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Pretreatment factors, response variables influence venetoclax efficacy in relapsed chronic lymphocytic leukemia
Pretreatment factors and depth of response appeared associated with duration of response to venetoclax among patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, according to results of a prospective trial published in Blood.
“Recently, favorable longer-term safety with venetoclax was reported when used continuously for up to 56 months (median duration of exposure, 16 months) in an analysis of pooled data from phase 1 and phase 2 clinical trials,” Andrew Roberts, MBBS, PhD, FRACP, FRCPA, Metcalf chair of leukemia research at the University of Melbourne in Australia, and colleagues wrote. “Here, we take a similar approach to define the longer-term efficacy of venetoclax through analysis of extended follow-up data of patients treated in four early phase trials.”
Roberts and colleagues analyzed 436 patients (median age, 66 years; range, 28-88) with relapsed CLL or small lymphocytic lymphoma to determine how patient and disease characteristics — such as chromosome 17p deletion, clinical parameters and other genetic abnormalities — correlated with response to and durability of benefit from venetoclax (Venclexta; AbbVie, Genentech), an oral, highly selective B-cell lymphoma 2 inhibitor.
Researchers pooled data from four phase 1 and phase 2 clinical trials. All patients received a median of three (range, 1-15) prior therapies. In total, 387 patients received venetoclax monotherapy and 49 received venetoclax in combination with rituximab (Rituxan, Genentech). Researchers planned to treat 347 patients with the standard 400-mg daily dose of venetoclax monotherapy.
Median follow-up was 35.5 months (range, 0-69.1) for all patients and 28.8 months (range, 0.03-64.5) for those in the 400-mg/day venetoclax monotherapy subset.
Results showed objective responses in 75.2% (95% CI, 70.9-79.2) of all patients, with 22% (95% CI, 18.2-26.2) achieving complete response or complete response with incomplete platelet recovery.
The overall responses rate among patients in the venetoclax monotherapy subset was 73.5% (95% CI, 68.5-78.1), with a complete remission rate of 15.9% (95% CI, 12.2-20.1).
All patients and those in the venetoclax subset demonstrated similar median duration of response (38.4 months vs. 36.2 months) and time to response (36.9 months vs. 33.2 months).
Among all patients, 27.3% (95% CI, 23.2-31.7) achieved undetectable minimal residual disease (MRD) in the peripheral blood and 16.1% (95% CI, 12.7-19.8) achieved undetectable MRD in bone marrow. Within the subset of patients receiving 400 mg/day venetoclax monotherapy, results showed undetectable MRD rates of 27.1% (95% CI, 22.5-32.1) in peripheral blood, and 10.7% (95% CI, 7.6-14.4) in bone marrow.
Researchers estimated median PFS of 30.2 months (95% CI, 27.2-36.9) for all patients and 28.2 months (95% CI, 24.7-34.1) for those in the venetoclax monotherapy subset.
Landmark analyses showed superior duration of response for patients who achieved complete responses or undetectable MRD. Fewer prior therapies appeared associated with a higher complete response rate but did not affect duration of response.
Patients who did not achieve a response had a 5.4-month (95% CI, 4.4-8) median PFS compared with 39.2 months (95% CI, 35.9-46.5) for responders. Among those with complete response or complete response with incomplete platelet recovery, estimated 3-year PFS was 83% (95% CI, 72-90).
Median OS had not been reached, however, researchers estimated 3-year survival rates of 71.3% (95% CI, 66-75.9) for all patients and 68% (95% CI, 61.6-73.6) for those in the venetoclax monotherapy subset.
Analyses showed consistent associations between del(17)p deletion and/or TP53 mutation, as well as NOTCH1 mutation, and shorter duration of response, however, these factors did not appear to affect likelihood of response.
Patients without bulky lymphadenopathy, B-cell receptor inhibitor-refractory CLL or an adverse mutation profile demonstrated the most durable benefits.
“Venetoclax monotherapy achieves deep responses in a significant proportion of patients, and patients achieving a complete response or undetectable MRD have excellent durability of response,” Roberts and colleagues wrote. “However, there is clear unmet need for the majority of patients whose disease does not respond as completely.” – by John DeRosier
Disclosures: Roberts reports research funding from AbbVie and Janssen and employment with Walter and Eliza Hall Institute of Medical Research. Please see the study for all other authors’ relevant financial disclosures.