Fedratinib with GI Prophylaxis Has Tolerable Safety Profile in Myelofibrosis After Prior Ruxolitinib


Fedratinib was shown to be generally well tolerated in older patients with myelofibrosis who had received at least 3 months of prior ruxolitinib, according to findings from the phase 3b FREEDOM trial.

Vikas Gupta, MD

Vikas Gupta, MD

Fedratinib (Inrebic) was shown to be generally well tolerated in older patients with myelofibrosis who had received at least 3 months of prior ruxolitinib (Jakafi), according to findings from the phase 3b FREEDOM trial (NCT03755518) that were presented at the 2022 EHA Congress.

The occurrence and grade of gastrointestinal (GI) adverse effects (AEs) were lower in the FREEDOM trial than in previous clinical trials involving fedratinib. GI events were mostly low grade, with the highest frequency observed during cycle 1; these effects were found to decrease over time with continued treatment. Moreover, no patients needed a dose interruption, reduction, or to discontinue fedratinib because of a treatment-related GI AE.

“The frequency and severity of nausea, vomiting, and diarrhea were substantially lower in FREEDOM than in previous clinical trials of fedratinib, suggesting these events can be prevented or mitigated by early implementation of GI prophylaxis,” lead study author Vikas Gupta, MD, a clinician investigator in the Cancer Clinical Research Unit at the Princess Margaret Cancer Centre, and colleagues, wrote in the poster.

Ruxolitinib has been shown to improve myelofibrosis symptoms and splenomegaly in patients with myelofibrosis. However, declining responses and treatment-related cytopenias cause many patients to discontinue this agent. Fedratinib, an oral, selective JAK2 inhibitor, is approved for use in patients with myelofibrosis, including those who were previously treated with ruxolitinib.

FREEDOM is an ongoing, multicenter, single-arm, open-label trial evaluating the tolerability and safety of fedratinib in adult patients with myelofibrosis who have discontinued ruxolitinib treatment. Because earlier fedratinib trials, such as the phase 2 JAKARTA2 study (NCT01523171), reported GI events to be common non-hematological AEs experienced with the agent, FREEDOM included strategies to proactively mitigate GI AEs, as well as other toxicities such as Wernicke’s encephalopathy (WE) and thiamine level decreases.

To be enrolled, patients needed to have primary, post–polycythemia vera, or post–essential thrombocythemia myelofibrosis. They were also required to have received prior ruxolitinib treatment for at least 3 months, or for at least 28 days with the development of a red blood cell transfusion requirement or grade 3 or higher anemia, thrombocytopenia, hemorrhage, or hematoma.

Additional eligibility criteria included a Dynamic International Prognostic Scoring System score of intermediate or high risk, an ECOG performance status of 2 or lower, a platelet count of at least 50 x 109/L, an absolute neutrophil count of at least 1 x 109/L, a peripheral blood blast count of 5% or less, and a spleen volume of at least 450 cm3 or a palpable spleen of at least 5 cm below the left costal margin.

All enrolled patients received fedratinib at 400 mg once daily in continuous 28-day cycles. To mitigate GI toxicities, anti-nausea, anti-vomiting, and anti-diarrheal treatments were used on a prophylactic and symptomatic basis. The study also allowed prophylactic thiamine supplementation, fedratinib dosing modifications, and the administration of fedratinib with food.

Patients were treated until a lack of efficacy with fedratinib, treatment intolerance, progressive disease (PD), or withdrawal of consent. After treatment discontinuation, patients were followed for 30 days to assess AEs and 12 months to assess survival.

At a data cutoff of April 9, 2021, 34 patients had enrolled in the trial, and 16 were still receiving fedratinib. A total of 18 patients discontinued the agent because of a lack of efficacy (n = 5), AEs (n = 4), PD (n = 2), patient decision (n = 2), hematopoietic stem cell transplantation (n = 2), or other reasons (n = 3). Of those 18 patients, 15 entered post-treatment follow-up. A total of 6 patients died during this follow-up.

All enrolled patients had previously received ruxolitinib for at least 3 months, with the most common reason for discontinuing this therapy being a loss of response or treatment failure, which was seen in 41% of patients.

The median age at study entry was 68.5 years (range, 49-82). Sixty-two percent (n = 21) of patients had primary myelofibrosis, 24% (n = 8) had post–polycythemia vera myelofibrosis, and 15% (n = 5) had post–essential thrombocythemia myelofibrosis.

The median duration of fedratinib treatment was 28.3 weeks (range, 1.6-101.3). Forty-one percent (n = 14) of patients completed over 12 cycles of fedratinib treatment.

The primary end point of the trial is spleen volume response rate, measured as the proportion of patients with a spleen volume reduction of at least 35% from baseline at the end of cycle 6. Secondary end points include safety, spleen size reduction, duration of spleen response, symptom response rate, symptom response duration, and risk-mitigation strategies for GI AEs, WE, and neurotoxicity.

Exploratory end points are survival, patient-reported outcomes, and biomarkers of fedratinib efficacy and biochemical activity.

Safety was evaluated for all patients who received at least 1 dose of fedratinib.

To mitigate GI toxicities, 65% (n = 22) of patients received ondansetron (Zofran), primarily prophylactically, and 32% (n = 11) of patients received loperamide (Imodium) on a symptomatic basis. In total, 85% (n = 29) of patients experienced GI AEs, with most being grade 1 or 2 in severity. No treatment-related grade 3 or 4 GI AEs occurred.

The most common GI AEs were constipation (any grade, 47%), diarrhea (any grade, 35%), nausea (any grade, 26%), abdominal pain (any grade, 24%; grade 3 or 4, 3%), and vomiting (any grade, 18%). The low-grade constipation may be related to the increased frequency of ondansetron and loperamide treatment, according to the study authors.

Regarding non-GI safety, 91% (n = 31) of patients experienced treatment-related AEs (TRAEs), the most frequent being anemia (any grade, 32%; grade 3 or 4, 21%), blood creatinine increase (any grade, 24%), thrombocytopenia (any grade, 15%; grade 3 or 4, 6%), vitamin B1 decrease (any grade, 15%), and fatigue (any grade, 12%; grade 3 or 4, 3%).

TRAEs led to dose reductions in 12% of patients and treatment interruptions in 18% of patients. Additionally, 3 patients experienced treatment-related hyperkalemia that required dose modifications but did not require permanent treatment discontinuation.

In total, 1 patient experienced grade 3 thrombocytopenia that led to fedratinib discontinuation. No treatment-related grade 4 thrombocytopenia was reported, and no TRAEs led to death.

Thiamine level decreases were uncommon and easily managed. Findings from thiamine monitoring showed that at baseline, 1 patient had a thiamine level below the lower limit of normal (LLN; 70 nmol/L), which was normalized before beginning fedratinib treatment. During treatment, thiamine levels fell below the LLN for 4 patients between cycles 2 and 3. Thiamine levels also dropped below the LLN for 1 patient at the end of treatment. In each of these patients, thiamine levels returned to normal with oral thiamine supplementation, and no patients required fedratinib interruption or dose reduction.

Additionally, 2 patients received thiamine supplementation before treatment, and 3 received thiamine supplementation during treatment with fedratinib. This supplementation was prophylactic for 4 of these patients and empirical to treat a non-TRAE for 1 patient.

No cases of encephalopathy, including WE, were reported. The successful management of thiamine level decreases on the trial supports the recommendation to monitor thiamine levels before fedratinib treatment, as well as periodically during treatment, according to the study authors.

The randomized, open-label, phase 3 FREEDOM2 trial (NCT03952039) is currently enrolling patients with myelofibrosis. This will be the first trial comparing fedratinib with other active myelofibrosis therapies, such as ruxolitinib.


Gupta V, Yacoub A, Verstovsek S, et al. Safety and tolerability results from the phase 3b FREEDOM trial of fedratinib, an oral, selective JAK inhibitor, in patients with myelofibrosis previously treated with ruxolitinib. Presented at: 2022 EHA Congress; June 9-12, 2022; Vienna, Austria. Abstract P1042.

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