Phase II Study of the JAK2 Inhibitor, INCB018424, In Patients with Refractory Leukemias Including Post-Myeloproliferative Disorder (MPD) Acute Myeloid Leukemia (sAML)

The JAK family of enzymes has a central role in normal hematopoiesis and immune response. Mutations of JAK2 gene that result in constitutive activation of JAK-STAT signaling and enhanced proliferation and survival signals have been described. This aberrant signaling pathway has been clearly demonstrated in myeloproliferative disorders (MPDs), but also reported in other hematological cancers including acute leukemias.

To explore the activity of INCB018424 in patients (pts) with advanced hematological cancers

We are conducting a phase II study of INCB018424 in pts with relapsed/refractory leukemias for which no standard therapies are anticipated to result in a durable remission. Pts with performance status 0 – 2 with adequate organ function and no active, uncontrolled intercurrent illness or infection, receive INCB018424 orally at 25 mg twice daily for 4 weeks (one cycle). Response is assessed after every 2 cycles of treatment. Responding pts or pts with stable disease are allowed to continue until progression. Dose escalation to 50 mg twice daily is permitted in pts demonstrating a benefit.

Thirty eight pts [median age, 69 years; (range, 45–88)] with relapsed and refractory leukemias (15 sAML, 13 AML, 3 ALL, 1 MDS, 4 CMML & 2 CML) have been treated. The median number of prior therapies is 2 (range, 1 to 6). Eleven pts (7 with sAML, 2 with AML, and 2 with CMML) had the JAK2 V617F mutation. Cytogenetic analysis showed diploid karyotype in 11, chromosome 5 and 7 abnormalities in 7, t(2;9) in 1, Philadelphia chromosome in 2 and other various abnormalities in 17. Pts who completed 2 cycles of INCB018424 are defined as having stable disease (SD). Pts have received a median of 2 cycles of therapy (range, 1 –18 cycles) with 15 pts having SD or better (5 for 2 cycles, 4 for 3 cycles, 3 for 4 cycles, 2 for 5 cycles and 1 for 18 cycles). Among these, 3 pts (2 with sAML and 1 with CMML with JAK2 mutation) have had a significant reduction in their bone marrow blasts (to < 5%) associated with a significant decrease in spleen size and clinical improvement. Three pts are too early for assessment of response. Pts having benefit include sAML (9, or 60% of pts with sAML), AML (2, 15%), CMML (3, 75%) & MDS (1, 100%). Overall, 22 pts have had no response or progressed (12 after 1 cycle, 4 after 2 cycles, 2 after 3 cycles, 2 after 4 cycles, and 2 after 5 cycles). Nine pts died from causes unrelated to the treatment with INCB018424. Four pts continue with treatment (1 after 18 cycles, 1 after 3 cycles, & 2 after 2 cycles). One pt had a successful allogeneic SCT after 3 cycles with SD. Two pts came off protocol for unrelated complications. Overall INCB018424 was tolerated very well. One pt had elevated liver enzymes (G3) along with neutropenia (G3), another pt had G3 liver enzyme elevation and 2 pts developed G2 thrombocytopenia. 1 pt had G5 intracranial hemorrhage.

INCB018424 is well-tolerated and has activity particularly in pts with sAML and CMML but also in AML and MDS, with or without JAK2 V617F mutation. Clinical studies combining INCB018424 with chemotherapy in sAML are warranted.

Off Label Use: Use of arsenic trioxide in frontline therapy of APL. Verstovsek:INCYTE: Research Funding. Cortes:NOVARTIS: Research Funding. Newton:Incyte Corporation: Employment. Kantarjian:NOVARTIS: Research Funding. Ravandi:Incyte Corporation: Research Funding; Novartis: Honoraria, Speakers Bureau.