Abstract
Bendamustine followed by obinutuzumab and venetoclax provides clinical benefit without unexpected toxicity.
Major finding: Bendamustine followed by obinutuzumab and venetoclax provides clinical benefit without unexpected toxicity.
Clinical relevance: This treatment regimen led to responses in 95% of patients with CLL in an open-label phase II trial.
Impact: Bendamustine followed by obinutuzumab and venetoclax warrants further investigation for the treatment of CLL.
The antiapoptotic protein BCL2 is upregulated in chronic lymphocytic leukemia (CLL), and the BCL2 inhibitor venetoclax induces apoptosis of CLL cells and has demonstrated clinical activity as a monotherapy in patients with relapsed or refractory CLL. Preclinical data suggested that venetoclax may synergize with the anti-CD20 antibody rituximab, and this was supported by a phase Ib trial in patients with CLL. Cramer and colleagues hypothesized that the more potent anti-CD20 antibody obinutuzumab might further enhance the efficacy of venetoclax. To test this hypothesis, a prospective, open-label, phase II trial evaluated the combination of venetoclax and obinutuzumab after debulking with the chemotherapeutic bendamustine. Overall, 66 patients were enrolled, and 63 were evaluable for efficacy; 34 patients (54%) were treatment naïve and 29 (46%) had relapsed or refractory disease. The primary endpoint was the proportion of patients achieving an overall response. In total, 60 of 63 (95%) evaluable patients responded, including all 34 treatment-naïve patients and 26 of 29 (90%) patients with relapsed or refractory disease. There were 25 complete and 35 partial responses. Further, deep minimal residual disease negativity was observed in the peripheral blood of 55 of 63 (87%) patients. The combination of bendamustine, obinutuzumab, and venetoclax produced no unexpected or cumulative toxicities. However, there were 89 serious adverse events, 69 of which were related to the study treatment. Five patients with relapsed or refractory disease died, and three of the deaths were deemed related to the study treatment. Taken together, the results of this trial indicate that bendamustine followed by obinutuzumab and venetoclax achieves a high response rate in patients with CLL without unexpected toxicity. These findings support further investigation of this combination and follow-up to determine if the remissions are durable after treatment discontinuation.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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