Micrograph showing MF

Researchers have reported results of the phase 3 JAKARTA trial, in which they evaluated the selective JAK2 inhibitor fedratinib in patients with myelofibrosis (MF).

Fedratinib was being developed as a treatment for myeloproliferative neoplasms (MPNs), but Sanofi Oncology stopped clinical development of the drug in 2013, after it was linked to a neurological condition known as Wernicke encephalopathy.

There were 4 confirmed cases of Wernicke encephalopathy in the JAKARTA trial, in addition to other adverse events (AEs). However, fedratinib also lessened the severity of MF symptoms in about 35% to 40% of patients.

These results have been published in JAMA Oncology alongside an invited commentary. The study was sponsored by Sanofi.

Treatment and response

The study enrolled 289 adult patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF. Patients were randomized to receive fedratinib at 400 mg once a day, fedratinib at 500 mg once a day, or placebo for at least 6 consecutive, 4-week cycles.

The study’s primary endpoint was spleen response, or a 35% or greater reduction in spleen volume from baseline (determined by MRI or CT) at week 24 and confirmed 4 weeks later.

Thirty-six percent (35/96) of patients in the 400 mg arm and 40% (39/97) in the 500 mg arm achieved the primary endpoint, compared to 1% (1/96) of patients in the placebo arm (P<0.001).

The main secondary endpoint was symptom response, or a 50% or greater reduction in total symptom score (assessed using the modified Myelofibrosis Symptom Assessment Form).

At week 24, symptom response rates were 36% (33/91) in the 400 mg arm, 34% (31/91) in the 500 mg arm, and 7% (6/85) in the placebo arm (P<0.001).

Safety data

Treatment-emergent AEs occurred in 100% of patients in the 400 mg arm, 98% in the 500 mg arm, and 94% in the placebo arm. Serious AEs occurred in 27%, 31%, and 23%, respectively. AEs leading to discontinuation occurred in 14%, 25%, and 8%, respectively.

Infections occurred in 42% of patients in the 400 mg arm, 39% of patients in the 500 mg arm, and 27% of patients of patients in the placebo arm.

Nonhematologic AEs occurring in at least 10% of patients in any group were diarrhea (66%, 56%, and 16%, respectively), vomiting (42%, 55%, and 5%, respectively), nausea (64%, 51%, and 15%, respectively), constipation (10%, 18%, and 7%, respectively), asthenia (9%, 16%, and 6%, respectively), abdominal pain (15%, 12%, and 16%, respectively), fatigue (16%, 10%, and 10%, respectively), dyspnea (8%, 10%, and 6%, respectively), and weight loss (4%, 10%, and 5%, respectively).

Hematologic AEs occurring in at least 10% of patients in any group were anemia (99%, 98%, and 91%, respectively), thrombocytopenia (63%, 57%, and 51%, respectively), lymphopenia (57%, 66%, and 54%, respectively), leukopenia (47%, 53%, and 19%, respectively), and neutropenia (28%, 44%, and 15%, respectively).

One patient in each fedratinib arm and 2 in the placebo arm transformed to acute myeloid leukemia.

There were 24 deaths during the first 24 weeks of the study—4 in the 400 mg arm, 10 in the 500 mg arm, and 10 in the placebo arm. Nine of the deaths were attributed to AEs—1, 4, and 4, respectively.

Wernicke encephalopathy

There were 4 cases of Wernicke encephalopathy, all in women who received fedratinib at 500 mg. All of these cases were confirmed by an independent expert safety panel, 3 on the basis of clinical features and MRI results, and 1 on the basis of clinical symptoms alone.

The patients developed symptoms 6 weeks to 44 weeks after beginning fedratinib treatment, and all discontinued treatment permanently.

Cognitive symptoms manifested in the context of persistent vomiting, malnutrition, and cachexia in 1 patient, vomiting and hyponatremia in 1 patient, and renal failure with mild hyponatremia in 1 patient.

All of the patients received intravenous thiamine and showed responses to the treatment, but all had persistent cognitive defects at last follow-up.

Team reports phase 3 results with abandoned MPN drug