Novel Treatments for Chronic Lymphocytic Leukemia

Jeffrey A. Jones, MD, MPH

At the 16th Annual International Congress on Hematologic Malignancies held in February in Snowbird, Utah, Jeffrey A. Jones, MD, MPH, assistant professor of Hematology at The Ohio State University, summarized results of recent trials investigating novel therapies for chronic lymphocytic leukemia (CLL).

The first approach discussed involved the immunomodulatory drug lenalidomide. As a single agent, overall response rates (ORRs) of 32% to 58% have been reported in relapsed CLL, but treatment has also been associated with a high rate of tumor-flare response and tumor lysis syndrome (TLS) at higher doses, as well as expected cytopenias. An ORR of 62% was reported in elderly patients who received lenalidomide as first-line therapy.

In an effort to further improve efficacy and reduce toxicity, lenalidomide was explored in combination with the monoclonal antibody rituximab, reporting an ORR of 66% in relapsed CLL and 75% overall survival (OS) at 36 months. Tumor flare and TLS, but not neutropenia, were reduced with the combination. A more recent phase II study conducted by the CLL Research Consortium examined a shorter course (7 cycles) of the combination in treatment-naïve CLL in two cohorts of patients (<65 years and ≥65 years). Tumor-flare reactions and cytopenias were seen frequently in both cohorts. ORRs of 95% and 78% were observed in younger and older patients, respectively.

These results suggest that lenalidomide alone or in combination with monoclonal antibody therapy may be a promising strategy in patients for whom aggressive chemoimmunotherapy approaches are not appropriate, such as the elderly or those with comorbid medical illnesses or renal insufficiency.

Cyclin-dependent kinase inhibitors (CDKIs) are another class of agents currently being evaluated in CLL. Studies of alvocidib (flavopiridol) have reported ORRs of 25% to 50%, but this agent has a narrow therapeutic index and is associated with a significant risk for TLS. Dinaciclib is a secondgeneration CDKI with a broader therapeutic index. A 45% partial response rate has been reported in 33 patients with CLL.

Finally, the greatest excitement in novel treatments for CLL is in the area of small-molecule signal-transduction inhibitors. “One of the most important insights in CLL biology in the last several decades has been the importance of signaling through the B cell receptor for the maintenance of the disease. And that’s led to a lot of investigation with downstream signal regulation from the B cell receptor and potential inhibitors,” said Jones. Novel inhibitors are at various stages of clinical development, but the two that are most advanced are GS-1101 and PCI-32765.

Downstream signaling from several cell surface receptors funnels through PI3Kδ, and according to Jones, “seems to drive both the proliferation and survival of the malignant clone as well as cell adhesion and homing.” GS-1101 is a small-molecule inhibitor of PI3Kδ that has been evaluated in phase Ib studies as a single agent, and in combination with either rituximab or bendamustine. Single-agent toxicities are relatively low with this agent, with an 18% rate of grade 3/4 neutropenia, and rates of less than 10% for other cytopenias. Approximately 80% to 90% of patients experience a nodal response with single-agent or combination therapy, but while peripheral blood lymphocytosis limited the ORR to 24% with single-agent GS-1101, the addition of rituximab or bendamustine increased the ORR to the nodal response level.

PCI-32765 is an oral inhibitor of Bruton’s tyrosine kinase (BTK), a downstream component of the B cell receptor signaling pathway. Sixtyone patients with relapsed/refractory CLL have been treated to date in a phase Ib study. Diarrhea was the most common adverse event, and rates of severe cytopenias were relatively low. As with GS-1101, there was a rapid nodal response in the majority of patients, accompanied by mobilization of lymphocytes from sanctuary sites into the peripheral blood.

According to Jones, “With continued exposure of the drug, many of these nodal responses will gradually convert to a more overt conventional response.” In addition, he said, “There’s a pretty significant benefit with respect to recovery of cytopenias very early on after initiation of therapy along with resolution of constitutional symptoms.”