Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia
| Autor: | Susan O'Brien, Paolo Ghia, William G. Wierda, S Devereux, Jennifer A. Woyach, Raquel Izumi, Jennifer R. Brown, Wayne Rothbaum, Ahmed Hamdy, Jesse McGreivy, Richard R. Furman, Jacqueline C. Barrientos, Amy J. Johnson, John M. Pagel, Thomas G. Diacovo, Xiaolin Wang, Jorge M. Chaves, Deborah M. Stephens, Maria Fardis, Allard Kaptein, Brian J. Lannutti, Dave Johnson, Bonnie K. Harrington, John C. Byrd, Jeffrey A. Jones, Farrukh T. Awan, Todd Covey, Jane Huang, Peter Hillmen, Anna Schuh |
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| Přispěvatelé: | Byrd, Jc, Harrington, B, O'Brien, S, Jones, Ja, Schuh, A, Devereux, S, Chaves, J, Wierda, Wg, Awan, Ft, Brown, Jr, Hillmen, P, Stephens, Dm, Ghia, PAOLO PROSPERO, Barrientos, Jc, Pagel, Jm, Woyach, J, Johnson, D, Huang, J, Wang, X, Kaptein, A, Lannutti, Bj, Covey, T, Fardis, M, Mcgreivy, J, Hamdy, A, Rothbaum, W, Izumi, R, Diacovo, Tg, Johnson, Aj, Furman, Rr |
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Oncology Male Lymphoma Chronic lymphocytic leukemia Administration Oral Medical and Health Sciences chemistry.chemical_compound 0302 clinical medicine Recurrence hemic and lymphatic diseases Agammaglobulinaemia Tyrosine Kinase Medicine Chronic 6.2 Cellular and gene therapies Cancer Leukemia biology Headache General Medicine Hematology Middle Aged Protein-Tyrosine Kinases Lymphocytic 030220 oncology & carcinogenesis Ibrutinib 6.1 Pharmaceuticals Pyrazines Administration Benzamides Acalabrutinib Female Drug Chromosome Deletion Idelalisib Oral Diarrhea medicine.medical_specialty Antineoplastic Agents Disease-Free Survival Dose-Response Relationship 03 medical and health sciences Rare Diseases Clinical Research Internal medicine General & Internal Medicine Genetics Bruton's tyrosine kinase Humans Adverse effect Protein Kinase Inhibitors Aged Dose-Response Relationship Drug business.industry B-Cell Evaluation of treatments and therapeutic interventions medicine.disease Leukemia Lymphocytic Chronic B-Cell 030104 developmental biology chemistry Pharmacodynamics Immunology biology.protein business |
| Zdroj: | The New England journal of medicine, vol 374, iss 4 |
| ISSN: | 1533-4406 |
| Popis: | Background Irreversible inhibition of Bruton's tyrosine kinase (BTK) by ibrutinib represents an important therapeutic advance for the treatment of chronic lymphocytic leukemia (CLL). However, ibrutinib also irreversibly inhibits alternative kinase targets, which potentially compromises its therapeutic index. Acalabrutinib (ACP-196) is a more selective, irreversible BTK inhibitor that is specifically designed to improve on the safety and efficacy of first-generation BTK inhibitors. Methods In this uncontrolled, phase 1-2, multicenter study, we administered oral acalabrutinib to 61 patients who had relapsed CLL to assess the safety, efficacy, pharmacokinetics, and pharmacodynamics of acalabrutinib. Patients were treated with acalabrutinib at a dose of 100 to 400 mg once daily in the dose-escalation (phase 1) portion of the study and 100 mg twice daily in the expansion (phase 2) portion. Results The median age of the patients was 62 years, and patients had received a median of three previous therapies for CLL; 31% had chromosome 17p13.1 deletion, and 75% had unmutated immunoglobulin heavy-chain variable genes. No dose-limiting toxic effects occurred during the dose-escalation portion of the study. The most common adverse events observed were headache (in 43% of the patients), diarrhea (in 39%), and increased weight (in 26%). Most adverse events were of grade 1 or 2. At a median follow-up of 14.3 months, the overall response rate was 95%, including 85% with a partial response and 10% with a partial response with lymphocytosis; the remaining 5% of patients had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%. No cases of Richter's transformation (CLL that has evolved into large-cell lymphoma) and only one case of CLL progression have occurred. Conclusions In this study, the selective BTK inhibitor acalabrutinib had promising safety and efficacy profiles in patients with relapsed CLL, including those with chromosome 17p13.1 deletion. (Funded by the Acerta Pharma and others; ClinicalTrials.gov number, NCT02029443 .). |
| Databáze: | OpenAIRE |
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