medwireNews: Obinutuzumab and venetoclax, preceded by bendamustine debulking for high tumor loads, shows high response rates without unexpected or cumulative toxicities in patients with chronic lymphocytic leukemia, a phase II trial suggests.
Among 66 patients enrolled in the CLL2-BAG trial, 53% were treatment naïve and 47% had relapsed or had refractory disease after receiving previous therapies.
All participants received six induction cycles of obinutuzumab plus venetoclax, and up to 24 months of maintenance with the combination, while those with a high tumor burden additionally received two cycles of bendamustine debulking prior to induction therapy.
Over a median follow-up of 16 months, 95% of the 63 evaluable patients reached the primary endpoint of an overall response at the end of induction treatment, with rates of 100% and 90% among the treatment-naïve and relapsed or refractory patients, respectively.
Additionally, 87% of the participants tested negative for minimal residual disease in their peripheral blood, which the researchers say “is impressive and compares favorably with the combination of fludarabine, cyclophosphamide, and rituximab, the gold standard for treatment-naive patients without high-risk genetic parameters.”
They add in The Lancet Oncology: “Cumulative evidence from two trials– 66 patients in this phase 2 study and the 13 patients from the safety run-in of the phase 3 CLL14 trial–suggests that the combination of venetoclax and obinutuzumab might be one of the most efficacious treatment options reported so far for chronic lymphocytic leukaemia.”
Nonetheless, Paula Cramer (University of Cologne, Germany) and team caution that until data from larger trials are available “the use of venetoclax combined with obinutuzumab in routine practice cannot be recommended, especially in the first-line setting.”
Adverse events of grade 3 or 4 were experienced by 34% of the 47 enrolled patients who received bendamustine debulking, the most common being neutropenia and anemia (11% each), followed by thrombocytopenia and infection (6% each).
Sixty-two percent of the 66 trial participants experienced grade 3–4 toxicities during induction, with neutropenia (44%), infection (14%), thrombocytopenia (12%), infusion-related reactions (8%), and secondary primary malignancy (6%) the most frequently observed events.
There were three laboratory cases of tumor lysis syndrome – only one related to venetoclax – during the course of the study, and none of the patients experienced clinical tumor lysis syndrome.
Three deaths, all among the relapsed or refractory patients and all due to sepsis, were attributed to adverse events related to the study treatment.
In a commentary accompanying the study, Avyakta Kallam and James Armitage, both from the University of Nebraska Medical Center in Omaha, USA, call the results “encouraging” but say infectious complications during debulking mean “the role of bendamustine in this regimen might have to be reconsidered.”
The commentators continue: “Although long-term follow-up is necessary to establish the duration of responses after venetoclax is stopped, venetoclax will probably become an integral part of chronic lymphocytic leukaemia therapy.
“There is reason to hope that combinations such as ibrutinib, obinutuzumab or rituximab, and venetoclax will induce true complete remissions in most treatment-naïve patients and that some of these complete responders will ultimately be cured.”
By Anita Chakraverty
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