Abstract LB-141: Potent single agent activity of Ibrutinib (PCI-32765) in patients with chronic lymphocytic leukemia (CLL): clinical and translational results from an ongoing phase II study.
Authors: Adrian Wiestner, Sarah Herman, Rashida Mustafa, Janet Valdez, Jade Jones, Nakhle Saba, Andrew Lipsky, Diane C. Arthur, Gerald Marti, Francine Thomas, Irina Maric, Stefania Pittaluga, Xin Tian, Susan Soto, Georg Aue, Mohammed Z. Farooqui
Journal: Cancer Research (2013)

Abstract Background: B-cell receptor (BCR) activation plays a pivotal role in the pathogenesis and for progression of CLL. Ibrutinib (PCI-32765), an irreversible inhibitor of Bruton's tyrosine kinase (BTK), can disrupt BCR signaling and has durable antitumor activity in CLL. We initiated a phase II single center trial to extend this experience and assess the impact of ibrutinib on tumor cells in vivo. Methods: Treatment naïve (TN) and relapsed/refractory (R/R) pts with CLL are treated with 420 mg ibrutinib daily. Pts are enrolled in 2 cohorts: 1) deletion (del) of chromosome 17p and 2) &amp;gt;65yo and treated until disease progression. Response is evaluated at 6 months (mo) and every 6 mo thereafter. 17p del was assessed by FISH cytogenetics. Spleen volume on computed tomography (CT) scans was computed using a General Electric Advanced Workstation Server. Results: With a median follow-up of 9 mo we report on the first 53 patients: for del 17p n=29; 15 TN, 14 R/R; and for &amp;gt;65yo n=24; 8 TN, 16 R/R. Estimated event free survival at 12 mo is 94%. Most adverse events were mild with non hematologic toxicities (regardless of causality) grade ≥3 in &amp;lt;13% of pts. Two deaths on study were not treatment related. At 6 mo 95% of pts (n=44 evaluable) had a nodal response (median reduction in lymph node size of 73%) and 52% of pts had a partial response (PR) by IWCLL criteria. One pt had progressive disease (presumed Richter's transformation). All pts had a decrease in splenomegaly. The median reduction of splenic volume computed from CTs was 55% (30-1716 ml). Tumor infiltration in bone marrow biopsies (n=26), decreased by a median 82% as assessed by immunohistochemistry for CD79a and the median ALC decreased from 79 k/µl (0.5-402) to 32 k/µl (0.8-167) at 6 mo for a median reduction of 62%. We evaluated the in vivo effects of ibrutinib using blood and tissue samples collected pre and during ibrutinib treatment. On treatment expression of genes known to be induced by B-cell receptor (BCR) activation (Herishanu et al 2011) was significantly reduced in CLL cells in the peripheral blood (PB) in all pts (n=15; median reduction 57%; P&amp;lt;.001). Consistent with inhibition of BCR signaling, we found concurrent reduction in PLCγ2 phosphorylation; a direct target of BTK. Patients also donated matched lymph node (LN) core biopsies pre-treatment and within the first 4 days on treatment. Ibrutinib inhibited BCR signaling in the LN (n=8, P=.004) to a similar degree as observed in the PB. Similarly, ibrutinib decreased expression of NF-κB target genes in PB and LN. In keeping with inhibition of BCR and NF-κB signaling surface markers of cellular activation such as CD38, CD69, and CD86 were significantly reduced by ibrutinib as measured by flow cytometry (P&amp;lt;.02). Finally, ibrutinib significantly reduced tumor proliferation as determined by the percentage of PB CLL cells expressing Ki67 (median reduction of 80%; P&amp;lt;.001). Conclusions: Ibrutinib as a single agent is well tolerated and highly effective in both TN and R/R pts achieving rapid disease control in blood, lymph nodes, spleen and bone marrow that is durable. Correlative studies on patient samples during ibrutinib treatment provide direct evidence for on target effects of ibrutinib in vivo demonstrating effective and sustained inhibition of BCR and NF-κB signaling in both PB and LNs. Ibrutinib deserves further investigation as targeted therapy for CLL. We thank our patients for participation and donation of blood and tissue samples. Supported by the Intramural Research Program of NIH. Citation Format: Adrian Wiestner, Sarah Herman, Rashida Mustafa, Janet Valdez, Jade Jones, Nakhle Saba, Andrew Lipsky, Diane C. Arthur, Gerald Marti, Francine Thomas, Irina Maric, Stefania Pittaluga, Xin Tian, Susan Soto, Georg Aue, Mohammed Z. Farooqui. Potent single agent activity of Ibrutinib (PCI-32765) in patients with chronic lymphocytic leukemia (CLL): clinical and translational results from an ongoing phase II study. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-141. doi:10.1158/1538-7445.AM2013-LB-141