Phase 2 Study of the JAK2 Inhibitor, INCB018424, in Patients With Refractory Leukemias Including Post-Myeloproliferative Disorder (MPD) Acute Myeloid Leukemia (sAML)
ORLANDO, Fla.—Alireza Eghtedar, MD, of the University of Texas in Houston, Texas, and colleagues conducted a study to evaluate the activity of INCB018424 in patients with advanced hematologic cancers and recently presented their findings at the 52nd American Society of Hematology Meeting and Exposition.
INCB018424 is a JAK2 inhibitor. JAK enzymes play a central role in normal hematopoiesis and immune response. Mutations in the JAK2 gene cause constitutive activation of JAK-STAT signaling and enhanced proliferation and survival signals. This irregular signaling due to mutations has been demonstrated in myeloproliferative disorders (MPDs) and other hematologic cancers, including acute leukemias.
This was a phase 2 study conducted to evaluate INCB018424 in patients with relapsed/refractory leukemias for which no standard therapies are anticipated to result in a durable remission. Patients were enrolled in this study if they had a performance status of 0 to 2 with adequate organ function and no active, uncontrolled intercurrent illness or infection. Patients were given INCB018424 25 mg orally twice daily for 4 weeks (one cycle). Response was assessed after every 2 cycles of treatment. Patients continued treatment until disease progression. Dose escalation to 50 mg twice daily was allowed in patients demonstrating a benefit.
A total of 38 patients with a median age of 69 years (range, 45-88) with relapsed and refractory leukemias (18 sAML, 10 AML, 3 ALL, 1 MDS, 4 CMML, 2 CML) have been treated with INCB018424. The number of prior therapies ranged from 1 to 6 with the median being 2 previous therapies. The JAK2 V617F mutation was detected in 11 patients. Cytogenetic analysis showed diploid karyotype in 13 patients, abnormalities in chromosomes 5 and 7 in 8 patients, t(2;9) abnormality in 3 patients, Philadelphia chromosome in 2 patients, and various other abnormalities in 14 patients. Patients were considered to have stable disease (SD) if they completed 2 cycles of treatment.
All patients have received a median of 2 cycles of therapy (range, 1-18) so far. Fifteen patients have been defined as having SD or better, and 3 of these patients (2 sAML, 1 CMML) have had a significant reduction in their bone marrow blasts (to <5%) associated with a significant decrease in spleen size and clinical improvement. Treatment benefit was observed in 9 patients with sAML, 2 with AML, 3 with CMML, and 1 with MDS. Three patients are too early for assessment of response. A total of 22 patients have had no response or progressed. Nine patients have died due to causes unrelated to treatment with INCB018424 and 2 patients came off protocol for unrelated complications. Four patients are currently still on treatment. One patient underwent a successful allogeneic SCT after 3 cycles of treatment and currently has SD.
Overall, treatment with INCB018424 was well tolerated. Two patients experienced elevations in liver enzymes, of which 1 patient had neutropenia as well; 3 patients developed thrombocytopenia; and 1 patient experienced intracranial hemorrhage.
Results indicate that INCB018424 is tolerable and has activity in patients with sAML, CMML, AML and MDS with or without JAK2 V617F mutation. Additional studies combing INCB018424 with chemotherapy in sAML are warranted.
Off Label Use: Use of arsenic trioxide in frontline therapy of APL.