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Emerging Treatments and Evolving Pathways for the Management of Chronic Lymphocytic Leukemia

September 09, 2017

Jennifer R Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute (Boston, MA), presented the emerging treatments and management options for front line and relapsed or refractory chronic lymphocytic leukemia (CLL) today at the Clinical Pathways Congress (September 8-10, 2017; Washington, DC).

The goals of the presentation were to explain the significance of CLL biomarkers and staging in prognostic assessment and subsequent treatment decisions, as well as to evaluate efficacy and safety date of novel CLL agents with respect to age, comorbidities, and overall health.

Dr Brown began her discussion by explaining that while high-risk CLL is conventionally defined solely by clinical features—such as stage, lymphocyte doubling time, and therapy resistance—biologic prognostic factors are becoming increasingly important. In particular, Dr Brown referenced fluorescence in situ hybridization (FISH), TP53 mutation, and IGHV mutation. She cited 17p deletion as one of the worst prognostic indicators and indicating high-risk CLL.

Among high-risk CLL determinants are patient factors (ie, age and comorbidities) and biologic factors (17P, UM, 11q, B2M).

Dr Brown then moved the discussion into the evolution of conventional treatment pathways for previously untreated CLL. While the early 2000s featured chemo-immunotherapy agents (ie, alemtuzumab monotherapy and bendamustine), recent years have witnessed a rise in novel agents (BCR/BCL-2 inhibitors).

In reference to the best available treatment for previously untreated disease, Dr Brown highlighted various studies that have demonstrated the benefits of ibrutinib. These studies further strengthened the prognostic value of 17p deletion, TP53 mutation, and IGHV mutation status. Additionally, the combination chemotherapy regimen of fludarabine, cyclophosphamide, and rituximab (FCR) has shown the ability to prolong survival in physically fit patients.

According to Dr Brown, ibrutinib is clearly the standard of care for upfront therapy in 17p deleted CLL, given the currently available data. However, ibrutinib’s effectiveness as a single agent is “unsatisfying,” due to the continuous relapse data seen in any trial with long-term follow up. No combination data in an upfront setting exist, and “17p remains an unmet need not yet adequately addressed in clinical trials.” Another issue in regard to ibrutinib as an upfront therapy is that the existing data stems from a non-representative population of healthy, older patients with low-risk disease.

“We’re not seeing in clinical practice the same rate of continuation and progression free survival as in the trials,” Dr Brown commented.

The discussion moved into the best option for heavily pretreated relapsed or refractory CLL. Dr Brown cited numerous studies that suggest single-agent venetoclax as the most data-supported therapy. Not only has venetoclax shown to achieve ORR of 76% in a study, but its activity is preserved in 17p deleted patients and those who have progressed on ibrutinib or idelalisib.

As for whether new biologic agents should replace traditional chemotherapy, there are many factors to consider. Biologic agents are well tolerated and highly-effective even in high-risk disease, but at the expense of increased toxicity, increased cost, and the unknown ability to salvage after relapse. To address the negative aspects of biologic agents, Dr Brown suggests implementing risk-adapted front-line therapy and to study combinations that induce effective, well-tolerated, deep remissions. Achieving these would appeal to the patients’ preference, reduce long-term side effects, reduce costs significantly, and improve the likelihood that subsequent relapse will still be sensitive to prior agents.

While the treatment landscape for CLL has yet to lend itself to a clinical pathway due to a lack of long-term follow up data, Dr Brown concluded her discussion by commenting that she would like to see clinical pathways designed for CLL take into consideration age stratification, risk stratification, and FISH testing.—Zachary Bessette

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