ASH 2011: Bruton’s tyrosine kinase inhibitor induces durable responses in relapsed leukaemia and lymphoma

12 Dec 2011
ASH 2011: Bruton’s tyrosine kinase inhibitor induces durable responses in relapsed leukaemia and lymphoma

A recent update of a multicenter Phase Ib/II clinical trial concludes that the novel Bruton’s Tyrosine Kinase (BTK) inhibitor PCI-32765 may be an important new targeted treatment approach for patients with chronic lymphocytic leukaemia (CLL).

Tyrosine kinase enzymes are important targets for cancer research because they function as “on/off switches” in many cell functions and can signal cells to either maintain normal functioning or to grow uncontrollably, leading to cancer.

BTK in particular is largely responsible for the signaling that drives normal B-cell development, making it a primary target for research on B-cell malignancies such as non-Hodgkin lymphoma (NHL).

PCI-32765 is an orally-administered BTK inhibitor that induces apoptosis, or programmed cell suicide, and inhibits function of malignant B-cells. Earlier promising studies of PCI-32765 have shown that the compound may be highly active and tolerable in patients with CLL.

The current analysis summarises results of an ongoing study using PCI-32756 as a treatment for patients with relapsed CLL. Two cohorts of CLL patients were treated with PCI-32765 at doses of either 420 mg (n=27) or 840 mg (n=34) daily for 28-day cycles until they showed signs of disease progression. Nearly three-fourths (72%) of participating patients had at least one high-risk feature, indicating that they may not respond well to treatment.

After a review of the current analysis, researchers concluded that PCI-32765 was associated with high rates of six-month progression-free survival in patients with relapsed CLL. At 10 months follow-up, 70 percent of patients in the 420 mg treatment group achieved an objective response to therapy (previously reported as 48%), and 44 percent of the patients in the 840 mg cohort achieved an objective response at six months follow-up.

An additional 19 percent of the 420 mg cohort and 35 percent of the 840 mg cohort had a nodal partial response, meaning their disease responded to therapy as represented by a 50 percent or greater reduction in lymph node size, but some lymph nodules persisted. Importantly, 82 percent of patients remain on treatment, and only 8 percent have experienced progressive disease.

Two patients discontinued the trial because of adverse events, and six patients required a dose reduction. The most frequently reported adverse events included diarrhea, fatigue, nausea, and ecchymosis (apparent skin bruising).

Serious adverse events (SAEs, which are considered relatively common among this immune-compromised patient population) occurred in 38 percent of patients, with 10 percent considered potentially related to treatment.

Grade ≥3 severe AEs considered potentially related to treatment occurred in 21 percent of patients. In addition, the majority of patients experienced high lymphocyte count, an event well-documented with this type of treatment, during the first two months of treatment that resolved over time.

“Our results suggest that PC-32765 has the potential to be highly effective and tolerable, and, more importantly, appears to be working well in patients with poor prognoses,” said lead author Susan O’Brien, MD, Professor in the Department of Leukaemia at The University of Texas MD Anderson Cancer Center in Houston. “As we become better equipped to target specific cellular functions, it is our hope that therapies like PCI-32765 will become effective interventions to manage disease in patients with CLL.”


Source: ASH