Acalabrutinib monotherapy in patients with Waldenström macroglobulinemia: a single-arm, multicentre, phase 2 study
| Autor: | Priti Patel, Dih-Yih Chen, Olivier Tournilhac, Thérèse Aurran-Schleinitz, Raquel Izumi, Efstathios Kastritis, Sheeba K. Thomas, Ahmed Hamdy, Monique C. Minnema, Francesco Forconi, Helen McCarthy, Richard R. Furman, Pier Luigi Zinzani, Diana Mittag, Shirley D'Sa, Daniel Reif Greenwald, Marie José Kersten, Simon Rule, Sunil Iyengar, Harriet S. Walter, Jaimal Kothari, Roger G. Owen, Sun Ku Lee, Melanie M. Frigault, Helen Wei, Bruce D. Cheson |
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| Přispěvatelé: | Department of Haematology, Derriford Hospital, University College London Hospitals (UCLH), Role of intra-Clonal Heterogeneity and Leukemic environment in ThErapy Resistance of chronic leukemias (CHELTER), Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), University of Southampton, University of Amsterdam [Amsterdam] (UvA), L. and A. Seràgnoli Hospital, University of Bologna, National and Kapodistrian University of Athens (NKUA), Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Lombardi Comprehensive Cancer Center, Acerta Pharma (Redwood City, CA), Alma Mater Studiorum Università di Bologna [Bologna] (UNIBO), CCA - Cancer Treatment and Quality of Life, AII - Cancer immunology, Clinical Haematology, Owen, Roger G, McCarthy, Helen, Rule, Simon, D'Sa, Shirley, Thomas, Sheeba K, Tournilhac, Olivier, Forconi, Francesco, Kersten, Marie José, Zinzani, Pier Luigi, Iyengar, Sunil, Kothari, Jaimal, Minnema, Monique C, Kastritis, Efstathio, Aurran-Schleinitz, Thérèse, Cheson, Bruce D, Walter, Harriet, Greenwald, Daniel, Chen, Dih-Yih, Frigault, Melanie M, Hamdy, Ahmed, Izumi, Raquel, Patel, Priti, Wei, Helen, Lee, Sun Ku, Mittag, Diana, Furman, Richard R |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
medicine.medical_specialty Neutropenia Gastrointestinal Diseases Pain Phases of clinical research Salvage therapy Antineoplastic Agents 03 medical and health sciences 0302 clinical medicine Recurrence Chemoimmunotherapy Lower respiratory tract infection Internal medicine Agammaglobulinaemia Tyrosine Kinase Journal Article Clinical endpoint Humans Medicine Molecular Targeted Therapy Adverse effect Protein Kinase Inhibitors Respiratory Tract Infections ComputingMilieux_MISCELLANEOUS Aged Salvage Therapy business.industry Waldenstrom macroglobulinemia [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology Hematology Middle Aged medicine.disease Neoplasm Proteins 3. Good health Treatment Outcome Acalabrutinib monotherapy Waldenström macroglobulinemia Pyrazines 030220 oncology & carcinogenesis Benzamides Myeloid Differentiation Factor 88 Quality of Life Female Waldenstrom Macroglobulinemia business 030215 immunology |
| Zdroj: | The Lancet Haematology The Lancet Haematology, Elsevier, 2020, 7 (2), pp.e112-e121. ⟨10.1016/S2352-3026(19)30210-8⟩ The Lancet Haematology, 2020, 7 (2), pp.e112-e121. ⟨10.1016/S2352-3026(19)30210-8⟩ Lancet haematology, 7(2), e112. Lancet Publishing Group Lancet. Haematology, 7(2), e112-e121. Lancet Publishing Group |
| ISSN: | 2352-3026 |
| Popis: | Summary Background Chemoimmunotherapy is typically the standard of care for patients with Waldenstrom macroglobulinemia; however, infectious and hematologic toxic effects are problematic. Acalabrutinib is a selective, potent Bruton tyrosine-kinase inhibitor. The aim of this trial was to evaluate the activity and safety of acalabrutinib in patients with Waldenstrom macroglobulinemia. Methods This single-arm, multicentre, phase 2 trial was done in 19 European academic centres in France, Italy, Greece, the Netherlands, and the UK, and eight academic centres in the USA. Eligible patients were 18 years or older and had treatment naive (declined or not eligible for chemoimmunotherapy) or relapsed or refractory (at least one previous therapy) Waldenstrom macroglobulinemia that required treatment, an Eastern Cooperative Oncology Group performance status of 2 or less, and received no previous Bruton tyrosine-kinase inhibitor therapy. Patients received 100 mg oral acalabrutinib twice per day in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed overall response (at least a minor response) according to the 6th International Workshop for Waldenstrom Macroglobulinemia (IWWM) and the modified 3rd IWWM workshop criteria. The primary outcome and safety were assessed in all patients who received at least one dose of treatment. This study is registered with ClinicalTrials.gov , number NCT02180724 , and is ongoing, but no longer enrolling. Findings Between Sept 8, 2014, and Dec 24, 2015, 122 patients were assessed for eligibility, of which 106 (87%) patients were given acalabrutinib (14 were treatment naive and 92 had relapsed or refractory disease). With a median follow-up of 27·4 months (IQR 26·0–29·7), 13 (93% [95% CI 66–100]) of 14 treatment naive patients achieved an overall response and 86 (93% [86–98]) of 92 relapsed or refractory patients per both the modified 3rd and 6th IWWM criteria. Seven (50%) of 14 treatment naive patients and 23 (25%) of 92 relapsed or refractory patients discontinued treatment on study. Grade 3–4 adverse events occurring in more than 5% of patients were neutropenia (17 [16%] of 106 patients) and pneumonia (7 [7%]). Grade 3–4 atrial fibrillation occurred in one (1%) patient and grade 3–4 bleeding occurred in three (3%) patients. The most common serious adverse events were lower respiratory tract infection (n=7 [7%]), pneumonia (n=7 [7%]), pyrexia (n=4 [4%]), cellulitis (n=3 [3%]), fall (n=3 [3%]), and sepsis (n=3 [3%]). Pneumonia (n=5 [5%]) and lower respiratory tract infection (n=4 [4%]) were considered treatment related. One treatment-related death was reported (intracranial hematoma). Interpretation This study provides evidence that acalabrutinib is active as single-agent therapy with a manageable safety profile in patients with treatment-naive, or relapse or refractory Waldenstrom macroglobulinemia. Further studies are needed to establish its efficacy against current standard treatments and to investigate whether outcomes can be improved with combination therapies. Funding Acerta Pharma. |
| Databáze: | OpenAIRE |
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