TG101348 may be a durable clinical option in myelofibrosis

Pardanani A. J Clin Oncol. 2011;doi:10.1200/JCO.2010.32.8021.

More than half of a cohort of patients with myelofibrosis achieved resolution of symptoms after treatment with TG101348, a selective small-molecule JAK2 inhibitor, according to study results.

Researchers from several sites in the United States conducted a phase 1 trial of oral TG101348 in 59 patients with high- or intermediate-risk primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. Eligible patients received the drug once a day.

There were 28 patients in a dose-escalation phase who received treatments ranging from 30 mg/day through 60, 120, 240, 360, 520, 680 and 800 mg/day. After escalation, it was determined that the maximum tolerated dose was 680 mg/day. Dose-limiting toxicity was an asymptomatic increase in the serum amylase level that proved reversible.

Six or more cycles of treatment were completed by 73% of patients. The median cumulative exposure to the study drug was 380 days.

The most commonly reported grade 3 or 4 adverse events were nausea (3%), vomiting (3%), diarrhea (10%), thrombocytopenia (24%) and anemia (35%).

Serum cytokine levels were modestly affected by TG101348, but more than 50% of patients with early satiety, night sweats, fatigue, pruritus and cough achieved rapid and durable improvement in these symptoms as a result of treatment with the drug.

Splenic response by International Working Group criteria was achieved by 39% of patients after six cycles and 47% of patients after 12 cycles.

There were 28 patients with leukocytosis and 10 patients with thrombocytosis at baseline. After six cycles, normalization of blood counts was achieved by 57% of patients with leukocytosis and 90% of patients with thrombocytosis; after 12 cycles, these figures were 56% and 88%, respectively.

At 6 months, the researchers observed a significant decrease in JAK2 V617F allele burden in 51 patients with mutation-positive disease (P=.04). In a subgroup of 23 patients with allele burden of more than 20%, the decrease was also significant (P<.01). This decrease was durable at 12 months, according to the results.

The study was conducted because patients with myelofibrosis frequently harbor JAK-STAT activating mutations that are sensitive to TG101348.

“TG101348 is well tolerated and produces significant reduction in disease burden and durable clinical benefit in patients with myelofibrosis,” the researchers wrote.

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