Novel B-Cell Receptor Signaling Inhibitors Show Promise

Jeffrey A. Jones, MD, MPH

Drugs targeting B-cell receptor (BCR) signaling pathways are improving outcomes for patients with B-cell lymphomas, including chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), and mantle cell lymphoma (MCL). These novel agents include PI3-Kinase (PI3K) inhibitors (eg, idelalisib) and Bruton’s tyrosine kinase (BTK) inhibitors (eg, ibrutinib), and are considered a breakthrough for CLL and other B-cell lymphomas.

At the recent NCCN 8th Annual Congress on Hematologic Malignancies, Jeffrey Jones, MD, from The Ohio State University Comprehensive Cancer Center and James Cancer Hospital and Solove Research Institute, updated listeners on these two new targeted drug classes.

The BCR is present on the surface of normal cells and cancer cells. BCR functioning is required for normal antibody production, and abnormal BCR signal transduction is implicated in B-cell malignancies, promoting leukemia cell survival and proliferation. Thus, BCR signaling is a therapeutic target.

“It is clear that B-cell receptor signaling plays an important role in chronic lymphocytic leukemia,” Jones said.

In CLL, initiation of treatment with the PI3K inhibitor idelalisib causes prompt and dramatic regression in lymph node volume with a concomitant risk in absolute lymphocyte count (ALC).

“Marked regression of lymphadenopathy—usually an 85% reduction in lymph node volume—is a common feature of treatment response, he noted. “Because the ALC rises and causes lymphocytosis, many patients fail to achieve complete response by conventional criteria,” Jones explained.

Grade 3 or 4 toxicity with idelalisib is relatively infrequent. The most common grade 3 or 4 adverse events are pneumonitis (about 24%) and neutropenia (about 18%) in clinical trials.

“Hematological toxicity with idelalisib is quite manageable. Many of the patients in these studies were heavily pretreated, and many did not achieve objective responses, so the interest is in combining it with other active agents, such as bendamustine and rituximab. Whichever agent is used with idelalisib, the same reduction in lymphadenopathy is observed,” Jones noted.

Studies of these combinations are ongoing in relapsed/refractory CLL, relapsed NHL, and MCL.

Recently, a phase III trial (Study 116) of idelalisib plus rituximab in previously treated CLL was stopped early when the Data Monitoring Committee determined that there was a highly statistically significant progression-free survival benefit in the treatment arm. In the study, patients with measurable lymphadenopathy with disease progression who were not candidates for chemotherapy were randomized to idelalisib plus rituximab or rituximab alone. Other ongoing studies are also evaluating the idelalisib/rituximab combination as frontline therapy for CLL. (Continued Reading: Positive Idelalisib Data Ends Late-Stage CLL Trial)

Gilead Sciences, Inc, has filed for regulatory approval for idelalisib for NHL and now plans to discuss a regulatory filing for CLL with the FDA.

Targeting Kinases in the B-Cell Receptor Pathway

Image redesigned from: Brown JR. Targeted Therapy for CLL: Focusing on the B Cell Receptor Pathway. Presented at 11th International Congress on Targeted Therapies; August 16-17, 2013; Washington, DC.

Far less is known about the PI3K inhibitor IPI-145, Jones said. Preliminary studies show a similar toxicity profile as with idelalisib. Infections have been reported, which are typically associated with impaired T-cell immunity. IPI-145 is associated with risk of pneumocystic pneumonia. In future studies of this agent, patients will receive pneumonia prophylaxis, he said.

“There have been some remarkable responses to IPI-145 in indolent lymphomas and NHL, even some complete responses, which is unique,” said Jones. At the highest dose, the overall response rate is up to 70%. IPI- 145 will enter phase III trials in the near future, Jones said.

BTK inhibitors are another new class of drug affecting BCR signaling. Most of the data on BTK inhibitors involves ibrutinib. The drug has been studied in CLL, and achieved a 68% response rate in treatment-naïve patients and a 71% in relapsed/refractory and high-risk patients.

“The majority of patients will achieve a complete response on ibrutinib and an additional proportion will get a partial response,” Jones noted. “Most interesting is that patients with deletions of 17p13.1 and deletions of 11q22.3 have similar survival on ibrutinib as those without these poor prognostic cytogenetic features,” he said. “The majority of CLL patients treated with ibrutinib remain in stable remission.”

The toxicity associated with ibrutinib is relatively mild and self-limiting and can include diarrhea, nausea, and fatigue. Infection rates are similar those observed in CLL patients over the first few months, and after 6 months the rates of infection fall.

Ofatumumab (Arzerra) has been added to ibrutinib to attenuate the drug-induced lymphocytosis, with good effect, Jones noted.

Ibrutinib has been studied in combination with rituximab in previously untreated high-risk CLL/small lymphocytic leukemia (SLL). The combination achieved marked reduction in lymphocytosis—faster than with ibrutinib alone—but the clinical significance is unknown, Jones said. Further study is needed to determine the effect on disease progression and survival, he added.

Ibrutinib has been studied at higher doses in MCL, with overall response rates above 70% and response improving with continued treatment. “As long as patients stayed on drug, they continued to respond,” Jones said. It is also being studied in large cell lymphoma in combination with R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone).

The FDA is currently reviewing new drug applications for ibrutinib to treat patients with MCL, CLL, or SLL. (Continued Reading: NDA Filed for Ibrutinib in CLL and MCL)