Limited activity of fedratinib in myelofibrosis patients relapsed/refractory to ruxolitinib 20 mg twice daily or higher: A real‐world experience

Abstract

To the editor, Fedratinib, an oral JAK2/FLT3 inhibitor is FDA-approved for myelofibrosis (MF), including primary MF (PMF), post-essential thrombocythaemia (post-ET MF) and post-polycythaemia vera (post-PV MF), for treatment-naïve and relapsed/refractory patients following ruxolitinib failure.1 The high ruxolitinib discontinuation rate of 50 and 75% at 3 and 5 years, respectively,2, 3 poses a therapeutic dilemma with fedratinib as the only FDA approved salvage therapy.1, 4 In the Phase 3 JAKARTA study with fedratinib in JAK inhibitor naïve patients with MF, spleen and symptom response rates were 47 and 40%, respectively.5 Similarly, in the JAKARTA-2 study which included MF patients with ruxolitinib failure, corresponding rates for spleen and symptom response were 31 and 27%.6 Historically, clinical development of fedratinib was halted in 2013 due to concern for Wernicke's encephalopathy, and after subsequent safety analysis, FDA approval was obtained in August 2019. Accordingly, safety remains an ongoing focus of investigation in the Phase 3b FREEDOM study while the FREEDOM2 trial seeks to evaluate the efficacy of fedratinib in comparison with best available therapy in patients with MF previously treated with ruxolitinib.7, 8 Herein, our primary objective was to describe our post-FDA approval experience with fedratinib in MF patients relapsed/refractory to ruxolitinib which includes an assessment of its efficacy, toxicity, and impact on survival. The current study includes 28 patients with MF relapsed/refractory to ruxolitinib that received treatment with fedratinib outside a clinical trial at the Mayo Clinic (Rochester MN, Arizona, Florida) between August 2019 and November 2021. Study patients were retrospectively recruited after institutional review board approval. Diagnosis of PMF, post-ET and post-PV MF was established by the World Health Organization 2016 criteria;9 patients with accelerated and blast phase disease were excluded. Clinical details at the time of initiation of fedratinib including prior ruxolitinib dose and duration, cytogenetic and molecular studies performed by conventional karyotype, and next-generation sequencing (NGS), respectively, were abstracted. All patients received at least one cycle of fedratinib, with dose adjusted based on toxicity per treating physician discretion. Response was assessed according to the International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria.10 Follow-up for each patient was updated in February 2022. Overall survival post-fedratinib was evaluated by the Kaplan–Meier method with differences in responders versus non-responders at 3- and 6-months post-therapy compared by the log-rank test. Analyses were performed using JMP Pro 16.0.0 software package, SAS Institute, Cary, NC. A total of 28 patients with MF (PMF, n = 11, post PV MF, n = 12, post ET MF, n = 5, median age 73 years, range 52–85; 54% females) received treatment with fedratinib. All patients were either relapsed or refractory following ruxolitinib therapy for a median treatment duration of 18 months (range; 3–62 months). A total of 18 patients (64%) were refractory to ruxolitinib which was defined as lack of response or disease progression after a minimum of 3 months of therapy. Median ruxolitinib treatment dose was 15 mg twice daily (range; 5 to 25 mg twice daily) with 11 (39%) patients receiving ruxolitinib ≥20 mg twice daily (n = 9, ruxolitinib 20 mg twice daily and n = 2 on ruxolitinib 25 mg twice daily). In 12 of 17 patients that were on ruxolitinib <20 mg twice daily, uptitration of ruxolitinib was limited by anaemia and/or thrombocytopenia. Driver mutation profile included JAK2 in 75% of patients, CALR in 18%, MPL in 4%, triple negative in 4%, other mutations included ASXL1 in eight patients (40%), TET2 in four (20%), NRAS in four (20%), SRSF2 in three (15%), U2AF1 in two (10%), EZH2 in one (5%) and TP53 in one (5%) of 20 informative cases. Cytogenetic abnormalities were present in 74% of patients and classified as either unfavourable (30%) or very high risk (5%). At the time of fedratinib initiation, dynamic international prognostic scoring system (DIPSS) risk distribution was high in 43%,11 and 69% of evaluable patients were high/very high risk by mutation enhanced international prognostic scoring system version 2.0 (MIPSS v2).12 Table 1 provides clinical information regarding disease characteristics at the time of initiation of fedratinib, response rates, toxicity and overall outcome stratified by prior ruxolitinib dose. A comparison of patients treated with ruxolitinib ≥20 mg versus < 20 mg twice daily illustrates no evidence of difference with the exception of spleen size; patients treated with a higher dose of ruxolitinib ≥20 mg twice daily had a median pretreatment spleen of 29.7 cm versus 22.1 cm in patients on ruxolitinib <20 mg twice daily (p = 0.05). Moreover, patients on ruxolitinib ≥20 mg twice daily were more likely to harbour unfavourable/high risk karyotype (45% vs. 13%, p = 0.05), U2AF1 (25% vs. 0%, p = 0.04), and NRAS mutations (38% vs. 8%, p = 0.11) while MIPSS v2 risk distribution was not different between the two groups (p = 0.59). Fedratinib 400 mg daily was initiated at a median of 4.8 years after MF diagnosis (range; 0.2–25 years) in 20 patients (71%), while four (14%), 3 (11%) and one (4%) patient received 300, 200 and 100 mg, respectively. At a median treatment duration of 8 months (range, 1–29 months), dose reductions were instituted in 15 (54%) patients, due to gastrointestinal toxicity in the form of nausea, vomiting and/or diarrhoea (n = 6, 21%), grade 3 anaemia (n = 7, 25%), grade 3/4 thrombocytopenia (n = 6, 21%) resulting in fatal subdural haematoma in one patient, and renal insufficiency (n = 4, 14%). Three of 24 (13%) evaluable patients demonstrated spleen response which was confirmed on imaging studies with spleen volume reduction >35% in two cases. Baseline myeloproliferative neoplasm symptom assessment form total symptom score (MPN-SAF TSS) ranged from 20 to 70; eight of 25 (32%) symptomatic patients demonstrated symptom score reduction of at least 50%. On the other hand, only one of 14 (7%) transfusion-dependent patients achieved anaemia response by IWG-MRT response criteria; moreover, resolution of leukocytosis was noted in two of 14 (14%) patients with leukocytosis >11 x 109/l at the time of treatment initiation. A total of 10 (36%) patients demonstrated either symptom and/or spleen response with median time to response of 2.5 months (range; 1–7.4 months). Six and nine patients achieved response by 3- and 6-months post therapy, respectively, with median response duration of 7.8 months (range; 0–26 months). Symptom and/or spleen response was impacted by prior ruxolitinib dose and was less likely in patients previously treated with higher doses of ruxolitinib; response rates were 9% (n = 1) versus 53% (n = 9) among patients on ruxolitinib ≥20 mg and <20 mg twice daily, respectively (p = 0.01). Notably, none of the patients on ruxolitinib ≥20 mg twice daily demonstrated a spleen response with fedratinib; moreover, pretreatment spleen size did not impact response (p = 0.48). Symptom and/or spleen response was similar with unfavourable/very high-risk karyotype (29% in presence vs. 35% in its absence %; p = 0.75) and NRAS mutations (25% in presence vs. 44% in its absence; p = 0.48). In addition, responses did not show significant correlation with fedratinib dose (40% vs. 25% with fedratinib 400 mg and <400 mg daily, p = 0.45). Disease progression while on therapy was documented in seven (25%) patients which included disease transformation to accelerated or blast phase in two and one patient each. Treatment was discontinued in 15 (54%) patients, primarily due to disease progression (n = 7), and toxicity (n = 6) while two patients were bridged to allogeneic transplant. At a median follow-up of 11.1 months (range; 1–29.1 months) following fedratinib therapy, a total of nine deaths were recorded due to progressive disease (n = 6), infectious complications (n = 2), and subdural haematoma (n = 1). Two of six (33%) responding patients versus seven of 22 (32%) non-responders at 3 months, and two of nine (22%) responders versus seven of 19 (37%) non-responders at 6 months post-therapy had died without significant difference in post-fedratinib survival among symptom/spleen responders versus non-responders (p = 0.82 and p = 0.46) (Figure 1A,B). In addition, longer duration of therapy ≥6 months versus <6 months did not impact survival (p = 0.30). The small number of patients with limited post-fedratinib follow-up precluded an accurate assessment of predictors of survival. The current study sheds light on the limited therapeutic value of fedratinib as salvage therapy for MF patients following ruxolitinib failure at higher doses of ≥20 mg twice daily. Spleen responses were inferior to clinical trial results and a recent real-world series which included 150 patients who received fedratinib following prior ruxolitinib failure.6, 13 In that particular study, details on prior ruxolitinib dose were not provided and spleen response was assessed by palpation alone which might explain the discrepant findings. Conversely, a third of our patients derived symptomatic benefit from fedratinib, which is consistent with prior observations;5, 6 however, symptom response was less likely in patients previously treated with higher doses of ruxolitinib. It is to be underscored that drug related toxicity was not trivial with half of patients requiring dose reductions. Moreover, the limited and short-lived efficacy coupled with toxicity resulted in treatment discontinuation in half of treated patients. The limitations of the current report include the retrospective design, small sample size, and lack of uniformity in timing of response assessments. Our observations suggest that prior to switching to fedratinib increasing the dose of ruxolitinib might be an option in select patients. Regardless, in the instance of MF patients failing higher doses of ruxolitinib, the therapeutic value from fedratinib might be minimal and an alternative management approach is advised. NG, AT designed the study, collected data, performed analysis and cowrote the manuscript. KM, AA, KHB, MMP, MRL, WH, MS, HA, AM, JMF, JMP, AP contributed patients. All authors reviewed and approved the final draft of the manuscript. No relevant conflicts. Please email the corresponding author.

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