BCL-2 Inhibitor Yields High Response in CLL and SLL

Preliminary results from an ongoing phase I clinical trial of the B-cell lymphoma-2 (BCL2) oral inhibitor ABT-199 (AbbVie and Genentech/Roche) show an overall response rate of 84% among 67 patients with relapsed or treatment-resistant chronic lymphocytic lymphoma (CLL) or small lymphocytic lymphoma (SLL). After a median follow-up of 10.9 months, 23% of enrolled patients who began daily ABT-199 treatment experienced a complete response and 61% experienced a partial response.

Among CLL patients at high risk of relapse, overall response rates were similar, at 82% in those with 17p-deletion disease and 89% in those with fludarabine-refractory disease.

Abnormal expression of BCL-2, which regulates apoptosis, helps blood cancer cells survive and proliferate, and has been linked to treatment resistance, says John Seymour, MBBS, PhD, director of the Hematology Service at the Peter MacCallum Cancer Centre in Melbourne, Australia. Seymour, who is a lead investigator on the trial, presented the initial findings on December 10 at the annual meeting of the American Society of Hematology in New Orleans, LA.

“BCL-2 is often considered a good target because it's responsible for cancer cells surviving when they shouldn't,” comments Andrew Roberts, MBBS, PhD, a hematologist at the Royal Melbourne Hospital and Walter and Eliza Hall Institute, and also a lead investigator on the trial. In addition, he says, preclinical data suggest that targeting the protein has the potential to restore a patient's sensitivity to treatment.

However, targeting BCL-2 has been tricky, Roberts says, because the protein is not an enzyme. Researchers had been attempting to target BCL-2 selectively for more than a decade before scientists at AbbVie, Genentech, and the Walter and Eliza Hall Institute produced ABT-199.

The most common adverse effects reported were diarrhea (43%), neutropenia (37%), fatigue (33%), upper respiratory tract infection (33%), and cough (22%). Twenty-four patients have discontinued the trial.

Seymour notes that even though the phase I study of ABT-199 shows high efficacy, “with that potency comes some need for vigilance and caution.”

Early in the trial, six patients experience tumor lysis syndrome (TLS), caused by the rapid breakdown of dying cancer cells. The investigators dropped the dosage and slowly raised it over the following weeks, and the incidence of TLS fell.

Enrollment for the phase I trial is still open, with new patients receiving the lower dose schedule to reduce the risk of TLS. The investigators have also launched phase II studies, including an ABT-199 single-agent trial on patients with relapsed 17p-deletion CLL and a trial that combines ABT-199 with either rituximab (Rituxan; Genentech) or obinutuzumab (Gazyva; Roche), also in patients with relapsed CLL.