Novel therapies suggest promise
Survival in CLL after BTKi resistance develops is quite short, according to the authors, and they expressed hope that continued research into novel agents would prolong this population’s survival.
Venetoclax, an oral inhibitor of the antiapoptotic protein BCL2, is approved for all patients with CLL, both as monotherapy and in combination with an anti-CD20 monoclonal antibody. Data support its use after BTKi resistance has been detected. Some evidence in CLL cell lines supports use of the oral phosphoinositide 3-kinases inhibitors idelalisib and duvelisib in relapsed CLL and the BTK C481S mutation. Early response data with third-generation BTKis, such as ARQ-531 and LOXO-305, suggest promise in this setting. Also, for young and healthy patients who have progressed on both BTKi and venetoclax therapy, allogeneic hematopoietic stem cell transplantation could be considered.
In patients with heavily pretreated CLL, early clinical data support chimeric antigen receptor T-cell therapy (CAR T), a novel therapy where patients’ own T cells are extracted, engineered, and reinfused. A related immunotherapy, using a similar process of retroviral vector insertion of an anti-CD19 CAR into donor NK cells before infusion into the patient, is termed CAR-NK cell therapy. It shows promise in early data from patients with CLL who all had previously been heavily treated with ibrutinib.
More research, more hope
Despite the significant advance that BTKis represent, BTKi resistance, with shortened survival, remains a clinical problem for patients with B-cell malignancies. BTKi resistance has been associated with several genetic and clinical risk factors, with mutations in BTK and PLCy2 the most common and most thoroughly researched. “Ongoing clinical trials of third-generation noncovalent BTKis and cellular therapies, such as CAR T, provide much hope for these patients. ... Continued additional research is needed to further prolong the survival of patients with BTKi-resistant B-cell malignancies.”
Dr. Stephens has received research funding and has served on advisory boards for a variety of pharmaceutical and biotechnology companies. Dr. Byrd has received research funding and has consulted for a variety of pharmaceutical and biotechnology companies.