A multicenter Mayo Clinic experience with fedratinib in twenty-eight MF patients who were relapsed or refractory to ruxolitinib was reported [15]. The investigators assessed the efficacy, toxicity, and impact on survival. Patients had previously been treated with ruxolitinib for a median duration of 18 months, with a median dose of 15 mg twice daily. Patient features were typical for this MF population: median age was 73 years, and 54% of the subjects were women. Based on imaging, splenomegaly was observed in 86% of the patients, with a median spleen size of 23 cm. Most patients (89%) reported constitutional symptoms, and 50% were transfusion-dependent. The most frequent driver mutation was JAK2 (75%), followed by CALR (18%), MPL (4%), and 4% of patients were triple-negative. Next-generation sequencing revealed mutations in ASXL1 (40%), TET2 (20%), NRAS (20%), SRSF2 (15%), U2AF1 (10%), EZH2 (5%), and TP53 (5%) among 20 informative cases. Cytogenetic abnormalities were present in 74% of patients, classified as unfavorable (30%) or very high risk (5%). The dynamic international prognostic scoring system (DIPSS) risk was high at 43%, and 69% of evaluable patients were high/very high risk by mutation-enhanced international prognostic scoring system version 2.0 (MIPSS v2). Fedratinib was initiated at a median of 4.8 years after MF diagnosis, and administered at a median daily dose of 400 mg for a median duration of 8 months. Patients who previously required >20 mg of ruxolitinib twice daily received fedratinib for a shorter median period (4 months) than those who required lower doses of ruxolitinib (9 months). Spleen response was evaluated in 24 patients and only three patients (13%) exhibited a reduction in spleen size. Symptom improvement was more frequently reported compared to the effect on the spleen size, with one-third of patients experiencing at least a 50% reduction in their symptom scores. Either symptoms and/or spleen response was achieved in 36% of patients. Overall, the median time to response was 2.5 months and the median duration of the response was 7.8 months.

Only one transfusion-dependent patient achieved anemia response by consensus response criteria. As expected, hematological and gastrointestinal toxicity were the most prevalent adverse events. Seven (25%) patients progressed while on treatment, including one transforming into blast phase. Treatment was discontinued in 54% of patients, due to disease progression and toxicity. At a median follow-up of 11.1 months following fedratinib therapy, 32% of the cohort had died, mostly due to progressive disease (67%). No significant differences in survival among symptom/spleen responders versus non-responders were observed. In addition, duration of therapy (≥6 months versus <6 months) did not impact survival. In summary, this study reported the efficacy of fedratinib in a cohort of patients with a long history of MF (average duration of 4.8 years), who had been treated with ruxolitinib for over a year and had significant splenomegaly. In this scenario, the evidence indicates that fedratinib’s main benefit may lie in providing symptomatic relief. Its effects on spleen size reduction appear to be less significant. Furthermore, patients who do not respond to increased doses of ruxolitinib may have limited therapeutic advantages from fedratinib.

Mascarenhas et al. reported on the outcomes of spleen size, MF-specific symptoms, and hematologic responses during the first 6 months of fedratinib therapy 150 patients from community oncology practices in the United States who had previously been treated with ruxolitinib [16]. The mean age of the population was 68 years. 50% of patients had received ruxolitinib at a dose ≥20 mg twice daily and the median duration of ruxolitinib before fedratinib was 7.6 months. 43% had International Prognostic Scoring System (IPSS)/DIPSS high-risk and 37% had intermediate-2 risk disease. Fedratinib was started at 400 mg once a day in 74% of patients. The median time of follow-up post-fedratinib initiation was 5 months and the median duration of fedratinib treatment was 4.4 months. At initiation, the mean spleen length was 16.0 cm, decreasing significantly to 13.2 cm at 3 months and 7.2 cm at 6 months. The mean number of symptoms decreased significantly, and the mean platelet count increased at 3 and 6 months. Interestingly, complete resolution of palpable spleen occurred in 21% of patients. Discontinuation of fedratinib was for disease progression in 43% of cases, and 29% of patients died after discontinuation. The authors concluded that this study provides real-world evidence of the effectiveness of fedratinib when used post ruxolitinib failure in patients with intermediate- or high-risk MF, and that a longer duration of fedratinib led to greater clinical benefits in spleen size and symptomatic burden reduction. It is important to highlight that in this study, the cohort was younger and had a shorter median exposure to ruxolitinib (7.6 months) compared to the Mayo Clinic patients [14]. Moreover, the population had a relatively good clinical profile with a mean number of symptoms of only 2.5, and only 38% of patients were transfusion-dependent. Details regarding prior ruxolitinib dose were not provided and spleen response was assessed by palpation alone. These differences may explain the discrepant findings between the reports.

A study presented in 2023 at the annual meeting of the Society of Hematologic Oncology described the outcomes of a retrospective US cohort study identified using the Integra Connect PrecisionQ database [17]. The authors reported data on 150 MF patients receiving fedratinib, pacritinib, or other therapies after ruxolitinib, with at least 6 months of follow-up. Thirty of them received fedratinib. This cohort had a median age of 75 years, showed a median time on treatment of 11 months, and a median overall survival (OS) was 27.1 months. At 6 months post-index, 96.6% of patients in the fedratinib arm were alive. In their conclusions, the authors remarked that this real-world US study suggests a longer time on treatment and OS with fedratinib in post-ruxolitinib setting compared with the other options. Full publication of these data is awaited.

Another claims-based retrospective observational study aimed to evaluate the real-world impact of fedratinib on survival in the post-ruxolitinib setting, utilizing data from the US Flatiron Health national database [18]. Patients included were stratified into two groups depending on the post-ruxolitinib care received, fedratinib (n = 70) and non-fedratinib (n = 159) cohorts. The authors subsequently identified 109 patients in the non-fedratinib subgroup who discontinued ruxolitinib following the FDA approval of fedratinib in August 2019, referred to as the non-fedratinib contemporary subgroup. The subjects were followed until death, loss to follow-up (last observed clinic visit or medication administration date), or end of the study period, whichever came first. Median age at index was 71.0 and 70.0 years, in the fedratinib and non-fedratinib groups, respectively, and approximately half of patients were female (55.7 and 50.3%). The proportion of patients with post PV/ET MF was 40% in the fedratinib group and 39.0% in the non-fedratinib group, and no patients and 9.4% of patients, respectively, had evidence of blast-phase/acute myeloid leukemia at index. Among patients with an available Eastern Cooperative Oncology Group (ECOG) performance status at index, the proportion with a score of 0–1 was higher in the fedratinib group than in the non-fedratinib group (90.2 vs 74.3%). The median time from MF diagnosis to the start of ruxolitinib therapy was 7.5 months for the fedratinib cohort and only 2.1 months for the non-fedratinib contemporary subgroup. The duration of the ruxolitinib treatment for those groups was 25.3 vs 13.7 months, respectively. Patients who began fedratinib did so after a median of 55.7 months from their MF diagnosis. The median duration of fedratinib therapy in the fedratinib group was 3.7 months. Overall, 47.1% of patients receiving fedratinib started treatment with a daily dose of 400 mg, while 21.4% began with a daily dose of 200 mg. In the non-fedratinib group, the most frequently received post-ruxolitinib treatments were hydroxyurea (7.5%), a clinical study drug (8.8%), or danazol (3.8%). Median OS was not reached in the fedratinib group and was 17 months in the non-fedratinib group (p = 0.0223). In the non-fedratinib contemporary subgroup, the median OS was 12 months (p = 0.0091). In a multivariate Cox model analysis, factors that were associated with poorer OS included Charlson Comorbidity Index ≥1 (versus 0), ECOG PS score 2–4 (versus 0–1), and baseline BMI < 18.5 kg/m2 (versus 18.5–25 kg/m2), as well as time from MF diagnosis to index date of 6–9 years (versus ≤3 years). The authors concluded that fedratinib significantly improves survival compared with non-fedratinib therapy. The fedratinib group had a lower percentage of patients with an ECOG score of ≥2 at index, and a higher percentage of patients without transformation to blast-phase/acute myeloid leukemia, compared with the non-fedratinib groups. However, even after excluding these patients, the mortality remained substantially higher in the non-fedratinib group (36.1%) compared with the fedratinib group (21.4%). It should be noted that the authors were unable to assess the impact of allogeneic stem cell transplantation therapy on these populations. In this study, the median duration of fedratinib therapy was only 3.7 months, compared to a median treatment duration of 24.4 weeks (range 0.7–79.4) in the JAKARTA2 trial (8) and a median treatment duration of 28.3 weeks (range 1.6–101.3) in the FREEDOM trial [11], both in patients who have previously failed ruxolitinib therapy.

Passamonti et al described the characteristics and clinical outcomes of patients with intermediate-2 and high-risk MF who received fedratinib as second line treamtment real-world settings [19]. Patients in this cohort discontinued ruxolitinib due to refractoriness, relapse or intolerance. Those undergoing allogeneic bone marrow transplantation were excluded. A total of 196 patients were included with a median age at fedratinib initiation of 68.7 years. Most patients were male (62.8%), white (82.7%), diagnosed with primary MF (76.5%), had intermediate-2 MF in 56.1%, and with the JAK2V617F mutation in 56.1% of cases. Duration of the previous treatment with ruxolitinib was not reported. The median time from ruxolitinib discontinuation to fedratinib initiation was 1.2 months. With a median follow-up period of 13.8 months, 55.1% (n = 108) of the population remained on fedratinib treatment. Those who discontinued fedratinib had a median treatment duration of only 6.3 months. In 42% of patients, symptoms resolved completely within 6 months of starting fedratinib. Overall, 66.8% of patients had a reduction in the palpable spleen size during the same period. The median time to spleen response was 4 months. It is important to note that the study lacked details regarding the duration of MF and ruxolitinib treatment, as well as the median spleen size at the initiation of fedratinib therapy.

We recently reported on 16 patients with a physician-reported diagnosis of MF, who initiated fedratinib after receiving ruxolitinib, on a national managed access program. 62.5% of the patients were women and the median age was 77 years [20]. The median duration of prior ruxolitinib therapy was 17 months (range: 3–84) months. Before the initiation of fedratinib, the median spleen length by palpation was 15.5 cm below the costal margin (range: 4–22 cm). After 3 months the median spleen length was 13 cm below the costal margin (range: 2–21 cm). 2 patients showed minimal improvement after 6 months, while 3 patients progressed, and 2 patients showed no change in the spleen size. The spleen response did not improve after 12 months of treatment at which time the median spleen size was 19 cm below the costal margin (range: 2–30 cm). Regarding the MF-related symptoms, 43.75% (n = 7) of patients reported some improvement, 37.5% (n = 6) showed no change and 18.75% (n = 3) of the population had worsening of their symptoms. Gastrointestinal toxicity was the most frequent adverse effect of the drug and while 31% of patients died during follow up. Our observations showed that in MF patients who have failed to ruxolitinib, the therapeutic value from fedratinib may be modest, especially when exposure time to ruxolitinib was >12 months.

The key features and efficacy outcomes of the real-world data discussed above are presented in Table 4.