Pooled analysis of safety data from clinical trials evaluating acalabrutinib monotherapy in mature B-cell malignancies

Furman, Richard R.; Byrd, John C.; Owen, Roger G.; O’Brien, Susan; Brown, Jennifer R.; Hillmen, Peter; Stephens, Deborah M.; Chernyukhin, Nataliya; Lezhava, Tamara; Hamdy, Ahmed; Izumi, Raquel; Patel, Priti; Baek, Marshall; Christian, Beth; Dyer, Martin J.S.; Streetly, Matthew; Sun, Clare; Rule, Simon; Wang, Michael; Ghia, Paolo; Jurczak, Wojciech; Pagel, John M.; Sharman, Jeff P.

doi:10.1038/s41375-021-01252-y

Cited by 28 publications

(12 citation statements)

References 35 publications

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“…The recently reported pooled analysis of 1040 patients on acalabrutinib found 46% of AEs related to hemorrhage events and included contusion (n=226, 22%), petechiae (n=11, 11%), epistaxis (n=73, 7%), ecchymosis (n=66, 6%) and increased tendency to bruise (n=55, 5%). 40 Of the reported bleeding events, only 3% were grade 3 or higher. Of the major hemorrhage events, 43% occurred in patients on concurrent anticoagulation or antiplatelet therapy.…”

Section: Safety and Tolerability Of Acalabrutinib In Cllmentioning

confidence: 98%

“…In a pooled analysis of clinical trials with acalabrutinib monotherapy that included 1040 patients with median duration of exposure at 24.6 months, the most common AEs of any grade reported with acalabrutinib therapy were headache (n=393, 38%), diarrhea (n=382, 37%), upper respiratory tract infection (n=229, 22%), contusion (n=226, 22%), nausea (n=226, 22%), fatigue (n=222, 21%) and cough (n=218, 21%). 40 For each AE, over 90% of those reported were grade 1 or 2. For AEs of grade 3 or higher, the three most common noted were neutropenia (n=116, 11.2%), anemia (n=81, 7.85%) and pneumonia (n=53, 5.1%).…”

Section: Safety and Tolerability Of Acalabrutinib In Cllmentioning

confidence: 99%

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Targeted Treatment of Chronic Lymphocytic Leukemia: Clinical Utility of Acalabrutinib

Vitale¹,

Gibbons²,

Ferrajoli³

2021

OTT

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In chronic lymphocytic leukemia (CLL), a deeper understanding of the disease biology led over the last decade to the development and clinical use of different targeted drugs, including Bruton tyrosine kinase (BTK) inhibitors. The first BTK inhibitor approved for clinical use is ibrutinib, which showed excellent efficacy and good tolerability. More recently, the interest is growing for novel more selective BTK inhibitors that may reduce the off-target effects of the drug, thus minimizing side effects and subsequent treatment interruptions or discontinuations. Acalabrutinib is an orally administered irreversible BTK inhibitor, characterized by the lack of inhibition towards other kinases. In this review, we present the most recent data from clinical trials on the clinical efficacy of acalabrutinib and acalabrutinib-based combinations for the treatment of patients with relapsed/refractory and treatment-naïve CLL. We delineate the safety profile of the drug, describe side effects of interest and discuss the clinical management of patients receiving acalabrutinib. Due to its efficacy and the favorable safety profile, acalabrutinib has emerged as a viable therapy option in the current landscape of multiple approved treatments for CLL.

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Section: Safety and Tolerability Of Acalabrutinib In Cllmentioning

confidence: 98%

Section: Safety and Tolerability Of Acalabrutinib In Cllmentioning

confidence: 99%

Targeted Treatment of Chronic Lymphocytic Leukemia: Clinical Utility of Acalabrutinib

Vitale¹,

Gibbons²,

Ferrajoli³

2021

OTT

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“…Due to a high burden of cardiotoxicity, namely the development of new or worsened hypertension or arrhythmias in follow-up, indefinite ibrutinib use has been limited to those without intolerable effects or disease progression [ 9 – 16 ]. In available initial clinical trials, acalabrutinib associates with similar efficacy, but lower rates of adverse events [ 3 , 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, with ibrutinib, post-trial clinical and disproportionality analyses revealed signals of higher cardiovascular event risks, often preceded by incident hypertension, not observed in initial clinical trials [ 11 – 16 ]. With acalabrutinib, available secondary analyses have suggested lower arrhythmia risks, but conflicting rates for hypertension and other cardiovascular events [ 1 , 3 – 5 , 17 ]. In ACE-CL-001, no cases of high-grade hypertension were reported 1 , while in ELEVATE-RR, 9% developed hypertension 18 ; and in a recent Phase 1/2a trial, up to 40% of patients treated with acalabrutinib developed incident hypertension (any-grade) [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Hypertension and incident cardiovascular events after next-generation BTKi therapy initiation

et al. 2022

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Background Post-market analyses revealed unanticipated links between first-generation Bruton’s tyrosine kinase inhibitor (BTKi) therapy, ibrutinib, and profound early hypertension. Yet, whether this is seen with novel selective second (next)-generation BTKi therapy, acalabrutinib, is unknown. Methods Leveraging a large cohort of consecutive B cell cancer patients treated with acalabrutinib from 2014 to 2020, we assessed the incidence and ramifications of new or worsened hypertension [systolic blood pressure (SBP) ≥ 130 mmHg] after acalabrutinib initiation. Secondary endpoints were major cardiovascular events (MACE: arrhythmias, myocardial infarction, stroke, heart failure, cardiac death) and disease progression. Observed incident hypertension rates were compared to Framingham heart-predicted and ibrutinib-related rates. Multivariable regression and survival analysis were used to define factors associated with new/worsened hypertension and MACE, and the relationship between early SBP increase and MACE risk. Further, the effect of standard antihypertensive classes on the prevention of acalabrutinib-related hypertension was assessed. Results Overall, from 280 acalabrutinib-treated patients, 48.9% developed new/worsened hypertension over a median of 41 months. The cumulative incidence of new hypertension by 1 year was 53.9%, including 1.7% with high-grade (≥ 3) hypertension. Applying the JNC 8 cutoff BP of ≥ 140/90 mmHg, the observed new hypertension rate was 20.5% at 1 year, > eightfold higher than the Framingham-predicted rate of 2.4% (RR 8.5, P < 0.001), yet 34.1% lower than ibrutinib (12.9 observed-to-expected ratio, P < 0.001). In multivariable regression, prior arrhythmias and Black ancestry were associated with new hypertension (HR 1.63, HR 4.35, P < 0.05). The degree of SBP rise within 1 year of treatment initiation predicted MACE risk (42% HR increase for each + 5 mmHg SBP rise, P < 0.001). No single antihypertensive class prevented worsened acalabrutinib-related hypertension. Conclusions Collectively, these data suggest that hypertension may be a class effect of BTKi therapies and precedes major cardiotoxic events.

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“…It is a Bruton tyrosine kinase inhibitor that is used in the treatment of mantle cell lymphoma, chronic lymphocytic leukaemia, and small lymphocytic lymphoma. Bruton Tyrosine Kinase (BTK) is a B-cell antigen receptor and cytokine receptor signalling protein [1] . BTK signalling activates pathways required for B-cell proliferation, trafficking, chemotaxis, and adhesion.…”

Section: Introductionmentioning

confidence: 99%

Analytical Method Development and Validation for Determination of Acalabrutinib by Using RP-HPLC

Mazumder¹,

Sundararajan²

2022

YMER

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A unique, selective, and precise RP-HPLC technique for quantifying acalabrutinib in pure and pharmaceutical dose form was developed and validated. Acalabrutinib is an oral kinase inhibitor with an antineoplastic effect and an apoptosis inducer. It is used for the treatment of adult patients with mantle cell lymphoma (MCL). The isolation was obtained on the BDS C18 column (150 x 4.6mm) with a 5µ particle size. At a flow rate of 1ml/min, an optimised mobile phase of 0.1 percent potassium di hydrogen ortho phosphate and acetonitrile (70:30 v/v) was utilised. The wavelength was chosen to be 294nm. Acalabrutinib had a retention time of 2.585 minutes. Acalabrutinib linearity was found to be 12.5-75 g/ml. The linearity equations for acalabrutinib were y = 71296x + 49305, with a correlation coefficient of 0.999. The precision percent RSD was found to be less than 2%. Acalabrutinib recovered at a rate of 99.81 percent. The LOD and LOQ for acalabrutinib were obtained as 0.408 µg/ml and 1.236 µg/ml respectively. The projected technique was recognized to be precise, accurate and ideal for use in QC laboratories for quantitative analysis of both individual and mixed dosage forms of pharmaceuticals. Keywords: RP-HPLC, Method Development and Validation

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Pooled analysis of safety data from clinical trials evaluating acalabrutinib monotherapy in mature B-cell malignancies

Cited by 28 publications

References 35 publications

Targeted Treatment of Chronic Lymphocytic Leukemia: Clinical Utility of Acalabrutinib

Targeted Treatment of Chronic Lymphocytic Leukemia: Clinical Utility of Acalabrutinib

Hypertension and incident cardiovascular events after next-generation BTKi therapy initiation

Analytical Method Development and Validation for Determination of Acalabrutinib by Using RP-HPLC

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