During the 26th Congress of the European Hematology Association (EHA2021), the MPN Hub Steering Committee member Claire Harrison presented results from the phase III, placebo-controlled JAKARTA (NCT01437787) and phase II (NCT01523171) JAKARTA2 trials on the overall survival (OS) and progression-free survival (PFS) of patients treated with fedratinib for myelofibrosis (MF).¹ In 2013, ongoing trials on fedratinib were placed on clinical hold, as eight participants developed neurological symptoms indicative of the thiamine-deficiency condition of Wernicke encephalopathy. In 2017, after additional safety data were provided to the US regulatory authorities, the clinical hold was lifted, and the JAKARTA data were re-analyzed.² The MPN Hub is happy to provide a summary of the key updated outcomes.

Additional resources

The MPN Hub has previously provided a summary for approval journey of fedratinib, where you can also find more information on the study design, detailed eligibility criteria, methods, and patient characteristics of both trials.

Claire Harrison has also kindly provided an interview discussing the JAKARTA trials, which you can watch below.

Results

JAKARTA trial

96 ruxolitinib-naïve patients were randomized to fedratinib (400 mg/day) as first-line MF treatment and 96 to placebo. Patients who demonstrated clinical benefit or stable disease per modified International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria at the end of six treatment cycles (EOC6) (i.e., 24 weeks) could continue treatment until progressive disease or unacceptable toxicity (or clinical hold). Here, we summarize the recently presented results of the trial (Table 1):

• The median range of treatment duration was 62.1 weeks (1.0–91.9) in the fedratinib arm and 24.0 weeks (1.7–43.7) in the placebo arm.
• The reasons for discontinuation of fedratinib were study termination (64%), adverse event (27%), disease progression (6%), patient decision (2%), poor compliance (1%).

Table 1. JAKARTA survival outcomes*

NS, not significant; OS, overall survival; PFS, progression-free survival. *Data from Harrison et al.1 †HR: 0.42; p = 0.004. ‡HR: 0.57; p = 0.094.
Outcome	PFS†		OS‡ (ITT)
	Fedratinib	Placebo	Fedratinib	Placebo
Median survival, months (95% CI)	23.2 (0.23–0.76)	17.5	N (0.30–1.10)	NS
1-year survival rate, %	83	67	92	86
18-month survival rate, %	—	—	87	80
Median follow-up, months	10.6	9.1	19.3	18.8
Patients followed for survival at the time of the clinical hold, %	42 (80/192)		72 (139/192)

• The difference in OS and PFS between the two arms suggests patients may benefit more from early treatment with fedratinib.
• At EOC6 or earlier, 74% of the patients who were randomized to receive placebo crossed over to the fedratinib arm due to disease progression.
• At EOC6 spleen volume was significantly reduced from baseline in the fedratinib arm in 37% vs 1% of patients receiving placebo (p < 0.0001).
• The reduction of MF symptom burden, based on the modified Myelofibrosis Symptom Assessment Form (MFSAF), from baseline at EOC6 was statistically significant in patients treated with fedratinib; 40% vs 9% in the placebo arm (p < 0.0001).
• Acute myeloid leukemia (AML) transformation was reported in three patients (3%) in the fedratinib arm and two patients (2%) in the placebo arm.

JAKARTA2 trial

97 patients with MF who were previously treated with ruxolitinib were enrolled for this trial. The key PFS and OS outcomes are detailed in Table 2 below:

• Median range of treatment duration was 24.4 weeks (0.7–79.4).
• The reasons for discontinuation of fedratinib were study termination (65%), adverse event (19%), patient decision (8%), disease progression (6%), and other (2%).

Table 2. JAKARTA2 survival outcomes*

NR, not reached; OS, overall survival; PFS, progression free survival. *Data from Harrison et al.1
Outcome	PFS	OS
Median survival, months	13.3 (95% CI, 8.4–17.1)	NR (95% CI, 17.1–NR)
1-year survival rate, %	59	84
18-month survival rate, %	—	67
Median follow-up, months	5.6	10.8
Patients followed for survival at the time of the clinical hold, %	64 (62/97)	81 (79/97)

• Fedratinib improved spleen volume in 31% of the patients.

• MF symptom response rate was successfully reduced in 27% of the patients.
• Leukemic transformation was low in this cohort. Two patients (2%) experienced transformation to AML during the treatment period.

Adverse events²

• The most common adverse events reported during the randomized treatment period were diarrhea, nausea, anemia, and vomiting.
• Gastrointestinal events were most frequent during early treatment and decreased in incidence as the treatment progressed.
• No patient receiving fedratinib developed Wernicke encephalopathy.

Conclusion

These results constitute the first reported survival data for fedratinib in MF demonstrating favorable outcomes despite the impact of the clinical hold. In the JAKARTA trial, first-line fedratinib significantly reduced the risk of disease progression, spleen volume, and symptom burden compared to placebo. The median PFS, median OS, and 1-year OS rate of patients in the JAKARTA2 trial were favorably comparable with real-world data of similar patient cohorts who also discontinued ruxolitinib use. The ongoing phase III FREEDOM (NCT03755518) and FREEDOM2 (NCT03952039) trials will provide more information about the survival of patients with MF who were previously treated with ruxolitinib.