December 2013, Vol 2, No 8

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Idelalisib and Ibrutinib Are Promising B-Cell Receptor Signaling Inhibitors in B-Cell Malignancies

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Targeted therapy to the B-cell receptor (BCR) signaling is paying off in chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Two novel agents – the PI3K inhibitor idelalisib and the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib – show great promise for these malignancies. These drugs have been studied in phase 3 trials, and current studies are focusing on combination strategies and new schedules to improve outcomes.

“These drugs are breakthrough drugs in [B-cell malignancies],” said Jeffrey Jones, MD, The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Solove Research Institute, speaking at the NCCN 8th Annual Congress: Hematologic Malignancies.

The BCR is present on the surface of healthy cells and cancer cells. Abnormal BCR signaling is implicated in B-cell malignancies, promoting leukemia cell survival and proliferation. Thus, BCR signaling is a therapeutic target.
Idelalisib achieves rapid regression in lymph node volume accompanied by a concomitant rise in absolute lymphocyte count (ALC). Many patients treated with the drug do not achieve a complete response because of the rise in ALC and lymphocytosis.

The toxicity profile is good, with relatively little grade 3 and 4 toxicity, with the exception of pneumonitis (~24%) and neutropenia (~18%) reported in clinical trials. Hematologic toxicity is easily managed.
Combination strategies are being studied to improve response rates in relapsed/refractory CLL, relapsed non-Hodgkin lymphoma (NHL), and mantle cell lymphoma (MCL). Also, idelalisib plus rituximab is under study for frontline CLL therapy.

Another PI3K inhibitor – IPI-145 – is less well studied. The drug has achieved excellent responses in indolent lymphomas and NHL. A major concern is risk of pneumocystis pneumonia, suggesting that patients should receive prophylaxis.

Approval of idelalisib is expected soon, and IPI-145 is about to enter phase 3 testing.
Most of the clinical data on BTK inhibitors – which also affect BCR signaling – are on ibrutinib. In CLL, response rates were 68% in treatment-naive patients and 71% in relapsed/refractory and high-risk patients (Byrd et al. N Engl J Med. 2013;369:32-42).

Ibrutinib achieves excellent responses even in patients with poor-risk cytogenetics, such as deletions of 17p13.1 and 11q22.3. Stable remission has been achieved in this group.

Ibrutinib causes mostly mild adverse events such as diarrhea, nausea, and fatigue.

Ibrutinib combined with rituximab achieves marked reduction in lymphocytosis in previously untreated high-risk CLL/small cell leukemia. However, longer-term follow-up is needed to determine the value of this strategy.
Higher doses of ibrutinib achieve overall response rates above 70% in patients with MCL, and response continues to improve on treatment. Ibrutinib is also being studied in combination with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) in large cell lymphoma.

Studies of CC-292, an oral BTK inhibitor, have not been as promising as those of ibrutinib.

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