Venetoclax plus rituximab ‘attractive potential option’ for relapsed, refractory CLL
medwireNews: Venetoclax plus rituximab is active and well tolerated in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma, shows a phase Ib trial.
A high proportion of the enrolled patients achieved deep and durable responses, says the team, suggesting that the dual regimen could be “an attractive potential treatment option” for this difficult-to-treat population.
A total of 49 participants were given the BCL2 inhibitor venetoclax daily with a stepwise escalation to the target doses of 200–600 mg, after which monthly rituximab was initiated, at a dose of 375 mg/m2 in the first month and 500 mg/m2 in months 2–6. Once combination treatment was completed, patients continued venetoclax monotherapy until unacceptable toxicity, disease progression, or drug cessation per protocol.
Seventy-six percent of patients experienced an adverse episode of grade 3 or 4, with neutropenia (53%), thrombocytopenia (16%), anemia (14%), febrile neutropenia (12%), and leucopenia (12%) the most common events. The adverse event profile and frequencies of individual toxicities were similar to those previously reported with venetoclax alone, “without substantially greater incidence or severity of neutropenia or increased proportion of patients with a severe infection,” the team notes.
Two patients, both of whom initiated venetoclax at a dose of 50 mg, developed clinical tumor lysis syndrome, resulting in one death. The researchers explain that the protocol was subsequently modified, such that venetoclax was initiated at a 20 mg dose and prophylactic measures against tumor lysis syndrome were enhanced, after which no further episodes were observed.
As reported in The Lancet Oncology, the maximum tolerated dose was not reached, and the recommended phase II dose of venetoclax was 400 mg when given alongside rituximab.
During a median follow-up of 28 months, 86% of patients achieved an overall response, including a complete response or a complete response with incomplete marrow recovery in 51%. Additionally, 57% of the cohort had no minimal residual disease (MRD).
At the time of analysis, median time to progression had not been reached, and the estimated 2-year progression-free survival and ongoing response rates were 82% and 89%, respectively, report John Seymour (Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia) and colleagues.
Thirteen (26%) patients with a deep response – complete response, complete response with incomplete marrow recovery, or partial response with no MRD – stopped venetoclax treatment after a median of 10 months. Of these, the 11 MRD-negative patients remained progression-free off treatment until last observation, whereas the two with MRD-positivity progressed after 24 months of treatment withdrawal. Both patients achieved a partial response after venetoclax monotherapy was re-initiated.
Commenting on these findings, Lorenzo De Paoli and Gianluca Gaidano (both from University of Eastern Piedmont and Maggiore Charity Hospital, Novara, Italy) say: “Remarkably, the maintenance of a response to venetoclax without the need for continuous exposure is a peculiar feature of this drug among the new small-molecule treatments available for chronic lymphocytic leukaemia, and represents an important added value for patients as well as for health-care systems.”
The study authors propose that “[a]bbreviated courses of treatment with venetoclax-containing combination regimens should be explored as alternatives to long-term therapy with B-cell receptor signalling inhibitors or venetoclax monotherapy in randomised trials.”
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