SAN DIEGO, CA—At the 53rd American Society of Hematology Annual Meeting and Exposition, study investigators presented data showing that bafetinib has therapeutic potential in the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL) who relapsed or were refractory to >1 course of treatment with either an alkylating agent, rituximab, or a fludarabine-based regimen.

Bafetinib, BCR-ABL/Lyn dual tyrosine kinase inhibitor, may suppress the growth of CLL cells by inhibition of Lyn kinase. Imatinib-resistant CLL cells are associated with an overexpression of Lyn kinase, a factor in the proliferation and survival of B-CLL cells. Bafetinib has no effect on c-Src kinase activity and is expected to be less toxic than other broad Src family kinase inhibitors.

In a single arm, open-label, Phase 2 trial, patients were given bafetinib 240mg orally twice daily initially; the dose could be adjusted up to 360mg twice daily. Treatment was continued for 12 months or until disease progression or unacceptable toxicity. The primary endpoint was response assessment (complete, partial, nodular partial, nodal) by International Workshop Chronic Lymphocytic Leukemia Criteria (IWCLL). Secondary endpoints included toxicity, response duration, and progression-free survival. At the time of analysis, a total of 16 patients in the intent-to-treat population had received bafetinib; to date, a total of 18 patients have been enrolled. The median age was 70.5 years (range 54–88). Of 12 patients tested, nine had the chromosomal aberration del(17p;13). The median number of prior treatment regimens was three (range 1–6). Five patients were Rai stage I (31%), five patients were Rai stage II (31%), one patient was Rai stage III (6%), and five patients were Rai stage IV (31%). Fourteen patients had ECOG performance scores of ≤1.

The median duration of treatment with bafetinib was two months (range 0.25–5). Twelve patients were evaluable for response (baseline plus at least one post-baseline evaluation). There were no objective responses following the IWCLL’s 2008 criteria. Nodal responses, defined as ≥30% reduction in sum of areas of measurable lymph nodes and ≥30% shrinkage in spleen size, were seen in six of the evaluable patients. Four patients had stable disease post baseline assessments, while two patients demonstrated progressive disease at their initial evaluation post baseline. During the first three months of treatment, 50% of evaluable patients had a >50% increase in their absolute lymphocyte counts.

Fourteen patients were evaluable for toxicity. No treatment-related serious adverse events occurred at the time of analysis. Grade 1/2 adverse events constituted the majority of treatment-related adverse events; elevated liver enzymes (64%), fatigue (25%), and nausea (19%) were the most common. One patient had Grade 3 elevated liver enzymes and was removed from the study. Anemia (13%) was the most frequently occurring Grade 3/4 adverse event.

Bafetinib shows activity, though limited, at a dose of 240mg orally twice daily, with no treatment-limiting toxicity seen, said Tapan Kadia, MD of MD Anderson Cancer Center, Houston, TX. However, at this dose, a preliminary pharmacokinetic analysis from a parallel solid tumor showed that peak bafetinib concentrations reached a level below that which inhibits the growth of B-CLL cells in vitro. A higher dose (360mg orally twice daily) is being studied. Based on the results of this trial, bafetinib should be further studied in combination with monoclonal antibodies and chemotherapy.