Toxicities and Outcomes of Acalabrutinib-Treated Patients with Chronic Lymphocytic Leukemia: A Retrospective Analysis of Real World Patients

Yazdy, Maryam Sarraf; Mato, Anthony R.; Roeker, Lindsey E.; Jarral, Umair; Ujjani, Chaitra S.; Shadman, Mazyar; Skarbnik, Alan P; Whitaker, Kate J.; Deonarine, Isaac; Kabel, Charlene; Stump, Sarah E.; Goodfriend, Julie M.; Pagel, John M.; Bailey, Neil; Patel, Krish; Jacobs, Ryan; Feldman, Tatyana; Leslie, Lori A.; Goy, André; Coombs, Catherine C.; Muluneh, Benyam; Khajavian, Sirin; Lamanna, Nicole; Weissbrot, Hanna; Weiss, Jessica; Cheson, Bruce D.

doi:10.1182/blood-2019-130062

Cited by 21 publications

(25 citation statements)

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“…This also means that in the clinical trials with long follow up, dermatological side-effects are scarce. However, if severe, they are among AEs that lead to ibrutinib discontinuation ( Sharman et al, 2017 ; Mato et al, 2018 ; Yazdy et al, 2019 ). In the retrospective analysis of real-world acalabrutinib-treated CLL patients, intolerant to ibrutinib, it was shown that rash led to discontinuation of ibrutinib in 10 (22%) of 46 patients.…”

Section: Mechanisms Underlying Rashmentioning

confidence: 99%

“…However, there are several limitations. At present clinical data from long-term clinical trials or real-world data are only available for a few of the inhibitors, namely for ibrutinib ( Mato et al, 2018 ; Munir et al, 2019 ), acalabrutinib ( Yazdy et al, 2019 ; Sharman et al, 2020 ) and zanubrutinib ( Tam et al, 2019b , 2020a ), but the follow-up time varies among the studies. Thus, the available dataset on AEs is limited for several of the inhibitors such as tirabrutinib ( Sekiguchi et al, 2020 ) or fenebrutinib ( Cohen et al, 2020 ), due to low patient enrollment, short-term trials or that the clinical data have not been published as yet.…”

Section: Brief Introductory Overview To Adverse Effectsmentioning

confidence: 99%

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Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Estupiñán

Berglöf

Zain

et al. 2021

Front. Cell Dev. Biol.

153

171

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The cytoplasmic protein-tyrosine kinase BTK plays an essential role for differentiation and survival of B-lineage cells and, hence, represents a suitable drug target. The number of BTK inhibitors (BTKis) in the clinic has increased considerably and currently amounts to at least 22. First-in-class was ibrutinib, an irreversible binder forming a covalent bond to a cysteine in the catalytic region of the kinase, for which we have identified 228 active trials listed at ClinicalTrials.gov. Next-generation inhibitors, acalabrutinib and zanubrutinib, are approved both in the United States and in Europe, and zanubrutinib also in China, while tirabrutinib is currently only registered in Japan. In most cases, these compounds have been used for the treatment of B-lymphocyte tumors. However, an increasing number of trials instead addresses autoimmunity and inflammation in multiple sclerosis, rheumatoid arthritis, pemphigus and systemic lupus erythematosus with the use of either irreversibly binding inhibitors, e.g., evobrutinib and tolebrutinib, or reversibly binding inhibitors, like fenebrutinib. Adverse effects (AEs) have predominantly implicated inhibition of other kinases with a BTKi-binding cysteine in their catalytic domain. Analysis of the reported AEs suggests that ibrutinib-associated atrial fibrillation is caused by binding to ERBB2/HER2 and ERBB4/HER4. However, the binding pattern of BTKis to various additional kinases does not correlate with the common assumption that skin manifestations and diarrhoeas are off-target effects related to EGF receptor inhibition. Moreover, dermatological toxicities, diarrhoea, bleedings and invasive fungal infections often develop early after BTKi treatment initiation and subsequently subside. Conversely, cardiovascular AEs, like hypertension and various forms of heart disease, often persist.

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Section: Mechanisms Underlying Rashmentioning

confidence: 99%

Section: Brief Introductory Overview To Adverse Effectsmentioning

confidence: 99%

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Estupiñán

Berglöf

Zain

et al. 2021

Front. Cell Dev. Biol.

153

171

View full text Add to dashboard Cite

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“…70 In a real-world setting involving ibrutinib-intolerant patients treated with acalabrutinib, the ORR was 62% after 5 months follow-up and discontinuation rates due to AEs were similar to those reported by Awan et al (2019). 71 Acalabrutinib combined with anti-CD20 antibody obinutuzumab was studied in a phase 1b/2 study, ACE-CL-003 (NCT02296918), in patients with R/R (n = 26) and treatment-naive CLL (n = 19). 72 At a median follow-up of 39 months in treatment-naive patients and 42 months in patients with R/R CLL, the ORRs were 95% and 92%, respectively.…”

Section: Clinical Studies Of Acalabrutinib In Patients With MCLmentioning

confidence: 99%

“…In a real‐world setting involving ibrutinib‐intolerant patients treated with acalabrutinib, the ORR was 62% after 5 months follow‐up and discontinuation rates due to AEs were similar to those reported by Awan et al . (2019) 71 …”

Section: Acalabrutinib In Cll and MCL Studiesmentioning

confidence: 99%

Incorporating acalabrutinib, a selective next‐generation Bruton tyrosine kinase inhibitor, into clinical practice for the treatment of haematological malignancies

Danilov

Persky

2020

Br J Haematol

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Greater understanding of the mechanisms involved in the disease progression of haematological malignancies has led to the introduction of novel targeted therapies with reduced toxicity compared with chemotherapy-based regimens, which has expanded the treatment options for patients with mantle cell lymphoma (MCL) and chronic lymphocytic leukaemia/ small lymphocytic lymphoma (CLL/SLL). Ibrutinib is a firstin-class Bruton tyrosine kinase (BTK) inhibitor indicated for the treatment of patients with CLL/SLL or relapsed/refractory MCL. However, next-generation BTK inhibitors have been developed with improved specificity and the potential to reduce the off-target toxicity observed with ibrutinib. Acalabrutinib is a highly selective, next-generation BTK inhibitor, which was granted accelerated approval by the US Food and Drug Administration in 2017 for the treatment of adult patients with MCL who have received at least one prior therapy. In November 2019, it was also granted approval for the treatment of adult patients with CLL/SLL on the basis of two phase 3 clinical trials. This review describes the current understanding of acalabrutinib according to clinical study data for the treatment of MCL and CLL/SLL and shares recommendations from our practice on how it should be used when treating patients in the clinic, including dosing, administration and management of adverse events.

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“…Additionally, retrospective and prospective data show acalabrutinib to be well tolerated in ibrutinib-intolerant patients with CLL. 46 , 47 These results suggest that increased selectivity towards BTK could reduce cardiac toxicity. The phase III ASCEND trial compared acalabrutinib therapy versus investigators choice of idelalisib with rituximab or BR in R/R CLL.…”

Section: Something New: Second Generation Btk Inhibitors Does Selectmentioning

confidence: 89%

The evolving role of Bruton’s tyrosine kinase inhibitors in chronic lymphocytic leukemia

Gordon

Danilov

2021

Therapeutic Advances in Hematology

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Ibrutinib, the first in class of the oral covalent Bruton tyrosine kinase (BTK) inhibitors, has profoundly changed the treatment landscape of chronic lymphocytic leukemia (CLL). The phase III RESONATE and RESONATE-2 trials first demonstrated the superiority of ibrutinib over ofatumumab in the relapsed/refractory setting and over chlorambucil in older patients with de novo disease. The phase III ECOG–ACRIN trial extended these results to young, fit patients, demonstrating a significant survival advantage to ibrutinib plus rituximab over fludarabine, cyclophosphamide, and rituximab. Similarly, the Alliance trial demonstrated the superiority of ibrutinib over bendamustine with rituximab as frontline in elderly patients. Challenges with ibrutinib include toxicity, development of resistance, and need for indefinite therapy. The second generation BTK inhibitor acalabrutinib may cause less off-target toxicity. The ELEVATE TN trial demonstrated the superiority of acalabrutinib with or without obinutuzumab over chlorambucil and obinutuzumab as frontline therapy for elderly or comorbid patients. Promising early results from the phase II CAPTIVATE and CLARITY trials, which combined ibrutinib with venetoclax, suggest a future role for minimal residual disease (MRD) testing to determine treatment duration. The ongoing phase III GAIA/CLL13, ECOG EA9161, Alliance A041702, CLL17, and [ClinicalTrials.gov identifier: NCT03836261] trials will assess various combinations of ibrutinib/acalabrutinib, venetoclax, and anti-CD20 antibodies. These trials will answer key questions in the treatment of CLL: should novel agents in CLL be used in combination or sequentially? What is the best frontline agent? Can treatment be safely stopped with BTK inhibitors? Can undetectable MRD be used to determine treatment duration? In this review, we will discuss these and other aspects of the evolving role of BTK inhibition in CLL.

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Toxicities and Outcomes of Acalabrutinib-Treated Patients with Chronic Lymphocytic Leukemia: A Retrospective Analysis of Real World Patients

Cited by 21 publications

References 0 publications

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects

Incorporating acalabrutinib, a selective next‐generation Bruton tyrosine kinase inhibitor, into clinical practice for the treatment of haematological malignancies

The evolving role of Bruton’s tyrosine kinase inhibitors in chronic lymphocytic leukemia

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