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Chen J, Li J, Zhou DB, Cao XX. Evidence of the modified staging system and comparative performance of IPSS and revised IPSS in a Single-Center Asian cohort with Waldenström macroglobulinemia. Leuk Lymphoma 2025:1-9. [PMID: 40382792 DOI: 10.1080/10428194.2025.2505705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 04/18/2025] [Accepted: 05/05/2025] [Indexed: 05/20/2025]
Abstract
Waldenström macroglobulinemia (WM), a rare incurable low-grade B-cell lymphoma, exhibits heterogeneous survival outcomes. We evaluated the prognostic performance of a novel modified staging system of WM (MSS-WM) through comparison with existing models in a single-center cohort of 294 symptomatic WM patients. MSS-WM demonstrated significant stratification capacity (p < 0.0001), with 5-year overall survival rates of 89% (low-risk), 84% (low-intermediate), and 52% (intermediate/high-risk). All MSS-WM factors, including age, serum albumin, and LDH demonstrated independent prognostic impact. In addition, high beta-2 microglobulin level also showed negative prognostic impacts (p = 0.0002). While high concordance of MSS-WM and the revised IPSS (rIPSS-WM) was confirmed, the rIPSS-WM exhibited better predictive accuracy. However, MSS-WM's simplified structure enhances clinical utility, enabling rapid risk stratification: 89% 5-year survival in low-risk vs 52% in high-risk groups. This practical staging system requires no complex calculations, making it preferable for routine clinical implementation while maintaining comparable prognostic discrimination.
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Affiliation(s)
- Jia Chen
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jian Li
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dao-Bin Zhou
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin-Xin Cao
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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2
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Xiong W, Yan Y, Wang T, Sui W, Yu Y, Yu T, Lyu R, Wang Y, Liu W, Liu H, An G, Xu Y, Huang W, Zou D, Qiu L, Yi S. Zanubrutinib plus Ixazomib and Dexamethasone in Newly Diagnosed Symptomatic Waldenström Macroglobulinemia: A Phase II Study. Clin Cancer Res 2025; 31:1856-1864. [PMID: 40053705 DOI: 10.1158/1078-0432.ccr-24-3490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/29/2024] [Accepted: 03/04/2025] [Indexed: 03/09/2025]
Abstract
PURPOSE Waldenström macroglobulinemia (WM) is a rare type of lymphoma, with no optimal treatment. Bruton's tyrosine kinase inhibitors have shown promising outcomes, yet achieving deep remission (very good partial remission or complete remission) remains challenging. and time-limited therapy with proteasome inhibition has not been reported. We conducted a phase II clinical trial (NCT04463953) to evaluate the efficacy and safety of combining zanubrutinib, ixazomib, and dexamethasone (ZID) in patients with newly diagnosed WM. PATIENTS AND METHODS A total of 27 patients were enrolled in the study. Patients received ZID induction therapy for up to six 28-day cycles, followed by consolidation therapy for a total of 24 cycles. The primary endpoint was the deep remission rate. RESULTS Overall, 24 of the 27 enrolled patients completed induction treatment. One patient (4.2%) achieved complete remission. Ten patients (41.6%) achieved very good partial remission. The overall, major, and deep remission rates were 100%, 95.8%, and 45.8%, respectively. The median time to response was 2 months (range, 1-5). Five of the 22 patients had a CXCR4 mutation, with no disparity in deep remission between the patients with and without a CXCR4 mutation (40% vs. 50%; P = 0.594). The median abnormal lymphocyte (7.6% vs. 1.6%; P = 0.0019) and plasma cells (0.28%-0.02%; P = 0.0306) in bone marrow were significantly reduced after treatment. The median follow-up was 30.9 months (range, 15-42). The estimated median progression-free survival and overall survival were 40 months (95% confidence interval, 35.5-44.5) and not reached, respectively, with no difference in patients with/without CXCR4 mutations. The most common adverse event was hematologic toxicity. CONCLUSIONS The ZID regimen might offer deep remission and provide a time-limited Bruton's tyrosine kinase inhibitor therapy in patients with WM.
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Affiliation(s)
- Wenjie Xiong
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Yuting Yan
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Tingyu Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Weiwei Sui
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Ying Yu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Tengteng Yu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Rui Lyu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Yi Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Wei Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Huimin Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Gang An
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Yan Xu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Wenyang Huang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Dehui Zou
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Lugui Qiu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Shuhua Yi
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
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3
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Liu X, Lin Y, Zhuang Q, Deng H, Liu A, Sun J. BTK inhibitors resistance in B cell malignancies: Mechanisms and potential therapeutic strategies. Blood Rev 2025; 71:101273. [PMID: 40000280 DOI: 10.1016/j.blre.2025.101273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 02/02/2025] [Accepted: 02/17/2025] [Indexed: 02/27/2025]
Abstract
Bruton tyrosine kinase inhibitors (BTKi) have shown prominent clinical efficacy in patients with B cell malignancies, such as chronic lymphocytic leukemia, mantle cell lymphoma, diffuse large B cell lymphoma, and Waldenström's macroglobulinemia. Nevertheless, numerous factors contribute to BTKi resistance, encompassing genetic mutations, chromosomal aberrations, dysregulation of protein expression, tumor microenvironment, and metabolic reprogramming. Accordingly, potential therapeutic strategies have been explored to surmount BTKi resistance, including noncovalent BTKi, BTK proteolysis-targeting chimeras, and combination therapies. Herein, we summarize the mechanisms responsible for BTKi resistance as well as the current preclinical and clinical strategies to address BTKi resistance in B cell malignancies treatment.
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Affiliation(s)
- Xin Liu
- Zhejiang Key Laboratory for Precision Diagnosis and Treatment of Hematological Malignancies, Hangzhou, China; Department of Hematology, Harbin Medical University Cancer Hospital, Harbin, China
| | - Yufan Lin
- Zhejiang Key Laboratory for Precision Diagnosis and Treatment of Hematological Malignancies, Hangzhou, China; Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Qiqi Zhuang
- Zhejiang Key Laboratory for Precision Diagnosis and Treatment of Hematological Malignancies, Hangzhou, China; Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Haoren Deng
- Zhejiang Key Laboratory for Precision Diagnosis and Treatment of Hematological Malignancies, Hangzhou, China
| | - Aichun Liu
- Department of Hematology, Harbin Medical University Cancer Hospital, Harbin, China.
| | - Jie Sun
- Zhejiang Key Laboratory for Precision Diagnosis and Treatment of Hematological Malignancies, Hangzhou, China; Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Zhejiang Provincial Clinical Research Center for Hematological Disorders, Hangzhou, China.
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4
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Kim HO. BTK inhibitors and next-generation BTK-targeted therapeutics for B-cell malignancies. Arch Pharm Res 2025; 48:426-449. [PMID: 40335884 DOI: 10.1007/s12272-025-01546-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Accepted: 05/01/2025] [Indexed: 05/09/2025]
Abstract
Bruton's tyrosine kinase (BTK) is a therapeutically validated drug target. Small-molecule inhibitors of BTK have changed the treatment paradigms of multiple B-cell malignancies and evolved over three generations to overcome clinical challenges. Four drugs are now approved by the FDA, including the first-in-class drug ibrutinib and successively approved acalabrutinib, zanubrutinib, and pirtobrutinib. The third-generation drug pirtobrutinib, which binds non-covalently to BTK, is expected to overcome resistance mutations at the covalent binding Cys481 residue of the first and second-generation drugs that covalently bind to BTK. However, some newly identified non-Cys481 resistance mutations to pirtobrutinib have shown their co-resistance to some of the covalent inhibitors, and this leaves a major unmet need that is promoting the development of next-generation BTK-targeted therapeutics. More non-covalent BTK inhibitors with differentiated binding modes are under development, and the ongoing development focus of next-generation therapeutics involves new and alternative directions to target BTK using dual-binding inhibitors and degraders of BTK, as well as its allosteric inhibitors. Recent exploration of the differentiated features of BTK inhibitors in various aspects has shown the possible link between their different features and different functional and therapeutic consequences. This review summarizes the key differentiated features of the BTK inhibitors approved by the FDA and others under development to add knowledge for their therapeutic application and future development. Long-term follow-up updates of clinical outcomes of the earlier developed drugs are also included, together with direct and indirect comparisons of efficacy and safety between the different generations of drugs. The ongoing development status of next-generation BTK-targeted therapeutics is described, with a discussion on their therapeutic potential and some limitations.
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Affiliation(s)
- Hyung-Ook Kim
- Department of Clinical Medicinal Sciences, Konyang University, 121 Daehakro, Nonsan, 32992, Republic of Korea.
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5
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Guijosa A, Sarosiek S, Castillo JJ. Current and emerging treatment perspectives for adults with Waldenström macroglobulinemia. Expert Rev Anticancer Ther 2025; 25:485-497. [PMID: 40176471 DOI: 10.1080/14737140.2025.2488312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2025] [Accepted: 03/31/2025] [Indexed: 04/04/2025]
Abstract
INTRODUCTION Waldenström Macroglobulinemia (WM) is distinguished from other indolent lymphomas by its unique molecular landscape and clinical behavior. With the emergence of new therapeutic options and improved survival rates, it has become increasingly important to balance the goal of prolonging survival with minimizing treatment-related toxicities. AREAS COVERED This review focuses on the current therapeutic strategies for WM, emphasizing the clinical effectiveness of various agents and treatment groups and their associated toxicity profiles. Additionally, we discuss emerging therapies and combinations, which have shown encouraging preliminary results. EXPERT OPINION WM remains an incurable disease, yet its indolent nature and the growing array of therapeutic options have significantly improved outcomes in first- and subsequent-line settings. Chemoimmunotherapy and BTK inhibitors have demonstrated high efficacy and durable responses, with the latter offering a stem-cell-sparing approach. However, unlike in CLL or multiple myeloma, evidence supporting the superiority of targeted agents over chemoimmunotherapy is not available. Consequently, treatment decisions depend on patient characteristics and shared decision-making to carefully balance risks, select appropriate regimens, and encourage clinical trial participation to advance in understanding this rare disease.
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Affiliation(s)
- Alberto Guijosa
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Shayna Sarosiek
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Jorge J Castillo
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
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6
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Castillo JJ, Autore F, Berinstein NL, Branagan AR, Dimopoulos MA, Fernandez de Larrea C, Ferrero S, Kapoor P, Kastritis E, Khwaja J, Minnema MC, Qiu L, Seymour JF, Vos JMI, Patterson CJ, Buske C, Matous JV, Treon SP, Palomba ML. Report of Consensus Panel 5 from the 12th International Workshop on Waldenström's Macroglobulinemia on the management of patients with intolerance or resistance to covalent BTK inhibitors. Semin Hematol 2025:S0037-1963(25)00014-9. [PMID: 40379542 DOI: 10.1053/j.seminhematol.2025.04.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2025] [Accepted: 04/06/2025] [Indexed: 05/19/2025]
Abstract
Over the last decade, covalent Bruton tyrosine kinase (BTK) inhibitors have become a standard option for treating patients with symptomatic Waldenström Macroglobulinemia (WM) in the frontline or relapsed settings. However, the definition of intolerance and resistance to covalent BTK inhibitors has not been established. Understanding the best approaches to managing such patients is crucial to avoiding premature abandonment of effective therapy or pursuing futile therapies unlikely to be effective in controlling symptomatic disease progression. With the advent of noncovalent BTK inhibitors and BCL2 antagonists, in addition to clinical trials evaluating phospholipid-drug conjugates, antibody-drug conjugates, and bispecific antibodies, the present Consensus Panel 5 aims to establish working definitions for intolerance and resistance to covalent BTK inhibitors, as well as provide strategies to identify and manage these issues not infrequently encountered in clinical practice.
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Affiliation(s)
- Jorge J Castillo
- Bing Center for Waldenström Macroglobulinemia, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA.
| | - Francesco Autore
- Institute of Hematology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Neil L Berinstein
- Odette Cancer Centre, Sunnybrook Research Institute, Toronto, Canada
| | - Andrew R Branagan
- Division of Hematology and Oncology, Massachusetts General Hospital, Boston, MA
| | - Meletios A Dimopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
| | - Carlos Fernandez de Larrea
- Department of Hematology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona, Barcelona, Spain
| | - Simone Ferrero
- Department of Molecular Biotechnologies and Health Sciences, Division of Hematology, University of Torino, Torino, Italy
| | | | - Efstathios Kastritis
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
| | - Jahanzaib Khwaja
- Department of Haematology, University College London Hospital, London, United Kingdom
| | - Monique C Minnema
- Department of Hematology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Lugui Qiu
- National Clinical Research Center for Hematological Diseases, State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - John F Seymour
- Peter MacCallum Cancer Centre, Royal Melbourne Hospital and University of Melbourne, Melbourne, Victoria, Australia
| | - Josephine M I Vos
- Department of Hematology, Amsterdam University Medical Center (A-UMC), University of Amsterdam, Amsterdam, The Netherlands
| | - Christopher J Patterson
- Bing Center for Waldenström Macroglobulinemia, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA
| | - Christian Buske
- Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital Ulm, Ulm, Germany
| | - Jeffrey V Matous
- Plasma Cell Diseases Group Colorado Blood Cancer Institute, Sarah Cannon Research Institute, Denver, CO
| | - Steven P Treon
- Bing Center for Waldenström Macroglobulinemia, Harvard Medical School, Dana-Farber Cancer Institute, Boston, MA
| | - M Lia Palomba
- Lymphoma Service, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY
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7
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Zhang M, Wu Y, Cheng Z, Zhang L, Liu L, Liu F, Cui G, Xia L, Hu Y, Mei H, Guo T, Fang J. Zanubrutinib plus R-CHOP improves the treatment effect of newly diagnosed diffuse large B cell lymphoma with double expression of MYC and BCL-2. Front Immunol 2025; 16:1526318. [PMID: 40145086 PMCID: PMC11936942 DOI: 10.3389/fimmu.2025.1526318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 02/24/2025] [Indexed: 03/28/2025] Open
Abstract
Background Relevant studies have demonstrated the poor treatment outcomes and prognosis for double-expressor diffuse large B cell lymphoma (DE-DLBCL) in the rituximab era. Zanubrutinib plus R-CHOP (rituximab, cyclophosphamide, doxorubicin/liposomal doxorubicin, vincristine, prednisone; ZR-CHOP) has shown efficacy in untreated non-GCB DLBCL patients with extranodal involvement. However, its efficacy in newly diagnosed DE-DLBCL remains uncertain. Objective This retrospective study sought to assess the efficacy and safety of ZR-CHOP in comparison to R-CHOP in treatment-naïve patients with DE-DLBCL. Method This study assessed 78 patients with newly diagnosed DE-DLBCL who were admitted between June 2017 and January 2024. Among them, 55 patients received the R-CHOP regimen, while 23 patients were treated with the ZR-CHOP regimen. The clinical characteristics were well balanced between the two groups. Results The complete response rates (CRR) were higher in the ZR-CHOP group than the R-CHOP group, regardless of whether patients completed 4 or 6 treatment cycles (P= 0.019; P= 0.025). ORR in the ZR-CHOP group showed a higher trend than that in the R-CHOP group (P= 0.624; P= 0.219). The median follow-up period was 23.3 months, and the predicted median progression free survival (PFS) in the R-CHOP group was 22.8 months, whereas the median PFS in the ZR-CHOP group was not reached. The 1-, 2-, and 3-year PFS rates in the ZR-CHOP group showed a beneficial trend compared with the R-CHOP group, but there was no statistical difference (P= 0.072). However, the PFS of the ZR-CHOP group was longer than that of the R-CHOP group in patients with Ki67 index >75% (P= 0.034) and p53 expression >50% (P= 0.0033). The predicted median overall survival (OS) in the ZR-CHOP and R-CHOP groups were not reached. The 1-, 2- and 3-year OS rates were not significantly different between the two groups (P= 0.29). The most common adverse event in both groups was hematotoxicity, but there was no significant difference in the incidence of all adverse events between the two groups. Conclusion First-line treatment with the ZR-CHOP regimen improved CRR in the untreated patients with DE-DLBCL and prolonged PFS in the Ki67 index >75% subgroup and the p53 expression >50% subgroup.
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MESH Headings
- Humans
- Lymphoma, Large B-Cell, Diffuse/drug therapy
- Lymphoma, Large B-Cell, Diffuse/mortality
- Lymphoma, Large B-Cell, Diffuse/metabolism
- Lymphoma, Large B-Cell, Diffuse/genetics
- Lymphoma, Large B-Cell, Diffuse/diagnosis
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Cyclophosphamide/therapeutic use
- Cyclophosphamide/adverse effects
- Cyclophosphamide/administration & dosage
- Male
- Vincristine/therapeutic use
- Vincristine/adverse effects
- Vincristine/administration & dosage
- Female
- Doxorubicin/therapeutic use
- Doxorubicin/adverse effects
- Doxorubicin/administration & dosage
- Prednisone/therapeutic use
- Prednisone/adverse effects
- Prednisone/administration & dosage
- Middle Aged
- Rituximab/administration & dosage
- Rituximab/therapeutic use
- Rituximab/adverse effects
- Aged
- Retrospective Studies
- Adult
- Proto-Oncogene Proteins c-bcl-2/genetics
- Proto-Oncogene Proteins c-bcl-2/metabolism
- Pyrimidines/administration & dosage
- Pyrimidines/therapeutic use
- Pyrimidines/adverse effects
- Proto-Oncogene Proteins c-myc/genetics
- Proto-Oncogene Proteins c-myc/metabolism
- Pyrazoles/administration & dosage
- Pyrazoles/therapeutic use
- Pyrazoles/adverse effects
- Treatment Outcome
- Piperidines/administration & dosage
- Piperidines/therapeutic use
- Aged, 80 and over
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Tao Guo
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun Fang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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8
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Chen M, Li Y, Chen P. Restore intestinal steady-state: new advances in the clinical management of chemotherapy-associated diarrhea and constipation. J Mol Histol 2025; 56:101. [PMID: 40056250 PMCID: PMC11890403 DOI: 10.1007/s10735-025-10367-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Accepted: 02/02/2025] [Indexed: 03/10/2025]
Abstract
Chemotherapy remains the primary therapeutic strategy for most tumors, particularly those at advanced stages with distant metastases and resistance to molecularly targeted therapy or immunotherapy. There are many manifestations of chemotherapy-induced gastrointestinal toxicity (CIGT), including chemotherapy-induced diarrhea (CID) and chemotherapy-induced constipation (CIC). Although the World Health Organisation and the International Association Against Cancer have different grading criteria and strategies for the prevention and treatment of CIGT, there are still many unanswered questions that need to be clarified. This review critically describes pathological mechanisms and clinical research, analyzing the variability in diagnostic criteria and the absence of standardization in grading severity. We identify a critical gap in understanding the molecular underpinnings of CID and CIC and suggest targeted areas for future research, including developing personalized treatment approaches based on genetic profiling. The findings suggest a comprehensive treatment approach combining pharmacological and non-pharmacological strategies to enhance life quality and treatment adherence. This review will offer a comprehensive bird-eye of pathophysiological mechanisms, clinical manifestations, and therapeutic strategies of CIGT, thereby enriching accessible references to clinicians, and helping them to prevent and control CID and CIC.
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Affiliation(s)
| | - Yamao Li
- Ningxia Medical University, Yinchuan, China
| | - Peijun Chen
- Yancheng Sixth People's Hospital, Yancheng, Jiangsu, China
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9
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Bibas M, Sarosiek S, Castillo JJ. Waldenström Macroglobulinemia - A State-of-the-Art Review: Part 2- Focus on Therapy. Mediterr J Hematol Infect Dis 2025; 17:e2025015. [PMID: 40084099 PMCID: PMC11906134 DOI: 10.4084/mjhid.2025.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2024] [Accepted: 02/08/2025] [Indexed: 03/16/2025] Open
Abstract
The diagnosis and treatment of Waldenstrom macroglobulinemia (WM) are the subjects of this two-part review, which aims to provide current and thorough knowledge of these topics. The first portion of the study, previously published, investigated the epidemiology, etiology, clinicopathological aspects, differential diagnosis, prognostic factors, and impact on WM-specific groups. Specifically, this second section examines both the standard consolidated method and the new therapeutic strategy to handle the complex topic of the treatment of WM. Key Points WM has no cure, but therapies can improve survival. Treatment for WM/LPL patients should be initiated when they exhibit symptoms, and the IgM level should not determine WM treatment.Current guidelines suggest various initial personalized therapy treatments, typically chemoimmunotherapy (CIT) or BTK inhibitors (BTKi).Patients with WM can be put into three groups based on their MYD88 and CXCR4 mutational status: those with MYD88 mutations but no CXCR4 mutations (MYD88MUT/CXCR4WT), those with both MYD88 and CXCR4 mutations (MYD88MUT/CXCR4MUT) and those who do not have both MYD88 and CXCR4 mutations (MYD88WT/CXCR4WT).The objective of treatment is to alleviate symptoms and mitigate the risk of organ impairment.The timing of response evaluations, including BM, should be established on a case-by-case basis, informed by clinical and laboratory assessments.Patients with relapsed/refractory WM following chemotherapy and covalent Bruton tyrosine kinase inhibitors may choose non-covalent Bruton tyrosine kinase inhibitors, novel anti-CD20 monoclonal antibodies, BCL-2 inhibitors, or more intensive chemotherapy regimens.Patients who are younger and healthier and have not responded to both CIT and BTKi may be good candidates for an autologous stem cell transplant (ASCT).Second-generation anti-CD19 CAR T cells exhibit anti-WM activity in both in vitro and in vivo settings.From 2.4% to 11% of patients with WM undergo histological transformation, predominantly to diffuse large B-cell lymphoma (DLBCL). The median duration between diagnosis and transformation is 4.6 years.WM patients have a higher risk of secondary cancers.HSV and HZV prophylaxis may be beneficial for patients needing extensive treatment. Screening for Hepatitis B is necessary. Pneumocystis jiroveci prophylaxis is highly recommended. SARS-CoV- 2 and seasonal flu vaccines should be available to all WM patients.
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Affiliation(s)
- Michele Bibas
- Department of Clinical Research, Hematology. National Institute for Infectious Diseases "Lazzaro Spallanzani" I.R.C.S.S. Rome Italy
| | - Shayna Sarosiek
- Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Jorge J. Castillo
- Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
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10
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Heyman BM, Opat SS, Wahlin BE, Dimopoulos MAC, Castillo JJ, Tedeschi A, Tam CS, Buske C, Owen RG, Leblond V, Trotman J, Barnes G, Chan WY, Schneider J, Allewelt H, Cohen A, Matous JV. Peripheral neuropathy in the phase 3 ASPEN study of Bruton tyrosine kinase inhibitors for Waldenström macroglobulinemia. Blood Adv 2025; 9:722-728. [PMID: 39626287 PMCID: PMC11869863 DOI: 10.1182/bloodadvances.2024014115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Accepted: 10/18/2024] [Indexed: 02/13/2025] Open
Abstract
ABSTRACT Peripheral neuropathy (PN) is a significant cause of morbidity associated with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of zanubrutinib with ibrutinib in patients with WM. This ad hoc analysis examined treatment outcomes with zanubrutinib or ibrutinib on PN symptoms associated with WM in patients enrolled in ASPEN. Logistic regression was performed between PN symptom resolution and several predictors. Health-related quality of life (HRQOL) was assessed using the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30. Forty-nine patients with PN symptoms were included (zanubrutinib treated, n = 27; ibrutinib treated, n = 22). Overall, 35 patients (71.4%) experienced resolution of PN symptoms, with a median time to resolution of 10.1 months (range, 1-46.8). In cohort 1 (MYD88 mutation), the median time to PN symptom resolution was 4.6 months (range, 1.1-46.8) with zanubrutinib and 14.1 months (range, 1-44) with ibrutinib. Logistic regression demonstrated a significant relationship between PN symptom resolution and both major response and lower baseline anti-myelin-associated glycoprotein antibody levels. Patients with PN symptom resolution had greater improvement in HRQOL. Physical functioning improved in patients with PN symptom resolution and was unchanged in patients without resolution. Improvements observed in PN symptoms may be in response to a reduction in immunoglobulin M. Although further investigation is required, this analysis supports the potential use and further exploration of Bruton tyrosine kinase inhibitors to treat PN symptoms in patients with WM. This trial was registered at www.clinicaltrials.gov as #NCT03053440.
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Affiliation(s)
| | - Stephen S. Opat
- Department of Haematology, Lymphoma Research Group, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
| | - Björn E. Wahlin
- Department of Medicine, Karolinska Universitetssjukhuset Solna, Solna, Sweden
| | - Meletios-Athanasios C. Dimopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Alexandra Hospital, Athens, Greece
| | - Jorge J. Castillo
- Bing Center for Waldenström’s Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | | | - Constantine S. Tam
- Alfred Hospital, Melbourne, VIC, Australia
- Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Christian Buske
- Institute of Experimental Cancer Research, Comprehensive Cancer Center Ulm, University Hospital Ulm, Ulm, Germany
| | - Roger G. Owen
- St James’s University Hospital, Leeds, United Kingdom
| | | | - Judith Trotman
- Concord Repatriation General Hospital, University of Sydney, Concord, NSW, Australia
| | | | | | | | | | | | - Jeffrey V. Matous
- Colorado Blood Cancer Institute, Sarah Cannon Research Institute, Denver, CO
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11
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Beavers CJ, Ferrari AM. Cardio-oncology Drug Interactions: A Primer for Clinicians on Select Cardiotoxic Oncologic Therapies. Cardiol Clin 2025; 43:169-194. [PMID: 39551557 DOI: 10.1016/j.ccl.2024.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Cardio-oncology is an emerging multidisciplinary field intended to mitigate and manage cardiovascular side effects and risks associated with cancer therapies. Clinician awareness of drug interaction management among cancer treatments, cardiovascular medications, and supportive care agents is important for optimizing efficacy and safety. Historically, chemotherapies have been associated with pharmacodynamic interactions with few, but important, pharmacokinetic interactions. The advent of oral targeted inhibitors has introduced more complex pharmacokinetic interactions, especially via cytochrome P450 pathways. Given the accelerated development of oncology therapies, clinicians need to be familiar with reviewing multiple sources for interaction information as well as adjusting and monitoring regimens when contending with drug interaction challenges.
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Affiliation(s)
- Craig J Beavers
- Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, 789 South Limestone, Lexington, KY 40508, USA. https://twitter.com/beaverspharmd
| | - Alana M Ferrari
- Department of Pharmacy, University of Virginia, 1215 Lee Street, Charlottesville, VA 22903, USA.
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12
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Saiki K, Sofue T, Higashiyama C, Shiga T, Aoki Y, Shiraishi A, Kunisho Y, Onishi K, Nakamura E, Ishida T, Minamino T. A case of hyperviscosity syndrome associated with Waldenström macroglobulinemia treated with membrane plasma exchange without predilution. CEN Case Rep 2025; 14:90-94. [PMID: 38963601 PMCID: PMC11785898 DOI: 10.1007/s13730-024-00912-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Accepted: 06/29/2024] [Indexed: 07/05/2024] Open
Abstract
A 75-year-old man with blurred vision and nasal bleeding was diagnosed with hyperviscosity syndrome and central retinal vein occlusion secondary to Waldenström macroglobulinemia. Serum total protein and IgM levels were undetectable. Because of the severe symptoms, we determined that immediate plasma-exchange treatment was required to decrease the blood viscosity. The initial plasma exchange was performed using the membrane isolation method with a predilution standby. A saline predilution replacement was prepared to decrease the total membrane pressure (TMP); however, the predilution protocol was not used because the planned treatment volume could be achieved without increasing the TMP. After two consecutive days of membrane plasma exchange, all serum biochemical tests were measurable, and IgM was below 4000 mg/dL. After chemotherapy, his visual symptoms improved, and he was discharged. Since it is difficult to assess the risk of elevated TMP prior to initial plasma exchange, membrane plasma exchange with a predilution standby may be a useful strategy for initial plasma exchange for hyperviscosity syndrome in terms of safety and efficiency.
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Affiliation(s)
- Koichi Saiki
- Department of CardioRenal and CerebroVascular Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Tadashi Sofue
- Department of CardioRenal and CerebroVascular Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan.
| | - Chikako Higashiyama
- Department of Clinical Engineering, Kagawa University Hospital, Kagawa, Japan
| | - Takafumi Shiga
- Department of CardioRenal and CerebroVascular Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Yuhei Aoki
- Department of CardioRenal and CerebroVascular Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Aiko Shiraishi
- Department of CardioRenal and CerebroVascular Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Yasushi Kunisho
- Department of CardioRenal and CerebroVascular Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Keisuke Onishi
- Department of CardioRenal and CerebroVascular Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Eisuke Nakamura
- Department of CardioRenal and CerebroVascular Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Tomoya Ishida
- Department of Hematology and Immunology and Respiratory Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tetsuo Minamino
- Department of CardioRenal and CerebroVascular Medicine, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
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13
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Solia E, Kastritis E. Optimal use of BTK inhibitors in Waldenström's macroglobulinemia: combination or single drug approach? Ther Adv Hematol 2024; 15:20406207241308771. [PMID: 39734591 PMCID: PMC11672393 DOI: 10.1177/20406207241308771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 12/04/2024] [Indexed: 12/31/2024] Open
Abstract
Waldenström macroglobulinemia is an indolent B-cell lymphoma which although remains incurable, there are a lot of treatment options. Today, Bruton tyrosine kinase inhibitors have a central role in the management of the disease either as monotherapy or combination with other regimens, due to their efficacy, ease of administration, and safety profile. However, there is still active clinical investigation to further increase their efficacy and improve safety profile. Combinations based on BTK inhibitors may offer advantages. Second- and third-generation BTK inhibitors are also evaluated in combinations aiming to improve the depth of response, overcome genetic factors associated with poorer outcomes and reduce toxicity and duration of therapy.
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Affiliation(s)
- Eirini Solia
- Department of Clinical Therapeutics, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Efstathios Kastritis
- Department of Clinical Therapeutics, Faculty of Medicine, National and Kapodistrian University of Athens, 80 Vassilisis Sofias Avenue, Athens 11527, Greece
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14
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Ceribelli M, Tosto FA, Zhang X, Melani CJ, Roschewski M, Beck E, Klumpp-Thomas C, Peer CJ, Wilson KM, Chen L, McKnight C, Michael S, Itkin Z, Shinn P, Figg WD, Wilson WH, Staudt LM, Thomas CJ. Multi-Component, Time-Course screening to develop combination cancer therapies based on synergistic toxicity. Proc Natl Acad Sci U S A 2024; 121:e2413372121. [PMID: 39585996 PMCID: PMC11626182 DOI: 10.1073/pnas.2413372121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 10/21/2024] [Indexed: 11/27/2024] Open
Abstract
Clinical trials in cancer are ideally built on a foundation of sound mechanistic rationale and well-validated drug activity in relevant disease models. The screening of approved and investigational drugs in cell-based phenotypic assays can provide evidence of drug activity, but alternative screening paradigms are needed to develop and optimize multidrug combination regimens. Here, we utilize in vitro screening outcomes across a panel of lymphoma cell lines to dissect the activity of four small-molecule drugs (Venetoclax, Ibrutinib, Prednisolone, and Lenalidomide) currently under investigation within ongoing clinical trials in lymphoma. Data from multiple concentration ranges and time points show that synergistic drug combinations promote apoptosis and cytotoxicity responses at concentrations and time points that are consistent with in vivo drug exposures. To fully map the interaction landscape of these agents in relevant cell models, we developed an in vitro assay format that facilitated time-course evaluations involving concurrent multidrug exposure which further highlighted rapid, synergistic apoptosis induction as a central engine for the activity of this multicomponent targeted therapy. In addition to several instances of exceptional drug+drug synergy, the genetically similar diffuse large B cell lymphoma models also displayed substantial heterogeneity in the degree of synergism between drug pairs. A parallel survey of chemotherapies exhibited limited combination benefit, supporting recent findings that multicomponent chemotherapy outcomes are driven by individual drug activity. Collectively, these data demonstrate how in vitro drug screening data can identify multidrug combinations that exploit drug synergy to overcome the functional diversity of human malignancies.
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Affiliation(s)
- Michele Ceribelli
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD20850
| | - Frances Anne Tosto
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD20850
| | - Xiaohu Zhang
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD20850
| | - Christopher J. Melani
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD20892
| | - Mark Roschewski
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD20892
| | - Erin Beck
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD20850
| | - Carleen Klumpp-Thomas
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD20850
| | - Cody J. Peer
- Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD20892
| | - Kelli M. Wilson
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD20850
| | - Lu Chen
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD20850
| | - Crystal McKnight
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD20850
| | - Sam Michael
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD20850
| | - Zina Itkin
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD20850
| | - Paul Shinn
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD20850
| | - William D. Figg
- Clinical Pharmacology Program, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD20892
| | - Wyndham H. Wilson
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD20892
| | - Louis M. Staudt
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD20892
| | - Craig J. Thomas
- Division of Preclinical Innovation, National Center for Advancing Translational Sciences, NIH, Rockville, MD20850
- Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD20892
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15
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Kothari J, Eyre T, Rismani A, Ediriwickrema K, Edwards D, Galani S, Wilson W, Lawrie A, Clifton‐Hadley L, McCarthy H, Collins A, Lewis D, Arulogan S, Auer R, Pratt G, de Tute R, Owen R, D'Sa S. PembroWM: A phase II trial to investigate the safety and efficacy of rituximab and pembrolizumab in relapsed/refractory Waldenström's Macroglobulinaemia. Br J Haematol 2024; 205:2273-2281. [PMID: 39160671 PMCID: PMC11637722 DOI: 10.1111/bjh.19706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 08/04/2024] [Indexed: 08/21/2024]
Abstract
The optimal therapeutic approach for relapsed/refractory (R/R) Waldenström's Macroglobulinaemia (WM) has not been clearly defined, especially after treatment with chemoimmunotherapy (CIT) and covalent Bruton's tyrosine kinase inhibitors (cBTKi). The PembroWM trial is a multi-centre, phase II, single-arm study assessing the safety, tolerability and efficacy of rituximab with pembrolizumab in R/R WM patients who had received at least one prior line of treatment, with all having relapsed post-CIT and most also exposed to cBTKi. A total of 17 patients were enrolled, with a median age of 70, and median of three prior lines of therapy with 15 either refractory or intolerant of a cBTKi. A significant proportion was identified as genomically high risk with BTKC481, CXCR4 and MYD88 L265P wild-type aberrations. Twenty-four-week overall response rate was 50% (60% CI 39.3%-60.7%), and median duration of response was 11.6 months (IQR: 6.3-17). The median progression-free survival was 13.6 months (95% CI 3-19.8), and the median overall survival (OS) was not reached. Treatment was well tolerated, with minimal numbers of immune-mediated AEs typically seen with checkpoint inhibitors. PembroWM is the first study to evaluate the feasibility of PD-1 axis modulation in WM and has shown that in combination with Rituximab the combination is safe and deliverable.
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Affiliation(s)
- Jaimal Kothari
- Oxford University Hospitals NHS TrustOxfordUnited Kingdom of Great Britain and Northern Ireland
| | - Toby Eyre
- Oxford University Hospitals NHS TrustOxfordUnited Kingdom of Great Britain and Northern Ireland
| | - Ali Rismani
- University College HospitalLondonUnited Kingdom of Great Britain and Northern Ireland
| | - Kushani Ediriwickrema
- University College HospitalLondonUnited Kingdom of Great Britain and Northern Ireland
- Cancer Research UK and University College London Cancer Trials CentreLondonUnited Kingdom of Great Britain and Northern Ireland
| | - Darren Edwards
- Cancer Research UK and University College London Cancer Trials CentreLondonUnited Kingdom of Great Britain and Northern Ireland
| | - Sevasti Galani
- Cancer Research UK and University College London Cancer Trials CentreLondonUnited Kingdom of Great Britain and Northern Ireland
| | - William Wilson
- Cancer Research UK and University College London Cancer Trials CentreLondonUnited Kingdom of Great Britain and Northern Ireland
| | - Anthony Lawrie
- Cancer Research UK and University College London Cancer Trials CentreLondonUnited Kingdom of Great Britain and Northern Ireland
| | - Laura Clifton‐Hadley
- Cancer Research UK and University College London Cancer Trials CentreLondonUnited Kingdom of Great Britain and Northern Ireland
| | - Helen McCarthy
- University Hospitals Dorset NHS Foundation TrustBournemouthUnited Kingdom of Great Britain and Northern Ireland
| | - Angela Collins
- Norfolk and Norwich University Hospital NHS TrustNorwichUnited Kingdom of Great Britain and Northern Ireland
| | - David Lewis
- Derriford HospitalPlymouthUnited Kingdom of Great Britain and Northern Ireland
| | - Suzanne Arulogan
- Guy's and St Thomas' Hospitals NHS TrustLondonUnited Kingdom of Great Britain and Northern Ireland
| | - Rebecca Auer
- St Bartholomew's HospitalLondonUnited Kingdom of Great Britain and Northern Ireland
| | - Guy Pratt
- University Hospitals Birmingham NHS Foundation TrustBirminghamUnited Kingdom of Great Britain and Northern Ireland
| | - Ruth de Tute
- Leeds Teaching Hospitals NHS TrustLeedsUnited Kingdom of Great Britain and Northern Ireland
| | - Roger Owen
- Leeds General InfirmaryLeedsUnited Kingdom of Great Britain and Northern Ireland
| | - Shirley D'Sa
- University College HospitalLondonUnited Kingdom of Great Britain and Northern Ireland
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16
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Chohan KL, Kapoor P. Novel Approaches to Managing Patients with Relapsed and Refractory Waldenström Macroglobulinemia. Curr Hematol Malig Rep 2024; 19:163-174. [PMID: 38970645 DOI: 10.1007/s11899-024-00730-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/26/2024] [Indexed: 07/08/2024]
Abstract
PURPOSE OF REVIEW Waldenström macroglobulinemia is a rare non-Hodgkin lymphoma (NHL) characterized by lymphoplasmacytic bone marrow infiltration associated with an immunoglobulin M (IgM) monoclonal gammopathy. Over the past two decades, a number of important novel therapies have emerged for the treatment of relapsed and refractory (R/R) WM. The purpose of this review is to discuss these novel agents. RECENT FINDINGS Chemoimmunotherapy which formed the basis treatment for R/R WM is slowly being replaced by novel targeted agents. These therapies, including Bruton's tyrosine kinase inhibitors, proteasome inhibitors, and B-cell lymphoma 2 inhibitors, have widened the landscape of management. Emerging therapies currently under investigation, such as bispecific T-cell engagers, chimeric antigen T-cell receptor therapy, and novel small molecule inhibitors, have additionally shown the potential to improve response and survival. The treatment of R/R WM has greatly evolved, in large part due to a greater understanding of the biology of WM, and the evaluation of novel targeted agents in the basket trials of NHL, showing early activity in the small WM cohorts. Combination regimens with these established and emerging novel therapies have the potential to further improve disease control and induce higher rates of deep responses. Strategies aimed at altering the disease trajectory would require randomized controlled trials to provide relevant data on optimal integration and sequencing of more effective and tolerable regimens earlier in the disease course.
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Affiliation(s)
| | - Prashant Kapoor
- Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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17
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Du J, Chen ZY, Gu XR, Wang T, Huang ZF. Bruton tyrosine kinase inhibitor-related atrial fibrillation and its implications in the treatment of B-cell lymphoma. Front Cardiovasc Med 2024; 11:1408983. [PMID: 39131702 PMCID: PMC11310794 DOI: 10.3389/fcvm.2024.1408983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Accepted: 07/12/2024] [Indexed: 08/13/2024] Open
Abstract
Adverse events of atrial fibrillation (AF) have been commonly reported in lymphoma patients in treating Bruton's tyrosine kinase inhibitors (BTKi). The incidence rate of AF can vary depending on the specific types of BTKi and the patient population. Totally 45 published studies have revealed that the overall incidence rate of AF is 5% (95% CI 4%-7%). By performing a subtype single-rate analysis, the second-generation BTKi shows a lower AF incidence rate and lower cardiovascular toxicity. In the subtype single-rate analysis, we conclude the different AF incidence rates of Ibrutinib (10%, 95% CI 7%-13%), Acalabrutinib (4%, 95% CI 1%-6%), Orelabrutinib (0%, 95% CI 0%-1%), and Zanubrutinib (0%, 95% CI 0%-1%). The comprehensive analysis of AF inspires us to better predict and manage AF and other cardiovascular events in treating lymphoma. Meticulous evaluation, collaboration between cardiologists and hematologists, and discovery of new biomarkers are essential for its management.
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Affiliation(s)
- Jun Du
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ze-Yu Chen
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao-Ran Gu
- Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ting Wang
- Department of Hematology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zou-Fang Huang
- Ganzhou Key Laboratory of Hematology, Department of Hematology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, Jiangxi, China
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18
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Zanwar S, Le-Rademacher J, Durot E, D’Sa S, Abeykoon JP, Mondello P, Kumar S, Sarosiek S, Paludo J, Chhabra S, Cook JM, Parrondo R, Dispenzieri A, Gonsalves WI, Muchtar E, Ailawadhi S, Kyle RA, Rajkumar SV, Delmer A, Fonseca R, Gertz MA, Treon SP, Ansell SM, Castillo JJ, Kapoor P. Simplified Risk Stratification Model for Patients With Waldenström Macroglobulinemia. J Clin Oncol 2024; 42:2527-2536. [PMID: 38788183 PMCID: PMC11268554 DOI: 10.1200/jco.23.02066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 02/20/2024] [Accepted: 03/12/2024] [Indexed: 05/26/2024] Open
Abstract
PURPOSE Patients with Waldenström macroglobulinemia (WM) have disparate outcomes. Newer therapies have emerged since the development of International Prognostic Scoring System, and MYD88L265P mutation is now frequently assessed at diagnosis, warranting reexamination of the prognostic parameters. PATIENTS AND METHODS We reviewed records of 889 treatment-naïve patients with active WM, consecutively seen between January 01, 1996, and December 31, 2017, to identify clinical predictors of overall survival (OS) in univariate analyses. Patients with complete data for the parameters significant on the univariate analyses (n = 341) were included in a multivariable analysis to derive a prognostic model, subsequently validated in a multi-institutional cohort. RESULTS In the derivation cohort (n = 341), age (hazard ratio [HR], 1.9 [95% CI, 1.2 to 2.1]; P = .0009), serum lactate dehydrogenase (LDH) above upper limit of normal (HR, 2.3 [95% CI, 1.3 to 4.5]; P = .007), and serum albumin <3.5 g/dL (HR, 1.5 [95% CI, 0.99 to 2.3]; P = .056) were independently prognostic. By assigning a score of 1 point each to albumin <3.5 g/dL (HR, 1.5) and age 66-75 years (HR 1.4) and 2 points for age >75 years (HR, 2.6) or elevated LDH (HR, 2.3), four groups with distinct outcomes were observed on the basis of the composite scores. Five-year OS was 93% for the low-risk (score 0), 82% for low-intermediate risk (score 1), 69% for intermediate-risk (score 2), and 55% for the high-risk (score ≥3; P < .0001) groups. In the validation cohort (N = 335), the model maintained its prognostic value, with a 5-year OS of 93%, 90%, 75%, and 57% for the four groups, respectively (P < .0001). CONCLUSION Modified Staging System for WM (MSS-WM), utilizing age, albumin, and LDH is a simple, clinically useful, and externally validated prognostic model that reliably risk-stratifies patients with symptomatic WM into four groups with distinct prognosis.
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Affiliation(s)
- Saurabh Zanwar
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Jennifer Le-Rademacher
- Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN
| | - Eric Durot
- Department of Hematology, University Hospital of Reims and UFR Médecine, Reims, France
| | - Shirley D’Sa
- University College of London, London, United Kingdom
| | - Jithma P. Abeykoon
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Patrizia Mondello
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - Shaji Kumar
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Jonas Paludo
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Joselle M. Cook
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Angela Dispenzieri
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Eli Muchtar
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Robert A. Kyle
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Alain Delmer
- Department of Hematology, University Hospital of Reims and UFR Médecine, Reims, France
| | | | - Morie A. Gertz
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Stephen M. Ansell
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
| | | | - Prashant Kapoor
- Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN
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Patel K, Ivanov A, Jocelyn T, Hantel A, Garcia JS, Abel GA. Patient-Reported Outcomes in Phase 3 Clinical Trials for Blood Cancers: A Systematic Review. JAMA Netw Open 2024; 7:e2414425. [PMID: 38829615 PMCID: PMC11148691 DOI: 10.1001/jamanetworkopen.2024.14425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Accepted: 04/01/2024] [Indexed: 06/05/2024] Open
Abstract
Importance Published research suggests that patient-reported outcomes (PROs) are neither commonly collected nor reported in randomized clinical trials (RCTs) for solid tumors. Little is known about these practices in RCTs for hematological malignant neoplasms. Objective To evaluate the prevalence of PROs as prespecified end points in RCTs of hematological malignant neoplasms, and to assess reporting of PROs in associated trial publications. Evidence Review All issues of 8 journals known for publishing high-impact RCTs (NEJM, Lancet, Lancet Hematology, Lancet Oncology, Journal of Clinical Oncology, Blood, JAMA, and JAMA Oncology) between January 1, 2018, and December 13, 2022, were searched for primary publications of therapeutic phase 3 trials for adults with hematological malignant neoplasms. Studies that evaluated pretransplant conditioning regimens, graft-vs-host disease treatment, or radiotherapy as experimental treatment were excluded. Data regarding trial characteristics and PROs were extracted from manuscripts and trial protocols. Univariable analyses assessed associations between trial characteristics and PRO collection or reporting. Findings Ninety RCTs were eligible for analysis. PROs were an end point in 66 (73%) trials: in 1 trial (1%) as a primary end point, in 50 (56%) as a secondary end point, and in 15 (17%) as an exploratory end point. PRO data were reported in 26 of 66 primary publications (39%): outcomes were unchanged in 18 and improved in 8, with none reporting worse PROs with experimental treatment. Trials sponsored by for-profit entities were more likely to include PROs as an end point (49 of 55 [89%] vs 17 of 35 [49%]; P < .001) but were not significantly more likely to report PRO data (20 of 49 [41%] vs 6 of 17 [35%]; P = .69). Compared with trials involving lymphoma (18 of 29 [62%]) or leukemia or myelodysplastic syndrome (18 of 28 [64%]), those involving plasma cell disorders or multiple myeloma (27 of 30 [90%]) or myeloproliferative neoplasms (3 of 3 [100%]) were more likely to include PROs as an end point (P = .03). Similarly, compared with trials involving lymphoma (3 of 18 [17%]) or leukemia or myelodysplastic syndrome (5 of 18 [28%]), those involving plasma cell disorders or multiple myeloma (16 of 27 [59%]) or myeloproliferative neoplasms (2 of 3 [67%]) were more likely to report PROs in the primary publication (P = .01). Conclusions and Relevance In this systematic review, almost 3 of every 4 therapeutic RCTs for blood cancers collected PRO data; however, only 1 RCT included PROs as a primary end point. Moreover, most did not report resulting PRO data in the primary publication and when reported, PROs were either better or unchanged, raising concern for publication bias. This analysis suggests a critical gap in dissemination of data on the lived experiences of patients enrolled in RCTs for hematological malignant neoplasms.
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Affiliation(s)
- Kishan Patel
- Department of Internal Medicine, Brigham & Women’s Hospital, Boston, Massachusetts
| | - Alexandra Ivanov
- Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Tajmah Jocelyn
- Center for Clinical Investigation, Brigham & Women’s Hospital, Boston, Massachusetts
| | - Andrew Hantel
- Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
- Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jacqueline S. Garcia
- Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Gregory A. Abel
- Division of Population Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts
- Division of Hematologic Malignancies, Dana-Farber Cancer Institute, Boston, Massachusetts
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20
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Moslehi JJ, Furman RR, Tam CS, Salem JE, Flowers CR, Cohen A, Zhang M, Zhang J, Chen L, Ma H, Brown JR. Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib. Blood Adv 2024; 8:2478-2490. [PMID: 38502198 PMCID: PMC11131064 DOI: 10.1182/bloodadvances.2023011641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 02/27/2024] [Accepted: 03/13/2024] [Indexed: 03/21/2024] Open
Abstract
ABSTRACT First-generation Bruton tyrosine kinase (BTK) inhibitor, ibrutinib, has been associated with an increased risk of cardiovascular toxicities. Zanubrutinib is a more selective, next-generation BTK inhibitor. In this analysis, incidence rates of atrial fibrillation, symptomatic (grade ≥2) ventricular arrhythmia, and hypertension were evaluated in a pooled analysis of 10 clinical studies with zanubrutinib monotherapy in patients (N = 1550) with B-cell malignancies and a pooled analysis of head-to-head studies comparing zanubrutinib with ibrutinib (ASPEN cohort 1; ALPINE). Among the 10 studies, most patients (median age, 67 years) were male (66.3%) and had CLL/SLL (60.5%). Overall incidence and exposure-adjusted incidence rates (EAIR) for atrial fibrillation, symptomatic ventricular arrhythmia, and hypertension were lower with zanubrutinib than ibrutinib. Despite a similar prevalence of preexisting cardiovascular events in ASPEN and ALPINE, atrial fibrillation/flutter incidence rates (6.1% vs 15.6%) and EAIR (0.2 vs 0.64 persons per 100 person-months; P < .0001) were lower with zanubrutinib than with ibrutinib. Symptomatic ventricular arrhythmia incidence was low for both zanubrutinib (0.7%) and ibrutinib (1.7%) with numerically lower EAIR (0.02 vs 0.06 persons per 100 person-months, respectively) for zanubrutinib. The hypertension EAIR was lower with zanubrutinib than ibrutinib in ASPEN but similar between treatment arms in ALPINE. The higher hypertension EAIR in ALPINE was inconsistent with other zanubrutinib studies. However, fewer discontinuations (1 vs 14) and deaths (0 vs 6) due to cardiac disorders occurred with zanubrutinib versus ibrutinib in ALPINE. These data support zanubrutinib as a treatment option with improved cardiovascular tolerability compared with ibrutinib for patients with B-cell malignancies in need of BTK inhibitors. These trials were registered at www.ClinicalTrials.gov as # NCT03053440, NCT03336333, NCT03734016, NCT04170283, NCT03206918, NCT03206970, NCT03332173, NCT03846427, NCT02343120, and NCT03189524.
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Affiliation(s)
- Javid J. Moslehi
- Section of Cardio-Oncology & Immunology, UCSF School of Medicine, San Francisco, CA
| | | | | | | | - Christopher R. Flowers
- Department of Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX
| | | | | | | | | | - Han Ma
- BeiGene Inc, San Mateo, CA
| | - Jennifer R. Brown
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
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21
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Xiang S, Shen R, Xiang J, Zhu N, Gu J, Shen J, Zhang Y, Ge H. A real-world pharmacovigilance study of FDA Adverse Event Reporting System (FAERS) events for Bruton's tyrosine kinase inhibitors (BTKis) single and its combination therapy. Expert Opin Drug Saf 2024; 23:627-636. [PMID: 38456691 DOI: 10.1080/14740338.2024.2327507] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 01/03/2024] [Indexed: 03/09/2024]
Abstract
BACKGROUND Bruton's tyrosine kinase inhibitors (BTKis) are targeted treatments for B-cell tumors but have significant side effects. This study assesses and contrasts the side effects of BTKis alone and its four combination therapies. RESEARCH DESIGN AND METHODS The reporting odds ratio (ROR) was used to analyze the data on three BTKis monotherapies and combinations of ibrutinib with rituximab, obinutuzumab, venetoclax, and lenalidomide in the FDA Adverse Event Reporting System (FAERS) database up to December 2022. RESULTS We analyzed the top 20 PTs for each treatment regimen. In monotherapies, atrial fibrillation (ROR (95% CI): 9.88 (9.47-10.32)) in zanubrutinib and rash (6.97 (5.42-8.98)) in acalabrutinib had higher associations. In combinations, infection (6.86 (6.11-7.70)), atrial fibrillation (27.96 (22.61-34.58)) and myelosuppression (10.09 (8.89-11.46)) were vital signals when ibrutinib was combined with obinutuzumab, and pyrexia (4.22 (2.57-6.93)) had a high signal value when combined with lenalidomide. Hemorrhage had a lower signal value when combined with venetoclax compared to ibrutinib alone (2.50 (2.18-2.87) vs 3.60 (3.52-3.68)). CONCLUSIONS The ibrutinib-obinutuzumab combo has the highest risk of infection, atrial fibrillation, and myelosuppression, and the ibrutinib-lenalidomide combo has the highest risk of pyrexia. However, the ibrutinib-venetoclax combo has a lower risk of hemorrhage than monotherapy.
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Affiliation(s)
- Sichun Xiang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Rongbin Shen
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Jingjing Xiang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Ni Zhu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Jianyou Gu
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Jianping Shen
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Yu Zhang
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
| | - Hangping Ge
- The First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, China
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22
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Grunenberg A, Buske C. How to manage waldenström's macroglobulinemia in 2024. Cancer Treat Rev 2024; 125:102715. [PMID: 38471356 DOI: 10.1016/j.ctrv.2024.102715] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/27/2024] [Accepted: 03/03/2024] [Indexed: 03/14/2024]
Abstract
Clinical management of Waldenström's Macroglobulinemia has seen major progress in the recent years, triggered by our improved understanding of the biology of the disease and the development of new therapies. Based on this there are multiple treatment options available for patients with WM ranging from classical immunochemotherapy to targeted approaches blocking key enzymes involved in lymphoma growth. This review summarizes our current knowledge about diagnostics and treatment of this rare but recurrent lymphoma subtype, which often presents a major clinical challenge in daily clinical life.
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Affiliation(s)
| | - Christian Buske
- Department of Internal Medicine III, University Hospital Ulm, Germany; Institute of Experimental Cancer Research, University Hospital, Germany.
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23
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Liang X, Ren H, Han F, Liang R, Zhao J, Liu H. The new direction of drug development: Degradation of undruggable targets through targeting chimera technology. Med Res Rev 2024; 44:632-685. [PMID: 37983964 DOI: 10.1002/med.21992] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 06/13/2023] [Accepted: 10/29/2023] [Indexed: 11/22/2023]
Abstract
Imbalances in protein and noncoding RNA levels in vivo lead to the occurrence of many diseases. In addition to the use of small molecule inhibitors and agonists to restore these imbalances, recently emerged targeted degradation technologies provide a new direction for disease treatment. Targeted degradation technology directly degrades target proteins or RNA by utilizing the inherent degradation pathways, thereby eliminating the functions of pathogenic proteins (or RNA) to treat diseases. Compared with traditional therapies, targeted degradation technology which avoids the principle of traditional inhibitor occupation drive, has higher efficiency and selectivity, and widely expands the range of drug targets. It is one of the most promising and hottest areas for future drug development. Herein, we systematically introduced the in vivo degradation systems applied to degrader design: ubiquitin-proteasome system, lysosomal degradation system, and RNA degradation system. We summarized the development progress, structural characteristics, and limitations of novel chimeric design technologies based on different degradation systems. In addition, due to the lack of clear ligand-binding pockets, about 80% of disease-associated proteins cannot be effectively intervened with through traditional therapies. We deeply elucidated how to use targeted degradation technology to discover and design molecules for representative undruggable targets including transcription factors, small GTPases, and phosphatases. Overall, this review provides a comprehensive and systematic overview of targeted degradation technology-related research advances and a new guidance for the chimeric design of undruggable targets.
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Affiliation(s)
- Xuewu Liang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Hairu Ren
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Fengyang Han
- School of Pharmacy, Fudan University, Shanghai, China
| | - Renwen Liang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
| | - Jiayan Zhao
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
| | - Hong Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China
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24
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Fares A, Carracedo Uribe C, Martinez D, Rehman T, Silva Rondon C, Sandoval-Sus J. Bruton's Tyrosine Kinase Inhibitors: Recent Updates. Int J Mol Sci 2024; 25:2208. [PMID: 38396884 PMCID: PMC10889086 DOI: 10.3390/ijms25042208] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/03/2024] [Accepted: 02/04/2024] [Indexed: 02/25/2024] Open
Abstract
Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the landscape for the treatment of hematological malignancies, solid tumors, and, recently, autoimmune disorders. The BTK receptor is expressed in several hematopoietic cells such as macrophages, neutrophils, mast cells, and osteoclasts. Similarly, the BTK receptor is involved in signaling pathways such as chemokine receptor signaling, Toll-like receptor signaling, and Fc receptor signaling. Due to their unique mechanism, these agents provide a diverse utility in a variety of disease states not limited to the field of malignant hematology and are generally well-tolerated.
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Affiliation(s)
- Amneh Fares
- Memorial Healthcare System, Pembroke Pines, FL 33021, USA; (C.C.U.); (D.M.)
- Moffitt Malignant Hematology at Memorial Healthcare System, Pembroke Pines, FL 33021, USA (J.S.-S.)
| | - Carlos Carracedo Uribe
- Memorial Healthcare System, Pembroke Pines, FL 33021, USA; (C.C.U.); (D.M.)
- Moffitt Malignant Hematology at Memorial Healthcare System, Pembroke Pines, FL 33021, USA (J.S.-S.)
| | - Diana Martinez
- Memorial Healthcare System, Pembroke Pines, FL 33021, USA; (C.C.U.); (D.M.)
- Moffitt Malignant Hematology at Memorial Healthcare System, Pembroke Pines, FL 33021, USA (J.S.-S.)
| | - Tauseef Rehman
- Memorial Healthcare System, Pembroke Pines, FL 33021, USA; (C.C.U.); (D.M.)
- Moffitt Malignant Hematology at Memorial Healthcare System, Pembroke Pines, FL 33021, USA (J.S.-S.)
| | - Carlos Silva Rondon
- Moffitt Malignant Hematology at Memorial Healthcare System, Pembroke Pines, FL 33021, USA (J.S.-S.)
| | - Jose Sandoval-Sus
- Moffitt Malignant Hematology at Memorial Healthcare System, Pembroke Pines, FL 33021, USA (J.S.-S.)
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25
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Yi S, Cai Z, Hu Y, He A, Gao S, Li Q, Sha L, Zhang N, Ren Y, Gai X, Yang X, Qin R, Qiu L. Ibrutinib Efficacy, Safety, and Pharmacokinetics in Chinese Patients with Relapsed or Refractory Waldenström's Macroglobulinemia: A Multicenter, Single-Arm, Phase 4 Study. Adv Ther 2024; 41:672-685. [PMID: 38079089 PMCID: PMC10838836 DOI: 10.1007/s12325-023-02720-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 10/26/2023] [Indexed: 02/06/2024]
Abstract
INTRODUCTION Waldenström's macroglobulinemia (WM) is a rare malignant B cell lymphoma which occurs in around 1-2% of all hematologic tumors. Ibrutinib was approved in China for WM on the basis of two global pivotal studies which enrolled no Chinese patients. The aim of this study was to determine the efficacy, safety, and pharmacokinetics of ibrutinib in Chinese patients with relapsed or refractory (r/r) WM. METHODS This was an open-label, single-arm, multicenter phase 4 study conducted across five sites in China. Enrolled patients with clinicopathological confirmed WM received ibrutinib 420 mg once daily orally until disease progression or unacceptable toxicity. The primary endpoint was major response rate (MRR, partial response [PR], or better) according to the modified consensus criteria from the Sixth International Workshop on WM. RESULTS Seventeen patients were enrolled; at data cutoff (March 19, 2022), MRR was 64.7% (90% confidence interval [CI] 42.0-83.4) and overall response rate was 100% (90% CI 83.8-100.0). One (5.9%) patient achieved very good PR, 10 (58.8%) achieved PR, and six (35.3%) achieved minor response. The median duration of response (PR or better) was 14.8 months (95% CI 10.8-not estimable [NE]). Median progression-free survival was 18.4 months (95% CI 12.9-NE). All patients experienced at least one treatment-emergent adverse event (TEAE) related to the study drug, and grade ≥ 3 TEAEs were reported in 13 (76.5%) patients. There were no TEAEs leading to dose reduction or death. The median model estimated maximum plasma concentration and area under the plasma concentration-time curve during 24 h after dosing at steady state were 40.5 ng/mL and 204 ng·h/mL, respectively. CONCLUSIONS Ibrutinib demonstrated durable responses in Chinese patients with r/r WM. Treatment was well tolerated with no new safety signals compared with the pivotal global studies. Ibrutinib exposure was also comparable between Chinese and non-Chinese patients. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT04042376.
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Affiliation(s)
- Shuhua Yi
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China
| | - Zhen Cai
- Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Aili He
- Department of Hematology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Sujun Gao
- Department of Hematology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Qian Li
- Janssen China Research & Development, Beijing, China
| | - Linlin Sha
- Janssen China Research & Development, Shanghai, China
| | - Nating Zhang
- Janssen China Research & Development, Shanghai, China
| | - Yupeng Ren
- Janssen China Research & Development, Shanghai, China
| | - Xue Gai
- Janssen China Research & Development, Beijing, China
| | - Xue Yang
- Janssen China Research & Development, Shanghai, China
| | - Rui Qin
- Janssen Research & Development, Raritan, NJ, USA
| | - Lugui Qiu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, 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, China.
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26
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Allouchery M, Brunet K, Tomowiak C, Singier A, Pambrun E, Pariente A, Bezin J, Pérault-Pochat MC, Salvo F. Invasive fungal infection incidence and risk factors in patients receiving ibrutinib in real-life settings: A nationwide population-based cohort study. Mycoses 2024; 67:e13676. [PMID: 37984556 DOI: 10.1111/myc.13676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 11/10/2023] [Accepted: 11/11/2023] [Indexed: 11/22/2023]
Abstract
BACKGROUND Data on the risk of invasive fungal infections (IFI) with ibrutinib treatment are scarce. OBJECTIVES This study aimed to determine IFI incidence and risk factors in ibrutinib-treated patients in real-life settings. METHODS We constituted a cohort of ibrutinib incident users in the French National Healthcare Database. All patients ≥18 years with a first dispensing of ibrutinib between 21 November 2014 and 31 December 2019 were included. Patients were followed from the cohort entry date until IFI, ibrutinib discontinuation, death, or 31 December 2020, whichever came first. The cumulative incidence function method was used to estimate the probability of IFI accounting for competing risk of death. A multivariate cause-specific Cox proportional hazards model was used to assess independent IFI risk factors. RESULTS Among 6937 ibrutinib-treated patients, 1-year IFI cumulative incidence was 1.3%, with invasive aspergillosis being the most frequent. Allogenic or autologous stem cell transplantation (ASCT) (hazard ratio [HR] 3.59, 95% confidence interval [1.74; 7.41]), previous anticancer treatment (HR 2.12, CI 95% [1.34; 3.35]) and chronic respiratory disease (HR 1.66, [1.03; 2.67]) were associated with higher risk of IFI. Besides neutropenia and corticosteroids, use of anti-CD20 agents was significantly more frequent in patients having experienced IFI (HR 3.68, [1.82; 7.45]). CONCLUSIONS In addition to patients with ASCT history, severe neutropenia or treated with corticosteroids, our findings support active surveillance of IFIs in those with chronic respiratory disease, previously treated, or treated with anti-CD20 agents in combination with ibrutinib. Further studies are needed to optimise IFI prophylaxis in these patient subgroups.
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Affiliation(s)
- Marion Allouchery
- Pharmacologie Clinique et Vigilances, CHU de Poitiers, Poitiers, France
- Faculté de Médecine et de Pharmacie, Université de Poitiers, Poitiers, France
- Univ. Bordeaux, INSERM, BPH, U1219, Team AHeaD, Bordeaux, France
| | - Kévin Brunet
- Faculté de Médecine et de Pharmacie, Université de Poitiers, Poitiers, France
- INSERM U1070 PHAR2, Université de Poitiers, Poitiers, France
- Laboratoire de Parasitologie et Mycologie Médicale, CHU de Poitiers, Poitiers, France
| | - Cécile Tomowiak
- Onco-Hématologie et Thérapie Cellulaire, CHU de Poitiers, Poitiers, France
- INSERM CIC 1402, CHU de Poitiers, Poitiers, France
| | - Allison Singier
- Univ. Bordeaux, INSERM, BPH, U1219, Team AHeaD, Bordeaux, France
| | - Elodie Pambrun
- Univ. Bordeaux, INSERM, BPH, U1219, Team AHeaD, Bordeaux, France
| | - Antoine Pariente
- Univ. Bordeaux, INSERM, BPH, U1219, Team AHeaD, Bordeaux, France
| | - Julien Bezin
- Univ. Bordeaux, INSERM, BPH, U1219, Team AHeaD, Bordeaux, France
- CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie médicale, Bordeaux, France
| | - Marie-Christine Pérault-Pochat
- Pharmacologie Clinique et Vigilances, CHU de Poitiers, Poitiers, France
- Laboratoire de Neurosciences Expérimentales et Cliniques, INSERM, UMR1084, Université de Poitiers, Poitiers, France
| | - Francesco Salvo
- Univ. Bordeaux, INSERM, BPH, U1219, Team AHeaD, Bordeaux, France
- CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie médicale, Bordeaux, France
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27
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Elamin G, Aljoundi A, Alahmdi MI, Abo-Dya NE, Soliman MES. Revealing the Role of the Arg and Lys in Shifting Paradigm from BTK Selective Inhibition to the BTK/HCK Dual Inhibition - Delving into the Inhibitory Activity of KIN-8194 against BTK, and HCK in the Treatment of Mutated BTKCys481 Waldenström Macroglobulinemia: A Computational Approach. Anticancer Agents Med Chem 2024; 24:813-825. [PMID: 36752293 DOI: 10.2174/1871520623666230208102609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 10/30/2022] [Accepted: 12/08/2022] [Indexed: 02/09/2023]
Abstract
BACKGROUND Despite the early success of Bruton's tyrosine kinase (BTK) inhibitors in the treatment of Waldenström macroglobulinemia (WM), these single-target drug therapies have limitations in their clinical applications, such as drug resistance. Several alternative strategies have been developed, including the use of dual inhibitors, to maximize the therapeutic potential of these drugs. OBJECTIVE Recently, the pharmacological activity of KIN-8194 was repurposed to serve as a 'dual-target' inhibitor of BTK and Hematopoietic Cell Kinase (HCK). However, the structural dual inhibitory mechanism remains unexplored, hence the aim of this study. METHODS Conducting predictive pharmacokinetic profiling of KIN-8194, as well as demonstrating a comparative structural mechanism of inhibition against the above-mentioned enzymes. RESULTS Our results revealed favourable binding affinities of -20.17 kcal/mol, and -35.82 kcal/mol for KIN-8194 towards HCK and BTK, respectively. Catalytic residues Arg137/174 and Lys42/170 in BTK and Arg303 and Lys75/173/244/247 in HCK were identified as crucial mediators of the dual binding mechanism of KIN-8194, corroborated by high per-residue energy contributions and consistent high-affinity interactions of these residues. Prediction of the pharmacokinetics and physicochemical properties of KIN-8194 further established its inhibitory potential, evidenced by the favourable absorption, metabolism, excretion, and minimal toxicity properties. Structurally, KIN-8194 impacted the stability, flexibility, solvent-accessible surface area, and rigidity of BTK and HCK, characterized by various alterations observed in the bound and unbound structures, which proved enough to disrupt their biological function. CONCLUSION These structural insights provided a baseline for the understanding of the dual inhibitory activity of KIN- 8194. Establishing the cruciality of the interactions between the KIN-8194 and Arg and Lys residues could guide the structure-based design of novel dual BTK/HCK inhibitors with improved therapeutic activities.
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Affiliation(s)
- Ghazi Elamin
- Department of Pharmaceutical Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
| | - Aimen Aljoundi
- Department of Pharmaceutical Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
| | - Mohamed I Alahmdi
- Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk, 7149, Saudi Arabia
| | - Nader E Abo-Dya
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Tabuk University, Tabuk, 71491, Saudi Arabia
- Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt
| | - Mahmoud E S Soliman
- Department of Pharmaceutical Sciences, University of KwaZulu-Natal, Westville Campus, Durban, 4001, South Africa
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Kapoor P, Rajkumar SV. Current approach to Waldenström macroglobulinemia. Blood Rev 2023; 62:101129. [PMID: 37659912 PMCID: PMC10841191 DOI: 10.1016/j.blre.2023.101129] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/24/2023] [Accepted: 08/25/2023] [Indexed: 09/04/2023]
Abstract
Waldenström macroglobulinemia (WM) is a unique CD20+, B-cell non-Hodgkin lymphoma, characterized by lymphoplasmacytic infiltration of the bone marrow and circulating monoclonal immunoglobulin M. The clinical manifestations and outcomes of patients are highly variable. High-level evidence supports integration of monoclonal anti-CD20 antibody, rituximab, to the chemotherapy backbone to treat WM. However, its contemporary management has become more nuanced, with deeper understanding of the pathophysiology and incorporation of Bruton's tyrosine kinase (BTK) inhibitors to the treatment paradigm. Prior knowledge of the patients' MYD88L265P and CXCR4 mutation status may aid in the treatment decision-making. Currently, the two frequently utilized approaches include fixed-duration chemoimmunotherapy and BTK inhibitor-based continuous treatment until progression. Randomized trials comparing these two vastly divergent approaches are lacking. Recent studies demonstrating efficacy of B cell lymphoma-2 (BCL2) inhibitors and non-covalent BTK inhibitors in patients, previously exposed to a covalent BTK inhibitor, are a testament to the rapidly expanding options against WM.
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Allouchery M, Tomowiak C, Singier A, Puyade M, Dari L, Pambrun E, Pariente A, Bezin J, Pérault-Pochat MC, Salvo F. Bleeding risk with concurrent use of anticoagulants and ibrutinib: A population-based nested case-control study. Br J Haematol 2023; 203:311-318. [PMID: 37485683 DOI: 10.1111/bjh.18995] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/22/2023] [Accepted: 07/13/2023] [Indexed: 07/25/2023]
Abstract
Data regarding the safety of co-administration of ibrutinib with anticoagulants in real-life settings are scarce. Using a nationwide database, we conducted a nested case-control study in a cohort of new users of ibrutinib to assess the risk of clinically relevant bleeding (CRB) associated with anticoagulation. Cases were patients with a diagnosis of CRB, defined as hospitalization with a diagnosis of bleeding. The date of CRB constituted the index date. Up to four controls were matched on sex, age at index date and duration of follow-up. The risk of CRB associated with anticoagulation in patients receiving ibrutinib was estimated using conditional logistic regression models, providing odds ratios (OR) adjusted for risk factors of bleeding. Among 614 cases and 2407 matched controls, the risk of CRB was significantly higher in patients receiving both ibrutinib and anticoagulants (adjusted OR [aOR] 2.54, confidence interval [CI] 95% [1.94; 3.32]). When considering anticoagulant class, aOR was 1.99 (CI 95% [1.19; 3.33]) for VKA, 2.48 (CI 95% [1.76; 3.47]) for direct oral anticoagulants and 3.40 (CI 95% [2.01; 5.75]) for parenteral anticoagulants. In conclusion, this study found a 2.5-fold increased risk of CRB in patients receiving both ibrutinib and anticoagulants in real-life settings, and similar aOR among oral anticoagulants.
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Affiliation(s)
- Marion Allouchery
- Pharmacologie Clinique et Vigilances, CHU de Poitiers, Poitiers, France
- Faculté de Médecine, Université de Poitiers, Poitiers, France
- Univ. Bordeaux, INSERM, BPH, U1219, Team AHeaD, Bordeaux, France
| | - Cécile Tomowiak
- Onco-Hématologie et Thérapie Cellulaire, CHU de Poitiers, Poitiers, France
- INSERM CIC 1402, CHU de Poitiers, Poitiers, France
| | - Allison Singier
- Univ. Bordeaux, INSERM, BPH, U1219, Team AHeaD, Bordeaux, France
| | - Mathieu Puyade
- INSERM CIC 1402, CHU de Poitiers, Poitiers, France
- Médecine Interne et Maladies Infectieuses, CHU de Poitiers, Poitiers, France
| | - Loubna Dari
- Univ. Bordeaux, INSERM, BPH, U1219, Team AHeaD, Bordeaux, France
- Médecine Vasculaire, CHU de Bordeaux, Bordeaux, France
| | - Elodie Pambrun
- Univ. Bordeaux, INSERM, BPH, U1219, Team AHeaD, Bordeaux, France
| | - Antoine Pariente
- Univ. Bordeaux, INSERM, BPH, U1219, Team AHeaD, Bordeaux, France
| | - Julien Bezin
- Univ. Bordeaux, INSERM, BPH, U1219, Team AHeaD, Bordeaux, France
- CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, Bordeaux, France
| | - Marie-Christine Pérault-Pochat
- Pharmacologie Clinique et Vigilances, CHU de Poitiers, Poitiers, France
- Laboratoire de Neurosciences Expérimentales et Cliniques, INSERM, UMR1084, Université de Poitiers, Poitiers, France
| | - Francesco Salvo
- Univ. Bordeaux, INSERM, BPH, U1219, Team AHeaD, Bordeaux, France
- CHU de Bordeaux, Pôle de Santé Publique, Service de Pharmacologie Médicale, Bordeaux, France
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Tam CS, Muñoz JL, Seymour JF, Opat S. Zanubrutinib: past, present, and future. Blood Cancer J 2023; 13:141. [PMID: 37696810 PMCID: PMC10495438 DOI: 10.1038/s41408-023-00902-x] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/01/2023] [Accepted: 08/14/2023] [Indexed: 09/13/2023] Open
Abstract
In recent years, Bruton tyrosine kinase (BTK) inhibitors have provided significant advances in the treatment of patients with B-cell malignancies. Ibrutinib was the first BTK inhibitor to be approved, and it changed the standard-of-care treatment for diseases such as chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, and Waldenström macroglobulinemia, improving efficacy outcomes and safety compared to chemotherapy. In this article, we review the development of zanubrutinib, a next-generation BTK inhibitor, from molecular design to patient-related outcomes. We start this journey by providing insights into the discovery of BTK and the physiologic, genetic, and molecular characterization of patients lacking this kinase, together with the brief treatment landscape in the era of chemo-immunotherapies. Zanubrutinib was originally developed by applying a structure-activity strategy to enhance the specificity as well as enzymatic and pharmacokinetic properties. Preclinical studies confirmed greater specificity and better bioavailability of zanubrutinib compared with that of ibrutinib, which supported the initiation of clinical trials in humans. Preliminary clinical results indicated activity in B-cell malignancies together with an improved safety profile, in line with less off-target effects described in the preclinical studies. The clinical program of zanubrutinib has since expanded significantly, with ongoing studies in a wide range of hemato-oncological diseases and in combination with many other therapies. Zanubrutinib currently is approved for various B-cell malignancies in multiple countries. This story highlights the importance of multidisciplinary collaborative research, from bench to bedside, and provides an example of how the commitment to finding improved treatment options should always run parallel to patient care.
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Affiliation(s)
| | | | - John F Seymour
- Peter MacCallum Cancer Centre, Royal Melbourne Hospital & University of Melbourne, Melbourne, VIC, Australia
| | - Stephen Opat
- Monash Health and Monash University, Clayton, VIC, Australia
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Chan WL, Chong VCL, Wee IJY, Poon LM, Chan EHL, Lee J, Chee YL, Jeyasekharan AD, Chng WJ, Samuel M, de Mel S. Efficacy and safety of front-line treatment regimens for Waldenstrom macroglobulinaemia: a systematic review and meta-analysis. Blood Cancer J 2023; 13:140. [PMID: 37679351 PMCID: PMC10485051 DOI: 10.1038/s41408-023-00916-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/15/2023] [Accepted: 08/29/2023] [Indexed: 09/09/2023] Open
Abstract
Rituximab-based chemo-immunotherapy is currently the standard first-line treatment for Waldenstrom macroglobulinaemia (WM), while ibrutinib has emerged as an alternative. In the absence of randomised trials (RCTs) comparing these regimens, the optimal first-line treatment for WM remains uncertain. In this systematic review and meta-analysis, we sought to assess the efficacy and safety of first-line treatment regimens for WM. We searched key databases from January 2007 to March 2023, including phase II and III trials, including treatment-naïve WM patients treated with rituximab-based regimens or ibrutinib. Response rates, progression-free survival (PFS), overall survival (OS), and toxicities were evaluated. Four phase III and seven phase II trials were included among 736 unique records. Pooled response rates from all comparative and non-comparative trials were 46%, 33% and 26% for bendamustine rituximab (BR), bortezomib-dexamethasone, cyclophosphamide, rituximab (BDRC) and ibrutinib rituximab (IR), respectively. Two-year pooled PFS was 89%, 81% and 82% with BR, BDRC and IR, respectively. Neuropathy was more frequent with bortezomib, while haematologic and cardiac toxicities were more common with chemo-immunotherapy and ibrutinib-based regimens respectively. Our findings suggest that BR yields higher response rates than bortezomib or ibrutinib-based combinations. RCTs comparing BR against emerging therapies, including novel Bruton Tyrosine Kinase Inhibitors, are warranted.
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Affiliation(s)
- Wee-Lee Chan
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | | | - Ian Jun Yan Wee
- Department of Surgery, Singapore General Hospital, Singapore, Singapore
| | - Li Mei Poon
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Esther Hian Lee Chan
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Joanne Lee
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Yen-Lin Chee
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
| | - Anand D Jeyasekharan
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Wee-Joo Chng
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Miny Samuel
- Research Support Unit, National University of Singapore, Singapore, Singapore
| | - Sanjay de Mel
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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Mak JWY, Law AWH, Law KWT, Ho R, Cheung CKM, Law MF. Prevention and management of hepatitis B virus reactivation in patients with hematological malignancies in the targeted therapy era. World J Gastroenterol 2023; 29:4942-4961. [PMID: 37731995 PMCID: PMC10507505 DOI: 10.3748/wjg.v29.i33.4942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Revised: 07/22/2023] [Accepted: 08/15/2023] [Indexed: 09/01/2023] Open
Abstract
Hepatitis due to hepatitis B virus (HBV) reactivation can be serious and potentially fatal, but is preventable. HBV reactivation is most commonly reported in patients receiving chemotherapy, especially rituximab-containing therapy for hematological malignancies and those receiving stem cell transplantation. Patients with inactive and even resolved HBV infection still have persistence of HBV genomes in the liver. The expression of these silent genomes is controlled by the immune system. Suppression or ablation of immune cells, most importantly B cells, may lead to reactivation of seemingly resolved HBV infection. Thus, all patients with hematological malignancies receiving anticancer therapy should be screened for active or resolved HBV infection by blood tests for hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen. Patients found to be positive for HBsAg should be given prophylactic antiviral therapy. For patients with resolved HBV infection, there are two approaches. The first is pre-emptive therapy guided by serial HBV DNA monitoring, and treatment with antiviral therapy as soon as HBV DNA becomes detectable. The second approach is prophylactic antiviral therapy, particularly for patients receiving high-risk therapy, especially anti-CD20 monoclonal antibody or hematopoietic stem cell transplantation. Entecavir and tenofovir are the preferred antiviral choices. Many new effective therapies for hematological malignancies have been introduced in the past decade, for example, chimeric antigen receptor (CAR)-T cell therapy, novel monoclonal antibodies, bispecific antibody drug conjugates, and small molecule inhibitors, which may be associated with HBV reactivation. Although there is limited evidence to guide the optimal preventive measures, we recommend antiviral prophylaxis in HBsAg-positive patients receiving novel treatments, including Bruton's tyrosine kinase inhibitors, B-cell lymphoma 2 inhibitors, and CAR-T cell therapy. Further studies are needed to determine the risk of HBV reactivation with these agents and the best prophylactic strategy.
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Affiliation(s)
- Joyce Wing Yan Mak
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong 852, China
| | | | | | - Rita Ho
- Department of Medicine, North District Hospital, Hong Kong 852, China
| | - Carmen Ka Man Cheung
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong 852, China
| | - Man Fai Law
- Department of Medicine and Therapeutics, Prince of Wales Hospital, Hong Kong 852, China
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García-Sanz R, Tedeschi A. The Management of Relapsed or Refractory Waldenström's Macroglobulinemia. Hematol Oncol Clin North Am 2023; 37:727-749. [PMID: 37246089 DOI: 10.1016/j.hoc.2023.04.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
Waldenström's macroglobulinemia (WM) is an immunoglobulin M monoclonal gammopathy produced by a bone marrow lymphoplasmacytic lymphoma, an indolent non-Hodgkin lymphoma in which the cure is still an unmet challenge. Combinations with alkylating agents, purine analogs, and monoclonal antibodies, Bruton tyrosine kinase, and proteasome inhibitors are used for the treatment of relapsed and refractory patients. Moreover, new additional agents can be seen on the horizon as potential effective therapies. No consensus on a preferred treatment in the relapsed setting is available yet.
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Affiliation(s)
- Ramón García-Sanz
- Department of Hematology, University Hospital of Salamanca, Research Biomedical Institute of Salamanca (IBSAL), Accelerator Project, Centro de Investigación Biomédica en Red-Cáncer (CIBERONC) CB16/12/00369 and Center for Cancer Research-IBMCC (USAL-CSIC), Paseo de San Vicente, 58-182, Salamanca 37007, Spain; Department of Hematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy.
| | - Alessandra Tedeschi
- Department of Hematology, University Hospital of Salamanca, Research Biomedical Institute of Salamanca (IBSAL), Accelerator Project, Centro de Investigación Biomédica en Red-Cáncer (CIBERONC) CB16/12/00369 and Center for Cancer Research-IBMCC (USAL-CSIC), Paseo de San Vicente, 58-182, Salamanca 37007, Spain; Department of Hematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
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Buske C, Palomba ML. Future Directions in the Frontline Management of Waldenström Macroglobulinemia. Hematol Oncol Clin North Am 2023; 37:719-725. [PMID: 37270384 DOI: 10.1016/j.hoc.2023.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Despite substantial progress in the clinical management of Waldenström's Macroglobulinemia (WM) and the emergence of chemotherapy-free approaches such as BTK inhibitors, WM is still a disease in which current treatments fail to cure and are in part associated with significant toxicities, compromising treatment outcome and quality of life. Thus, the vision for future front-line therapy should be to develop regimens which combine improved efficacy and excellent applicability with a low toxicity profile. Conventional immunochemotherapy such as bendamustine-rituximab is highly active but limited by hematotoxicity and long-lasting immunosuppression. Thus, further intensification of this treatment concept will most likely not be successful. Chemotherapy-free approaches such as BTK inhibitors have already changed the treatment landscape in WM, but still have major limitations such as the need for non-fixed duration treatment. Most probably, the combination of non-chemotherapy based, targeted approaches with different modes of action will ensure that we at least come closer to our vision of achieving functional cure in WM in the near future.
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Affiliation(s)
- Christian Buske
- University Hospital Ulm, Institute for Experimental Cancer Research, Albert - Einstein Allee 11, Ulm 89081, Germany.
| | - Maria Lia Palomba
- Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
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Varettoni M, Matous JV. BTK Inhibitors in the Frontline Management of Waldenström Macroglobulinemia. Hematol Oncol Clin North Am 2023; 37:707-717. [PMID: 37246088 DOI: 10.1016/j.hoc.2023.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/30/2023]
Abstract
The discovery of MYD88 (L265P) mutation led to investigating BTK inhibitors in Waldenström macroglobulinemia (WM). Ibrutinib, the first-in-class agent, was approved based on a phase II trial in relapsed/refractory patients. In the phase III iNNOVATE study, the combination of rituximab and ibrutinib was compared with rituximab and placebo in treatment-naïve and relapsed/refractory patients. Second-generation BTK inhibitor, zanubrutinib, was compared with Ibrutinib in MYD88-mutated WM patients in the phase III ASPEN trial, whereas acalabrutinib was investigated in a phase II trial. Here, we discuss the role of BTK inhibitors in treatment-naïve patients with WM based on currently available evidence.
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Affiliation(s)
- Marzia Varettoni
- Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Via Golgi 19, 27100 Pavia, Italy.
| | - Jeffrey V Matous
- Colorado Blood Cancer Institute, Sarah Cannon Research Institute, Denver, CO, USA
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García-Sanz R, Hunter ZR, Poulain S, Varettoni M, Owen RG. New developments in the diagnosis and characterization of Waldenström's macroglobulinemia. Expert Rev Hematol 2023; 16:835-847. [PMID: 37905549 DOI: 10.1080/17474086.2023.2270779] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 10/10/2023] [Indexed: 11/02/2023]
Abstract
INTRODUCTION Waldenström's macroglobulinemia (WM) is defined as a lymphoplasmacytic lymphoma (LPL) with immunoglobulin M (IgM) monoclonal gammopathy and morphologic evidence of bone marrow infiltration by LPL. Immunophenotyping and genotyping provide a firm pathological basis for diagnosis and are particularly valuable in differential diagnosis between WM and related diseases. Emerging technologies in mutational analysis present new opportunities, but challenges remain around standardization of methodologies and reporting of mutational data across centers. AREAS COVERED The review provides an overview of the diagnosis of WM, with a particular focus on the role of immunophenotyping and genotyping. EXPERT OPINION Demonstration of LPL with a bone marrow biopsy is essential to reach a definitive diagnosis of WM. However, MYD88L265P and a typical WM immunophenotypic profile are valuable for the differential diagnosis of WM and related diseases, such as marginal zone lymphoma, multiple myeloma, and chronic lymphocytic leukemia. These methodologies must be utilized across centers and with appropriate standards followed in the evaluation and reporting of sensitivities and specificities. The diagnostic and/or prognostic value of mutations in genes such as CXCR4 and TP53 that are currently not routinely evaluated in the diagnosis of WM should be explored.
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Affiliation(s)
- Ramón García-Sanz
- Hematology Department, University Hospital of Salamanca, IBSAL, CIBERONC, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain
| | - Zachary R Hunter
- Bing Center for Waldenström's Macroglobulinemia, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Stéphanie Poulain
- Service d'Hématologie Cellulaire, CHRU de Lille, University of Lille, Lille, France
| | - Marzia Varettoni
- Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Roger G Owen
- Haematological Malignancy Diagnostic Service, St James's University Hospital, Leeds, UK
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Nguyen TT, Nhu NT, Tran VK, Viet-Nhi NK, Ho XD, Jhan MK, Chen YP, Lin CF. Efficacy and safety of add-on anti-CD20 monoclonal antibody to Bruton tyrosine kinase inhibitor treatment for chronic lymphocytic leukemia: a meta-analysis. Sci Rep 2023; 13:9775. [PMID: 37328530 PMCID: PMC10276018 DOI: 10.1038/s41598-023-36279-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 05/31/2023] [Indexed: 06/18/2023] Open
Abstract
The efficacy of Bruton tyrosine kinase inhibitors (BTKi) remains suboptimal in chronic lymphocytic leukemia (CLL) treatment. A systematic review and meta-analysis were conducted to compare the outcomes of combining anti-CD20 monoclonal antibodies (mAb) with BTKi therapy versus BTKi monotherapy for patients with CLL. We searched for relevant studies in the Pubmed, Medline, Embase, and Cochrane databases until December 2022. We estimated the effective results using a hazard ratio (HR) for survival outcomes and relative risk (RR) for response outcomes and safety. Four randomized controlled trials (including 1056 patients) were found until November 2022 and fulfilled the inclusion criteria. Progression-free survival was significantly improved with the addition of anti-CD20 mAb to BTKi over BTKi (HR 0.70, 95% confidence interval (CI) 0.51-0.97), whereas pooled analysis of overall survival did not favor combination therapy compared to BTKi monotherapy (HR 0.72, 95% CI 0.50-1.04). Combination therapy was related to a statistically better complete response (RR, 2.03; 95% CI 1.01 to 4.06) and an undetectable minimal residual disease rate (RR, 6.43; 95% CI 3.54 to 11.67). The risk of grade ≥ 3 adverse events was comparable between the two groups (RR, 1.08; (95% CI 0.80 to 1.45). Overall, adding anti-CD20 mAb to BTKi revealed superior efficacy than BTKi alone in untreated or previously treated CLL patients without affecting the safety of single-agent BTKi. Conducting further randomized studies to confirm our results and determine the optimal therapy for managing patients with CLL is essential.
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Affiliation(s)
- Thi Thuy Nguyen
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
- Department of Oncology, Hue University of Medicine and Pharmacy, Hue University, Hue, Vietnam
| | - Nguyen Thanh Nhu
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
- Faculty of Medicine, Can Tho University of Medicine and Pharmacy, Can Tho, Vietnam
| | - Van Khoi Tran
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
- Department of Surgery, Hue University of Medicine and Pharmacy, Hue University, Hue, Vietnam
| | - Nguyen-Kieu Viet-Nhi
- International Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Xuan Dung Ho
- Department of Oncology, Hue University of Medicine and Pharmacy, Hue University, Hue, Vietnam
| | - Ming-Kai Jhan
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, No. 25, Wuxing St, Xinyi District, Taipei, 110, Taiwan
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | - Ya-Ping Chen
- Division of Hematology, Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 704, Taiwan
| | - Chiou-Feng Lin
- Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, No. 25, Wuxing St, Xinyi District, Taipei, 110, Taiwan.
- Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan.
- Core Laboratory of Immune Monitoring, Office of Research & Development, Taipei Medical University, Taipei, 110, Taiwan.
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Kumar V, Montgomery ND, van Deventer HW, Whang YE. Waldenström macroglobulinemia with secondary pure red cell aplasia in a patient with metastatic castrate resistant prostate cancer receiving an immune checkpoint inhibitor: a case report. J Med Case Rep 2023; 17:220. [PMID: 37245043 DOI: 10.1186/s13256-023-03948-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 04/24/2023] [Indexed: 05/29/2023] Open
Abstract
BACKGROUND Hypoproliferative anemia is a frequently encountered adverse event in cancer patients receiving immune checkpoint inhibitors (ICI). Secondary pure red cell aplasia (PRCA) is a rare but recognized immune related adverse event. With the burgeoning use of ICIs, the association of secondary PRCA with an underlying lymphoproliferative disorder is often overlooked. CASE PRESENTATION We report a case of a 67-year-old non-Hispanic Caucasian male with metastatic castrate resistant prostate cancer, who developed severe transfusion dependent anemia with reticulocytopenia while receiving treatment with olaparib and pembrolizumab. His bone marrow findings demonstrated erythroid hypoplasia, in addition to a CD5-negative, CD10-negative monotypic B-cell population and a somatic MYD88L265P mutation. With a presence of an IgM-paraprotein, he was diagnosed with Waldenström macroglobulinemia (WM) with secondary PRCA and treated with 6 cycles of bendamustine and rituximab. He achieved a complete response with this regimen and was transfusion independent. CONCLUSION In this case, underlying WM was uncovered through systematic investigation of anemia caused by ICI therapy. This report highlights the possibility of a lymphoproliferative disorder in patients with concerns for PRCA with prior ICI exposure. If identified, treating the underlying lymphoproliferative disorder is highly efficacious in the management of the secondary PRCA.
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Affiliation(s)
- Vaibhav Kumar
- Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Division of Oncology, Department of Medicine, University of North Carolina at Chapel Hill, 170 Manning Drive, Chapel Hill, NC, 27599-7305, USA
| | - Nathan D Montgomery
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Hendrik W van Deventer
- Division of Hematology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Young E Whang
- Division of Oncology, Department of Medicine, University of North Carolina at Chapel Hill, 170 Manning Drive, Chapel Hill, NC, 27599-7305, USA.
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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Johnson G, Baviriseaty N, Massanet N, Kooper J. Serositis causing pericardial and pleural effusions after eight years of maintenance ibrutinib for Waldenstrom's macroglobulinemia. J Oncol Pharm Pract 2023:10781552231171925. [PMID: 37097903 DOI: 10.1177/10781552231171925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/26/2023]
Abstract
INTRODUCTION Ibrutinib is a tyrosine kinase inhibitor approved for multiple B-cell malignancies, including Waldenstrom's macroglobulinemia in 2014. Although the drug portends favorable outcomes, it also bears a profile of side effects. Current literature describes only two cases of nonhemorrhagic pericardial effusion associated with ibrutinib use, and here we present the third. This case recounts an episode of serositis causing pericardial and pleural effusions and diffuse edema after eight years of maintenance ibrutinib for Waldenstrom's macroglobulinemia (WM). CASE REPORT A 90-year-old male with WM and atrial fibrillation presented to the emergency department for a week of progressive periorbital and upper and lower extremity edema, dyspnea, and gross hematuria, despite increasing at-home diuretic dose. The patient was on 140 mg ibrutinib twice daily. Labs showed stable creatinine, serum IgMs of 97, and negative serum and urine protein electrophoresis. Imaging revealed bilateral pleural effusions and pericardial effusion with impending tamponade. All other workup was unrevealing, diuretics were ceased, pericardial effusion was monitored with serial echocardiograms, and ibrutinib was exchanged for low-dose prednisone. MANAGEMENT AND OUTCOME After five days, the effusions and edema dissipated, hematuria resolved, and patient was discharged. Resumption of lower dose ibrutinib one month later led to a subsequent return of edema, which again subsided with cessation. Reevaluation of maintenance therapy continues outpatient. CONCLUSION Patients on ibrutinib presenting with dyspnea and edema should be monitored for pericardial effusion; the drug should be held in exchange for anti-inflammatory therapy, and future management should involve cautious, low-dose resumption, or exchange for alternative therapy.
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Affiliation(s)
- Grace Johnson
- University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | | | - Nicholas Massanet
- University of South Florida Morsani College of Medicine, Tampa, FL, USA
| | - Jeffrey Kooper
- James A Haley Veteran's Affairs Hospital, Tampa, FL, USA
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Heini AD, Beck P, Bacher U, Seipel K, Zander T, Daskalakis M, Pabst T. BeEAM Conditioning including High-Dose Bendamustine before Autologous Stem Cell Transplantation Is Safe and Effective in Patients with Waldenstrom's Macroglobulinemia. J Clin Med 2023; 12:jcm12062378. [PMID: 36983378 PMCID: PMC10057504 DOI: 10.3390/jcm12062378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Revised: 03/12/2023] [Accepted: 03/15/2023] [Indexed: 03/30/2023] Open
Abstract
High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is an option to consolidate remission in Waldenstrom's macroglobulinemia (WM), particularly in selected younger patients with chemosensitive disease. BEAM, consisting of BCNU, etoposide, cytarabine, and melphalan, is often used as a conditioning regimen. However, problems with BCNU, including pneumotoxicity, tolerance, and availability, necessitate the search for alternatives. In this pilot study, we investigated high-dose chemotherapy with BeEAM, in which BCNU is replaced with high-dose bendamustine as an alternative conditioning regimen in six subsequent patients with WM. Bendamustine treatment was well tolerated without unexpected toxicities. The overall response rate was 6/6 patients (2 very good partial responses (VGPR) and 4 PR). After a median follow-up of 72 months, two (33%) patients relapsed. Median progression-free and overall survivals were not reached, and no severe late-onset toxicities were observed so far. In this pilot study, BeEAM conditioning before ASCT seems feasible, safe, and effective in patients with WM.
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Affiliation(s)
- Alexander D Heini
- Department of Medical Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland
| | - Philipp Beck
- Department of Medical Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland
| | - Ulrike Bacher
- Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, 3010 Bern, Switzerland
- Department for Biomedical Research, University of Bern, 3010 Bern, Switzerland
| | - Katja Seipel
- Department of Medical Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland
| | - Thilo Zander
- Division of Medical Oncology, Luzerner Kantonsspital, 6004 Lucerne, Switzerland
| | - Michael Daskalakis
- Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, 3010 Bern, Switzerland
- Department for Biomedical Research, University of Bern, 3010 Bern, Switzerland
| | - Thomas Pabst
- Department of Medical Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland
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Buske C, Castillo JJ, Abeykoon JP, Advani R, Arulogun SO, Branagan AR, Cao X, D'Sa S, Hou J, Kapoor P, Kastritis E, Kersten MJ, LeBlond V, Leiba M, Matous JV, Paludo J, Qiu L, Tam CS, Tedeschi A, Thomas SK, Tohidi-Esfahani I, Varettoni M, Vos JM, Garcia-Sanz R, San-Miguel J, Dimopoulos MA, Treon SP, Trotman J. Report of consensus panel 1 from the 11 th International Workshop on Waldenstrom's Macroglobulinemia on management of symptomatic, treatment-naïve patients. Semin Hematol 2023; 60:73-79. [PMID: 37099027 DOI: 10.1053/j.seminhematol.2023.03.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 03/09/2023] [Indexed: 03/31/2023]
Abstract
Consensus Panel 1 (CP1) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) was tasked with updating guidelines for the management of symptomatic, treatment-naïve patients with WM. The panel reiterated that watchful waiting remains the gold standard for asymptomatic patients without critically elevated IgM or compromised hematopoietic function. For first-line treatment, chemoimmunotherapy (CIT) regimens such as dexamethasone, cyclophosphamide, rituximab (DRC), or bendamustine, rituximab (Benda-R) continue to play a central role in managing WM, as they are effective, of fixed duration, generally well-tolerated, and affordable. Covalent BTK inhibitors (cBTKi) offer a continuous, generally well-tolerated alternative for the primary treatment of WM patients, particularly those unsuitable for CIT. In a Phase III randomized trial updated at IWWM-11, the second-generation cBTKi, zanubrutinib, was less toxic than ibrutinib and induced deeper remissions, thus categorizing zanubrutinib as a suitable treatment option in WM. While the overall findings of a prospective, randomized trial updated at IWWM-11 did not show superiority of fixed duration rituximab maintenance over observation following attainment of a major response to Benda-R induction, a subset analysis showed benefit in patients >65 years and those with a high IPPSWM score. Whenever possible, the mutational status of MYD88 and CXCR4 should be determined before treatment initiation, as alterations in these 2 genes predict sensitivity towards cBTKi activity. Treatment approaches for WM-associated cryoglobulins, cold agglutinins, AL amyloidosis, Bing-Neel syndrome (BNS), peripheral neuropathy, and hyperviscosity syndrome follow the common principle of reducing tumor and abnormal protein burden rapidly and deeply to improve symptoms. In BNS, ibrutinib can be highly active and produce durable responses. In contrast, cBTKi are not recommended for treating AL amyloidosis. The panel emphasized that continuous improvement of treatment options for symptomatic, treatment-naïve WM patients critically depends on the participation of patients in clinical trials, whenever possible.
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Affiliation(s)
- Christian Buske
- University Hospital Ulm, Institute of Experimental Cancer Research, Ulm, Germany.
| | | | | | | | | | | | - Xinxin Cao
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | | | | | | | - Efstathios Kastritis
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
| | - Marie J Kersten
- Department of Hematology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam/LYMMCARE, Amsterdam, Netherlands
| | - Veronique LeBlond
- Groupe Hospitalier Pitié-Salpêtrière, Sorbonne University, Paris France
| | - Merav Leiba
- Faculty of Health Science, Ben- Gurion University of the Negev, Israel Assuta Ashdod University Hospital; Faculty of Health Science, Ben-Gurion University of the Negev, Negev, Israel Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jeffrey V Matous
- Colorado Blood Cancer Institute, Sarah Cannon Research Institute, Denver, CO
| | | | - Lugui Qiu
- National Clinical Medical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | | | | | | | | | - Marzia Varettoni
- Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Josephine M Vos
- Department of Hematology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam/LYMMCARE, Amsterdam, Netherlands
| | - Ramon Garcia-Sanz
- Hematology Department, University Hospital of Salamanca, Research Biomedical Institute of Salamanca, CIBERONC and Center for Cancer Research-IBMCC (University of Salamanca-CSIC), Salamanca, Spain
| | - Jesus San-Miguel
- Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Centro de Investigación Biomédica en Red Cáncer, Pamplona, Spain
| | - Meletios A Dimopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
| | - Steven P Treon
- Dana Farber Cancer Institute, Harvard Medical School, Boston MA
| | - Judith Trotman
- Concord Repatriation General Hospital, University of Sydney, Sydney, Australia
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Karam S, Haidous M, Dalle IA, Dendooven A, Moukalled N, Van Craenenbroeck A, Bazarbachi A, Sprangers B. Monoclonal gammopathy of renal significance: Multidisciplinary approach to diagnosis and treatment. Crit Rev Oncol Hematol 2023; 183:103926. [PMID: 36736510 DOI: 10.1016/j.critrevonc.2023.103926] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 01/13/2023] [Accepted: 01/20/2023] [Indexed: 02/05/2023] Open
Abstract
Monoclonal gammopathy of renal significance (MGRS) is a hemato-nephrological term referring to a heterogeneous group of kidney disorders characterized by direct or indirect kidney injury caused by a monoclonal immunoglobulin (MIg) produced by a B cell or plasma cell clone that does not meet current hematologic criteria for therapy. MGRS-associated kidney diseases are diverse and can result in the development of end stage kidney disease (ESKD). The diagnosis is typically made by nephrologists through a kidney biopsy. Many distinct pathologies have been identified and they are classified based on the site or composition of the deposited Mig, or according to histological and ultrastructural findings. Therapy is directed towards the identified underlying clonal population and treatment decisions should be coordinated between hematologists and nephrologists in a multidisciplinary fashion, depend on the type of MGRS, the degree of kidney function impairment and the risk of progression to ESKD.
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Affiliation(s)
- Sabine Karam
- Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, MN, United States
| | - Mohammad Haidous
- Department of Medicine, Saint Vincent Charity Medical Center, Cleveland, OH, United States
| | - Iman Abou Dalle
- Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Amélie Dendooven
- Department of Pathology, University Hospital Ghent, Ghent, Belgium
| | - Nour Moukalled
- Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Amaryllis Van Craenenbroeck
- Department of Microbiology, Immunology and Transplantation, Laboratory of Nephrology, KU Leuven, Leuven, Belgium; Division of Nephrology, University Hospitals Leuven, Leuven, Belgium
| | - Ali Bazarbachi
- Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon; Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut Medical Center, Beirut, Lebanon
| | - Ben Sprangers
- Biomedical Research Institute, Department of Immunology and Infection, University Hasselt, Diepenbeek, Belgium; Department of Nephrology, Ziekenhuis Oost-Limburg, Genk, Belgium.
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43
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Tam CS, Kapoor P, Castillo JJ, Buske C, Ansell SM, Branagan AR, Kimby E, Li Y, Palomba ML, Qiu L, Shadman M, Abeykoon JP, Sarosiek S, Vos J, Yi S, Stephens D, Roos-Weil D, Roccaro AM, Morel P, Munshi NC, Anderson KC, San-Miguel J, Garcia-Sanz R, Dimopoulos MA, Treon SP, Kersten MJ. Report of consensus panel 7 from the 11th international workshop on Waldenström macroglobulinemia on priorities for novel clinical trials. Semin Hematol 2023; 60:118-124. [PMID: 37099031 DOI: 10.1053/j.seminhematol.2023.03.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 03/09/2023] [Indexed: 04/27/2023]
Abstract
Recent advances in the understanding of Waldenström macroglobulinemia (WM) biology have impacted the development of effective novel agents and improved our knowledge of how the genomic background of WM may influence selection of therapy. Consensus Panel 7 (CP7) of the 11th International Workshop on WM was convened to examine the current generation of completed and ongoing clinical trials involving novel agents, consider updated data on WM genomics, and make recommendations on the design and prioritization of future clinical trials. CP7 considers limited duration and novel-novel agent combinations to be the priority for the next generation of clinical trials. Evaluation of MYD88, CXCR4 and TP53 at baseline in the context of clinical trials is crucial. The common chemoimmunotherapy backbones, bendamustine-rituximab (BR) and dexamethasone, rituximab and cyclophosphamide (DRC), may be considered standard-of-care for the frontline comparative studies. Key unanswered questions include the definition of frailty in WM; the importance of attaining a very good partial response or better (≥VGPR), within stipulated time frame, in determining survival outcomes; and the optimal treatment of WM populations with special needs.
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Affiliation(s)
- C S Tam
- Alfred Health, Monash University, Melbourne, Victoria, Australia.
| | | | - J J Castillo
- Harvard Medical School, Dana Farber Cancer Institute, Boston. MA
| | - C Buske
- Institute of Experimental Cancer Research, University Hospital Ulm, Ulm, Germany
| | | | | | - E Kimby
- Karolinska Institut, Stockholm, Sweden
| | - Y Li
- Baylor College of Medicine, Houston, TX
| | - M L Palomba
- Memorial Sloan Kettering Cancer Center, New York, NY
| | - L Qiu
- National National Clinical Medical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - M Shadman
- Fred Hutchinson Cancer Research Center, University of Washington, Seattle, WA
| | | | - S Sarosiek
- Harvard Medical School, Dana Farber Cancer Institute, Boston. MA
| | - Jmi Vos
- Department of Hematology, Cancer Center Amsterdam/LYMMCARE, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - S Yi
- National National Clinical Medical Research Center for Blood Diseases, 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 301600, China
| | - D Stephens
- University of Utah Huntsman Cancer Institute, Salt Lake City, UT
| | - D Roos-Weil
- Sorbonne University, Hematology Unit, Pitié-Salpêtrière Hospital, AP-HP, Paris, France
| | | | - P Morel
- Hematologie Clinique et Therapie Cellulaire, University Hospital Amiens Picardie, University of Picardie Jules Verne, France
| | - N C Munshi
- Institute of Experimental Cancer Research, University Hospital Ulm, Ulm, Germany
| | - K C Anderson
- Institute of Experimental Cancer Research, University Hospital Ulm, Ulm, Germany
| | - J San-Miguel
- Clinica Universidad de Navarra, CCUN, CIMA, IDISNA, CIBERONC, Navarra, Spain
| | - R Garcia-Sanz
- Hematology Department, University Hospital of Salamanca, Research Biomedical Institute of Salamanca, CIBERONC and Center for Cancer Research-IBMCC (University of Salamanca-CSIC), Salamanca, Spain
| | - M A Dimopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
| | - S P Treon
- Institute of Experimental Cancer Research, University Hospital Ulm, Ulm, Germany
| | - M J Kersten
- Tianjin Institutes of Health Science, Tianjin 301600, China
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Treon SP, Tedeschi A, San-Miguel J, Garcia-Sanz R, Anderson KC, Kimby E, Minnema MC, Benevolo G, Qiu L, Yi S, Terpos E, Tam CS, Castillo JJ, Morel P, Dimopoulos M, Owen RG. Report of consensus Panel 4 from the 11th International Workshop on Waldenstrom's macroglobulinemia on diagnostic and response criteria. Semin Hematol 2023; 60:97-106. [PMID: 37173155 DOI: 10.1053/j.seminhematol.2023.03.009] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 03/28/2023] [Indexed: 05/15/2023]
Abstract
Consensus Panel 4 (CP4) of the 11th International Workshop on Waldenstrom's Macroglobulinemia (IWWM-11) was tasked with reviewing the current criteria for diagnosis and response assessment. Since the initial consensus reports of the 2nd International Workshop, there have been updates in the understanding of the mutational landscape of IgM related diseases, including the discovery and prevalence of MYD88 and CXCR4 mutations; an improved recognition of disease related morbidities attributed to monoclonal IgM and tumor infiltration; and a better understanding of response assessment based on multiple, prospective trials that have evaluated diverse agents in Waldenstrom's macroglobulinemia. The key recommendations from IWWM-11 CP4 included: (1) reaffirmation of IWWM-2 consensus panel recommendations that arbitrary values for laboratory parameters such as minimal IgM level or bone marrow infiltration should not be used to distinguish Waldenstrom's macroglobulinemia from IgM MGUS; (2) delineation of IgM MGUS into 2 subclasses including a subtype characterized by clonal plasma cells and MYD88 wild-type, and the other by presence of monotypic or monoclonal B cells which may carry the MYD88 mutation; and (3) recognition of "simplified" response assessments that use serum IgM only for determining partial and very good partial responses (simplified IWWM-6/new IWWM-11 response criteria). Guidance on response determination for suspected IgM flare and IgM rebound related to treatment, as well as extramedullary disease assessment was also updated and included in this report.
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Affiliation(s)
- Steven P Treon
- Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute, Boston, MA.
| | | | - Jesus San-Miguel
- Clinica Universidad de Navarra, CCUN, CIMA, IDISNA, CIBERONC, Navarra, Spain
| | | | | | - Eva Kimby
- Division of Hematology, Department of Medicine Huddinge, Karolinska Institute, Stockholm Sweden
| | | | - Giulia Benevolo
- SSD Mieloma Unit e Clinical Trial e S.C. Hematology Univ., Turin Italy
| | - Lugui Qiu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science...Tianjin 301600, China
| | - Shuhui Yi
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China; Tianjin Institutes of Health Science...Tianjin 301600, China
| | | | | | - Jorge J Castillo
- Bing Center for Waldenstrom's Macroglobulinemia, Dana Farber Cancer Institute, Boston, MA
| | - Pierre Morel
- Hematology Department, University Hospital Amiens- Picardie, Amiens, France
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D'Sa S, Matous JV, Advani R, Buske C, Castillo JJ, Gatt M, Kapoor P, Kersten MJ, Leblond V, Leiba M, Palomba ML, Paludo J, Qiu L, Sarosiek S, Shadman M, Talaulikar D, Tam CS, Tedeschi A, Thomas SK, Tohidi-Esfahani I, Trotman J, Varettoni M, Vos J, Garcia-Sanz R, San-Miguel J, Dimopoulos MA, Treon SP, Kastritis E. Report of consensus panel 2 from the 11th international workshop on Waldenström's macroglobulinemia on the management of relapsed or refractory WM patients. Semin Hematol 2023; 60:80-89. [PMID: 37147252 DOI: 10.1053/j.seminhematol.2023.03.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 03/09/2023] [Indexed: 03/29/2023]
Abstract
The consensus panel 2 (CP2) of the 11th International Workshop on Waldenström's macroglobulinemia (IWWM-11) has reviewed and incorporated current data to update the recommendations for treatment approaches in patients with relapsed or refractory WM (RRWM). The key recommendations from IWWM-11 CP2 include: (1) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. (2) In selecting treatment, biological age, co-morbidities and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. (3) The trigger for initiating treatment in RRWM should utilize knowledge of patients' prior disease characteristics to avoid unnecessary delays. (4) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.
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Affiliation(s)
- S D'Sa
- UCLH Centre for Waldenström Macroglobulinaemia and Related Conditions, University College London Hospitals NHS Foundation Trust, London, UK.
| | - J V Matous
- Colorado Blood Cancer Institute, Sarah Cannon Research Institute, Denver, CO
| | - R Advani
- Stanford University Medical Center, Stanford, CA
| | - C Buske
- University Hospital Ulm, Ulm, Germany
| | - J J Castillo
- Dana Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - M Gatt
- Hadassah University Medical Center, Jerusalem, Israel
| | | | - M J Kersten
- Amsterdam UMC, University of Amsterdam, Department of Hematology, Cancer Center Amsterdam/LYMMCARE, Amsterdam, Netherlands
| | - V Leblond
- Groupe Hospitalier Pitié-Salpêtrière, Sorbonne University, Paris, France
| | - M Leiba
- Assuta Ashdod University Hospital; Faculty of Health Science, Ben-Gurion University of the Negev, Negev, Israel Memorial Sloan Kettering Cancer Center, New York, NY
| | - M L Palomba
- Memorial Sloan Kettering Cancer Center, New York NY US
| | | | - L Qiu
- National Clinical Medical Research Center for Blood Diseases, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
| | - S Sarosiek
- Dana Farber Cancer Institute, Harvard Medical School, Boston, MA
| | | | - D Talaulikar
- ANU College of Health and Medicine, Canberra, Australia
| | - C S Tam
- Alfred Health, Monash University, Melbourne, Australia
| | - A Tedeschi
- A. O. Ospedale Niguarda Ca' Granda, Milan, Italy
| | - S K Thomas
- University of Texas, MD Anderson Cancer Center, Houston TX USA
| | - I Tohidi-Esfahani
- Concord Repatriation General Hospital, University of Sydney, Sydney, Australia
| | - J Trotman
- Concord Repatriation General Hospital, University of Sydney, Sydney, Australia
| | - M Varettoni
- Division of Hematology, Fondazione iRCCS Policlinico, San Matteo, Italy
| | - Jmi Vos
- Amsterdam UMC, University of Amsterdam, Department of Hematology, Cancer Center Amsterdam/LYMMCARE, Amsterdam, Netherlands
| | - R Garcia-Sanz
- Hematology Department, University Hospital of Salamanca, Research Biomedical Institute of Salamanca, CIBERONC and Center for Cancer Research-IBMCC (University of Salamanca-CSIC), Salamanca, Spain
| | - J San-Miguel
- Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Centro de Investigación Biomédica en Red Cáncer, Pamplona, Spain
| | - M A Dimopoulos
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
| | - S P Treon
- Dana Farber Cancer Institute, Harvard Medical School, Boston, MA
| | - E Kastritis
- Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
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Kaur J, Valisekka SS, Hameed M, Bandi PS, Varma S, Onwughalu CJ, Ibrahim H, Mongia H. Monoclonal Gammopathy of Undetermined Significance: A Comprehensive Review. CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA 2023; 23:e195-e212. [PMID: 36966041 DOI: 10.1016/j.clml.2023.02.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 02/13/2023] [Accepted: 02/16/2023] [Indexed: 02/24/2023]
Abstract
Monoclonal Gammopathy of Undetermined Significance (MGUS) is an asymptomatic premalignant plasma cell dyscrasia with a predominate rise of the IgG immunoglobulin fraction without end-organ damage, often diagnosed incidentally. Despite its progression into various subsequent forms of hematological malignancies, MGUS remains underdiagnosed. A literature search was conducted using the Medline, Cochrane, Embase, and Google Scholar databases, including articles published until December 2022. Keywords used encompassed "Monoclonal Gammopathy of Undetermined Significance," "Plasma Cell dyscrasia," "Monoclonal gammopathy of renal significance," and "IgM Monoclonal gammopathy of Undetermined Significance," This study aimed to conduct a critical review to update knowledge regarding the pathophysiology, risk factors, clinical features, diagnostic protocols, complications, and current and novel treatments for MGUS. We recommend a multidisciplinary approach to manage MGUS due to the complexity of the illness's etiology, diagnosis, and therapy. This comprehensive review also highlights future prospects, such as developing screening protocols for at-risk populations, prevention of disease progression by early diagnosis through genome-wide association studies, and management using Daratumumab and NSAIDs.
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Affiliation(s)
- Jasneet Kaur
- Internal Medicine, Nassau University Medical Center, East Meadow, New York, USA..
| | | | - Maha Hameed
- Internal Medicine, Florida State University/Sarasota Memorial Hospital, Sarasota, Florida, USA.
| | | | | | | | - Hany Ibrahim
- Ain Shams University, Faculty of Medicine, Cairo, Egypt.
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Castillo JJ, Buske C, Trotman J, Sarosiek S, Treon SP. Bruton tyrosine kinase inhibitors in the management of Waldenström macroglobulinemia. Am J Hematol 2023; 98:338-347. [PMID: 36415104 PMCID: PMC10107762 DOI: 10.1002/ajh.26788] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 11/08/2022] [Accepted: 11/14/2022] [Indexed: 11/24/2022]
Abstract
Bruton tyrosine kinase (BTK) inhibitors have taken a central role in the management of patients with Waldenström macroglobulinemia and are the only agents approved by the Food and Drug Administration (FDA) to treat these patients. Although associated with high rates of durable responses, unmet needs with BTK inhibitor therapy include indefinite duration therapy, high cost, scarcity of complete responses, and lower rates and shorter duration of response in patients with CXCR4 mutations. Herein, we review the data supporting the use of covalent BTK inhibitors, selected management issues, clinical trials with covalent BTK inhibitor combination regimens, and up-and-coming non-covalent BTK inhibitors.
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Affiliation(s)
- Jorge J Castillo
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Christian Buske
- Comprehensive Cancer Center Ulm, Institute of Experimental Cancer Research, University Hospital Ulm, Ulm, Germany
| | - Judith Trotman
- Department of Haematology, Concord Repatriation General Hospital, Faculty of Medicine, University of Sydney, Concord, Australia
| | - Shayna Sarosiek
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
| | - Steven P Treon
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA
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Khwaja J, Uppal E, Bristogiannis S, McCarthy H, Kothari J, Rismani A, Scorer H, Nicholson J, El‐Sharkawi D, D'Sa S, Kyriakou C. Patient reported outcome measures in Waldenström macroglobulinaemia: A real-world data analysis from the WMUK Rory Morrison Registry. EJHAEM 2023; 4:221-225. [PMID: 36819170 PMCID: PMC9928784 DOI: 10.1002/jha2.640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Accepted: 12/22/2022] [Indexed: 12/31/2022]
Abstract
Waldenström macroglobulinaemia (WM) is an incurable chronic B-cell malignancy, but highly responsive to treatment. Treatments include fixed-duration chemotherapy and continuous oral chemoimmunotherapy. In this expanding field, it is important to have reliable information on the impact of the various therapies on patients' quality of life (QoL). Patient reported outcome measures (PROMs) are increasingly recognised as important to understand patient experience of disease beyond traditional clinical outcome measures. Four QoL questionnaires (EORTC QLQ-C30 [European Organisation for Research and Treatment of Cancer quality of life core questionnaire], BIPQ [Brief Illness Perception Questionnaire], HADS [Hospital Anxiety and Depression Scale], EQ-5D-5L [EuroQoL 5-dimensional descriptive system questionnaire]) are embedded in the UK national WM registry, the Rory Morrison Registry. We reviewed the results from a snapshot of PROMs. As of November 2021, 155 patients completed PROM data with 98% completion rate across all 58 questions. Complete clinical information was available for 52 patients. The majority of QoL questions (69%) failed to elicit a notable median response. Only four questions elicited statistically significant responses when comparing groups, and these were exclusively found in the EuroQoL-5D-5L and HADS questionnaires. Our data suggest that widely used questionnaires may not be suitable for patients with WM. We advocate the development of WM-specific outcome measures to overcome this.
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Affiliation(s)
- Jahanzaib Khwaja
- Department of HaematologyUniversity College London Hospitals NHS Foundation TrustLondonUK
| | - Encarl Uppal
- Department of HaematologyUniversity College London Hospitals NHS Foundation TrustLondonUK
| | - Sotirios Bristogiannis
- Department of HaematologyUniversity College London Hospitals NHS Foundation TrustLondonUK
| | - Helen McCarthy
- Department of HaematologyRoyal Bournemouth HospitalBournemouthUK
| | - Jaimal Kothari
- Department of HaematologyOxford University Hospitals NHS Foundation TrustOxfordUK
| | - Ali Rismani
- Department of HaematologyUniversity College London Hospitals NHS Foundation TrustLondonUK
| | | | | | - Dima El‐Sharkawi
- Department of HaematologyThe Royal Marsden Hospital NHS Foundation TrustLondonUK
| | - Shirley D'Sa
- Department of HaematologyUniversity College London Hospitals NHS Foundation TrustLondonUK
| | - Charalampia Kyriakou
- Department of HaematologyUniversity College London Hospitals NHS Foundation TrustLondonUK
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49
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Uppal E, Khwaja J, Bomsztyk J, McCarthy H, Kothari J, Walton P, Scorer H, Kyriakou C, El-Sharkawi D, D'Sa S. The Rory Morrison WMUK Registry for Waldenström macroglobulinaemia: The growth of a national registry for a rare disorder. Br J Haematol 2023; 201:905-912. [PMID: 36698318 DOI: 10.1111/bjh.18680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 12/25/2022] [Accepted: 01/04/2023] [Indexed: 01/27/2023]
Abstract
National registries are used globally to characterise patient demographics, treatment choices and mortality to inform and improve clinical management. Waldenström macroglobulinaemia (WM) is a rare, treatment-responsive B-cell lymphoproliferative disorder with diverse clinical features and variable outcomes. To prospectively chart changes in the management of WM in the UK, the Rory Morrison Registry (RMR) was developed to systematically collect real-world data. Here we describe the development of the RMR, demonstrate its feasibility and describe preliminary observations. The RMR was devised as a collaborative project between patients and clinicians, under the auspices of the UK Charity for WM in 2016. Patients may be registered after the point of diagnosis and those with historic diagnosis were also eligible. Data collection fields were compiled by focus groups of clinicians, patients, industry and commissioning partners. The RMR launched in November 2017 and as of March 2022, there were 22 participating centres and 1305 patients registered. Median follow-up was 6.4 years, five-year overall survival 90.7% (95% confidence interval [CI] 88.4%-92.5%) and 10-year overall survival 79.3% (95% CI 75.7%-82.4%). There has been a clear evolution in treatments including a rapid growth in the use of Bruton's tyrosine kinase inhibitors in relapsed disease since their availability in the UK.
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Affiliation(s)
| | | | | | - Helen McCarthy
- University Hospitals Dorset NHS Foundation Trust, Dorset, UK
| | - Jaimal Kothari
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
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50
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Sarosiek S, Gustine JN, Flynn CA, Leventoff C, Little M, White T, Meid K, Treon SP, Castillo JJ. Dose reductions in patients with Waldenström macroglobulinaemia treated with ibrutinib. Br J Haematol 2023; 201:897-904. [PMID: 36626914 DOI: 10.1111/bjh.18643] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Revised: 12/19/2022] [Accepted: 12/28/2022] [Indexed: 01/12/2023]
Abstract
Waldenström macroglobulinaemia (WM) is characterized by the presence of a MYD88L265P mutation. This mutation promotes growth and survival of malignant cells through Bruton tyrosine kinase (BTK) activation. Ibrutinib was the first BTK inhibitor approved for WM. Intolerance to ibrutinib frequently leads to dose reductions, though the impact of reducing ibrutinib dosing has not been systematically studied. We performed a retrospective study to determine the frequency and impact of reducing ibrutinib dosing in WM patients. With a median treatment time of 64 months, 96 (27%) of 353 WM patients required a dose reduction due to adverse events such as musculoskeletal symptoms, cardiac events, dermatologic symptoms, cytopenias, and gastrointestinal symptoms. The median time to initial dose reduction was 9.3 months (range, 0.5-74). Dose reductions were more common in those 65 years of age or older versus under 65 [hazard ratio (HR) 2.46, 95% confidence interval (CI) 1.55-3.90; p < 0.001], and in females versus males (HR 2.20, 95% CI 1.41-3.28, p < 0.001). Most patients (65%) had improvement or resolution of adverse effects after initial dose reduction. With a median follow-up of three years from dose reduction, hematologic response sustained or deepened in 79% of patients. These data suggest that dose reduction of ibrutinib is a reasonable treatment approach for patients with intolerable side effects.
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Affiliation(s)
- Shayna Sarosiek
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Joshua N Gustine
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Catherine A Flynn
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Carly Leventoff
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Megan Little
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Timothy White
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Kirsten Meid
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Steven P Treon
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
| | - Jorge J Castillo
- Bing Center for Waldenström Macroglobulinemia, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
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