Safety and efficacy of CYT387, a JAK-1/2 inhibitor, for the treatment of myelofibrosis.

JAK inhibitors for myeloproliferative neoplasms: clarifying facts from myths

“…However, differences in molecular mechanisms of action, including drug pharmacokinetics, probably contribute to the overt expression of both on-target and off-target drug effects and might underlie the association of neuropathy, for example, with both JAK2-selective (XL019) and JAK1/JAK2 inhibitors (eg, CYT387; Table 2). Finally, the antianemia effect of CYT387, 70 which is also occasionally seen with ruxolitinib, 58 might represent alleviation of cytokinemediated ineffective erythropoiesis, improved red cell survival stemming from drug-induced reduction in spleen size, or engagement of yet to be identified erythropoietic target.…”

“…82 DLT included grade 3 hyperlipasemia and grade 3 headaches, and the MTD was declared at 300 mg/day; current starting doses are 150 mg/day, 300 mg/day, or 150 mg twice a day. In the first 60 patients completing at least 3 cycles of treatment with CYT387, spleen, anemia, and constitutional symptom response rates, per conventional response criteria, 76 were 45%, 50%, and more than or equal to 50%, respectively.…”

Janus kinase Inhibition and its effect upon the therapeutic landscape for myelofibrosis: from palliation to cure?

“…A signal was again seen for 58% of transfusion-dependent patients becoming transfusion-independent for >12 weeks. This patient group importantly included patients previously treated with SAR302503, ruxolitinib and pomalidomide (Pardanani et al, 2011c). These early results highlight a potential activity and favourable toxicity profile of CYT387, however, longer follow up and larger patient numbers are necessary to confirm the nature and durability of these responses.…”

“…Activation of these pathways leads to increased cellular proliferation and resistance to apoptosis. JAK2, as shown by JAK2-deficient embryos, is essential for signalling through at least the EPO and MPL receptor(s) (Parganas et al, 1998).…”

Ruxolitinib: a potent and selective Janus kinase 1 and 2 inhibitor in patients with myelofibrosis. An update for clinicians

“…A signal was seen for 58% of transfusion-dependent patients becoming transfusion independent for more than 12 weeks. This patient group importantly included patients previously treated with SAR302503, ruxolitinib and pomalidomide [Pardanani et al 2011a]. SAR302503 may reduce JAK2 V617F allele burden and may in some patients reduce bone marrow fibrosis.…”