Three-drug combination induces deep remission in treatment-naive, relapsed/refractory CLL
A combination of obinutuzumab, ibrutinib and venetoclax induced deep remissions in patients with treatment-naive or relapsed/refractory chronic lymphocytic leukemia, according to study results published in Journal of Clinical Oncology.
“The whole field has shifted away from use of traditional cytotoxic chemotherapies and more toward targeted agents,” Kerry A. Rogers, MD, assistant professor in the division of hematology at The Ohio State University, told Healio. “The chemotherapy experience ended with an effective regimen [of fludarabine, cyclophosphamide and rituximab (Rituxan; Genentech, Biogen)] called FCR, which has outwinding results in younger patients; however, these new targeted agents have better disease outcome and are much more tolerable than chemotherapy. There’s a lot of excitement for these new regimens.
“The major drawback to chemotherapy, besides the toxicity, is that it doesn’t work with patients with deletion-17p CLL or with complex karyotype,” she added. “So, you have a fraction of patients with CLL who don’t benefit from chemotherapy very much at all.”
Ibrutinib (Imbruvica; Janssen, Pharmacyclics), which inhibits Bruton tyrosine kinase in the B-cell receptor signaling cascade, and venetoclax (Venclexta; AbbVie, Genentech), which inhibits B-cell lymphoma protein 2 (BCL2) interaction with select BH3 domain proteins, both confer superior PFS compared with chemoimmunotherapy, according to study background.
Researchers sought to evaluate responses to a combination of ibrutinib, venetoclax and obinutuzumab (Gazyva, Genentech), as well as safety of the regimen, among 50 patients (median age, 59 years; range, 24-77; 38% women) with either treatment-naive (n = 25) or relapsed or refractory (n = 25) CLL.
The investigators included obinutuzumab in the phase 2 study regimen because anti-CD20 monoclonal antibodies have consistently improved outcomes in combination with chemotherapy for this patient population. Obinutuzumab specifically has shown superior efficacy and higher rates of undetectable minimal residual disease (MRD) compared with rituximab.
“The study started as an effort to combine the three most effective nonchemotherapy drugs we have in CLL,” Rogers said. “The other benefits of this regimen are that it’s short and given over the course of just a year.”
The rate of complete remission with undetectable MRD by flow cytometry in both the blood and bone marrow 2 months after completion of treatment served as the study’s primary endpoint. Results showed 28% (95% CI, 12-49) of patients in both the treatment-naive and relapsed/refractory cohorts achieved this outcome.
The cohorts also had similar overall response rates at the end of therapy (84% vs. 88%).
Researchers reported undetectable MRD in both the blood and marrow of 67% of treatment-naive patients and 50% of patients with relapsed or refractory disease.
Median PFS and OS were not reached after median follow-up of 24.2 months in treatment-naive cohort and 21.5 months in the relapsed/refractory cohort. One patient in the relapsed/refractory cohort experienced disease progression and one patient in the treatment-naive cohort died due to sepsis.
Frequent adverse events included neutropenia, thrombocytopenia and hypertension. About two-thirds of patients (66%) experienced grade 3 or grade 4 neutropenia.
“More work needs to be done before this regimen is put out for widespread use,” Rogers said. “This trial established this combination and allows it to go onto the phase 3 trials. I am really excited because I think there is a good chance this will become the standard of care.”
For more information:
Kerry A. Rogers, MD, can be reached at The Ohio State University, 410 W. 12th Ave., Wiseman Hall, CCC Rm 458, Columbus, OH 43210; e-mail: kerry.rogers@osumc.edu.
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