson AM, Douglas E, Lendrem C, Daly AK, Palm L, Piechocki K, Jeffries S, Bornhäuser M, Röllig C, Altmann H, Ruhnke L, Kunadt D, Wagenführ L, Cordell HJ, Darlay R, Andersen MK, Fontana MC, Martinelli G, Marconi G, Sanz MA, Cervera J, Gómez-Seguí I, Cluzeau T, Moreilhon C, Raynaud S, Sill H, Voso MT, Lo-Coco F, Dombret H, Cheok M, Preudhomme C, Gale RE, Linch D, Gaal-Wesinger J, Masszi A, Nowak D, Hofmann WK, Gilkes A, Porkka K, Milosevic Feenstra JD, Kralovics R, Grimwade D, Meggendorfer M, Haferlach T, Krizsán S, Bödör C, Stölzel F, Onel K, and Allan JM
- Subjects
- Aldehyde Reductase genetics, Case-Control Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Leukemia, Myeloid, Acute mortality, Middle Aged, Reproducibility of Results, White People genetics, HLA Antigens genetics, Leukemia, Myeloid, Acute genetics, Polymorphism, Single Nucleotide
- Abstract
Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10
-8 ; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10-10 ; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA)., (© 2021. The Author(s).)- Published
- 2021
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19. Integrated genomic-metabolic classification of acute myeloid leukemia defines a subgroup with NPM1 and cohesin/DNA damage mutations.
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Simonetti G, Mengucci C, Padella A, Fonzi E, Picone G, Delpino C, Nanni J, De Tommaso R, Franchini E, Papayannidis C, Marconi G, Pazzaglia M, Perricone M, Scarpi E, Fontana MC, Bruno S, Tebaldi M, Ferrari A, Bochicchio MT, Ghelli Luserna Di Rorà A, Ghetti M, Napolitano R, Astolfi A, Baldazzi C, Guadagnuolo V, Ottaviani E, Iacobucci I, Cavo M, Castellani G, Haferlach T, Remondini D, Capozzi F, and Martinelli G
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Chromatin genetics, Female, Genomics methods, Humans, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Nucleophosmin, Prognosis, Young Adult, Cohesins, Cell Cycle Proteins genetics, Chromosomal Proteins, Non-Histone genetics, DNA Damage genetics, Leukemia, Myeloid, Acute genetics, Mutation genetics, Nuclear Proteins genetics
- Abstract
Although targeting of cell metabolism is a promising therapeutic strategy in acute myeloid leukemia (AML), metabolic dependencies are largely unexplored. We aimed to classify AML patients based on their metabolic landscape and map connections between metabolic and genomic profiles. Combined serum and urine metabolomics improved AML characterization compared with individual biofluid analysis. At intracellular level, AML displayed dysregulated amino acid, nucleotide, lipid, and bioenergetic metabolism. The integration of intracellular and biofluid metabolomics provided a map of alterations in the metabolism of polyamine, purine, keton bodies and polyunsaturated fatty acids and tricarboxylic acid cycle. The intracellular metabolome distinguished three AML clusters, correlating with distinct genomic profiles: NPM1-mutated(mut), chromatin/spliceosome-mut and TP53-mut/aneuploid AML that were confirmed by biofluid analysis. Interestingly, integrated genomic-metabolic profiles defined two subgroups of NPM1-mut AML. One was enriched for mutations in cohesin/DNA damage-related genes (NPM1/cohesin-mut AML) and showed increased serum choline + trimethylamine-N-oxide and leucine, higher mutation load, transcriptomic signatures of reduced inflammatory status and better ex-vivo response to EGFR and MET inhibition. The transcriptional differences of enzyme-encoding genes between NPM1/cohesin-mut and NPM1-mut allowed in silico modeling of intracellular metabolic perturbations. This approach predicted alterations in NAD and purine metabolism in NPM1/cohesin-mut AML that suggest potential vulnerabilities, worthy of being therapeutically explored., (© 2021. The Author(s).)
- Published
- 2021
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20. Safety of FLT3 inhibitors in patients with acute myeloid leukemia.
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Cerchione C, Peleteiro Raíndo A, Mosquera Orgueira A, Mosquera Torre A, Bao Pérez L, Marconi G, Isidori A, Pérez Encinas MM, and Martinelli G
- Subjects
- Humans, Mutation, Protein Kinase Inhibitors adverse effects, Sorafenib pharmacology, Sorafenib therapeutic use, fms-Like Tyrosine Kinase 3 genetics, Antineoplastic Agents adverse effects, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics
- Abstract
Introduction: Acute myeloblastic leukemia (AML) is the most frequent type of acute leukemia in adults with an incidence of 4.2 cases per 100,000 inhabitants and poor 5-year survival. Patients with mutations in the FMS-like tyrosine kinase 3 ( FLT3) gene have poor survival and higher relapse rates compared with wild-type cases. Areas covered: Several FLT3 inhibitors have been proved in FLT3
mut AML patients, with differences in their pharmacokinetics, kinase inhibitory and adverse events profiles. First-generation multi-kinase inhibitors (midostaurin, sorafenib, lestaurtinib) target multiple proteins, whereassecond-generation inhibitors (crenolanib, quizartinib, gilteritinib) are more specific and potent inhibitors of FLT3, so they are associated with less off-target toxic effects. All of these drugs have primary and acquired mechanisms of resistance, and therefore their combinations with other drugs (checkpoint inhibitors, hypomethylating agents, standard chemotherapy) and its application in different clinical settings are under study. Expert opinion: The recent clinical development of various FLT3 inhibitors for the treatment of FLT3mut AML is an effective therapeutic strategy. However, there are unique toxicities and drug-drug interactions that need to be resolved. It is necessary to understand the mechanisms of toxicity in order to recognize and manage them adequately.- Published
- 2021
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21. The safety profile of FLT3 inhibitors in the treatment of newly diagnosed or relapsed/refractory acute myeloid leukemia.
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Marconi G, Giannini MB, Bagnato G, Simonetti G, Cerchione C, Mosquera Orgueira A, Musuraca G, and Martinelli G
- Subjects
- Aniline Compounds administration & dosage, Aniline Compounds adverse effects, Aniline Compounds pharmacology, Antineoplastic Agents administration & dosage, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacology, Benzothiazoles administration & dosage, Benzothiazoles adverse effects, Benzothiazoles pharmacology, Humans, Leukemia, Myeloid, Acute enzymology, Leukemia, Myeloid, Acute pathology, Phenylurea Compounds administration & dosage, Phenylurea Compounds adverse effects, Phenylurea Compounds pharmacology, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors pharmacology, Pyrazines administration & dosage, Pyrazines adverse effects, Pyrazines pharmacology, Randomized Controlled Trials as Topic, Staurosporine administration & dosage, Staurosporine adverse effects, Staurosporine analogs & derivatives, Staurosporine pharmacology, Leukemia, Myeloid, Acute drug therapy, Protein Kinase Inhibitors administration & dosage, fms-Like Tyrosine Kinase 3 antagonists & inhibitors
- Abstract
Introduction: FLT3 inhibitors are important drugs in the therapy of FLT3 positive acute myeloid leukemia (AML). Midostaurin was registered in combination with chemotherapy to treat newly diagnosed AML. Gilteritinib and quizartinib demonstrate effectiveness in a randomized trial in relapsed/refractory AML. Several promising FLT3 inhibitors are being evaluated in clinical research., Areas Covered: This review will report the safety of FLT3 inhibitors that are registered for acute myeloid leukemia induction and rescue therapy., Expert Opinion: In the near future, it is possible that all the FLT3 positive non M3-AML patients will receive a FLT3 inhibitor. Therapy adherence and strategies to mitigate adverse events must be pursued. The treatment with FLT3 inhibitors may be optimized in terms of toxicities with a rational evaluation of antifungal prophylaxis and concomitant therapy, cardiology monitoring, and keeping in mind rare adverse events. Future studies on unfit patients, special populations, and maintenance settings are warranted, together with post-market studies and real-life experiences. Whenever new FLT3 inhibitors will come to the clinic, we could face a scenario in which profound knowledge of effectiveness, toxicities, and off-target effects will be relevant to choose the best drug for each patient.
- Published
- 2021
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22. Concentration-QTc analysis of quizartinib in patients with relapsed/refractory acute myeloid leukemia.
- Author
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Kang D, Ludwig E, Jaworowicz D, Huang H, Fiedler-Kelly J, Cortes J, Ganguly S, Khaled S, Krämer A, Levis M, Martinelli G, Perl A, Russell N, Abutarif M, Choi Y, and Yin O
- Subjects
- Adult, Aged, Aged, 80 and over, Benzothiazoles therapeutic use, Cytochrome P-450 CYP3A Inhibitors pharmacology, Dose-Response Relationship, Drug, Female, Humans, Male, Middle Aged, Phenylurea Compounds therapeutic use, Benzothiazoles pharmacology, Electrocardiography drug effects, Leukemia, Myeloid, Acute drug therapy, Phenylurea Compounds pharmacology
- Abstract
Purpose: This analysis evaluated the relationship between concentrations of quizartinib and its active metabolite AC886 and QT interval corrected using Fridericia's formula (QTcF) in patients with relapsed/refractory acute myeloid leukemia (AML) treated in the phase 3 QuANTUM-R study (NCT02039726)., Methods: The analysis dataset included 226 patients with AML. Quizartinib dihydrochloride was administered as daily doses of 20, 30, and 60 mg. Nonlinear mixed-effects modeling was performed using observed quizartinib and AC886 concentrations and time-matched mean electrocardiogram measurements., Results: Observed QTcF increased with quizartinib and AC886 concentrations; the relationship was best described by a nonlinear maximum effect (E
max ) model. The predicted mean increase in QTcF at the maximum concentration of quizartinib and AC886 associated with 60 mg/day was 21.1 ms (90% CI, 18.3-23.6 ms). Age, body weight, sex, race, baseline QTcF, QT-prolonging drug use, hypomagnesemia, and hypocalcemia were not significant predictors of QTcF. Hypokalemia (serum potassium < 3.5 mmol/L) was a statistically significant covariate affecting baseline QTcF, but no differences in ∆QTcF (change in QTcF from baseline) were predicted between patients with versus without hypokalemia at the same quizartinib concentration. The use of concomitant QT-prolonging drugs did not increase QTcF further., Conclusion: QTcF increase was dependent on quizartinib and AC886 concentrations, but patient factors, including sex and age, did not affect the concentration-QTcF relationship. Because concomitant strong cytochrome P450 3A (CYP3A) inhibitor use significantly increases quizartinib concentration, these results support the clinical recommendation of quizartinib dose reduction in patients concurrently receiving a strong CYP3A inhibitor., Clinical Trial Registration: NCT02039726 (registered January 20, 2014).- Published
- 2021
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23. Gene expression profiling identifies FLT3 mutation-like cases in wild-type FLT3 acute myeloid leukemia.
- Author
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Mosquera Orgueira A, Peleteiro Raíndo A, Cid López M, Antelo Rodríguez B, Díaz Arias JÁ, Ferreiro Ferro R, Alonso Vence N, Bendaña López Á, Abuín Blanco A, Bao Pérez L, Melero Valentín P, González Pérez MS, Cerchione C, Martinelli G, Montesinos Fernández P, Pérez Encinas MM, and Bello López JL
- Subjects
- Biomarkers metabolism, DNA (Cytosine-5-)-Methyltransferases genetics, DNA Methyltransferase 3A, Gene Expression Profiling methods, Humans, Nuclear Proteins genetics, Nucleophosmin, Staurosporine analogs & derivatives, Staurosporine pharmacology, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, Leukemia genetics, Leukemia, Myeloid, Acute genetics, Mutation genetics, fms-Like Tyrosine Kinase 3 genetics
- Abstract
Background: FLT3 mutation is present in 25-30% of all acute myeloid leukemias (AML), and it is associated with adverse outcome. FLT3 inhibitors have shown improved survival results in AML both as upfront treatment and in relapsed/refractory disease. Curiously, a variable proportion of wild-type FLT3 patients also responded to these drugs., Methods: We analyzed 6 different transcriptomic datasets of AML cases. Differential expression between mutated and wild-type FLT3 AMLs was performed with the Wilcoxon-rank sum test. Hierarchical clustering was used to identify FLT3-mutation like AMLs. Finally, enrichment in recurrent mutations was performed with the Fisher's test., Results: A FLT3 mutation-like gene expression pattern was identified among wild-type FLT3 AMLs. This pattern was highly enriched in NPM1 and DNMT3A mutants, and particularly in combined NPM1/DNMT3A mutants., Conclusions: We identified a FLT3 mutation-like gene expression pattern in AML which was highly enriched in NPM1 and DNMT3A mutations. Future analysis about the predictive role of this biomarker among wild-type FLT3 patients treated with FLT3 inhibitors is envisaged., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2021
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24. Clinical Outcomes in Patients with FLT3-ITD-Mutated Relapsed/Refractory Acute Myelogenous Leukemia Undergoing Hematopoietic Stem Cell Transplantation after Quizartinib or Salvage Chemotherapy in the QuANTUM-R Trial.
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Ganguly S, Cortes JE, Krämer A, Levis MJ, Martinelli G, Perl AE, Russell NH, Arunachalam M, Santos CD, Gammon G, Lesegretain A, Mires DE, Pham H, Wang Y, and Khaled SK
- Subjects
- Benzothiazoles, Humans, Phenylurea Compounds, fms-Like Tyrosine Kinase 3 genetics, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy
- Abstract
Despite the substantial clinical activity of fms-related tyrosine kinase 3 (FLT3) inhibitors in relapsed or refractory (R/R) FLT3-ITD‒positive acute myelogenous leukemia (AML), durable remissions and prolonged survival in this population require allogeneic hematopoietic stem cell transplantation (allo-HSCT). Quizartinib, a once-daily oral, highly potent, and selective FLT3 inhibitor, significantly prolonged overall survival (OS) and improved clinical benefit compared with salvage chemotherapy (median OS, 6.2 months versus 4.7 months; hazard ratio [HR], .76; 95% confidence interval [CI], .58 to .98; P = .018; composite complete remission [CRc] rate, 48% versus 27%; median duration of CRc, 2.8 months versus 1.2 months; mortality rate, .8% versus 14% by day 30, 7% versus 24% by day 60) in patients with R/R FLT3-ITD AML in the phase 3 QuANTUM-R trial. In this post hoc analysis, we described the characteristics of and clinical outcomes in patients who underwent on-study HSCT in QuANTUM-R at the investigator's discretion and institutional practices. Of 367 randomized patients, 78 (32%) in the quizartinib arm and 14 (11%) in the salvage chemotherapy arm underwent on-study allo-HSCT without any intervening therapy for AML after quizartinib or study-specified salvage chemotherapy. Pooled data of patients from both treatment arms showed a longer median overall survival (OS) in transplant recipients versus those treated without allo-HSCT (12.2 months versus 4.4 months; HR, .315; 95% CI, .233 to .427). Pooled data also showed a longer median OS in patients with a last recorded response of CRc before allo-HSCT versus patients without a CRc (20.1 months versus 8.8 months; HR, .506; 95% CI, .296 to .864). By treatment arm, the median OS was 25.1 months with quizartinib and 20.1 months with salvage chemotherapy in patients with a last recorded response of CRc before allo-HSCT. Forty-eight patients in the quizartinib arm continued quizartinib treatment after allo-HSCT. In the 31 patients with a last recorded response of CRc before allo-HSCT who continued quizartinib after allo-HSCT, the median OS was 27.1 months. Continuation of quizartinib after allo-HSCT was tolerable, and no new safety signals were identified. These results suggest that post-transplantation survival following salvage chemotherapy and quizartinib treatment are similar. However, quizartinib response occurs more frequently than with salvage chemotherapy, potentially allowing more patients to undergo transplantation and achieve durable clinical benefit. In addition, post-transplant quizartinib was found to be tolerable and may be associated with prolonged survival in some patients, highlighting its potential value in the management of patients with FLT3-ITD R/R AML., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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25. Safety profile and impact on survival of tyrosine kinase inhibitors versus conventional therapy in relapse or refractory FLT3 positive acute myeloid leukemia patients.
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Marconi G, De Polo S, Martinelli G, Nanni J, Bertamini L, Talami A, Olivi M, Ragaini S, Abbenante MC, Sartor C, Ottaviani E, Bochicchio MT, Parisi S, Fontana MC, Cristiano G, Raffini M, Baldazzi C, Testoni N, Bonifazi F, Paolini S, Curti A, Cavo M, and Papayannidis C
- Subjects
- Adolescent, Adult, Aged, Disease-Free Survival, Female, Humans, Male, Middle Aged, Survival Rate, Antineoplastic Agents administration & dosage, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute enzymology, Leukemia, Myeloid, Acute genetics, Mutation, Protein Kinase Inhibitors administration & dosage, Quality of Life, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, fms-Like Tyrosine Kinase 3 genetics, fms-Like Tyrosine Kinase 3 metabolism
- Abstract
Relapsed or refractory (R/R) acute myeloid leukemia (AML) has a poor prognosis, and new therapies are a major clinical need. When mutated, FLT3 drives neoplastic cell proliferation. New drugs (i.e., tyrosine kinase inhibitors, TKIs) showed effectiveness in FLT3-AML and promise to change disease history and outcome. We evaluated the benefit conferred by TKIs in terms of survival, burden of complications and surrogate endpoint of quality of life in a retrospective cohort of 49 FLT3 positive, R/R AML patients. Patients who received TKIs were compared to those treated with conventional chemotherapy. Treatment with TKIs conferred a better OS and wea associated with a lower burden and severity of adverse events. Importantly, patients who received TKIs showed reduced time of hospitalization. In conclusion, treatment with TKI in R/R FLT3-AML was related to a better survival, less and milder AEs, and shorter hospitalization., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Published
- 2021
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26. Loss of PALB2 predicts poor prognosis in acute myeloid leukemia and suggests novel therapeutic strategies targeting the DNA repair pathway.
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Padella A, Fontana MC, Marconi G, Fonzi E, Petracci E, Ferrari A, Baldazzi C, Papayannidis C, Ghelli Luserna Di Rorá A, Testoni N, Castellani G, Haferlach T, Martinelli G, and Simonetti G
- Subjects
- Adult, Aged, Aged, 80 and over, Female, Gene Deletion, Humans, Leukemia, Myeloid, Acute diagnosis, Male, Middle Aged, Polymorphism, Single Nucleotide, Prognosis, Young Adult, DNA Repair, Fanconi Anemia Complementation Group N Protein genetics, Leukemia, Myeloid, Acute genetics
- Published
- 2021
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27. Murine double minute 2 inhibition alone or with cytarabine in acute myeloid leukemia: Results from an idasanutlin phase 1/1b study⋆.
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Yee K, Papayannidis C, Vey N, Dickinson MJ, Kelly KR, Assouline S, Kasner M, Seiter K, Drummond MW, Yoon SS, Lee JH, Blotner S, Jukofsky L, Pierceall WE, Zhi J, Simon S, Higgins B, Nichols G, Monnet A, Muehlbauer S, Ott M, Chen LC, and Martinelli G
- Subjects
- Adult, Aged, Aged, 80 and over, Cytarabine administration & dosage, Female, Follow-Up Studies, Humans, Leukemia, Myeloid, Acute pathology, Male, Maximum Tolerated Dose, Middle Aged, Prognosis, Pyrrolidines administration & dosage, Remission Induction, Tissue Distribution, Young Adult, para-Aminobenzoates administration & dosage, Antineoplastic Combined Chemotherapy Protocols pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy, Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors
- Abstract
The prognosis remains poor for patients with relapsed or refractory (r/r) acute myeloid leukemia; thus, novel therapies are needed. We evaluated idasanutlin-a new, potent murine double minute 2 antagonist-alone or with cytarabine in patients with r/r acute myeloid leukemia, de novo untreated acute myeloid leukemia unsuitable for standard treatment or with adverse features, or secondary acute myeloid leukemia in a multicenter, open-label, phase 1/1b trial. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) and characterize the safety profile of idasanutlin monotherapy and combination therapy. Clinical activity and pharmacokinetics were secondary objectives. Two idasanutlin formulations were investigated: a microprecipitate bulk powder (MBP) and optimized spray-dried powder (SDP). Following dose escalation, patients (N = 122) received idasanutlin at the RDE in the extension cohorts. No formal MTD was identified. Idasanutlin was tolerable alone and in combination with cytarabine. The RDE was determined as 600 mg twice a day for the MBP formulation and 300 mg twice a day for the SDP formulation. Adverse events were mostly grade 1/2 (76.2 %). The most common any-grade adverse events were gastrointestinal (including diarrhea [90.2 %]). The early death rate across all patients was 14.8 %. Plasma idasanutlin exposure was dose related. In TP53 wild-type patients, composite complete remission rates were 18.9 % with monotherapy and 35.6 % with combination therapy. Based on these results, idasanutlin development continued with further investigation in the treatment of acute myeloid leukemia. ClinicalTrials.gov: NCT01773408., (Copyright © 2020. Published by Elsevier Ltd.)
- Published
- 2021
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28. Mutant Isocitrate Dehydrogenase 1 Inhibitor Ivosidenib in Combination With Azacitidine for Newly Diagnosed Acute Myeloid Leukemia.
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DiNardo CD, Stein AS, Stein EM, Fathi AT, Frankfurt O, Schuh AC, Döhner H, Martinelli G, Patel PA, Raffoux E, Tan P, Zeidan AM, de Botton S, Kantarjian HM, Stone RM, Frattini MG, Lersch F, Gong J, Gianolio DA, Zhang V, Franovic A, Fan B, Goldwasser M, Daigle S, Choe S, Wu B, Winkler T, and Vyas P
- Subjects
- Aged, Aged, 80 and over, Apoptosis drug effects, Drug Therapy, Combination, Female, Glycine administration & dosage, Humans, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute genetics, Male, Middle Aged, Azacitidine administration & dosage, Enzyme Inhibitors administration & dosage, Glycine analogs & derivatives, Leukemia, Myeloid, Acute drug therapy, Pyridines administration & dosage
- Abstract
Purpose: Ivosidenib is an oral inhibitor of the mutant isocitrate dehydrogenase 1 (IDH1) enzyme, approved for treatment of IDH1 -mutant (m IDH1 ) acute myeloid leukemia (AML). Preclinical work suggested that addition of azacitidine to ivosidenib enhances mIDH1 inhibition-related differentiation and apoptosis., Patients and Methods: This was an open-label, multicenter, phase Ib trial comprising dose-finding and expansion stages to evaluate safety and efficacy of combining oral ivosidenib 500 mg once daily continuously with subcutaneous azacitidine 75 mg/m
2 on days 1-7 in 28-day cycles in patients with newly diagnosed m IDH1 AML ineligible for intensive induction chemotherapy (ClinicalTrials.gov identifier: NCT02677922)., Results: Twenty-three patients received ivosidenib plus azacitidine (median age, 76 years; range, 61-88 years). Treatment-related grade ≥ 3 adverse events occurring in > 10% of patients were neutropenia (22%), anemia (13%), thrombocytopenia (13%), and electrocardiogram QT prolongation (13%). Adverse events of special interest included all-grade IDH differentiation syndrome (17%), all-grade electrocardiogram QT prolongation (26%), and grade ≥ 3 leukocytosis (9%). Median treatment duration was 15.1 months (range, 0.3-32.2 months); 10 patients remained on treatment as of February 19, 2019. The overall response rate was 78.3% (18/23 patients; 95% CI, 56.3% to 92.5%), and the complete remission rate was 60.9% (14/23 patients; 95% CI, 38.5% to 80.3%). With median follow-up of 16 months, median duration of response in responders had not been reached. The 12-month survival estimate was 82.0% (95% CI, 58.8% to 92.8%). m IDH1 clearance in bone marrow mononuclear cells by BEAMing (beads, emulsion, amplification, magnetics) digital polymerase chain reaction was seen in 10/14 patients (71.4%) achieving complete remission., Conclusion: Ivosidenib plus azacitidine was well tolerated, with an expected safety profile consistent with monotherapy with each agent. Responses were deep and durable, with most complete responders achieving m IDH1 mutation clearance.- Published
- 2021
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29. Population Pharmacokinetic Analysis of Quizartinib in Healthy Volunteers and Patients With Relapsed/Refractory Acute Myeloid Leukemia.
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Kang D, Ludwig E, Jaworowicz D, Huang H, Fiedler-Kelly J, Cortes J, Ganguly S, Khaled S, Krämer A, Levis M, Martinelli G, Perl A, Russell N, Abutarif M, Choi Y, Mendell J, and Yin O
- Subjects
- Administration, Oral, Adolescent, Adult, Aged, Aged, 80 and over, Area Under Curve, Benzothiazoles administration & dosage, Benzothiazoles metabolism, Body Surface Area, Clinical Trials as Topic, Cytochrome P-450 CYP3A Inhibitors administration & dosage, Cytochrome P-450 CYP3A Inhibitors pharmacology, Drug Interactions, Female, Healthy Volunteers, Humans, Male, Middle Aged, Phenylurea Compounds administration & dosage, Phenylurea Compounds metabolism, Protein Kinase Inhibitors administration & dosage, Protein Kinase Inhibitors metabolism, Young Adult, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, Benzothiazoles pharmacokinetics, Leukemia, Myeloid, Acute drug therapy, Phenylurea Compounds pharmacokinetics, Protein Kinase Inhibitors pharmacokinetics
- Abstract
Quizartinib is an FMS-like tyrosine kinase 3 (FLT3) inhibitor that has shown robust clinical activity in patients with FLT3-internal tandem duplication-mutated relapsed/refractory acute myeloid leukemia (AML). This analysis evaluated the population pharmacokinetics (PK) of quizartinib and its active metabolite, AC886, in a pooled analysis of data from 649 healthy volunteers or patients with AML from 8 clinical trials including the phase 3 QuANTUM-R study. Quizartinib was given as a single dose or multiple once-daily doses of 20, 30, 60, or 90 mg. Nonlinear mixed-effects modeling was performed using observed concentrations of quizartinib and AC886. Strong CYP3A inhibitor use resulted in an 82% increase in the area under the curve (AUC) and a 72% increase in the maximum concentration (C
max ) of quizartinib. Albumin level, age, and body surface area were statistically significant covariates on quizartinib PK. However, their individual effects on quizartinib AUC and Cmax were <20%. For AC886, strong CYP3A inhibitor use, body surface area and black/African American race were significant covariates. Except for strong CYP3A inhibitor use, the effects on the overall exposure (AUC of quizartinib + AC886) were <20%. The population PK model provided an adequate description of the observed concentrations of quizartinib and AC886 in both healthy volunteers and patients with AML. Only concomitant use of strong CYP3A inhibitors had a clinically meaningful effect on quizartinib PK exposure., (© 2020 Daiichi Sankyo, Inc. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)- Published
- 2020
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30. CPX-351 daunorubicin-cytarabine liposome: a novel formulation to treat patients with newly diagnosed secondary acute myeloid leukemia.
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Cafaro A, Giannini MB, Silimbani P, Cangini D, Masini C, Ghelli Luserna Di Rorà A, Simonetti G, Martinelli G, and Cerchione C
- Subjects
- Age Factors, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic pharmacokinetics, Clinical Trials as Topic, Cytarabine administration & dosage, Cytarabine pharmacokinetics, Daunorubicin administration & dosage, Daunorubicin pharmacokinetics, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Liposomes, Middle Aged, Mutation, Myelodysplastic Syndromes complications, Antimetabolites, Antineoplastic pharmacology, Cytarabine pharmacology, Daunorubicin pharmacology, Leukemia, Myeloid, Acute drug therapy
- Abstract
Over the last few years, we assisted to an increasing knowledge about acute myeloid leukemia (AML) pathobiology. However, outcomes remain unsatisfactory particularly for adult patients over 60 years old. Not surprisingly several cases of therapy-related AML (tAML) and secondary AML, both characterized by poorer prognosis, are more common in older population. For several decades initial therapy for AML remained unchanged and typically treatment consisted of an anthracycline combined with continuous infusion of cytarabine for 7 days, the so-called "7+3" standard regimen. The efforts made by the researchers to improve this standard schedule, have led to only modest improvement in the response rate (RR) but no change in overall survival (OS), until the recent evolution seen with new target specific mutation therapies. In 2017, a new liposomal-encapsulated formulation with daunorubicin and cytarabine (CPX-351) was approved by the US Food and Drug Administration for the treatment of newly diagnosed tAML or AML with myelodysplasia-related changes (AML-MRCs). Based on the findings that ratiometric delivery may be more effective than administration of either drug at their maximum tolerated dose (MTD), CPX-351 was designed to deliver a fixed 5:1 molar ratio of the two molecules historically used in the standard "7+3" regimen, cytarabine and daunorubicin respectively. CPX-351 did show improvements of overall survival compared to traditional "7+3" in newly diagnosed secondary and therapy-related AML in adult patients. However, questions remain regarding how to select across AML patient subgroups to maximize the clinical benefit. Possible future directions include evaluating CPX-351 dose intensification, combining this liposomal formulation with targeted therapies and not least important a better understanding about the mechanism of improved responses in tAML and AML-MRC, two entities recognized to be less chemo-sensitive than other hematologic malignancies. In summary, CPX-351 offers finally something new in the landscape of AML therapy. Herein we will review the rationale behind this new drug product development, the main pharmacological characteristics, and discuss the results of clinical trials that led to its FDA approval at first and by EMA in 2018.
- Published
- 2020
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31. Kevetrin induces apoptosis in TP53 wild‑type and mutant acute myeloid leukemia cells.
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Napolitano R, De Matteis S, Carloni S, Bruno S, Abbati G, Capelli L, Ghetti M, Bochicchio MT, Liverani C, Mercatali L, Calistri D, Cuneo A, Menon K, Musuraca G, Martinelli G, and Simonetti G
- Subjects
- Aged, Aged, 80 and over, Annexin A5 genetics, Apoptosis drug effects, Cell Cycle drug effects, Female, Gene Expression Regulation, Leukemic drug effects, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, Mutation drug effects, Primary Cell Culture, Antineoplastic Agents pharmacology, Cell Proliferation drug effects, Leukemia, Myeloid, Acute drug therapy, Tumor Suppressor Protein p53 genetics
- Abstract
Tumor protein p53 is a key regulator of several cellular pathways, including DNA repair, cell cycle and angiogenesis. Kevetrin exhibits p53‑dependent as well as‑independent activity in solid tumors, while its effects on leukemic cells remain unknown. The aim of the present study was to analyze the response of acute myeloid leukemia (AML) cell lines (TP53 wild‑type: OCI‑AML3 and MOLM‑13; and TP53‑mutant: KASUMI‑1 and NOMO‑1) to kevetrin at a concentration range of 85‑340 µM. The cellular and molecular effects of the treatment were analyzed in terms of cell growth, viability [Annexin V‑propidium iodide (PI) staining] and cell cycle alterations (PI staining). Gene expression profiling, western blotting and immunofluorescence were performed to elucidate the pathways underlying kevetrin activity. Pulsed exposure exerted no effect on the wild‑type cells, but was effective on mutant cells. After continuous treatment, significant cell growth arrest and apoptosis were observed in all cell lines, with TP53‑mutant models displaying a higher sensitivity and p53 induction. Kevetrin also displayed efficacy against TP53 wild‑type and mutant primary AML, with a preferential cytotoxic activity against blast cells. Gene expression profiling revealed a common core transcriptional program altered by drug exposure and the downregulation of glycolysis, DNA repair and unfolded protein response signatures. These findings suggest that kevetrin may be a promising therapeutic option for patients with both wild‑type and TP53‑mutant AML.
- Published
- 2020
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32. Enasidenib and ivosidenib in AML.
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Martelli MP, Martino G, Cardinali V, Falini B, Martinelli G, and Cerchione C
- Subjects
- Aminopyridines adverse effects, Antineoplastic Agents adverse effects, Cell Differentiation drug effects, Clinical Trials as Topic, Glutarates metabolism, Glycine adverse effects, Glycine therapeutic use, Humans, Isocitrate Dehydrogenase genetics, Isocitrate Dehydrogenase metabolism, Isocitrates metabolism, Ketoglutaric Acids metabolism, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute metabolism, Leukemia, Myeloid, Acute pathology, Multicenter Studies as Topic, Mutation, Missense, NADP biosynthesis, Pyridines adverse effects, Syndrome, Triazines adverse effects, Aminopyridines therapeutic use, Antineoplastic Agents therapeutic use, Glycine analogs & derivatives, Isocitrate Dehydrogenase antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Pyridines therapeutic use, Triazines therapeutic use
- Abstract
The isocitrate dehydrogenases enzymes, IDH1 and IDH2, catalyze the conversion of isocitrate to α-ketoglutarate (αKG) in the cell cytoplasm and mitochondria, respectively, and contribute to generating the dihydronicotinamide-adenine dinucleotide phosphate (NADPH) as reductive potential in different cellular processes. Mutations in IDH1 and IDH2 genes are found collectively in about 20-25% of acute myeloid leukemia (AML) patients. Mutant IDH enzymes have neomorphic activity and convert αKG to the oncometabolite R-2-hydroxyglutarate (R-2-HG) which accumulates at high levels in the cell and hampers the function of αKG-dependent enzymes, including epigenetic regulators, thus leading to altered gene expression and block of differentiation and contributing to leukemia development. Inhibition of the neomorphic mutants induces marked decrease in R-2-HG levels and restores myeloid differentiation. Enasidenib and ivosidenib are potent and selective inhibitors of mutant IDH2 and IDH1, respectively, act as differentiating agents and showed clinical activity in relapsed/refractory (R/R) AML harboring the specific mutation. As single agents, both drugs have been approved by the Food and Drug Administration (FDA) for the treatment of R/R AML. The relevance of IDH targeting within either single agent approach or, most importantly, combinatorial treatments in AML will be discussed.
- Published
- 2020
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33. Current strategies for detection and approach to measurable residual disease in acute myeloid leukemia.
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Palmieri R, Buccisano F, Maurillo L, Del Principe MI, Paterno G, Venditti A, Martinelli G, and Cerchione C
- Subjects
- Chromosome Aberrations, Core Binding Factor Alpha 2 Subunit genetics, High-Throughput Nucleotide Sequencing, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute therapy, Mutation, Neoplasm, Residual, Nuclear Proteins genetics, Nucleophosmin, Oncogene Proteins, Fusion genetics, Prognosis, RUNX1 Translocation Partner 1 Protein genetics, Recurrence, Remission Induction, Sensitivity and Specificity, Flow Cytometry methods, Leukemia, Myeloid, Acute diagnosis, Reverse Transcriptase Polymerase Chain Reaction methods
- Abstract
Baseline cytogenetic/genetic features have been widely recognized to play a critical prognostic role in acute myeloid leukemia (AML) and have proven useful in designing risk-adapted treatment strategies. Nevertheless, to improve further the outcome of AML patients we are still in need of accurate methods to explore the quality of response and to adequately discriminate patients who are likely to relapse over time from those who are in deep and stable remission. In this view, is it well established that measurement of leukemic cells surviving chemotherapy (called measurable residual disease, MRD) during the course of treatment may be a reliable biomarker in predicting relapse. Detection of MRD relies on highly sensitive techniques, such as quantitative polymerase chain reaction and multiparametric flow cytometry, which, due to their levels of specificity and sensitivity, are increasingly included in the decision-making process of AML treatment. In the present manuscript, we will review the current techniques of MRD investigation and their clinical contribution to AML management.
- Published
- 2020
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34. FLT3 inhibitors in the treatment of acute myeloid leukemia: current status and future perspectives.
- Author
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Mosquera Orgueira A, Bao Pérez L, Mosquera Torre A, Peleteiro Raíndo A, Cid López M, Díaz Arias JÁ, Ferreiro Ferro R, Antelo Rodríguez B, González Pérez MS, Albors Ferreiro M, Alonso Vence N, Pérez Encinas MM, Bello López JL, Martinelli G, and Cerchione C
- Subjects
- Aniline Compounds pharmacology, Benzimidazoles pharmacology, Benzothiazoles pharmacology, Carbazoles pharmacology, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Forecasting, Furans, Hematopoietic Stem Cell Transplantation, Humans, Imidazoles pharmacology, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Maintenance Chemotherapy methods, Mutation, Phenylurea Compounds pharmacology, Piperidines pharmacology, Point Mutation, Pyrazines pharmacology, Pyridazines pharmacology, Recurrence, Staurosporine analogs & derivatives, Staurosporine pharmacology, Antineoplastic Agents pharmacology, Leukemia, Myeloid, Acute drug therapy, Protein Kinase Inhibitors pharmacology, Sorafenib pharmacology, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, fms-Like Tyrosine Kinase 3 genetics
- Abstract
Mutations in the FMS-like tyrosine kinase 3 (FLT3) gene arise in 25-30% of all acute myeloid leukemia (AML) patients. These mutations lead to constitutive activation of the protein product and are divided in two broad types: internal tandem duplication (ITD) of the juxtamembrane domain (25% of cases) and point mutations in the tyrosine kinase domain (TKD). Patients with FLT3 ITD mutations have a high relapse risk and inferior cure rates, whereas the role of FLT3 TKD mutations still remains to be clarified. Additionally, growing research indicates that FLT3 status evolves through a disease continuum (clonal evolution), where AML cases can acquire FLT3 mutations at relapse - not present in the moment of diagnosis. Several FLT3 inhibitors have been tested in patients with FLT3-mutated AML. These drugs exhibit different kinase inhibitory profiles, pharmacokinetics and adverse events. First-generation multi-kinase inhibitors (sorafenib, midostaurin, lestaurtinib) are characterized by a broad-spectrum of drug targets, whereas second-generation inhibitors (quizartinib, crenolanib, gilteritinib) show more potent and specific FLT3 inhibition, and are thereby accompanied by less toxic effects. Notwithstanding, all FLT3 inhibitors face primary and acquired mechanisms of resistance, and therefore the combinations with other drugs (standard chemotherapy, hypomethylating agents, checkpoint inhibitors) and its application in different clinical settings (upfront therapy, maintenance, relapsed or refractory disease) are under study in a myriad of clinical trials. This review focuses on the role of FLT3 mutations in AML, pharmacological features of FLT3 inhibitors, known mechanisms of drug resistance and accumulated evidence for the use of FLT3 inhibitors in different clinical settings.
- Published
- 2020
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35. Gemtuzumab ozogamicin in acute myeloid leukemia: past, present and future.
- Author
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Gottardi M, Sperotto A, Ghelli Luserna Di Rorà A, Padella A, Cangini D, Giannini MB, Simonetti G, Martinelli G, and Cerchione C
- Subjects
- Aged, Animals, Antineoplastic Agents therapeutic use, Antineoplastic Agents, Immunological adverse effects, Antineoplastic Agents, Immunological pharmacokinetics, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Arsenicals therapeutic use, Calicheamicins metabolism, Chlorides therapeutic use, Clinical Trials as Topic, Cytarabine administration & dosage, Daunorubicin administration & dosage, Daunorubicin adverse effects, Drug Approval, Drug Evaluation, Preclinical, Drug Resistance, Neoplasm, Gemtuzumab adverse effects, Gemtuzumab pharmacokinetics, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute immunology, Leukemia, Promyelocytic, Acute drug therapy, Leukemia, Promyelocytic, Acute genetics, Mice, Middle Aged, Multicenter Studies as Topic, Recurrence, Sialic Acid Binding Ig-like Lectin 3 genetics, Sialic Acid Binding Ig-like Lectin 3 metabolism, Tretinoin therapeutic use, Antineoplastic Agents, Immunological therapeutic use, Gemtuzumab therapeutic use, Leukemia, Myeloid, Acute drug therapy, Sialic Acid Binding Ig-like Lectin 3 antagonists & inhibitors
- Abstract
After being in the therapeutic wilderness for several decades, acute myeloid leukemia has been recently thrust into the limelight with a series of drug approvals. Technical refinements in production, genetic manipulation and chemical modification of monoclonal antibodies led to growing interest in antibodies-based treatment strategies. Much of the focus of these efforts in acute myeloid leukemia has been on CD33 as a target. On September 2, 2017, the U.S. Food and Drug Administration approved gemtuzumab ozogamicin for treatment of relapsed or refractory CD33
+ acute myeloid leukemia. This signals a new chapter in the long and unusual story of gemtuzumab ozogamicin, which was the first antibody-drug conjugate approved for human use by the Food and Drug Administration. In this review we have analyzed the history of this drug which, among several mishaps, is experiencing a second youth and still represents a field to be further explored.- Published
- 2020
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36. Midostaurin in acute myeloid leukemia: current evidence and practical considerations in routine clinical use.
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Abdul-Hamil NA, Wong GC, Nagarajan C, Martinelli G, and Cherchione C
- Subjects
- Aniline Compounds therapeutic use, Anthracyclines therapeutic use, Antifungal Agents therapeutic use, Antineoplastic Agents metabolism, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Clinical Trials as Topic, Cytarabine therapeutic use, Cytochrome P-450 CYP3A Inhibitors pharmacology, Drug Interactions, Echinocandins therapeutic use, Forecasting, Hematopoietic Stem Cell Transplantation, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy, Maintenance Chemotherapy, Mutation, Mycoses prevention & control, Protein Kinase Inhibitors metabolism, Pyrazines therapeutic use, Randomized Controlled Trials as Topic, Recurrence, Staurosporine metabolism, Staurosporine therapeutic use, Triazoles therapeutic use, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute drug therapy, Protein Kinase Inhibitors therapeutic use, Staurosporine analogs & derivatives, fms-Like Tyrosine Kinase 3 genetics
- Abstract
Mutation within the FMS-like tyrosine kinase 3 (FLT3) gene are one of the most frequent genetic alterations in acute myeloid leukemia. A high mutation fraction of FLT3-ITD molecules on the surface of leukemia cells is associated with short remissions and overall adverse outcomes in AML. In this article we summarize the clinical trial data of midostaurin - one of the FLT3 inhibitors. We review its use in various combinations both in relapsed/refractory acute myeloid leukemia as well as in the newly diagnosed patients and recollect the evidence of its use as maintenance therapy post allogenic stem cell transplantation. We enumerate the practical issues faced in the use of midostaurin like antifungal prophylaxis, dosage of concomitant chemotherapy agents as well as available data on sequencing of the FLT3 inhibitors. Lastly, we provide our perspective of the future directions for FLT3 inhibition especially midostaurin, the underlying resistance mechanisms and the need for standardization of the FLT3 tests.
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- 2020
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37. Hedgehog Pathway Inhibitors: A New Therapeutic Class for the Treatment of Acute Myeloid Leukemia.
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Jamieson C, Martinelli G, Papayannidis C, and Cortes JE
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- Hedgehog Proteins metabolism, Humans, Signal Transduction, Stem Cells metabolism, Antineoplastic Agents pharmacology, Leukemia, Myeloid, Acute drug therapy
- Abstract
Targeting Hedgehog (Hh) pathway components, such as Smoothened (SMO), is a developing strategy for the treatment of acute myeloid leukemia (AML) and for overcoming relapsed/refractory forms of this disease. Several SMO inhibitors are in clinical development for the treatment of various tumor types and the results from some clinical trials in AML have been reported. This review will discuss the role of Hh signaling in AML pathogenesis, describe the preclinical and clinical development of Hh pathway inhibitors for the treatment of AML, and examine the current evidence on Hh pathway inhibitor resistance and the implications for treatment selection in AML., Significance: In acute myeloid leukemia (AML), components of the Hedgehog (Hh) signaling pathway, such as Smoothened (SMO), have been implicated in the development, maintenance, and expansion of leukemic stem cells (LSC), as well as sensitization to chemotherapy and the development of drug resistance in AML. Observations in preclinical studies of AML, as well as from samples of patients with AML, demonstrate that Hh pathway inhibitors act primarily on the stem cell pathway as differentiation agents. The current data for hematologic malignancies indicate the potential for a synergistic effect when a Hh pathway inhibitor is administered in combination with chemotherapy or investigational agents. It is thought that Hh pathway inhibitors act as agents that reduce LSC dormancy and promote LSC differentiation, thus the newly dividing LSCs can then be targeted by other chemotherapeutic drugs., Competing Interests: C. Jamieson reports having equity ownership in Impact Biomedicines and Wintherix LLC.; receives research funding from Celgene and Johnson & Johnson; and patents and royalties from Forty Seven, Inc. G. Martinelli is a consultant for Amgen, Ariad Pharmaceuticals, Incyte, Pfizer, Roche, Celgene, Janssen, Jazz, Daichii Sankyo, and AbbVie, speakers bureau honoraria from Pfizer, Celgene, Novartis; and reports receiving trial grants from Pfizer, and AbbVie. C. Papayannidis reports receiving honoraria from Pfizer, Amgen, and Novartis. J. E. Cortes is a consultant for Astellas Pharma, Bristol-Myers Squibb, Daiichi Sankyo, FORMA Therapeutics, Novartis, Pfizer, and Takeda; reports receiving research funding from Amphivena Therapeutics, Astellas Pharma, Bristol-Myers Squibb, Daiichi Sankyo, FORMA Therapeutics, ImmunoGen, Merus, Novartis, Pfizer, Sun Pharma, and Takeda. No other potential conflicts of interest were disclosed., (©2020 American Association for Cancer Research.)
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- 2020
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38. MEC (mitoxantrone, etoposide, and cytarabine) induces complete remission and is an effective bridge to transplant in acute myeloid leukemia.
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Marconi G, Talami A, Abbenante MC, Sartor C, Parisi S, Nanni J, Bertamini L, Ragaini S, Olivi M, de Polo S, Cristiano G, Fontana MC, Bochicchio MT, Ottaviani E, Arpinati M, Sessa M, Baldazzi C, Caso L, Testoni N, Baccarani M, Bonifazi F, Martinelli G, Paolini S, Cavo M, Papayannidis C, and Curti A
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Cytarabine adverse effects, Cytarabine therapeutic use, Disease Management, Etoposide adverse effects, Etoposide therapeutic use, Hematopoietic Stem Cell Transplantation methods, Humans, Induction Chemotherapy, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute etiology, Leukemia, Myeloid, Acute mortality, Mitoxantrone adverse effects, Mitoxantrone therapeutic use, Prognosis, Recurrence, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy, Preoperative Care
- Abstract
Introduction: Clinical response and chemosensitivity of relapse or refractory AML patients were evaluated after rescue and bridge-to-transplant MEC (mitoxantrone, etoposide, and cytarabine) regimen., Methods and Patients: Fifty-five consecutive AML patients were treated with MEC from 2009 to 2018. Chemosensitivity was evaluated by WT1 quantification., Results: 27/55 patients (49.1%) had AML resistant to induction and 28/55 patients (50.9%) had AML relapse. 25/55 patients (45.5%) achieved a CR after one course of MEC, and 12 patients (21.8%) achieved WT1 negativity. In 12 patients, a second MEC was administered. Four out of 12 patients improved significantly their response with the 2nd MEC. MEC was an effective bridge to transplant, 32/55 patients (58.2%) received an allogenic stem cell transplant. Median overall survival (OS) from MEC was 455 days (95% CI 307-602 days.); patient with WT1 negative CR had the best OS (P<.000)., Conclusion: WT1 is a useful marker of chemosensitivity after MEC as rescue and bridge-to-transplant therapy., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2020
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39. MIRROS: a randomized, placebo-controlled, Phase III trial of cytarabine ± idasanutlin in relapsed or refractory acute myeloid leukemia.
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Montesinos P, Beckermann BM, Catalani O, Esteve J, Gamel K, Konopleva MY, Martinelli G, Monnet A, Papayannidis C, Park A, Récher C, Rodríguez-Veiga R, Röllig C, Vey N, Wei AH, Yoon SS, and Fenaux P
- Subjects
- Adolescent, Female, Humans, Leukemia, Myeloid, Acute metabolism, Male, Proto-Oncogene Proteins c-mdm2 metabolism, Remission Induction, Tumor Suppressor Protein p53 metabolism, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Cytarabine therapeutic use, Leukemia, Myeloid, Acute drug therapy, Pyrrolidines therapeutic use, para-Aminobenzoates therapeutic use
- Abstract
Patients with refractory or relapsed acute myeloid leukemia (R/R AML) have a poor prognosis, with a high unmet medical need. Idasanutlin is a small-molecule inhibitor of MDM2, a negative regulator of tumor suppressor p53. By preventing the p53-MDM2 interaction, idasanutlin allows for p53 activation, particularly in patients with TP53 wild-type (WT) status. MIRROS (NCT02545283) is a randomized Phase III trial evaluating idasanutlin + cytarabine versus placebo + cytarabine in R/R AML. The primary end point is overall survival in the TP53 -WT population. Secondary end points include complete remission rate (cycle 1), overall remission rate (cycle 1) and event-free survival in the TP53 -WT population. MIRROS has an innovative design that integrates a stringent interim analysis for futility; continuation criteria were met in mid-2017 and accrual is ongoing. Trial registration number: NCT02545283.
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- 2020
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40. Long-term follow-up of a trial comparing post-remission treatment with autologous or allogeneic bone marrow transplantation or intensive chemotherapy in younger acute myeloid leukemia patients.
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Baron F, Efficace F, Cannella L, Willemze R, Vignetti M, Muus P, Marie JP, Ferrero D, Fazi P, La Sala E, Bourhis JH, Fabbiano F, Bosi A, Sborgia M, Martinelli G, Wittnebel S, Trisolini S, Petti MC, Halkes CJM, van der Velden WJFM, de Witte T, Amadori S, Zittoun RA, and Suciu S
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Bone Marrow Transplantation, Cytarabine therapeutic use, Follow-Up Studies, Humans, Remission Induction, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy
- Published
- 2020
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41. The acetyltransferase GCN5 maintains ATRA-resistance in non-APL AML.
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Kahl M, Brioli A, Bens M, Perner F, Kresinsky A, Schnetzke U, Hinze A, Sbirkov Y, Stengel S, Simonetti G, Martinelli G, Petrie K, Zelent A, Böhmer FD, Groth M, Ernst T, Heidel FH, Scholl S, Hochhaus A, and Schenk T
- Subjects
- Apoptosis, Bone Marrow metabolism, Cell Differentiation, Cell Line, Tumor, Cell Membrane metabolism, Epigenesis, Genetic, Genotype, HEK293 Cells, HL-60 Cells, Histone Demethylases antagonists & inhibitors, Histones chemistry, Humans, Leukocytes, Mononuclear cytology, Drug Resistance, Neoplasm, Leukemia, Myeloid, Acute drug therapy, Leukemia, Promyelocytic, Acute drug therapy, Tretinoin pharmacology, p300-CBP Transcription Factors metabolism
- Abstract
To date, only one subtype of acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) can be effectively treated by differentiation therapy utilizing all-trans retinoic acid (ATRA). Non-APL AMLs are resistant to ATRA. Here we demonstrate that the acetyltransferase GCN5 contributes to ATRA resistance in non-APL AML via aberrant acetylation of histone 3 lysine 9 (H3K9ac) residues maintaining the expression of stemness and leukemia associated genes. We show that inhibition of GCN5 unlocks an ATRA-driven therapeutic response. This response is potentiated by coinhibition of the lysine demethylase LSD1, leading to differentiation in most non-APL AML. Induction of differentiation was not correlated to a specific AML subtype, cytogenetic, or mutational status. Our study shows a previously uncharacterized role of GCN5 in maintaining the immature state of leukemic blasts and identifies GCN5 as a therapeutic target in AML. The high efficacy of the combined epigenetic treatment with GCN5 and LSD1 inhibitors may enable the use of ATRA for differentiation therapy of non-APL AML. Furthermore, it supports a strategy of combined targeting of epigenetic factors to improve treatment, a concept potentially applicable for a broad range of malignancies.
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- 2019
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42. Gilteritinib or Chemotherapy for Relapsed or Refractory FLT3 -Mutated AML.
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Perl AE, Martinelli G, Cortes JE, Neubauer A, Berman E, Paolini S, Montesinos P, Baer MR, Larson RA, Ustun C, Fabbiano F, Erba HP, Di Stasi A, Stuart R, Olin R, Kasner M, Ciceri F, Chou WC, Podoltsev N, Recher C, Yokoyama H, Hosono N, Yoon SS, Lee JH, Pardee T, Fathi AT, Liu C, Hasabou N, Liu X, Bahceci E, and Levis MJ
- Subjects
- Administration, Oral, Adult, Aged, Aged, 80 and over, Aniline Compounds adverse effects, Antineoplastic Agents adverse effects, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Drug Resistance, Neoplasm, Female, Follow-Up Studies, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Liver drug effects, Male, Middle Aged, Pyrazines adverse effects, Recurrence, Remission Induction, Survival Analysis, Aniline Compounds therapeutic use, Antineoplastic Agents therapeutic use, Leukemia, Myeloid, Acute drug therapy, Mutation, Pyrazines therapeutic use, Salvage Therapy, fms-Like Tyrosine Kinase 3 genetics
- Abstract
Background: Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene ( FLT3 ) infrequently have a response to salvage chemotherapy. Gilteritinib is an oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory FLT3 -mutated AML., Methods: In a phase 3 trial, we randomly assigned adults with relapsed or refractory FLT3 -mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure [i.e., relapse or lack of remission] or death) and the percentage of patients who had complete remission., Results: Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%)., Conclusions: Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory FLT3 -mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.)., (Copyright © 2019 Massachusetts Medical Society.)
- Published
- 2019
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43. GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia.
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Venditti A, Piciocchi A, Candoni A, Melillo L, Calafiore V, Cairoli R, de Fabritiis P, Storti G, Salutari P, Lanza F, Martinelli G, Luppi M, Mazza P, Martelli MP, Cuneo A, Albano F, Fabbiano F, Tafuri A, Chierichini A, Tieghi A, Fracchiolla NS, Capelli D, Foà R, Alati C, La Sala E, Fazi P, Vignetti M, Maurillo L, Buccisano F, Del Principe MI, Irno-Consalvo M, Ottone T, Lavorgna S, Voso MT, Lo-Coco F, Arcese W, and Amadori S
- Subjects
- Adolescent, Adult, Age Factors, Combined Modality Therapy, Cytogenetics, Female, Humans, Induction Chemotherapy methods, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Molecular Targeted Therapy methods, Neoplasm, Residual, Prognosis, Remission Induction methods, Risk Assessment, Young Adult, Consolidation Chemotherapy methods, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute therapy, Precision Medicine methods
- Abstract
We designed a trial in which postremission therapy of young patients with de novo acute myeloid leukemia (AML) was decided combining cytogenetics/genetics and postconsolidation levels of minimal residual disease (MRD). After induction and consolidation, favorable-risk patients (FR) were to receive autologous stem cell transplant (AuSCT) and poor-risk patients (PR) allogeneic stem cell transplant (AlloSCT). Intermediate-risk patients (IR) were to receive AuSCT or AlloSCT depending on the postconsolidation levels of MRD. Three hundred sixty-one of 500 patients (72%) achieved a complete remission, 342/361 completed the consolidation phase and were treatment allocated: 165 (48%) to AlloSCT (122 PR, 43 IR MRD-positive) plus 23 rescued after salvage therapy, for a total of 188 candidates; 150 (44%) to AuSCT (115 FR, 35 IR MRD-negative) plus 27 IR patients (8%) with no leukemia-associated phenotype, for a total of 177 candidates. Overall, 110/177 (62%) and 130/188 (71%) AuSCT or AlloSCT candidates received it, respectively. Two-year overall (OS) and disease-free survival (DFS) of the whole series was 56% and 54%, respectively. Two-year OS and DFS were 74% and 61% in the FR category, 42% and 45% in the PR category, 79% and 61% in the IR MRD-negative category, and 70% and 67% in the IR MRD-positive category. In conclusion, AuSCT may still have a role in FR and IR MRD-negative categories. In the IR MRD-positive category, AlloSCT prolongs OS and DFS to equal those of the FR category. Using all the available sources of stem cells, AlloSCT was delivered to 71% of the candidates.This trial was registered at www.clinicaltrials.gov as #NCT01452646 and EudraCT as #2010-023809-36., (© 2019 by The American Society of Hematology.)
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- 2019
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44. Quizartinib versus salvage chemotherapy in relapsed or refractory FLT3-ITD acute myeloid leukaemia (QuANTUM-R): a multicentre, randomised, controlled, open-label, phase 3 trial.
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Cortes JE, Khaled S, Martinelli G, Perl AE, Ganguly S, Russell N, Krämer A, Dombret H, Hogge D, Jonas BA, Leung AY, Mehta P, Montesinos P, Radsak M, Sica S, Arunachalam M, Holmes M, Kobayashi K, Namuyinga R, Ge N, Yver A, Zhang Y, and Levis MJ
- Subjects
- Adult, Aged, Benzothiazoles pharmacology, Female, Humans, Leukemia, Myeloid, Acute genetics, Male, Middle Aged, Neoplasm Recurrence, Local genetics, Phenylurea Compounds pharmacology, Survival Rate, Tandem Repeat Sequences, fms-Like Tyrosine Kinase 3 antagonists & inhibitors, fms-Like Tyrosine Kinase 3 genetics, Benzothiazoles therapeutic use, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute mortality, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local mortality, Phenylurea Compounds therapeutic use, Salvage Therapy
- Abstract
Background: Patients with relapsed or refractory FLT3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia have a poor prognosis, including high frequency of relapse, poorer response to salvage therapy, and shorter overall survival than those with FLT3 wild-type disease. We aimed to assess whether single-agent quizartinib, an oral, highly potent and selective type II FLT3 inhibitor, improves overall survival versus salvage chemotherapy., Methods: QuANTUM-R is a randomised, controlled, phase 3 trial done at 152 hospitals and cancer centres in 19 countries. Eligible patients aged 18 years or older with ECOG performance status 0-2 with relapsed or refractory (duration of first composite complete remission ≤6 months) FLT3-ITD acute myeloid leukaemia after standard therapy with or without allogeneic haemopoietic stem-cell transplantation were randomly assigned (2:1; permuted block size of 6; stratified by response to previous therapy and choice of chemotherapy via a phone-based and web-based interactive response system) to quizartinib (60 mg [30 mg lead-in] orally once daily) or investigator's choice of preselected chemotherapy: subcutaneous low-dose cytarabine (subcutaneous injection of cytarabine 20 mg twice daily on days 1-10 of 28-day cycles); intravenous infusions of mitoxantrone (8 mg/m
2 per day), etoposide (100 mg/m2 per day), and cytarabine (1000 mg/m2 per day on days 1-5 of up to two 28-day cycles); or intravenous granulocyte colony-stimulating factor (300 μg/m2 per day or 5 μg/kg per day subcutaneously on days 1-5), fludarabine (intravenous infusion 30 mg/m2 per day on days 2-6), cytarabine (intravenous infusion 2000 mg/m2 per day on days 2-6), and idarubicin (intravenous infusion 10 mg/m2 per day on days 2-4 in up to two 28-day cycles). Patients proceeding to haemopoietic stem-cell transplantation after quizartinib could resume quizartinib after haemopoietic stem-cell transplantation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02039726, and follow-up is ongoing., Findings: Between May 7, 2014, and Sept 13, 2017, 367 patients were enrolled, of whom 245 were randomly allocated to quizartinib and 122 to chemotherapy. Four patients in the quizartinib group and 28 in the chemotherapy group were not treated. Median follow-up was 23·5 months (IQR 15·4-32·3). Overall survival was longer for quizartinib than for chemotherapy (hazard ratio 0·76 [95% CI 0·58-0·98; p=0·02]). Median overall survival was 6·2 months (5·3-7·2) in the quizartinib group and 4·7 months (4·0-5·5) in the chemotherapy group. The most common non-haematological grade 3-5 treatment-emergent adverse events (within ≤30 days of last dose or >30 days if suspected to be a treatment-related event) for quizartinib (241 patients) and chemotherapy (94 patients) were sepsis or septic shock (46 patients [19%] for quizartinib vs 18 [19%] for chemotherapy), pneumonia (29 [12%] vs eight [9%]), and hypokalaemia (28 [12%] vs eight [9%]). The most frequent treatment-related serious adverse events were febrile neutropenia (18 patients [7%]), sepsis or septic shock (11 [5%]), QT prolongation (five [2%]), and nausea (five [2%]) in the quizartinib group, and febrile neutropenia (five [5%]), sepsis or septic shock (four [4%]), pneumonia (two [2%]), and pyrexia (two [2%]) in the chemotherapy group. Grade 3 QT prolongation in the quizartinib group was uncommon (eight [3%] by central reading, ten [4%] by investigator report); no grade 4 events occurred. There were 80 (33%) treatment-emergent deaths in the quizartinib group (31 [13%] of which were due to adverse events) and 16 (17%) in the chemotherapy group (nine [10%] of which were due to adverse events)., Interpretation: Treatment with quizartinib had a survival benefit versus salvage chemotherapy and had a manageable safety profile in patients with rapidly proliferative disease and very poor prognosis. Quizartinib could be considered a new standard of care. Given that there are only a few available treatment options, this study highlights the value of targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor., Funding: Daiichi Sankyo., (Copyright © 2019 Elsevier Ltd. All rights reserved.)- Published
- 2019
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45. Aneuploid acute myeloid leukemia exhibits a signature of genomic alterations in the cell cycle and protein degradation machinery.
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Simonetti G, Padella A, do Valle IF, Fontana MC, Fonzi E, Bruno S, Baldazzi C, Guadagnuolo V, Manfrini M, Ferrari A, Paolini S, Papayannidis C, Marconi G, Franchini E, Zuffa E, Laginestra MA, Zanotti F, Astolfi A, Iacobucci I, Bernardi S, Sazzini M, Ficarra E, Hernandez JM, Vandenberghe P, Cools J, Bullinger L, Ottaviani E, Testoni N, Cavo M, Haferlach T, Castellani G, Remondini D, and Martinelli G
- Subjects
- Adult, Aged, Aged, 80 and over, Aneuploidy, Cell Cycle, Chromosome Banding, Female, Gene Dosage, Gene Expression Regulation, Leukemic, Genetic Predisposition to Disease, Humans, Male, Middle Aged, Mutation, Proteolysis, Exome Sequencing, Young Adult, Gene Expression Profiling methods, Gene Regulatory Networks, Genomics methods, Leukemia, Myeloid, Acute genetics
- Abstract
Background: Aneuploidy occurs in more than 20% of acute myeloid leukemia (AML) cases and correlates with an adverse prognosis., Methods: To understand the molecular bases of aneuploid acute myeloid leukemia (A-AML), this study examined the genomic profile in 42 A-AML cases and 35 euploid acute myeloid leukemia (E-AML) cases., Results: A-AML was characterized by increased genomic complexity based on exonic variants (an average of 26 somatic mutations per sample vs 15 for E-AML). The integration of exome, copy number, and gene expression data revealed alterations in genes involved in DNA repair (eg, SLX4IP, RINT1, HINT1, and ATR) and the cell cycle (eg, MCM2, MCM4, MCM5, MCM7, MCM8, MCM10, UBE2C, USP37, CK2, CK3, CK4, BUB1B, NUSAP1, and E2F) in A-AML, which was associated with a 3-gene signature defined by PLK1 and CDC20 upregulation and RAD50 downregulation and with structural or functional silencing of the p53 transcriptional program. Moreover, A-AML was enriched for alterations in the protein ubiquitination and degradation pathway (eg, increased levels of UHRF1 and UBE2C and decreased UBA3 expression), response to reactive oxygen species, energy metabolism, and biosynthetic processes, which may help in facing the unbalanced protein load. E-AML was associated with BCOR/BCORL1 mutations and HOX gene overexpression., Conclusions: These findings indicate that aneuploidy-related and leukemia-specific alterations cooperate to tolerate an abnormal chromosome number in AML, and they point to the mitotic and protein degradation machineries as potential therapeutic targets., (© 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.)
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- 2019
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46. Comparative analysis of azacitidine and intensive chemotherapy as front-line treatment of elderly patients with acute myeloid leukemia.
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Maurillo L, Buccisano F, Spagnoli A, Voso MT, Fianchi L, Papayannidis C, Gaidano GL, Breccia M, Musto P, De Bellis E, Del Principe MI, Lunghi M, Lessi F, Martinelli G, and Venditti A
- Subjects
- Age Factors, Aged, Aged, 80 and over, Bone Marrow pathology, Cytarabine administration & dosage, Disease-Free Survival, Etoposide administration & dosage, Female, Humans, Idarubicin administration & dosage, Kaplan-Meier Estimate, Karyotype, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Mitoxantrone administration & dosage, Neoplasms, Second Primary chemically induced, Remission Induction, Risk, Treatment Outcome, Antimetabolites, Antineoplastic therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Azacitidine therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
The present observational study aimed to compare the efficacy of azacitidine (AZA) and intensive chemotherapy (IC) in elderly patients with untreated acute myeloid leukemia (AML), diagnosed according to WHO criteria. In the two groups, we evaluated complete remission (CR), overall survival (OS), and disease-free survival (DFS). The AZA group included 89 patients; median age was 73 years (range 61-80) and median white blood cell count (WBCc) 2.5 × 10
9 /L (range 0.27-83), 45% of the patients had BM blasts ≥ 30%, and 44 (49%) had a secondary AML (sAML). Karyotype was evaluable in 69 patients: 51 (74%) had intermediate-risk abnormalities and 18 (26%) an unfavorable risk karyotype. IC group consisted of 110 patients who received an induction course with mitoxantrone, cytarabine, and etoposide, followed by two consolidation cycles including idarubicin, cytarabine, and etoposide. Median age was 67 years (range 61-78) and median WBCc 8.0 × 109 /L (range 0.69-258); 44 (40%) had a sAML. Karyotype was evaluable in 88 patients, 71 (81%) had intermediate risk, and 17 (19%) unfavorable risk karyotype. To minimize the effects of treatment selection bias, adjustments were made using the propensity-score matching method, which yielded 74 patient pairs. CR rate was significantly higher in IC vs AZA group (73 vs 25%, respectively) (p < 0.0001), but the 3-year OS rates and median OS were not significantly different (21.6 vs 11% and 15.8 vs 13 months, respectively). Our analysis suggests similar outcomes with AZA compared to IC. Controlled, randomized clinical trials are warranted to confirm this conclusion.- Published
- 2018
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47. MYC-containing amplicons in acute myeloid leukemia: genomic structures, evolution, and transcriptional consequences.
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L Abbate A, Tolomeo D, Cifola I, Severgnini M, Turchiano A, Augello B, Squeo G, D Addabbo P, Traversa D, Daniele G, Lonoce A, Pafundi M, Carella M, Palumbo O, Dolnik A, Muehlematter D, Schoumans J, Van Roy N, De Bellis G, Martinelli G, Merla G, Bullinger L, Haferlach C, and Storlazzi CT
- Subjects
- Adult, Aged, Aged, 80 and over, Chromosome Aberrations, Chromosome Banding methods, Chromosomes, Human, Pair 8 genetics, Female, Genomics methods, Humans, Karyotyping methods, Male, Middle Aged, RNA, Long Noncoding genetics, Young Adult, Gene Amplification genetics, Genes, myc genetics, Leukemia, Myeloid, Acute genetics, Transcription, Genetic genetics
- Abstract
Double minutes (dmin), homogeneously staining regions, and ring chromosomes are vehicles of gene amplification in cancer. The underlying mechanism leading to their formation as well as their structure and function in acute myeloid leukemia (AML) remain mysterious. We combined a range of high-resolution genomic methods to investigate the architecture and expression pattern of amplicons involving chromosome band 8q24 in 23 cases of AML (AML-amp). This revealed that different MYC-dmin architectures can coexist within the same leukemic cell population, indicating a step-wise evolution rather than a single event origin, such as through chromothripsis. This was supported also by the analysis of the chromothripsis criteria, that poorly matched the model in our samples. Furthermore, we found that dmin could evolve toward ring chromosomes stabilized by neocentromeres. Surprisingly, amplified genes (mainly PVT1) frequently participated in fusion transcripts lacking a corresponding DNA template. We also detected a significant overexpression of the circular RNA of PVT1 (circPVT1) in AML-amp cases versus AML with a normal karyotype. Our results show that 8q24 amplicons in AML are surprisingly plastic DNA structures with an unexpected association to novel fusion transcripts and circular RNAs.
- Published
- 2018
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48. Phase 2b study of 2 dosing regimens of quizartinib monotherapy in FLT3 -ITD-mutated, relapsed or refractory AML.
- Author
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Cortes JE, Tallman MS, Schiller GJ, Trone D, Gammon G, Goldberg SL, Perl AE, Marie JP, Martinelli G, Kantarjian HM, and Levis MJ
- Subjects
- Adult, Aged, Antineoplastic Agents adverse effects, Antineoplastic Agents therapeutic use, Benzothiazoles adverse effects, Benzothiazoles therapeutic use, Dose-Response Relationship, Drug, Female, Gastrointestinal Diseases chemically induced, Gene Duplication, Heart Diseases chemically induced, Hematologic Diseases chemically induced, Humans, Kaplan-Meier Estimate, Leukemia, Myeloid, Acute genetics, Male, Middle Aged, Oncogene Proteins, Fusion genetics, Phenylurea Compounds adverse effects, Phenylurea Compounds therapeutic use, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors therapeutic use, Tandem Repeat Sequences genetics, Young Adult, fms-Like Tyrosine Kinase 3 genetics, Antineoplastic Agents administration & dosage, Benzothiazoles administration & dosage, Leukemia, Myeloid, Acute drug therapy, Phenylurea Compounds administration & dosage, Protein Kinase Inhibitors administration & dosage, Salvage Therapy
- Abstract
This randomized, open-label, phase 2b study (NCT01565668) evaluated the efficacy and safety of 2 dosing regimens of quizartinib monotherapy in patients with relapsed/refractory (R/R) FLT3 -internal tandem duplication (ITD)-mutated acute myeloid leukemia (AML) who previously underwent transplant or 1 second-line salvage therapy. Patients (N = 76) were randomly assigned to 30- or 60-mg/day doses (escalations to 60 or 90 mg/day, respectively, permitted for lack/loss of response) of single-agent oral quizartinib dihydrochloride. Allelic frequency of at least 10% was defined as FLT3 -ITD-mutated disease. Coprimary endpoints were composite complete remission (CRc) rates and incidence of QT interval corrected by Fridericia's formula (QTcF) of more than 480 ms (grade 2 or greater). Secondary endpoints included overall survival (OS), duration of CRc, bridge to transplant, and safety. CRc rates were 47% in both groups, similar to earlier reports with higher quizartinib doses. Incidence of QTcF above 480 ms was 11% and 17%, and QTcF above 500 ms was 5% and 3% in the 30- and 60-mg groups, respectively, which is less than earlier reports with higher doses of quizartinib. Median OS (20.9 and 27.3 weeks), duration of CRc (4.2 and 9.1 weeks), and bridge to transplant rates (32% and 42%) were higher in the 60-mg groups than in the 30-mg group. Dose escalation occurred in 61% and 14% of patients in the 30- and 60-mg groups, respectively. This high clinical activity of quizartinib at the evaluated doses is consistent with previous reports with an improved safety profile. Need to dose-escalate more than half of patients who received quizartinib 30 mg also supports further investigation of treatment with quizartinib 60 mg/day., (© 2018 by The American Society of Hematology.)
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- 2018
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49. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial.
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Cortes J, Perl AE, Döhner H, Kantarjian H, Martinelli G, Kovacsovics T, Rousselot P, Steffen B, Dombret H, Estey E, Strickland S, Altman JK, Baldus CD, Burnett A, Krämer A, Russell N, Shah NP, Smith CC, Wang ES, Ifrah N, Gammon G, Trone D, Lazzaretto D, and Levis M
- Subjects
- Administration, Oral, Adult, Aged, Canada, Disease-Free Survival, Dose-Response Relationship, Drug, Drug Administration Schedule, Europe, Female, Humans, Internationality, Leukemia, Myeloid, Acute mortality, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Recurrence, Local diagnosis, Neoplasm Recurrence, Local mortality, Prognosis, Survival Rate, Treatment Outcome, United States, Young Adult, fms-Like Tyrosine Kinase 3 administration & dosage, Benzothiazoles therapeutic use, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute drug therapy, Neoplasm Recurrence, Local drug therapy, Phenylurea Compounds therapeutic use, fms-Like Tyrosine Kinase 3 antagonists & inhibitors
- Abstract
Background: Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia., Methods: We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed., Findings: Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [<1%]) and hepatic failure (two [1%]). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten [6%] of 157 patients in cohort 1 and eight [5%] of 176 in cohort 2., Interpretation: Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine quizartinib at lower starting doses., Funding: Ambit Biosciences/Daiichi Sankyo., (Copyright © 2018 Elsevier Ltd. All rights reserved.)
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- 2018
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50. Chromothripsis in acute myeloid leukemia: biological features and impact on survival.
- Author
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Fontana MC, Marconi G, Feenstra JDM, Fonzi E, Papayannidis C, Ghelli Luserna di Rorá A, Padella A, Solli V, Franchini E, Ottaviani E, Ferrari A, Baldazzi C, Testoni N, Iacobucci I, Soverini S, Haferlach T, Guadagnuolo V, Semerad L, Doubek M, Steurer M, Racil Z, Paolini S, Manfrini M, Cavo M, Simonetti G, Kralovics R, and Martinelli G
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor, Chromosome Banding, Female, Genetic Predisposition to Disease, Humans, In Situ Hybridization, Fluorescence, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute therapy, Male, Middle Aged, Mutation, Nucleophosmin, Polymorphism, Single Nucleotide, Prognosis, Proportional Hazards Models, Ring Chromosomes, Treatment Outcome, Young Adult, Chromothripsis, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality
- Abstract
Chromothripsis is a one-step genome-shattering catastrophe resulting from disruption of one or few chromosomes in multiple fragments and consequent random rejoining and repair. This study defines incidence of chromothripsis in 395 newly diagnosed adult acute myeloid leukemia (AML) patients from three institutions, its impact on survival and its genomic background. SNP 6.0 or CytoscanHD Array (Affymetrix
® ) were performed on all samples. We detected chromothripsis with a custom algorithm in 26/395 patients. Patients harboring chromothripsis had higher age (p = 0.002), ELN high risk (HR) (p < 0.001), lower white blood cell (WBC) count (p = 0.040), TP53 loss, and/or mutations (p < 0.001) while FLT3 (p = 0.025), and NPM1 (p = 0.032) mutations were mutually exclusive with chromothripsis. Chromothripsis-positive patients showed a worse overall survival (OS) (p < 0.001) compared with HR patients (p = 0.011) and a poor prognosis in a COX-HR optimal regression model. Chromothripsis presented the hallmarks of chromosome instability [i.e., TP53 alteration, 5q deletion, higher mean of copy number alteration (CNA), complex karyotype, alterations in DNA repair, and cell cycle] and focal deletions on chromosomes 4, 7, 12, 16, and 17. CBA. FISH showed that chromothripsis is associated with marker, derivative, and ring chromosomes. In conclusion, chromothripsis frequently occurs in AML (6.6%) and influences patient prognosis and disease biology.- Published
- 2018
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