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Novel Agents Will Completely Change CLL Treatment

August 2012 Vol 5, No 5, Special Issue ASCO 2012 Payers' Perspective - Leukemia

Chicago, IL—The treatment of chronic lymphocytic leukemia (CLL) is becoming more personalized and more effective as prognostic markers are refined and as agents with novel mechanisms of action show robust activity.

CLL is a heterogeneous entity. Although some patients live for 10 years or more, others die within 1 year. The Rai staging system stratifies patients based on blood counts and symptoms, but this system does not reflect the variability in disease aggressiveness. Thus, the ability to determine prognosis and predict response to treatment is an important goal in CLL research, said Neil E. Kay, MD, of the Mayo Clinic, Rochester, MN, at the 2012 ASCO meeting.

Newer molecular-based prognostic factors have been established that can strongly predict CLL disease progression, such as chromosomal deletions and alterations (17p deletion and 11q deletion are common ones), and the expression of cell-surface markers such as CD38 and ZAP-70. These prognostic parameters, which can usually be determined at the time of diagnosis, can help define risk categories upon diagnosis.

Risk models that incorporate both conventional and novel prognostic factors have been developed, and these can predict disease progression and overall survival. They will, therefore, be useful in risk-stratifying patients with early-stage disease, Dr Kay said.

Promising Drugs for CLL
There is a clear unmet need for more effective therapies in CLL, said Peter Hillmen, PhD, of St. James’s Uni­versity Hospital, West Yorkshire, United Kingdom. Current regimens, which are not molecularly targeted, are associated with significant toxicity and are especially hard on elderly patients.

Moreover, these regimens typically do not lead to true complete remissions; leukemic cells become resistant and the disease relapses.

An effective treatment should target the disease pathophysiologically, Dr Hillmen said, as imatinib does for chronic myelogenous leukemia. There­fore, much emphasis is being placed on understanding the molecular and genetic profiles of CLL, to guide drug development. Among the promising new approaches to CLL are:

  • The immunomodulatory drug lena­lidomide, which shows immune-mediated effects and also direct antitumor activity against CLL cells; it has been studied as a single agent and in combination with rituximab
  • PI3 kinase-delta inhibitor GS-1101, an orally available small-molecule inhibitor that has substantial anti­tumor activity in refractory disease
  • Ibrutinib (PCI-32765), an orally available selective inhibitor of Bruton’s tyrosine kinase (Btk). The combination of ibrutinib, bendamustine, and rituximab has produced response rates exceeding 90% in patients with relapsed/refractory CLL
  • Bcl-2 (anti-apoptosis) inhibitors, such as navitoclax (ABT-263) and GDC-0199.

Btk Inhibitor Shows Strong Activity
In an update of a study that made news at the American Society of Hematology 2011 meeting, the Btk inhibitor ibrutinib produced high response rates in treatment-naive patients with CLL. In a related study by the same investigators, ibrutinib was combined with ofatumumab, an anti-CD20 monoclonal antibody.

This oral agent is the first drug designed to target Btk, a protein that is critical for B-cell receptor signaling in B lymphocytes and essential for cell survival and proliferation in CLL.

This single-agent phase 2 clinical trial included 31 patients with previously untreated disease. The overall response rate was 75%, including 10% complete and 65% partial responses with daily dosing. The rate of progression-free survival at 15 months was 96%. Investigators had previously reported on the cohort of treatment-refractory patients, 70% of whom responded to the novel drug.

“All subgroups responded equally well. Overall, the great majority of patients gained benefit from this therapy,” said John C. Byrd, MD, of Ohio State University, Columbus. “This drug is like red wine. With time, it gets better. Responses increase, and many patients are still in follow-up. The continued daily dosing was well tolerated, which allows for extended treatment.”

Samantha Jaglowski, MD, also of Ohio State University, reported that the combination of ibrutinib and ofatumumab produced a 100% response rate in 27 patients with relapsed/ refractory CLL and related diseases. At 6.5-month follow-up, only 2 patients have progressed. “The rapid onset of response, low relapse rate, and favorable safety profile make this noncytotoxic combination worthy of further study,” she said.

Constantine S. Tam, MBBS, MD, St Vincent’s Hospital, Melbourne, Aus­tralia, commented on these findings, “There is a long list of novel agents in chronic lymphocytic leukemia. I think some of the most promising are those targeting the B-cell receptor pathway.” He added that this group of drugs is going to completely change how we manage CLL.
 

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Last modified: August 30, 2021