An investigational oral agent targeting the B-cell receptor achieved high rates of remission with little toxicity in patients with chronic lymphocytic leukemia (CLL) refractory to at least 2 previous treatments, according to results from a phase 2 study presented at the 53rd Annual Meeting of the American Society of Hematology (ASH).
The agent, called PCI-32765, is a first-in-class Bruton’s tyrosine kinase (Btk) inhibitor. Btk mediates B-cell receptor signaling, and this protein is essential for CLL cell survival and proliferation. PCI-32765 is an irreversible inhibitor of Btk that induces apoptosis and inhibits cellular migration and adhesion in malignant B cells.
“It is very exciting to have agents that are this effective and are not myelosuppressive. The efficacy of this agent increases over time, there is a relative lack of toxicity, and there is a lack of myelosuppression. These agents should really change the paradigm for the treatment of CLL,” stated lead author Susan O’Brien, MD, of The University of Texas MD Anderson Cancer Center, Houston.
An earlier analysis of the phase 1b/2 study showed that PCI-32765 was highly active and tolerable in patients with CLL. The data O’Brien presented at ASH were based on longer-term follow-up of a multicenter phase 1b/2 trial. The study enrolled 61 CLL patients aged 65 or older with previously untreated or relapsed/refractory CLL after at least 2 prior therapies. Patients received oral PCI-32765 daily in 28-day cycles until disease progression. Seventy-two percent of patients had at least 1 poor-risk molecular feature: del(17p) 31%, del(11q) 33%, or IgVH unmutated 57%.
The study evaluated 2 doses of the Btk inhibitor: 420 mg and 840 mg daily. The analysis presented at ASH included patients with relapsed/refractory disease, but not those who were previously untreated. Median follow-up for the 420 mg cohort was 10.2 months and 6.5 months for the 840 mg cohort.
For the 420 mg cohort, objective response rates (ORRs) improved from 48% at 6 months of follow-up to 70% at 10 months; in the 840 mg cohort, ORR was 44% at a median follow-up of 6.5 months. The Btk inhibitor seems to be effective in shrinking CLL in the lymph node compartment. At the time of the ASH meeting, nodal partial response was observed in 35% of patients (>50% reduction in aggregate lymph node size), with residual lymphocytosis. ORR appears to be independent of molecular risk features, O’Brien commented.
The novel agent was well tolerated. Two patients discontinued treatment due to adverse events; 6 patients required dose reductions. Grade 1/2 diarrhea, fatigue, nausea, and ecchymosis were the most frequently reported side effects. Ten percent of serious adverse events were attributed to PCI-32765, as were 21% of grade ≥3 adverse events. “Myelosuppression has not been a problem with this agent,” O’Brien said.
At the time of the ASH meeting, 82% of patients remained on treatment with PCI-32765. Only 8% (5/61) progressed; 6-month progression-free survival was 92% in the 420 mg cohort and 90% in the 840 mg cohort.
Pharmacyclics, the company developing the novel Btk inhibitor, is planning phase 3 trials of PCI-32765.