VIENNA (FRONTLINE MEDICAL NEWS) – A daily dose of the investigational BCL-2 inhibitor venetoclax plus rituximab induced responses in 84% of patients with relapsed or refractory chronic lymphocytic leukemia in a phase Ib study.

Of the 49 patients, 20 (41%) achieved a complete response by standard assessment and 13 (27%) achieved a complete response with no evidence of residual disease on flow cytometry.

Moreover, six patients elected to stop venetoclax after achieving a complete response and, to date, only one has had recurrence of disease after 24 months without therapy, lead investigator Dr. Andrew W. Roberts reported at the annual congress of the European Hematology Association.

Not only were patients able to come off treatment and continue to remain in complete response, but responses were seen at the same frequencies across all classes of cytogenetic and molecular abnormalities, he noted.

“The greatest advance that this drug brings is for those patients who currently have a terrible prognosis with all other drugs that we now have,” Dr. Roberts of Royal Melbourne Hospital said in a press briefing.

“This is an important step forward in finding chemotherapy-free regimens in these vulnerable, elderly patients,” said press briefing moderator Dr. Anton Hagenbeek of the University Medical Center, Utrecht, the Netherlands.

Patients in the open-label, dose-escalation study had received a median of two prior lines of therapy (range, one to five) for chronic lymphocytic leukemia (CLL); their median age was 68 years (50-88 years). They began treatment with 20 mg or 50 mg venetoclax daily, increasing weekly to final cohort doses of 200 mg to 600 mg. Six cycles of monthly standard rituximab were added after the weekly lead-in phase.

CLL depends on high levels of B-cell lymphoma-2 (BCL-2) to stay alive. Venetoclax binds to and switches off the BCL-2 protein function, triggering the death of the CLL cell.

Grade 3 or 4 adverse events occurring in more than 10% of patients were neutropenia (51%), thrombocytopenia (16%), and anemia (14%). There was one treatment-emergent case of tumor lysis syndrome leading to death early in the trial. This phenomenon can occur when the CLL breaks down very quickly and, as a consequence, the study was redesigned and a lower starting dose is now used, Dr. Roberts said.

“That problem has been eliminated, but we still see a very large improvement in patients in a few weeks,” he said. “Other than that, there is a little bit of neutropenia, but that is very manageable.”

“So do you think you are curing patients with this approach?” Dr. Hagenbeek asked, to which Dr. Roberts replied, “Too early to say.”

Venetoclax is currently being evaluated in less heavily pretreated patients and a phase III trial is comparing the combination of venetoclax and rituximab with standard bendamustine chemotherapy plus rituximab, he said.

In May, the Food and Drug Administration granted venetoclax breakthrough therapy designation for use in relapsed or refractory chronic lymphocytic leukemia with a 17p deletion mutation.

AbbVie, which is developing venetoclax in partnership with Roche and Genentech, plans to submit regulatory applications for venetoclax to the FDA and the European Medicines Agency before the end of 2015.

On Twitter @pwendl


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