In patients with chronic lymphocytic leukemia (CLL), deletion of chromosome 17p [del(17p)] or mutation in TP53 is associated with poor prognosis and resistance to many standard therapies. The recent emergence of targeted therapies has expanded available treatment options for these patients. The B-cell lymphoma 2 inhibitor venetoclax was approved for the treatment of CLL with del(17p) in 2016 based on initial results from a phase II trial, in which venetoclax resulted in an objective response rate (ORR) of 79% in 107 patients with relapsed/refractory CLL with del(17p) after a median 1-year follow-up.
In the final analysis of this trial, venetoclax was evaluated in a total of 158 patients with del(17p) CLL, including 5 who were treatment-naïve. In addition to del(17p), patients had other high-risk characteristics, including unmutated immunoglobulin heavy chain variable gene region (78%), deletion of chromosome 11q (24%), and TP53 mutation (71%). Furthermore, nearly half of the patients had bulky lymphadenopathy before therapy. The objective response rate (ORR) in all patients was 77% by investigator assessment, with a 20% rate of complete remission (CR). The median duration of response (DoR) was 33.2 months. At 24 months, the estimated rate of progression-free survival (PFS) was 54%, with a median PFS of 27.2 months. The estimated 24-month rate of overall survival (OS) was 73%; median OS cannot currently be estimated. Minimal residual disease (MRD) negativity in the blood at a sensitivity level of 10-4 was achieved in 30% of all patients. Estimated PFS in patients who achieved MRD negativity was 78%, versus 51% for those who were MRD-positive.
In the 16 patients who had received prior treatment with a B-cell receptor pathway inhibitor (BCRi), the ORR was 63%, with 2 patients achieving CR. The 24-month rates of PFS and OS were 50% and 55%, respectively. One patient who had previously failed BCRi therapy achieved MRD negativity on venetoclax.
Venetoclax was well tolerated and the safety profile was consistent with previous reports. The most common adverse events (AEs) of any grade were neutropenia (42%), diarrhea (39%), nausea (37%), anemia (25%), fatigue (23%), and thrombocytopenia (20%). Of note, no patient experienced clinical tumor lysis syndrome (TLS), though laboratory TLS was observed in 5% of patients, with all cases resolving and all patients reaching the target dose of 400 mg daily.
In their conclusions, the investigators highlighted that monotherapy with venetoclax results in durable responses in high-risk relapsed/refractory patients with del(17p) CLL, including in those previously treated with BCRi therapy. They highlighted the importance of following label recommendation to minimize the risk of TLS associated with venetoclax.