Monitoring and Managing BTK Inhibitor Treatment-Related Adverse Events in Clinical Practice.

Susan M O'Brien,John C Byrd,William G Wierda,Richard R Furman,Jeff P Sharman,Paolo Ghia,Jennifer R Brown

doi:10.3389/fonc.2021.720704

Abstract

Bruton tyrosine kinase (BTK) inhibitors represent an important therapeutic advancement for B cell malignancies. Ibrutinib, the first-in-class BTK inhibitor, is approved by the US FDA to treat patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), and mantle cell lymphoma (MCL; after ≥1 prior therapy); and by the European Medicines Agency (EMA) for adult patients with relapsed/refractory (R/R) MCL and patients with CLL. Ibrutinib treatment can be limited by adverse events (AEs) including atrial fibrillation, arthralgias, rash, diarrhea, and bleeding events, leading to drug discontinuation in 4%–26% of patients. Acalabrutinib, a second-generation BTK inhibitor, is approved by the FDA to treat adult patients with CLL/SLL or MCL (relapsed after 1 prior therapy); and by the EMA to treat adult patients with CLL or R/R MCL. The most common AE associated with acalabrutinib is headache of limited duration, which occurs in 22%–51% of patients, and is mainly grade 1–2 in severity, with only 1% of patients experiencing grade ≥3 headache. Furthermore, acalabrutinib is associated with a low incidence of atrial fibrillation. Zanubrutinib, a selective next-generation covalent BTK inhibitor, is approved by the FDA to treat adult patients with MCL who have received ≥1 prior therapy, and is under investigation for the treatment of patients with CLL. In the phase 3 SEQUOIA trial in patients with CLL, the most common grade ≥3 AEs were neutropenia/neutrophil count decreased and infections. This review provides an overview of BTK inhibitor-related AEs in patients with CLL, and strategies for their management.

Highlights

Ibrutinib, the first-in-class Bruton tyrosine kinase (BTK) inhibitor, is approved by the US Food and Drug Administration (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL) after at least 1 prior therapy, Waldenstrom’s macroglobulinemia, marginal zone lymphoma in patients who haveBTK Inhibitor Treatment-Related Adverse Events received at least 1 prior anti-CD20-based therapy, and chronic graft-versus-host disease after failure of at least 1 systemic therapy (1); and by the European Medicines Agency (EMA) for adult patients with relapsed or refractory (R/R) MCL, and patients with CLL (2)
The results demonstrated that acalabrutinib met the primary efficacy endpoint with noninferior progression-free survival (PFS) compared to ibrutinib in previously treated patients with high-risk CLL after a median follow-up period of 40.9 months (34)
Rates of other adverse events (AEs) that were lower in the zanubrutinib group versus the ibrutinib group included major bleeding (2.9% vs 3.9%), cardiac disorders of any grade (13.7% vs 25.1%) or grade ≥3 (2.5% vs 6.8%), and AEs leading to discontinuation (7.8% vs 13.0%) or death (3.9% vs 5.8%), respectively (35, 37)

Summary

INTRODUCTION

The first-in-class Bruton tyrosine kinase (BTK) inhibitor, is approved by the US Food and Drug Administration (FDA) for the treatment of patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL) after at least 1 prior therapy, Waldenstrom’s macroglobulinemia, marginal zone lymphoma in patients who have. After a median follow-up duration of 31.3 months, the most common grade ≥3 treatment-emergent AEs occurring in ≥5% of patients in the ibrutinib plus obinutuzumab group were neutropenia (36%), thrombocytopenia (19%), pneumonia (7%), and atrial fibrillation (5%) (33). In patients who received acalabrutinib monotherapy, the most common AEs of any grade were headache (22%), neutropenia (19%), diarrhea (18%), cough (15%), upper respiratory tract infection and anemia (14% each), after a median follow-up of 16.1 months (12). After a median follow-up period of 18.2 months (range, 5.0–26.3 months), AEs (of any grade; reported in ≥10% of treated patients) were contusion (20.2%), upper respiratory tract infection (19.3%), neutropenia/neutrophil count decreased (17.4%), diarrhea (16.5%), nausea (14.7%), constipation (13.8%), rash (13.8%), back pain (12.8%), cough (11.9%), arthralgia (11.0%), and fatigue (10.1%) (10). Thrombocytopenia is frequently observed in patients with unfavorable biological risk factors for CLL, and is commonly caused by splenomegaly, bone marrow failure secondary to tumor infiltration, recent chemotherapy, or megakaryocyte dysplasia (50)

DISCUSSION

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Results