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
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
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%,
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
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.