Newswise — WASHINGTON, D.C. — The drug ibrutinib was well tolerated and highly effective in patients with untreated, relapsed and unresponsive chronic lymphocytic leukemia (CLL), according to phase II data presented at the AACR Annual Meeting 2013, held in Washington, D.C., April 6-10.

“The degree of tumor reduction achieved by once-daily oral therapy was impressive,” said Adrian Wiestner, M.D., Ph.D., investigator and head of the Lymphoid Malignancies Section in the Hematology Branch at the National Heart, Lung, and Blood Institute at the National Institutes of Health (NIH) in Bethesda, Md. “We have seen patients with more than 90 percent reduction of lymph node disease within just two months.”

Many elderly patients with CLL are unable to tolerate current aggressive standard therapies, and those with a deletion in the short arm of chromosome 17, referred to as “del 17p,” have particularly poor outcomes with chemotherapy. These two CLL patient populations that are enrolled in the NIH phase II study have the greatest need for novel treatment therapies, according to Wiestner.

Ibrutinib is a selective inhibitor of Bruton’s tyrosine kinase, a component of the B-cell receptor signaling pathway that plays a key role in the development and progression of CLL. This study confirms the single-agent antileukemia activity seen in prior phase I/II studies and extends this experience, particularly in del 17p CLL, according to Wiestner.

He and his colleagues enrolled 53 patients with CLL into two cohorts — 29 patients with del 17p and 24 patients without del 17p who were aged 65 years or older. They assigned all patients to 420 mg of ibrutinib daily and evaluated response to the drug at six months and every six months thereafter, until disease progression.

Most adverse events were mild and included diarrhea, fatigue and rash in less than 13 percent of the patients.

At six months, 95 percent of patients showed at least a 50 percent reduction in lymph node disease, and all showed reduction in spleen enlargement, with a median reduction of 55 percent. In 26 patients for whom a bone marrow biopsy was done, tumor infiltration decreased by 82 percent. Absolute lymphocyte count decreased by a median of 62 percent. Using standard CLL response criteria, 52 percent of patients had a partial response. At 12 months, the estimated event-free survival rate was 94 percent.

Using blood and tissue samples of lymph nodes collected from 15 patients before and during ibrutinib treatment, Wiestner and his colleagues showed effective inhibition of B-cell receptor signaling and tumor proliferation, which was reduced by more than 80 percent, as measured by Ki67 staining.

“Ibrutinib was highly efficacious as a single agent in patients with untreated, relapsed and unresponsive CLL, irrespective of their del 17p status,” Wiestner said. “Responses appear to be durable, and the drug is effective against the disease in lymph nodes, spleen and bone marrow. This is important because existing therapies often fail to effectively eliminate cancer cells in these tissue sites. Targeted therapy for CLL is becoming a reality, and this new approach will greatly improve the lives of patients with this disease.”

This research was supported by the Intramural Research Program of the National Heart, Lung, and Blood Institute at the NIH. # # #

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Abstract Number: LB-141

Presenter: Adrian Wiestner, M.D., Ph.D.

Title: 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

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) >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 >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 <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<.001). Consistent with inhibition of BCR signaling, we found concurrent reduction in PLC2 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<.02). Finally, ibrutinib significantly reduced tumor proliferation as determined by the percentage of PB CLL cells expressing Ki67 (median reduction of 80%; P<.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.