ORLANDO, Fla.—In patients with polycythemia vera (PV) and essential thrombocythemia (ET) refractory or intolerant to hydroxyurea, use of the JAK1/JAK2 inhibitor, INCB018424, results in rapid and durable clinical benefits, including normalization of hematologic parameters, resolution of splenomegaly, and alleviation of symptoms, long-term follow-up data from an ongoing open-label phase 2 study have found.

Previously, these patients have had limited therapeutic options, while remaining at high risk for thrombosis. The rationale for developing a molecularly targeted therapy for these diseases was identification of a dominant gain-of-function mutation in the JAK2 kinase, V617F, in myeloproliferative neoplasms, including PV and ET, reported Srdan Verstovsek, MD, PhD, of MD Anderson Cancer Center, Houston, Texas, and colleagues.

The study, being conducted at 6 sites in the United States and Italy, includes 34 patients with PV and 39 with ET. An initial 8-week run-in evaluation established 10 mg bid as the starting dose for the PV expansion cohort and 25 mg bid for the ET cohort. Each patient is titrated to the most appropriate dose based on safety and efficacy. For those with PV, response was defined based on hematocrit (Hct) control in the absence of phlebotomy; improvement or elimination of palpable splenomegaly, when present; and normalization of leukocytosis and thrombocytosis. For ET, response was defined based on improvement or normalization of WBC and platelet counts and, when present, elimination of palpable splenomegaly, said Dr. Verstovsek in an oral presentation during the 52nd American Society of Hematology Annual Meeting and Exposition.

At a median follow-up of 15 months (range, 8-21 months), 97% of 34 patients with PV (median 108 months from diagnosis) achieved Hct control to <45% in the absence of phlebotomy, and, at last follow-up visit, all had continued to maintain phlebotomy independence. At study entry, splenomegaly was present in 74%; 59% of those achieved ≥50% reduction in palpable spleen length, or the spleen became nonpalpable, with all maintaining spleen response at the last follow-up visit. Leukocytosis >15×109/L, present in 47% of patients, was found to improve (≤15×109/L) in 88% or normalize (≤ upper limit of normal [ULN]) in 63%.

Thrombocytosis >600×109/L was present in 38% and improved (≤600×109/L) in 92% or normalized (≤ULN) in 69%. Phlebotomy independence, resolution of splenomegaly, and normalization of leukocytosis and thrombocytosis was achieved in 59%. Six patients discontinued therapy (3 due to adverse events [AEs]; 2 withdrew consent; and 1 for lack of response). Grade 3 AEs potentially related to study medication included thrombocytopenia (2 patients), neutropenia (1), renal tumor (1), asthenia (1), viral infection (1), and atrial flutter (1). No grade 4 drug-related AEs have occurred to date.

For the 39 patients with ET (median 84 months from diagnosis), following a median of 15 months (range, 4-21 months), 49% had normalized platelet counts to ≤ULN after a median of 0.5 months, for a median duration of 3.5 months; 82% maintained platelet counts <600×109/L, for a median duration of 9.8 months. Of 14 patients with baseline platelet counts >1000×109/L, 13 experienced >50% reduction and 88% maintained normal WBC (median duration, 14.5 months).

Palpable spleens resolved in 3 of 4 patients, 1 of which reduced >50% from baseline. In the presence of nonpalpable splenomegaly, 49% achieved normalization of WBC and platelet counts. Nine patients discontinued therapy (4 due to AEs; 2 withdrew consent; 3 for lack of response). Grade 3 AEs potentially related to study medication included leukopenia (2 patients), GI disorder (1), and peripheral neuropathy (1). No grade 4 drug-related AEs occurred.

Both the PV and ET groups demonstrated reductions in patient-reported symptom scores for pruritus, night sweats, and bone pain. Of 26 patients with PV reporting pruritus at baseline (median score of 6 on a 10-point scale), 24 reported scores of 0 after a median duration of 1 month, for a median duration of 7 months. At least a 20% decrease in JAK2V617F allele burden was observed in 42% of PV and 56% of ET patients; 6% of PV and 12% of ET patients had >50% decrease. Clinical responses were unrelated to the presence or absence of JAK2V617F mutation at entry or to the allele burden changes following treatment.