Cell-Signaling Pathways Explored in Hematologic Malignancies
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ALL indicates acute lymphocyctic leukemia; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; DLBCL, diffuse large B-cell lymphoma; ET, essential thrombocythemia; FL, follicular lymphoma; MCL, mantle cell lymphoma; MDS, myelodysplastic syndrome; MF, myelofibrosis; NHL, non-Hodgkin lymphoma; PV, polycythemia vera; SLL, small lymphocytic lymphoma.
Targeted agents have a history of success in the treatment of hematologic malignancies, illustrated by the number of monoclonal antibodies and small-molecule inhibitors currently in clinical use. However, none of these agents are curative, and new treatment options are needed for patients who experience disease relapse.
Increased understanding of the molecular mechanisms underlying the pathogenesis of these cancers has led to the development of several promising new classes of targeted therapies. The first JAK pathway inhibitor, ruxolitinib (Jakafi; Incyte), gained FDA approval last year, and other drugs in this class are being explored. (Related: JAK Pathway Yielding Results
At the 16th Annual International Congress on Hematologic Malignancies, held February 23-26, 2012, in Utah, a special workshop session was devoted to reviewing recent data regarding emerging signal transduction inhibitors currently in clinical development, which have the potential to impact the treatment of hematologic cancers. Highlights of the presentations are summarized below.
Bruton’s Tyrosine Kinase
Signaling through the B-cell receptor (BCR) is necessary for the proliferation and survival of many B-cell malignancies, and Bruton’s tyrosine kinase (BTK) is a key downstream mediator of this signal. In preclinical studies, inhibitors of BTK have been shown to block BCR signaling and induce apoptosis, making this molecule an attractive therapeutic target.
PCI-32765 (Ibrutinib; Pharmacyclics), a selective and irreversible inhibitor of BTK, is currently in the early stages of clinical investigation. A phase I study was conducted in previously treated, recurrent B-cell malignancies. While grade 1 events were common, there were no grade 4 toxicities, and grade 2/3 events were infrequent. In addition, there were no serious hepatic or renal toxicities, and no evidence of cumulative hematologic toxicity. PCI-32765 was most active in indolent malignancies, with both partial and complete responses seen in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), and follicular lymphoma (FL), although partial responses were also observed in more aggressive lymphoma subtypes.
A phase II trial in relapsed/refractory MCL recently reported an overall response rate (ORR) of 69%, with no difference in outcome between bortezomib-naïve versus bortezomib-treated patients. In addition, a phase II study in relapsed/refractory CLL reported ORRs of 70% (420-mg cohort) and 44% (840-mg cohort), with six-month progression- free survival (PFS) >90%. Transient lymphocytosis peaking at two months after drug initiation was also observed.
A pilot study is also ongoing in activated B-cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), based on the observation that NF-κB signaling is constitutively active in this subtype, often as a result of chronically active signaling through the BCR. A number of responses have been observed in the 10 patients enrolled to date. A phase II trial will evaluate PCI-32765 in both ABC and germinal center DLBCL, and will assess whether there is a differential response between these two subtypes.
PI3 kinases (PI3K) are a family of lipid kinases that play an integral role in regulating intracellular signaling networks involved in cell growth, survival, and metabolism. Dysregulation of this pathway has been implicated in the development and progression of many forms of cancer, as well as resistance to current therapies. There are four different isoforms (alpha, beta, gamma, and delta), each with different biologic roles. The delta isoform in particular is expressed in leukocytes and plays a key role in B-cell signaling, development, and survival, leading to interest in the evaluation of PI3K inhibitors in B-cell malignancies.