Study Reveals First Real-World Evidence of Fedratinib Efficacy for Refractory Myelofibrosis

Ruxolitinib has been the mainstay first-line treatment for myelofibrosis, yet its efficacy can wane over time. The oral JAK2 inhibitor fedratinib (Inrebic®) provides significant reductions in spleen size and other symptoms in patients with myelofibrosis previously treated with ruxolitinib, according to recent findings of a multi-center study reported at the recent annual meeting of the American Society of Hematology.

Until August 2019, when fedratinib became approved for intermediate- or high-risk primary or secondary myelofibrosis, patients diagnosed with this rare bone cancer had few treatment options. This research is some of the first real-world evidence of the clinical benefit of fedratinib for patients previously treated with ruxolitinib).

Patients with myelofibrosis often suffer from abdominal discomfort as a result of an enlarged spleen, as well as cytokine-related symptoms, anemia and thrombocytopenia. The original JAKARA-2 trial of fedratinib occurred in 2011, and was halted in 2013 while FDA investigators delved into the potential risk of encephalopathy before ultimately granting drug approval in 2019. “The treatment landscape has changed in the ensuing years, and we wanted to know if the data from JAKARTA-2 held up over time,” says Aaron T. Gerds, MD, MS, a co-author of the study and Associate Professor of Medicine (Hematology and Medical Oncology) at the Cleveland Clinic Taussig Cancer Institute.

Demonstrated benefits of second-line treatment

The researchers followed patients with intermediate- or high-risk myelofibrosis who initiated FEDR on or after its FDA approval date of August 16, 2019, evaluating clinical characteristics, medication dose, spleen size, a symptom list from the Myelofibrosis Symptom Assessment Form, platelet count, hemoglobin and white blood cell count at each provider visit up to the first six months of fedratinib therapy. The study found a longer duration of fedratinib led to greater clinical benefits, demonstrating the benefits of the treatment when used after discontinuation of ruxolitinib. “Fedratinib is still able to lead to spleen volume and symptom burden improvements in patients previously treated with standard-of-care medication,” says Dr. Gerds.

Study results

For the study, data were collected for 150 eligible patients from community oncology practices in the U.S. Patients had been treated with ruxolitinib for a median duration of 7.6 months, with 50% receiving a dose of ≥ 20 mg twice a day. At the start of fedratinib, 43% of patients had high-risk disease and 37% had intermediate-risk disease, according to the International Prognostic Scoring System (IPSS)/Dynamic IPSS. The remainder had unknown risk. Seventy-four percent of patients received FEDR starting at 400 mg once a day, with the remainder receiving between 100-300 mg a day.

Upon initiating fedratinib, 88% of patients had a palpable spleen, with a mean size of 16.0 cm, which was reduced to 13.2 cm at three months and 7.2 cm at six months. Complete resolution of palpable spleen occurred in 21% of patients. The mean number of symptoms also declined significantly while mean platelet count increased at six months.

The median duration of fedratinib treatment was 4.4 months, with a median time of follow-up post-fedratinib initiation of five months. At data cutoff, 55% of patients were still receiving fedratinib. Of the patients who discontinued FEDR, this was due to disease progression (43%), patient choice (19%), allogeneic stem cell transplant (18%), toxicity (6%), persistent symptoms (5%) and other reasons (9%). 44 patients died after discontinuing therapy, as a result of disease progression and other causes.

Confidence in fedratinib

These data are expected to give clinicians a better understanding of patients’ experiences with this lesser-known medication. “Many doctors who treat patients with myelofibrosis have little experience with fedratinib,” explains Dr. Gerds. “I hope this study will help them to feel confident in prescribing it to patients who aren’t realizing the best benefit from ruxolitinib.”

The researcher noted that it is crucial to be proactive about managing gastrointestinal side effects, as well as monitoring patients’ thiamine levels and providing thiamine supplements to protect against encephalopathy.

Diagnostic criteria for selecting therapies

One notable point in patient selection is that JAK2 inhibitors like fedratinib work equally well in patients whether they have a JAK2 mutation or not. Dr. Gerds cautions that regardless of this, genetic testing remains an important tool to aid diagnosis and prognosis. “Some mutations can predict a more aggressive disease course,” he explains. “Additionally, while JAK inhibitors work equally well in patients regardless of JAK2 mutation, there are other therapies that are mutation specific.”

Emerging treatment options

Fedratinib and ruxolitinib are no longer the only medications available for treating myelofibrosis — bringing new promise but added complexity. “Pacritinib was approved in February, and momelotinib may be approved as early as 2023,” says Dr. Gerds. “The challenge for us as clinicians is how do we use these medications and which populations will they work best for. If one therapy doesn’t work, it becomes a sequencing question of what to try going forward.”