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Venetoclax produces durable responses in high-risk CLL
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ORLANDO, Fla. — Venetoclax monotherapy conferred sustained remissions and produced a high overall response rate in patients with relapsed and/or refractory chronic lymphocytic leukemia with deletion of 17p, according to phase 2 study results presented at the ASH Annual Meeting and Exposition.
The depths of responses appeared greater than any previously reported in this very high-risk population, according to the researchers.
“This is a very special population, with the most dismal outcomes in CLL,” Stephan Stilgenbauer, MD, PhD, professor in the department of internal medicine at University of Ulm in Germany, said during a presentation. “To date, these patients have not only relapsed on conventional treatments, and the 17p deletion defines these patients as resistant to conventional therapies.”
A phase 1 study of venetoclax (ABT-199/GDC-0199; AbbVie, Genentech) produced strong response rates in patients with relapsed and/or refractory CLL, including patients with a 17p deletion.
Thus, Stilgenbauer and colleagues conducted a single-arm, multicenter phase 2 trial to evaluate venetoclax monotherapy in 107 patients (median age, 67 years; range 37-85) with relapsed/refractory CLL. Men comprised 65% of the cohort, and patients had a median of two prior treatment regimens (range, 1-10).
All but one patient had confirmed 17p deletion; further, 72% of 83 patients with available data (n = 60) had mutated TP53.
The researchers assigned patients to daily venetoclax on a weekly dose-escalation schedule (20 mg, 50 mg, 100 mg, 200 mg and 400 mg) over the course of 5 weeks, along with tumor lysis syndrome prophylaxis. Patients then received 400-mg daily venetoclax until disease progression or treatment cessation.
Overall response rate (ORR) served as the primary endpoint. Secondary endpoints included complete and partial remission rates, duration of response, PFS, OS, the proportion of patients proceeding to allogeneic hematopoietic stem cell transplantation (HSCT) and safety.
At data cutoff, the median time on study was 12.1 months (range, 0.03-21.5).
The ORR was 79.4% (95% CI, 70.5-86.6). Deep responses included 7.5% of patients who achieved complete remission or complete remission with incomplete hematologic recovery (CRi) and 2.8% of patients with nodular partial remission.
Among patients who achieved partial remission (69.2%) or who were nonresponders (20.6%), 17 patients (15.9%) exhibited no morphological evidence of CLL in bone marrow.
Among 45 patients who underwent a minimal residual disease (MRD) assessment, 18 patients had no detectable MRD in the peripheral blood and six patients had no MRD in the bone marrow.
Median time to first response was 0.8 months (range, 0.1-8.1) and median time to complete remission or CRi was 8.2 months (range 3-16.3).
Median OS, PFS and duration of response have not been reached. The actuarial PFS rate was 72% and the actuarial OS rate was 86.7%. The 12-month actuarial duration of response among all responding patients (n = 85) was 84.7%.
Thirty-seven patients discontinued treatment due to progressive disease (n = 22), adverse events (n = 9), consent withdrawal (n = 2) or noncompliance (n = 1). Three patients proceeded to HSCT.
Eleven patients died within 30 days from last venetoclax dose, seven of whom died due to progressive disease and four due to adverse events. Seven additional deaths occurred more than 30 days from last treatment dose (range, 39-328), all due to progressive disease.
Common treatment-emergent adverse events included neutropenia (43%), diarrhea (29%), nausea (29%), anemia (27%) and fatigue (22%). Grade 3 to grade 4 adverse events included neutropenia (40%), anemia (18%) and thrombocytopenia (15%). The researchers noted that 22.4% of patients had neutropenia at study entry.
Grade 3 or worse infections occurred in 20% of patients, including pneumonia (5%). Further, five patients reported laboratory tumor lysis syndrome; however, none experienced clinical consequences.
“Venetoclax showed favorable risk-to-benefit profile, with the risk for clinically relevant tumor lysis syndrome effectively mitigated with proper measures,” Stilgenbauer said. “Neutropenia and infections were actually lower than expected in this high-risk population. Based on these data, there is a prospect to incorporate venetoclax as an attractive component to novel combinations or sequencing with other agents in the treatment of CLL with 17p deletion.” – by Cameron Kelsall
Reference:
Stilgenbauer S, et al. Abstract LBA-6. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: Stilgenbauer reports research funding and honoraria from and advisory board roles with AbbVie, Amgen, Boehringer Ingelheim, Celgene, Genentech, Genzyme, Gilead, GlaxoSmithKline, Janssen, Mundipharma, Novartis, Pharmacyclics and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.
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Javier Pinilla-Ibarz, MD, PhD
We have known the data for venetoclax (ABT-199/GDC-0199; AbbVie, Genentech) for quite a while, as this drug has been in development for at least 2 years. Obviously, there was early concern about tumor lysis syndrome, which caused several deaths in early phase trials. However, we have learned how to really manage the adverse events and the researchers have described no further fatal events.
The data that are presented by Stilgenbauer and colleagues in venetoclax monotherapy really present a new mechanism of action for the treatment of chronic lymphocytic leukemia. What is really quite outstanding are the rates of complete remission that we are starting to see with minimal residual disease-negative patients.
This is just the beginning, and this is a great first step. But we will be even more excited about further data combining venetoclax with monoclonal antibodies. Overall, we are looking forward to having this drug in our hands, because it is going to save more and more patients in the relapsed and refractory setting.
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