Evaluating Fixed-Duration Ibrutinib and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia

A fixed-duration combination of the first-generation Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the first-generation BCL2 inhibitor venetoclax appeared to be a well-tolerated, effective, all-oral regimen for patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Tanya Siddiqi, MD, from City of Hope National Medical Center in Duarte, California, presented findings from the phase II trial at the 2021 ASH Annual Meeting. Dr. Siddiqi added that most patients achieved an undetectable measurable residual disease (MRD) in bone marrow.  

“[Ibrutinib and venetoclax] are both oral agents that have been shown to work synergistically together with no unexpected toxicities beyond what is already known about each of them,” Dr. Siddiqi explained. The combination has proven effective in frontline treatment of CLL, including fixed-duration therapy for 15 cycles which produces high complete remissions (CR) and undetectable MRD rates, as well as high progression-free survival (PFS) and overall survival (OS). 

In this study, researchers examined the combination in the relapsed/refractory setting, enrolling 22 patients. The median number of prior treatments was one (range = 1-3). No patients had prior exposure to a BTK inhibitor or venetoclax, 

Treatment consisted of ibrutinib 420 mg as monotherapy for eight weeks, after which venetoclax ramp-up treatment was introduced, then escalated to a full dose of 400 mg daily over five weeks. The combination of ibrutinib and venetoclax was then continued for a total of two years. 

Overall, 21 patients initiated venetoclax and 18 patients completed full trial treatment. Three patients discontinued treatment due to Hodgkin transformation, kidney failure, and need for a coronary stent. Five patients interrupted dosing due to toxicity and five patients had dose reductions. 

At week 62, the CR rate in the intent-to-treat population of 22 patients was 55%, while the overall response rate was 91%. Two-year rates of PFS and OS were 95% and 100%, respectively. After one year of combination therapy, 13 of 20 (65%) evaluable patients had achieved undetectable MRD in bone marrow.  

After two years of follow-up, an additional two patients achieved undetectable MRD in bone marrow, the researchers noted.  

Seven patients experienced 11 serious treatment-related adverse events (AEs), including sepsis (n = 3), pneumonia (n = 3), atrial fibrillation (n = 2), and diarrhea, dehydration, and pulmonary embolism (n = 1 each). There were no events of tumor lysis syndromes, the investigators reported.