Pipeline Series: Chronic Lymphocytic Leukemia (CLL)

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The ACS estimates that 18,960 new cases of chronic lymphocytic leukemia will be diagnosed in the United States in 2016.
The ACS estimates that 18,960 new cases of chronic lymphocytic leukemia will be diagnosed in the United States in 2016.

The American Cancer Society estimates that 18,960 new cases of chronic lymphocytic leukemia (CLL) will be diagnosed in the United States in 2016, accounting for about 31.5% of all new cases of leukemia.1

The mainstay of CLL treatment used to be chemotherapy with regimens comprising fludarabine, chlorambucil, bendamustine, cyclophosphamide, and cladribine. Immunotherapeutic agents, such as rituximab, alemtuzumab, ofatumumab, and obinutuzumab, became integrated with chemotherapy regimens between 2007 and 2013, and in the last few years, targeted oral agents, like ibrutinib and idelalisib, became common therapies. Some patients, however, relapse, require further treatment, or are intolerant to therapy, and  novel agents are therefore required to improve outcomes for patients with CLL.

Cancer Therapy Advisor spoke with Matthew S. Davids, MD, MMSc, medical oncologist at Dana-Farber Cancer Institute in Boston, Massachusetts, to discuss which therapies he believes are the most important in the future of CLL treatment.

Dr Davids has an active translational research program in CLL, which was formed to study mechanisms of treatment resistance and how resistance can be overcome in the laboratory, and to develop clinical trials aimed at evaluating these strategies for patients with CLL.

Acalabrutinib

Acalabrutinib is an irreversible, selective Bruton's tyrosine kinase inhibitor, which is more selective than the first-generation Bruton's kinase inhibitor, ibrutinib. The novel agent demonstrated clinical efficacy in patients with relapsed CLL in a phase 1/2 trial.2

Results of that study showed that acalabrutinib induced an overall response rate of 95% of 61 patients. A total of 85% achieved a partial response and 10% had a partial response with lymphocytosis; 5% had stable disease. Among patients with chromosome 17p13.1 deletion, the overall response rate was 100%.2

"Acalabrutinib looks very efficacious," Dr Davids told Cancer Therapy Advisor. "Albeit with relatively limited follow-up, a nice durability of response was observed. Only 1 patient in the study had progressed."

In a phase 1/2 study presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2016, acalabrutinib achieved high durable response rates in 72 patients with previously untreated CLL. Researchers found that in this patient group, the best overall response rate was 96%. A total of 86% had a partial response, 10% had a partial response with lymphocytosis, and 4% had stable disease. The median time to response was 2 months.3

The most common adverse events in both studies were headache, diarrhea, arthralgia, confusion, nausea, and increased weight, most of which were grade 1 or 2. No CLL progression or Richter's transformation occurred in either study.2,3

"More importantly, the toxicity profile looked excellent," Dr Davids said. "We don't see any events of atrial fibrillation that we see with ibrutinib, nor any major bleeding events with acalabrutinib, with the major caveat that this was not a head-to-head study."

A head-to-head trial of acalabrutinib versus ibrutinib in patients with relapsed/refractory CLL is currently underway.

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