In ultra-high-risk chronic lymphocytic leukemia patients with the 17p gene deletion, the investigational agent venetoclax achieved high responses, reported a single-arm phase 2 study. The study – presented as a late-breaking abstract at the annual meeting of the American Society of Hematology – which took place between 5th-8th December 2015, in Orlando, FL – showed acceptable toxicity.

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Leukemia is cancer of the blood cells, which form in the bone marrow. In leukemia, cancerous blood cells crowd out the healthy blood cells in the bone marrow.

“Venetoclax may be an attractive component to incorporate into novel combinations or to sequence in patients with this very high-risk disease characterized by 17 p deletion,” said lead author Stephan Stilgenbauer, from the University of Ulm in Germany.

Approximately 3-10% of patients with chronic lymphocytic leukemia (CLL) have 17p deletions (del17p) at diagnosis (where part of chromosome 17 is absent), with the deletion occurring in 30-50% of patients with relapsed/refractory CLL.

Patients with 17p deletions have faster-moving disease, with a median progression-free survival of fewer than 12 months with frontline chemotherapy. “This is a very special population with the most dismal outcome,” said Stilgenbauer.

Venetoclax is an orally bioavailable, selective inhibitor of the BCL-2 protein that directly induces apoptosis in CLL cells independent of p53. The BCL-2 protein is significant since it prevents apoptosis of some cells, including lymphocytes, and can be overexpressed in certain cancer types.

In the study, venetoclax monotherapy was evaluated in 107 relapsed or refractory del17p CLL patients, median age 67 years, who had received a median of three prior regimens (1-10).

Patients received venetoclax once daily with a weekly dose ramp-up schedule (20, 50, 100, 200 and 400 mg) over a period of 5 weeks, with tumor lysis syndrome (TLS) prophylaxis. Patients continued to receive daily venetoclax until disease progression or unacceptable toxicity.

Results showed overall response was 79.4% (85/107) (95% CI, 70.5-86.6), as assessed by an independent review committee. Furthermore, this included eight patients (7.5%) with a complete response (CR) or a CR with incomplete marrow recovery (Cri). A year later, response was maintained in 84.7% of patients.

Of 45 patients tested for minimal residual disease (MRD), 18 attained MRD-negative status in peripheral blood and 25 of 48 patients who were assessed also had no CLL in bone marrow, determined by immunohistochemistry.

Of 103 evaluable patients, 96% experienced a treatment-emergent adverse event )AE) of any grade, including 76% with grade 3/4 events. The most common all-grade AEs included neutropenia (43%), diarrhea (29%) and nausea (29%).

Infections occurred in 72% of patients (77), but only 15% (16) experienced upper respiratory tract infections of any grade, including 2% (2) with grade 3/4 upper respiratory tract infections. The neutropenia and infection incidence, Stilgenbauer commented, was similar to frontline chemotherapy.

The phase 2 data was presented at the same time as the results of the first-in-human phase 1 dose-escalation study of venetoclax in CLL were published in The New England Journal of Medicine.

In the phase 1 study involving 116 CLL patients refractory to their last treatment (but not restricted to patients with the 17p deletion), the overall response rate was 79%, including complete response in 20% of participants. Furthermore, the 15-month progression-free survival estimate for patients receiving the highest dose of 400 mg per day venetoclax was 69%.

Venetoclax has already received breakthrough therapy designation from the Food and Drug Administration (FDA) for patients with relapsed or refractory CLL harboring the 17p deletion, and the results of the clinical trial have been submitted as part of new drug applications to the European Medicines Agency and FDA.