Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study
Abstract: Some patients with chronic lymphocytic leukemia who develop progressive disease (PD) during covalent Bruton tyrosine kinase (BTK) inhibitor treatment acquire resistance mutations in BTK or PLCG2. Here, we report gene mutation data from paired baseline and PD peripheral blood samples from 5...
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| Format: | Article |
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Elsevier
2025-04-01
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| Series: | Blood Advances |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2473952925000473 |
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| author | Jennifer R. Brown Jessica Li Barbara F. Eichhorst Nicole Lamanna Susan M. O’Brien Constantine S. Tam Lugui Qiu Ruiqi Huang Yang Shi Adam Idoine Tommi Salmi Aileen Cleary Cohen Mazyar Shadman |
| author_facet | Jennifer R. Brown Jessica Li Barbara F. Eichhorst Nicole Lamanna Susan M. O’Brien Constantine S. Tam Lugui Qiu Ruiqi Huang Yang Shi Adam Idoine Tommi Salmi Aileen Cleary Cohen Mazyar Shadman |
| author_sort | Jennifer R. Brown |
| collection | DOAJ |
| description | Abstract: Some patients with chronic lymphocytic leukemia who develop progressive disease (PD) during covalent Bruton tyrosine kinase (BTK) inhibitor treatment acquire resistance mutations in BTK or PLCG2. Here, we report gene mutation data from paired baseline and PD peripheral blood samples from 52 patients (zanubrutinib, n = 24; ibrutinib, n = 28) who, at an early median follow-up of 25.7 months, progressed on zanubrutinib or ibrutinib treatment in ALPINE. No BTK mutations were observed at baseline; at PD, 8 patients (zanubrutinib, n = 5; ibrutinib, n = 3) acquired 17 BTK mutations, 82.4% (zanubrutinib, n = 11/14; ibrutinib, n = 3/3) at C481. Non-C481 mutations occurred in 12.5% (3/24) of zanubrutinib-treated patients (L528W: n = 2; cancer cell fraction [CCF] = 9.58% and 17.6%; A428D: n = 1; CCF = 37.03%). At baseline, 48 of 52 patients had ≥1 driver gene mutation(s), most frequently in NOTCH1 (n = 21), TP53 (n = 19), BRAF (n = 10), SF3B1 (n = 8), and ATM (n = 8). At PD, acquired mutations occurred in 1 zanubrutinib-treated patient (TP53, XPO1) and 5 ibrutinib-treated patients (TP53, n = 1 patient; SETD2, n = 1; SF3B1, n = 1; ASXL1, n = 2). Baseline driver gene mutations were not associated with development of BTK mutations, but patients with ≥2 baseline driver gene mutations were more likely to acquire BTK mutations at PD. The short treatment duration and a low BTK mutations incidence suggests that mechanisms other than BTK/PLCG2 mutations drive most early PD. This trial was registered at www.ClinicalTrials.gov as #NCT03734016. |
| format | Article |
| id | doaj-art-00f926768bb84de18cb1d6ea2384dea4 |
| institution | OA Journals |
| issn | 2473-9529 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Advances |
| spelling | doaj-art-00f926768bb84de18cb1d6ea2384dea42025-08-20T02:09:26ZengElsevierBlood Advances2473-95292025-04-01981918192610.1182/bloodadvances.2024014206Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE studyJennifer R. Brown0Jessica Li1Barbara F. Eichhorst2Nicole Lamanna3Susan M. O’Brien4Constantine S. Tam5Lugui Qiu6Ruiqi Huang7Yang Shi8Adam Idoine9Tommi Salmi10Aileen Cleary Cohen11Mazyar Shadman12Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Correspondence: Jennifer R. Brown, Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215;BeiGene Inc, San Mateo, CADepartment of Internal Medicine, University of Cologne, Center for Integrated Oncology Aachen Bonn Köln Düsseldorf, Cologne, GermanyHematology/Oncology Division, Columbia University, New York, NYDivision of Hematology/Oncology, University of California, Irvine, Irvine, CADepartment of Haematology, Alfred Hospital and Centre for Blood Diseases, Monash University, Melbourne, VIC, AustraliaNational Clinical Research Center for Hematological Disorders, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Tianjin Institutes of Health Science, Tianjin, ChinaBeiGene Co, Ltd, Shanghai, ChinaBeiGene Co, Ltd, Beijing, ChinaBeiGene Inc, San Mateo, CABeiGene International GmbH, Basel, SwitzerlandBeiGene Inc, San Mateo, CAClinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WAAbstract: Some patients with chronic lymphocytic leukemia who develop progressive disease (PD) during covalent Bruton tyrosine kinase (BTK) inhibitor treatment acquire resistance mutations in BTK or PLCG2. Here, we report gene mutation data from paired baseline and PD peripheral blood samples from 52 patients (zanubrutinib, n = 24; ibrutinib, n = 28) who, at an early median follow-up of 25.7 months, progressed on zanubrutinib or ibrutinib treatment in ALPINE. No BTK mutations were observed at baseline; at PD, 8 patients (zanubrutinib, n = 5; ibrutinib, n = 3) acquired 17 BTK mutations, 82.4% (zanubrutinib, n = 11/14; ibrutinib, n = 3/3) at C481. Non-C481 mutations occurred in 12.5% (3/24) of zanubrutinib-treated patients (L528W: n = 2; cancer cell fraction [CCF] = 9.58% and 17.6%; A428D: n = 1; CCF = 37.03%). At baseline, 48 of 52 patients had ≥1 driver gene mutation(s), most frequently in NOTCH1 (n = 21), TP53 (n = 19), BRAF (n = 10), SF3B1 (n = 8), and ATM (n = 8). At PD, acquired mutations occurred in 1 zanubrutinib-treated patient (TP53, XPO1) and 5 ibrutinib-treated patients (TP53, n = 1 patient; SETD2, n = 1; SF3B1, n = 1; ASXL1, n = 2). Baseline driver gene mutations were not associated with development of BTK mutations, but patients with ≥2 baseline driver gene mutations were more likely to acquire BTK mutations at PD. The short treatment duration and a low BTK mutations incidence suggests that mechanisms other than BTK/PLCG2 mutations drive most early PD. This trial was registered at www.ClinicalTrials.gov as #NCT03734016.http://www.sciencedirect.com/science/article/pii/S2473952925000473 |
| spellingShingle | Jennifer R. Brown Jessica Li Barbara F. Eichhorst Nicole Lamanna Susan M. O’Brien Constantine S. Tam Lugui Qiu Ruiqi Huang Yang Shi Adam Idoine Tommi Salmi Aileen Cleary Cohen Mazyar Shadman Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study Blood Advances |
| title | Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study |
| title_full | Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study |
| title_fullStr | Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study |
| title_full_unstemmed | Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study |
| title_short | Acquired mutations in patients with relapsed/refractory CLL who progressed in the ALPINE study |
| title_sort | acquired mutations in patients with relapsed refractory cll who progressed in the alpine study |
| url | http://www.sciencedirect.com/science/article/pii/S2473952925000473 |
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