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

Abstract

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.

The Role of Bruton’s Kinase Inhibitors in Chronic Lymphocytic Leukemia: Current Status and Future Directions

“…In an attempt to improve the efficacy of ibrutinib treatment in R/R CLL, studies have examined its efficacy in combination with rituximab, ofatumumab, venetoclax, or rituximab and bendamustine (BR) [35][36][37]. Ibrutinib alone was compared with ibrutinib with rituximab in a trial encompassing 208 patients with CLL and 181 with recurrent CLL.…”

“…Finally, fixed-duration treatment with ibrutinib and venetoclax was investigated in a phase 2 study in R/R patients (CLARITY), and in previously untreated patients (CAP-TIVATE) [35,51,52]. In the CLARITY study, the primary end point was the eradication of minimal residual disease (MRD) after 12 months of treatment with ibrutinib and venetoclax [35]. Therapy was given for a limited period and then stopped if patients achieved deep remission with MRD negativity.…”

New Potential Agents for Malignant Melanoma Treatment—Most Recent Studies 2020–2022

“…Moreover, its promising activity against solid tumors has been shown [ 61 , 62 , 63 , 64 ]. Related to the widespread drug resistance and significant side effects [ 65 , 66 , 67 ], it is necessary to search for new drugs with increased effectiveness and lower toxicity. As a result, modifications to the structure of ibrutinib are of great interest to scientists looking for anticancer drugs [ 68 ].…”

Multiparametric Flow Cytometry for MRD Monitoring in Hematologic Malignancies: Clinical Applications and New Challenges

“…The progressive improvements in the quality of responses following the adoption of new therapeutic approaches have pointed out the need to measure increasingly lower MRD levels [ 88 ]. Nonetheless, the clinical relevance of U-MRD has been challenged in recent years with the advent of Bruton tyrosin kinase (BTK) inhibitors, particularly ibrutinib (the first-in-class BTK inhibitor) [ 89 ]. Despite their unprecedented efficacy allowing long-term control of the disease, BTK inhibitors rarely induce U-MRD as single agents, and a long-lasting lymphocytosis, not associated with an inferior outcome, is frequently observed in patients treated with ibrutinib alone, due to the redistribution of CLL cells into the bloodstream [ 90 , 91 ].…”