Roxanne Nelson

December 11, 2011

December 11, 2011 (San Diego, California) — A novel agent holds promise as a new treatment strategy for chronic lymphocytic leukemia (CLL).

The Bruton's tyrosin kinase (BTK) inhibitor PCI 32765 (under development by Pharmacyclics) showed high rates of progression-free survival and low toxicity in patients with relapsed CLL, according to data presented here at American Society of Hematology (ASH) 53rd Annual Meeting. The drug is now in a phase 3 clinical trial, but the results from earlier studies have impressed experts.

"I don't want to hype this, but we are hoping for a repeat of the success that was enjoyed by the poster child of targeted therapy, imatanib (Gleevec [Norvartis Oncology]), for the treatment of chronic myeloid leukemia," commented ASH President J. Evan Sadler, MD, PhD, professor of medicine in the Division of Hematology at Washington University in St. Louis, Missouri. Subsequent tyrosine kinase inhibitors have not shown such spectacular results, he noted, "but this one looks encouraging. There have been some striking responses described."

Targeting B-Cell Signaling

PCI-32765 is an orally administered irreversible inhibitor of Btk, and an earlier analysis of this phase 1b/2 trial showed PCI-32765 to be highly active and tolerable in patients with CLL, explained lead study author Susan O'Brien, MD, professor of medicine at the University of Texas MD Anderson Cancer Center in Houston.

"This is an exciting class of compounds that are now in clinical trials, and all of these drugs interfere with B-cell signaling," Dr. O'Brien said.

"What we're seeing with all of these drugs that are targeting enzymes in the B-cell receptor pathway is that the initial pattern of response is very different to what we see in chemotherapy," she added. "What we see is dramatic shrinkage in the lymph nodes, but at the same time, the absolute lymphocyte count goes up. So initially there seems to be a compartment shift, and there's some nice preclinical data to show why that happens."

One of the big questions, she noted, was if the lymphocyte count would eventually go down over time."It is interesting as it gets presented at different meetings how the responses are evolving."

High Progression-Free Survival

PCI-32765 is the first drug developed to target BTK, and the trial included 2 cohorts of patients with CLL (n = 61): those who were previously untreated and were aged 65 years or older, and those with relapsed/refractory disease after at least 2 prior therapies, including fludarabine. Patients were treated with oral PCI-32765 administered daily for 28-day cycles until progression of disease.

One group (n = 27) received 420 mg (previously untreated and relapsed/refractory), and the other group (n = 34) received 840 mg daily (relapsed/refractory). Dr. O'Brien reported only on the patients with relapsed/refractory disease.

The median follow-up time for the 420-mg cohort was 10.2 months; it was 6.5 months for the 840-mg cohort. The median number of prior treatment regimens for the 420-mg cohort was 3 (range, 2 - 10), and for the 840-mg cohort it was 5 (range, 1 - 12). In addition, 72% of patients had at least 1 poor-risk molecular feature: del(17p), 31%; del(11q), 33%; immunoglobulin heavy chain unmutated, 57%.

At a median of 10.2 months of follow-up, 70% of patients who received a lower dose of PC-32765 achieved an objective response. This is an increase from 48%, which was initially reported at 6.2 months median follow-up.

The objective response rate was 44% at 6.5 months median follow-up for patients who received a higher dose of the agent. In addition, 19% of patients in the low-dose group and 35% who received the larger dosing achieved a nodal partial response (>50% reduction in aggregate lymph node size) with residual lymphocytosis.

The authors note that in the majority of patients, there was a transient phase of lymphocytosis, which typically peaked during the first 2 months of therapy and resolved over time. The overall response rate appears to be independent of molecular risk features, and 82% of patients (50/61; 420-mg cohort, 22/27; 840-mg cohort, 28/34) continue to receive PCI-32765. Thus far, only 8% (5/61) of patients have had progressive disease.

At 6 months, progression-free survival is 92% among patients receiving 420 mg PCI-32765, and 90% in the 840-mg cohort.

Low Toxicity

Another exciting result of this study is the relative lack of toxicity noted with this agent, commented Dr. O'Brien. The primary adverse event was diarrhea, which was mostly mild and usually self-limiting.

Only 2 patients discontinued therapy because of adverse events, whereas 6 patients required dose reduction of PCI-32765 dose (420-mg cohort, 2/27; 840-mg cohort, 4/34). Grade 1 or 2 diarrhea, fatigue, nausea, and ecchymosis have been the most frequently reported toxicities, and serious events have occurred in 38% of patients. Serious adverse events that were potentially considered to be related to the experimental agent occurred in 10% of patients, and toxicities that were grade 3 or higher that were potentially related to PCI-32765 occurred in 21% of patients.

The drug is not myelosuppressive, added Dr. O'Brien, noting that this is a "big deal in CLL" because all current therapies are myelosuppressive, and these patients are very vulnerable to infection. "It is exciting to see the efficacy increase over time, and the lack of myelosuppression," she said. "I think they will change the paradigm of the treatment of CLL."

"Very Attractive Paradigm"

"Therapeutic targeting of downstream molecules of the B-cell receptor represents a very attractive paradigm for treating CLL," said Eyal C. Attar, MD, assistant professor of medicine, Massachusetts General Hospital, Boston, who was approached by Medscape Medical News for independent commentary.

"What is so interesting about this abstract is that of the patients treated, approximately 70% had high-risk molecular and cytogenetic features, and that the median number of prior treatments was between 3 and 5, depending on the dose cohort looked at," he continued. "So the objective responses are really remarkable for this heavily pretreated high-risk population."

He noted that he was "really surprised to see that the 6-month progression-free survival was 90% in both of the doses," adding that "it's a very interesting compound and a very interesting study."

American Society of Hematology (ASH) 53rd Annual Meeting: Abstract 983. Will be presented on December 13, 2011.

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