Abstract
6508 Background: Btk is essential to B-cell development and function. Btk is highly-expressed in CLL and its inhibition by the potent irreversible inhibitor PCI32765 (P) promotes apoptosis and inhibition of cytokine, chemokine, microenvironment-mediated signaling, proliferation, and chemotaxis ex vivo. We report interim results of a large Phase Ib/II trial of P in CLL/SLL. Methods: Two cohorts (previously untreated [PU] >65 yrs old and relapsed/refractory [R/R] disease following at least 2 prior therapies [Rx] including fludarabine) of CLL patients (pts) were treated with oral P administered daily for 28-d cycles until progression of disease (PD). Doses of 420mg (24 PU and 27 R/R) and 840 QD (31 R/R) were examined. Results: Of the 78 pts enrolled, data from the first 39 pts will be sufficiently mature as of May 2011 to assess IWCLL2008/Cheson response criteria. R/R pts had a median age of 64, 37% were Rai III/IV, and median of 3 (range 2-10) prior Rx. 87% had at least one poor-risk molecular feature: del(17p)-30%, del(11q)-21%, IgVH un-mutated 70%. Treatment has been well tolerated with grade >3 AEs potentially related to P in 26% of pts. >Gr 3 cytopenias have been noted in <5% of pts. No pts have had LFT elevations. In evaluable pts with lymphadenopathy, the rate of nodal response (LNR; >50% reduction in target lesions) is 89% (25/28 pts). An increase in absolute lymphocyte counts (ALC) occurred in 75% of pts and has decreased over time in the vast majority. At a median follow-up of 4 months, 17 (44%) have a PR (n=15, 39%) or CR/CRu (n=2, 5%). Response has been similar in all genomic groups. Notably, 4 of 12 pts with del(17p) have responded and 7 others remain on P Rx with improving SD. Mature response data will be updated. At a median follow-up of 4 months, 34/39 pts in the 420 mg cohort remain on P therapy with only one PD. Conclusions: PCI32765 is highly active and well tolerated in CLL/SLL pts irrespective of high risk genomic abnormalities. Although follow-up is short, the high response rate and very low progression rate suggests that PCI-32765 may be an important new targeted treatment approach for CLL pts, including those with del(17p).
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