Risk of bleeding complications and atrial fibrillation associated with ibrutinib treatment: A systematic review and meta-analysis

Pellegrini, Luca; Novak, Urban; Andres, Martin; Suter, Thomas M.; Nagler, Michael

doi:10.1016/j.critrevonc.2021.103238

Cited by 14 publications

(16 citation statements)

References 61 publications

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“…The BTK inhibitor ibrutinib, alone or with a CD20 antibody, demonstrated better efficacy versus chemoimmunotherapy in treatment-naïve (TN) CLL [2][3][4]. However, cardiovascular toxicity is a concern with continuous ibrutinib use [5,6].Acalabrutinib is a next-generation, selective BTK inhibitor approved for CLL/small lymphocytic leukemia (SLL). Acalabrutinib, alone or with obinutuzumab, showed favorable efficacy in clinical trials [7,8].…”

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confidence: 99%

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Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia

et al. 2022

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TO THE EDITOR Bruton tyrosine kinase (BTK) inhibitors have improved chronic lymphocytic leukemia (CLL) outcomes and offer a chemotherapyfree option [1]. The BTK inhibitor ibrutinib, alone or with a CD20 antibody, demonstrated better efficacy versus chemoimmunotherapy in treatment-naïve (TN) CLL [2][3][4]. However, cardiovascular toxicity is a concern with continuous ibrutinib use [5,6].Acalabrutinib is a next-generation, selective BTK inhibitor approved for CLL/small lymphocytic leukemia (SLL). Acalabrutinib, alone or with obinutuzumab, showed favorable efficacy in clinical trials [7,8]. ELEVATE-TN demonstrated superior efficacy for acalabrutinib-obinutuzumab versus obinutuzumab-chlorambucil with acceptable tolerability in TN CLL [9]. We report 4-year followup results from ELEVATE-TN.ELEVATE-TN is a phase 3, randomized, multicenter, open-label study (NCT02475681) that enrolled patients aged ≥65 years, or 18-65 years with comorbidities (Cumulative Illness Rating Scale-Geriatric score >6, creatinine clearance 30-69 mL/min by Cockcroft-Gault), who had TN CLL or SLL requiring treatment, Eastern Cooperative Oncology Group performance status score of ≤2, and adequate hematologic, hepatic, and renal function [9]. Patients were randomized (1:1:1) to acalabrutinib 100 mg twice daily (until disease progression or unacceptable toxicity) with or without obinutuzumab (fixed-duration, up to 6 cycles) or obinutuzumab plus chlorambucil (up to 6 cycles). Crossover to acalabrutinib monotherapy was permitted in patients who progressed on obinutuzumab-chlorambucil. The primary study endpoint was independent review committee (IRC)-assessed progression-free survival (PFS). After primary analysis, PFS was investigatorassessed.Key secondary/exploratory endpoints were investigator-assessed PFS, investigator-assessed overall response rate (ORR), overall survival (OS), undetectable minimal residual disease (uMRD) rate, and safety. The study was not powered to compare acalabrutinib versus acalabrutinib-obinutuzumab. Informed consent was obtained from all patients before enrollment. Study details were previously published [9].In total, 535 patients were randomized (acalabrutinib-obinutuzumab, n = 179; acalabrutinib, n = 179; obinutuzumab-chlorambucil, n = 177). Median age was 70 years (range, 41.0-91.0); 14% had del(17)(p13.1) and/or mutated TP53 and 63% had unmutated immunoglobulin heavy chain variable (IGHV) gene (Supplementary Table 1).At a median follow-up of 46.9 months (range, 0.0-59.4), treatment was ongoing in 74.9% (n = 134) and 69.3% (n = 124) of patients in the acalabrutinib-obinutuzumab and acalabrutinib monotherapy arms, respectively (Supplementary Table 2). Sixty-

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confidence: 99%

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Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia

et al. 2022

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“…Approximately 30-50% of CLL and MCL patients treated with ibrutinib or acalabrutinib have low-grade (grade 1-2) bleeding. However, ibrutinib treatment is associated with an increased risk of major bleeding (grade 3-4), which is much reduced with acalabrutinib treatment (Byrd et al, 2016;Wang et al, 2018;Pellegrini et al, 2021). After initiation of ibrutinib therapy, the majority of CLL patients show a small decrease in platelet counts on day 2, which is followed by a rapid increase in platelet counts several days later (Lipsky et al, 2015;Huang et al, 2021).…”

Section: Megakaryocytes and Plateletsmentioning

confidence: 99%

“…However, a unique set of toxicities has also been reported, even though ibrutinib is generally more tolerable than chemoimmunotherapy (CIT) regimens. Common adverse effects of ibrutinib include bleeding, atrial fibrillation, hypertension, neutropenia, arthralgias, myalgias, headache, diarrhea, nausea, fatigue, rash and infection (Bitar et al, 2018;Ball et al, 2020;Kin and Schiffer, 2020;Lasica and Tam, 2020;Lipsky and Lamanna, 2020;Los-Arcos et al, 2020;Pileri et al, 2020;Estupinan et al, 2021;Pellegrini et al, 2021;Steingrimsson et al, 2021). These side effects are mediated by both on-target inhibition of BTK and variable off-target inhibition of other kinases such as interleukin-2-inducible T-cell kinase (ITK), tyrosine kinase expressed in hepatocellular carcinoma (TEC), CSK, SRC, BMX, JAK3, epidermal growth factor receptor (EGFR), c-Kit and platelet-derived growth factor receptor (PDGFR), etc.…”

Section: Introductionmentioning

confidence: 99%

Multifaceted Immunomodulatory Effects of the BTK Inhibitors Ibrutinib and Acalabrutinib on Different Immune Cell Subsets – Beyond B Lymphocytes

Zhu

Gokhale

Jung

et al. 2021

Front. Cell Dev. Biol.

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The clinical success of the two BTK inhibitors, ibrutinib and acalabrutinib, represents a major breakthrough in the treatment of chronic lymphocytic leukemia (CLL) and has also revolutionized the treatment options for other B cell malignancies. Increasing evidence indicates that in addition to their direct effects on B lymphocytes, both BTK inhibitors also directly impact the homeostasis, phenotype and function of many other cell subsets of the immune system, which contribute to their high efficacy as well as adverse effects observed in CLL patients. In this review, we attempt to provide an overview on the overlapping and differential effects of ibrutinib and acalabrutinib on specific receptor signaling pathways in different immune cell subsets other than B cells, including T cells, NK cells, monocytes, macrophages, granulocytes, myeloid-derived suppressor cells, dendritic cells, osteoclasts, mast cells and platelets. The shared and distinct effects of ibrutinib versus acalabrutinib are mediated through BTK-dependent and BTK-independent mechanisms, respectively. Such immunomodulatory effects of the two drugs have fueled myriad explorations of their repurposing opportunities for the treatment of a wide variety of other human diseases involving immune dysregulation.

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“…However, a unique set of toxicities has been reported for ibrutinib. Common adverse effects of ibrutinib observed in CLL and MCL patients include bleeding, atrial fibrillation, hypertension, neutropenia, arthralgias, myalgias, headache, diarrhea, nausea, fatigue, rash and infection (38,162,166,(173)(174)(175)(176)(177)(178)(179)(180). Based on the preliminary results posted at ClinicalTrials.gov, commonly observed adverse effects of ibrutinib in patients with other human diseases include fatigue, anemia, gastrointestinal disorders, thrombocytopenia, myalgia, arthralgia, bleeding and infection (Table 2).…”

Section: Major Toxicities and Potential Limitations Of Ibrutinib And Acalabrutinib In Therapeutic Usementioning

confidence: 99%

Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies

et al. 2021

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The BTK inhibitors ibrutinib and acalabrutinib are FDA-approved drugs for the treatment of B cell malignances. Both drugs have demonstrated clinical efficacy and safety profiles superior to chemoimmunotherapy regimens in patients with chronic lymphocytic leukemia. Mounting preclinical and clinical evidence indicates that both ibrutinib and acalabrutinib are versatile and have direct effects on many immune cell subsets as well as other cell types beyond B cells. The versatility and immunomodulatory effects of both drugs have been exploited to expand their therapeutic potential in a wide variety of human diseases. Over 470 clinical trials are currently registered at ClinicalTrials.gov to test the efficacy of ibrutinib or acalabrutinib not only in almost every type of B cell malignancies, but also in hematological malignancies of myeloid cells and T cells, solid tumors, chronic graft versus host disease (cGHVD), autoimmune diseases, allergy and COVID-19 (http:www.clinicaltrials.gov). In this review, we present brief discussions of the clinical trials and relevant key preclinical evidence of ibrutinib and acalabrutinib as monotherapies or as part of combination therapies for the treatment of human diseases beyond B cell malignancies. Adding to the proven efficacy of ibrutinib for cGVHD, preliminary results of clinical trials have shown promising efficacy of ibrutinib or acalabrutinib for certain T cell malignancies, allergies and severe COVID-19. However, both BTK inhibitors have no or limited efficacy for refractory or recurrent solid tumors. These clinical data together with additional pending results from ongoing trials will provide valuable information to guide the design and improvement of future trials, including optimization of combination regimens and dosing sequences as well as better patient stratification and more efficient delivery strategies. Such information will further advance the precise implementation of BTK inhibitors into the clinical toolbox for the treatment of different human diseases.

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Risk of bleeding complications and atrial fibrillation associated with ibrutinib treatment: A systematic review and meta-analysis

Cited by 14 publications

References 61 publications

Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia

Efficacy and safety in a 4-year follow-up of the ELEVATE-TN study comparing acalabrutinib with or without obinutuzumab versus obinutuzumab plus chlorambucil in treatment-naïve chronic lymphocytic leukemia

Multifaceted Immunomodulatory Effects of the BTK Inhibitors Ibrutinib and Acalabrutinib on Different Immune Cell Subsets – Beyond B Lymphocytes

Clinical Trials of the BTK Inhibitors Ibrutinib and Acalabrutinib in Human Diseases Beyond B Cell Malignancies

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