Progression-free Survival 96% in CLL With Ibrutinib

Becky McCall

June 19, 2012

June 19, 2012 (Amsterdam, the Netherlands) — Ibrutinib, an investigational compound for the treatment of chronic lymphocytic leukemia (CLL), has shown an initial dramatic reduction in lymph node mass; however, that is accompanied by a simultaneous increase in lymphocytes in the circulation, researchers reported here at the 17th Congress of the European Hematology Association show.

This has made it difficult to assess response to the drug, but experts believe that it shows a redistribution rather than a progression of disease, and have been enthusiastic about the early data reported for this agent.

Ibrutinib (formerly PCI-32765, under development by Pharmacyclics) is a first-in-class oral agent that selectively inhibits Bruton's tyrosine kinase, which is a critical signaling kinase in the B-cell receptor pathway.

When data on this agent were first reported earlier this year, experts hailed the results as potentially practice changing, even though they were from early-stage clinical trials. "This is one of the most exciting new targets and I think it will change the way that we treat lymphoma," José Baselga, MD, chief of hematology/oncology at the Massachusetts General Hospital Cancer Center in Boston, said at the time.

Now, updated data show that progression-free survival in patients with treatment-naïve CLL was 96% at 15 months and in relapsed/refractory patients was 87.7% at 18 months.

Susan O'Brien, MD, from the Department of Leukemia in the division of cancer medicine at the University of Texas M.D. Anderson Cancer Center in Houston, gave the first of 2 presentations on ibrutinib from the PCYC-1102-CA phase 1b/2 trial. Her talk focused on overall response rates (ORR) and progression-free survival in treatment-naïve and relapsed/refractory patients. "We see a faster response and more complete responders in treatment-naïve patients" than in relapsed/refractory patients, she said.

The ORR, based on International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria, was 81% in treatment-naïve patients receiving ibrutinib 420 mg/day (low-dose group) and 40% in those receiving ibrutinib 840 mg/day (high-dose group). The higher-dose cohort was closed early because results were comparable in the 2 treatment groups.

"The overall response rate [in both doses] in this treatment-naïve population was 74%, with a median follow-up of 12.8 months," reported Dr. O'Brien. When nodal responses were added in, 87% of patients had more than a 50% reduction in lymph nodes. "We are starting to see some complete remissions at this point, too," she added.

The fact that complete responses were seen was highlighted previously by Dr. Baselga, who explained that this is a "very difficult population to treat."

In the PCYC-1102-CA trial there were 5 treatment groups — 3 groups receiving ibrutinib 420 mg/day and 2 receiving ibrutinib 840mg/day. The low-dose groups consisted of relapsed/refractory patients, treatment-naïve patients older than 65 years, and high-risk relapsed/refractory patients. The high-dose groups consisted of relapse/refractory patients older than 65 years, and treatment-naïve patients over older than 65 years. The majority of patients in the treatment-naïve cohorts were older than 75 years. Only 6% of treatment-naïve patients had a deletion of the 17p13 chromosomal region, whereas 36% of relapsed/refractory patients did.

Dr. O'Brien focused on progression-free survival in the 27 relapsed/refractory patients in the low-dose group at 18.0-month follow-up and in the 34 relapsed/refractory patients in the high-dose group at 13.8-month follow-up.

Only 1 patient in the low-dose group progressed. Four patients in the low-dose group and 1 in the high-dose group discontinued ibrutinib. The most common adverse effect was diarrhea, which was self-limiting. "These agents are not myelosuppressive.... Grade 3/4 hematology toxicity was minimal, with 3 grade 3/4 infections in this over-65 population," Dr. O'Brien reported.

Interesting Pattern of Response

Dr. O'Brien described the pattern of response with ibrutinib. "Initially we see dramatic reduction in lymph node mass, but at the same time we see...lymphocytes increasing in the circulation," she said. "Over time, the lymphocytes drop off and these patients become partial responders."

Many patients had a reduction in lymph node mass of more than 50% after 2 months; however, because of their lymphocytosis, they failed to meet the iwCLL criteria for remission.

Thomas Kipps, MD, professor of medicine and deputy director for research at Moores UCSD Cancer Center at the University of California San Diego, California, explained that ibrutinib might actually affect enzymes in addition to Bruton's tyrosine kinase. "We need to keep these extra enzyme inhibitory activities in mind. It's been shown that the drug does dramatically induce lymphocytosis, which is thought to be due to an emptying of the lymph nodes into the blood."

He pointed out that if the leukemic cells inside the lymph nodes gain the survival and growth signals that contribute to the elevation in white cell count, this might actually be a desired effect, despite initially appearing problematic.

However, Dr. O'Brien added that over time as the lymphocyte level comes down, "many of these nodal responders become partial responders by standard criteria."

Dr. O'Brien concluded that these data supported phase 3 trials in treatment-naïve and relapsed/refractory patients with CLL.

Ibrutinib in Combinations

Jennifer Brown, MD, assistant professor in the Department of Medicine at Harvard Medical School in Cambridge, Massachusetts, presented interim data on ibrutinib in combination with bendamustine and rituximab (Rituxan).

Patients received ibrutinib 420 mg/day in 28-day cycles plus bendamustine 70 mg/m² on days 1 and 2 and rituximab 375 mg/m² in cycle 1 and 500 mg/m² in cycles 2 to 6, until disease progression.

Dr. Brown noted that 23% of patients were older than 70 years, and that 40% of patients had received 3 previous regimens.

"The combination with bendamustine and rituximab largely diminishes the early lymphocytosis" seen with single-agent ibrutinib, said Dr. Brown. "Normal response is preserved and, if anything, is a little deeper, earlier, with the combination."

Currently, median follow-up is 8.1 months, with 77% of patients still on the study drugs. "Overall, the response rate at median follow-up was 93%, with 13% achieving complete response and 3% achieving total response with lymphocytosis [or nodal response]," Dr. Brown reported.

She added that these results compare favorably with historic data published last year (J Clin Oncol. 2011;29:3559-3566), in which bendamustine and rituximab showed an overall response rate of 59% in relapsed patients (with 9% achieving a complete response).

Dr. Brown reported that no additional toxic effects were seen when ibrutinib was added to bendamustine and rituximab.

She explained that ibrutinib plus bendamustine and rituximab will now enter a phase 3 study.

Dr. Kipps said that the toxicities related to ibrutinib are not dissimilar to those related to standard chemotherapy and, over time, patients appear to have a decline in lymphocyte count. "It's encouraging that there might be some longer-term therapeutic benefit."

Dr. Kipps pointed out the need to reassess whether the rise in the lymphocyte count truly represents disease progression, given that it is concomitant with reductions in lymph node size. Does this represent "an increase in tumor burden or just a redistribution of tumor burden? I think we have to give license to the fact that this is part of the response and should not be deemed progressive disease. As such further testing of these drugs in registration trials should not be precluded," he said.

Despite the increase in lymphocytes, Dr. Kipps said that he welcomes ibrutinib. "The hoped-for outcome is that we will have another agent with which to treat patients with this disease, with a different mechanism of action, and the ability to treat patients either alone or in combination with other agents may provide a desirable therapeutic benefit," he said.

This trial was sponsored by Pharmacyclics, which developed ibrutinib. Dr. O'Brien reports receiving research support from Pharmacyclics. Dr. Brown reports serving as a consultant to Pharmacyclics, Avila Therapeutics, Calistoga Pharmaceuticals, Celgene, Genentech, and Emergent Biosolutions; and receiving research funding from Genzyme and Celgene. Dr. Kipps reports being a consultant to GlaxoSmithKline and Genmab; and receiving research funding from Abbott, GlaxoSmithKline, Genmab, Genentech, sanofi-aventis, Celgene, Cephalon, and Memgen.

17th Congress of the European Hematology Association (EHA): Abstracts O0542 and O0543. Presented June 15, 2012.

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