Pharmacy & Therapeutics - December 2008 - (Page 714)

MEETING HIGHLIGHTS: Chemotherapy Foundation Symposium XXVI response. Overall, therapy was well tolerated; the most common grade 3 and 4 adverse events were hematological (i.e., cytopenia) and reversible in this heavily pretreated population. Patient compliance was excellent with the single-agent oral dosing regimen. Dr. Czuczman concluded that salvage lenalidomide had significant activity in these patients with relapsed or refractory aggressive NHL, a poor prognostic group often having limited therapeutic options. Lenalidomide’s mechanism of action allowed significant anti-lymphoma therapy even in patients with rituximab-based combination immunochemotherapyresistant disease. Further research is needed to establish the optimal dosing and schedule for lenalidomide alone and in combination with other active agents. phase, 27% in the myeloid blast phase and 46% in the lymphoid blast phase. The duration of response correlated with stage of the disease, with progression free-survival at 80% and 24% for those with chronic phase CML and at 46% for those with accelerated-phase CML. Significant adverse events included myelosuppression (grade 3 and 4 neutropenia and thrombocytopenia in almost 50% each); pleural effusion; and gastrointestinal hemorrhage, particularly in advanced disease. Alternative schedules may improve the toxicity profile. In a randomized study, dasatinib 100 mg once daily was associated with significantly less myelosuppression and pleural effusion when compared with 70 mg twice daily and with 50 mg twice daily or 140 mg once daily. The response to therapy was identical, with a trend for improved progression-free survival with 100 mg once daily. This regimen has now become standard for dasatinib in chronic-phase CML. Nilotinib. Derived from the structure of imatinib, nilotinib has been modified to improve its binding affinity. It has increased selectivity for Bcr-Abl, with an increased potency of almost 30-fold while maintaining similar activity as imatinib against PDGF-R and c-kit. Significant activity has been documented in patients receiving imatinib after treatment failure with nilotinib 400 mg twice daily. Toxic reactions include myelosuppression and biochemical abnormalities, such as elevated levels of bilirubin, lipase, and glucose; these have been usually transient and asymptomatic. There is also the potential for prolongation of the corrected QT (QTc) interval; however, fewer than 3% of patients have experienced significant QTc prolongation, which has frequently been asymptomatic. Bosutinib. Bosutinib (SKI 606) is an orally bioavailable inhibitor of Bcr-Abl and the Src kinase family, with little if any inhibitory effect over PDGF-R and kit. Phase 2 studies suggest that this is also an active compound, with major cytogenetic responses (MCyRs) reported in 41% of patients in chronicphase CML for whom imatinib therapy failed despite a median follow-up of only three months. A potential advantage with bosutinib is the occurrence of fewer adverse events. INNO-406. This potent Bcr-Abl inhibitor also inhibits Lyn, a member of the Src family, but not other members of this family. INNO-406 is under evaluation in an ongoing phase 1 study. Despite its very early stages of development and the fact that most patients treated with INNO-406 have not responded to imatinib or to at least one other tyrosine kinase inhibitor, responses have been observed in seven of 24 patients treated. MK-0457. MK-0457 is a multi-kinase inhibitor with activity against Aurora, a family that plays a role in later stages of the cell cycle (from G2/M to the mitotic checkpoint and to late mitosis). Janus kinase-2 (JAK-2), the most important tyrosine kinase inhibitor in erythropoietin signaling, is also involved in granulocyte–colony-stimulating factor (G-CSF), granulocyte– monocyte CSF, and interleukin-3 (IL-3). MK-0457 has activity against FLT3, a class III receptor tyrosine kinase structurally related to the receptors for PDGF, CSF-1, and the kit ligand (KL) in addition to Bcr-Abl. Early repor ts suggest that continued on page 719 Chronic Myelogenous Leukemia: Is There Hope After Therapeutic Failure with Imatinib (Gleevec)? • Jorges Cortes, MD Anderson Cancer Center, Houston, Tex. Despite the success of imatinib (Gleevec, Novartis) among most patients with chronic myeloid leukemia (CML), some do not achieve the desired response, or eventually they might not respond adequately. The standard criteria that define treatment failure emphasize that it is not only important to achieve a complete cytogenetic response (cyR); the time needed to achieve such a response also determines the long-term outcome. Patients meeting the criteria for failure have inferior outcomes. Those who are still in the chronic phase at the time of treatment failure have a median survival of five years, but survival is considerably shorter for patients with more advanced disease at the time of failure. In addition, a small percentage of patients are intolerant to imatinib, although the definition of “intolerance” has varied. Second-generation tyrosine kinase inhibitors (TKIs) have been developed to overcome resistance and intolerance to imatinib. Dasatinib and nilotinib. Dasatinib (Sprycel, Bristol-Myers Squibb) and nilotinib (Tasigna, Novartis) have already been approved for use in this setting and few other agents are being developed. These drugs are significantly more potent inhibitors of Bcr-Abl kinase activity, compared with imatinib, and they retain activity in the presence of most of the common mutations identified in patients who have not responded to imatinib, one exception being the mutation T315l. All of these drugs have shown clinical activity in patients with resistance or intolerance to imatinib and have resulted in improved outcomes compared with previous treatments. However, there is significant variability in other properties, such as actual potency, the extent of other kinases inhibited, and their toxicity profile. Dasatinib. Dasatinib is 300 times more potent than imatinib against Bcr-Abl. It is also a potent inhibitor of other kinases such as the Src family of kinases, platelet-derived growth factor receptor (PDGF-R), and c-kit. In an early study, dasatinib 70 mg twice daily showed significant activity in all stages of CML after imatinib failure, with complete cytogenetic response (CyR) rates of 53% in the chronic phase, 33% in the accelerated 714 P&T® • December 2008 • Vol. 33 No. 12

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Pharmacy & Therapeutics - December 2008 Contents Editorial Medication Errors Prescription: Washington New Drugs/Drug News/ New Medical Devices Drug Forecast Interpreting Estimates of Treatment Effects Chemotherapy Foundation Symposium XXVI: Innovative Cancer Therapy for Tomorrow Third Annual Onmark National Payor/Provider Forum Fourth Annual Ophthalmic Drug Development and Delivery Summit Classification and Pharmacological Management Of Obesity CE Test and Forms Season’s Greetings: Thanks to Our Readers and Reviewers

Pharmacy & Therapeutics - December 2008

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