In the case of FL, front-line treatment consists of rituximab usually in combination with chemotherapy. Common regimens include R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-CVP (cyclophosphamide, vincristine, and prednisone), with ORRs nearing 90%.9More recently, a trial comparing BR to R-CHOP for front-line treatment of indolent non-Hodgkin’s lymphomas (iNHL) including FL demonstrated a longer PFS with less toxicity with BR compared to R-CHOP (median PFS of 69 vs 31 months, respectively).10 Although initial response rates are high, treatment is not curative, and there is decreased efficacy with retreatment. In addition, there are cumulative toxic effects to chemotherapy, including myelosuppression, cardiomyopathy, and secondary malignancies. This necessitates alternative options.
More in-depth understanding of the dependence of B-cell malignancies on the B-cell receptor (BCR) signaling pathway has led to the development of novel orally-bioavailable small-molecule inhibitors of several kinases downstream of the BCR. These include two compounds that have been approved to date, the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, as well as idelalisib, a potent selective inhibitor of a key kinase, the phosphatidylinositol 3-kinase (PI3K) delta isoform. Idelalisib will be reviewed here, highlighting data from recent clinical trials.
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KINASE INHIBITORS AND BCR SIGNALING
BCR activation triggers a cascade of downstream events involving sequential activation of intracellular transduction molecules with kinase function that ultimately modulate cell proliferation, cell survival, differentiation, and function. Several orally-bioavailable small-molecule inhibitors of these kinases have been developed.11,12 Ibrutinib, the first approved BTK inhibitor demonstrated impressive clinical activity in high-risk patients with previously treated CLL with a reported PFS of 75% and an overall survival (OS) of 83% at 26 months. Side effects are generally manageable, but some cases of clinically significant bleeding and atrial fibrillation occur.13,14
Another BCR pathway member that is critical to both CLL and FL cell survival is PI3K. Idelalisib (formerly GS-1101, CAL-101) is a first-in-class, reversible, potent, selective PI3Kδ inhibitor. Idelalisib was approved by the US Food and Drug Association in 2014 for treatment of relapsed/refractory CLL and FL.15
PI3Ks are signal transduction enzymes, found in four isoforms p110 (alpha, beta, gamma, and delta).16 Though the p110 alpha and beta isoforms are expressed widely, gamma and delta isoforms of PI3K are restricted to hematopoietic cells.15,17,18 The delta isoform is expressed in B-cell malignancies, while the gamma isoform is also expressed in T-cells, macrophages, and mesenchymal stromal cells. The activation of the gamma isoform promotes chemotactic signals and maintains the tumor microenvironment.19
PI3K promotes activation of protein kinase B (Akt) by phosphorylation of its threonine/serine molecules, which in turn activate the mammalian target of rapamycin pathway. This cascade promotes cell differentiation and prolongs survival in lymphocytes.20 The activation of BCR can occur through antigen-dependent or through tonic (antigen-independent) pathways, both of which involve PI3K. Both cascades are upregulated in CLL and FL cells.18,21 Idelalisib induces cell cycle arrest in G0/G1 phase, thus inhibiting proliferation; furthermore, it induces apoptosis in B-cells by caspase activation.
