Bruton’s Tyrosine Kinase: An Exciting New Target for Treatment of B-Cell Malignancies

A Phase II trial of patients with relapsed or refractory MCL who received PCI-32765 560 mg daily in continuous 28-day cycles until disease progression was presented at the 2011 Annual Meeting of the American Society of Hematology.⁹ MCL is an aggressive type of non-Hodgkin’s lymphoma, and there is no consensus on the optimal treatment approach. The disease is considered incurable with standard combination chemotherapy. Aggressive, high-dose multi-agent regimens, followed by consolidation and stem-cell rescue have been more effective, but are generally reserved for younger patients.⁹ More effective, yet tolerable, regimens are clearly needed.

At time of presentation, 68 patients had been enrolled in the Phase II trial, of which 61 had received at least one cycle of therapy and were evaluable for safety, and 51 had been restaged after cycle 2 and were evaluable for efficacy.⁹  For purposes of analysis, patients were classified as either bortezomib-exposed for at least 2 cycles (n=27) or bortezomib -naïve (n=41). The group possessed many poor prognosis characteristics: 79% had an MIPI (mantle cell lymphoma international prognostic index) score of intermediate or high, 62% were three years or longer since diagnosis, 43% had three or more prior lines of therapy, and 40% had disease that was refractory to the last therapy. The median time on-study was 3.7 months.

PCI-32765 was generally well tolerated, with the most frequent side effects being grade 1 and 2 fatigue and diarrhea (Figure 2). Hematologic grade 3/4 AEs occurred in less than 5% of patients and the only grade 4 non-hematologic event was an episode of abdominal pain. A unique observation of marked lymphocytosis, being termed a “compartment shift,” had been observed where the lymphocyte count doubled from about day 8 to 28 of cycle 1, and then slowly declined to about 40% above baseline with subsequent cycles. A separate poster presentation described these lymphocytes as being CD5⁺and CD45^lo, consistent with circulating, mobilized lymphoma cells.¹¹ The mechanism may be related to inhibition of tissue-homing cytokines CXCL12 and CXCL13, and inhibition of adhesion molecule functioning.⁶ No detrimental clinical events have been noted during this phenomenon.

Figure 2.

The objective response rate (ORR) in these patients with MCL was 69% (CR 16%, PR 53%). PCI-32765 had similar activity in bortezomib-naïve and bortezomib-exposed patients (ORR 71% and 65%, respectively). Prior refractoriness to therapy, presence of bulky disease, and MIPI score did not influence response rates. The impressive activity of PCI-32765 in a poor prognosis disease such as relapsed/refractory MCL and the lack of hematologic toxicity are encouraging results.