Significant Activity of the JAK2 Inhibitor, INCB018424 in Patients with Secondary, Post-Myeloproliferative Disorder (MPD) Acute Myeloid Leukemia (sAML): Results of An Exploratory Phase II Study.

Abstract 631

Background: Mutations of JAK2 gene have been identified in a significant proportion of patients with MPDs with the selective JAK2 inhibitors demonstrating significant activity. Patients with AML following prior MPD (sAML) respond poorly to standard cytotoxic chemotherapy and have a poor outcome. Abnormalities of the Jak-Stat signaling pathway have also been identified in a number of other hematological malignancies; chromosomal translocations resulting in TEL-JAK2 constructs lead to the constitutive activation of STAT5, IL-3-independent cellular proliferation, and leukemogenesis. Similarly, infection with oncogenic viruses such as human T-cell lymphotrophic virus, type I, and Abelson murine leukemia viruses results in enhanced kinase activity of Jaks, possibly accounting for their leukemogenic potential. Furthermore, disrupted Jak-Stat signaling has been reported in a number of leukemias. Aim: To identify potential activity of INCB018424 in patients with advanced hematological cancers. Methods: We are conducting a phase II study of INCB018424 in patients with relapsed/refractory leukemias for which no standard therapies are anticipated to result in a durable remission. Patients with performance status 0,1,and 2 with adequate organ function and no active, uncontrolled intercurrent illness or infection receive INCB018424 orally at 25 mg BID daily for 4 weeks (cycle #1). Response is assessed after 2 cycles of treatment. Responding patients or patients with stable disease are allowed to continue until progression. Predetermined dose modifications to 15 mg or 10 mg BID are allowed for drug related toxicities. Results: Eighteen patients [median age, 68 years; (range, 53-88] with relapsed and refractory leukemias (9 de novo AML, 3 sAML, 2 ALL, 1 MDS, 2 CMML, 1 CML) have been treated. The median number of prior therapies is 2 (range,1 to 6). Five patients (1 with AML, 2 with sAML, and 3 with CMML) had the JAK2 V617F mutation. Cytogenetic abnormalities include diploid in 7, chromosome 5 and 7 in 5, t(2;9) in 1, and the Philadelphia chromosome in 2. Pts have received a median of 1 cycle of therapy (range, 1-5 cycles) with 8 pts having stable disease (3 for 2 cycles, 2 for 3 cycles, 1 for 4 cycles, and 2 for 5 cycles). Three patients (including 2 with sAML and 1 with CMML, all with JAK2 mutation) have had significant declines in their bone marrow blasts (to <5%) associated with significant decrease in the size of the spleen and clinical improvement. The regimen has been very well tolerated with only grade 3 side effects being elevation of liver enzymes in 2 patients (thought not to be related to the study drug) and grade 3 thrombocytopenia in 1 patient. Conclusion: INCB018424 has significant activity in sAML and CMML associated with JAK2 V617F mutation. Clinical studies combining it with chemotherapy in sAML are warranted.