Spleen Size Prior to Fedratinib Treatment May Impact Spleen Responses and Symptom Reduction in Myelofibrosis Patients

Approved JAK inhibitors such as ruxolitinib (RUX) and fedratinib (FEDR) effectively treat patients with intermediate- or high-risk myelofibrosis (MF). Despite its approval, RUX is often not well-tolerated and many patients must discontinue its use due to lack or loss of response, unrelenting cytopenias, and continued disease progression. Evidence has also suggested that patients on RUX therapy with palpable spleen size >10 cm below the left costal margin at baseline are less likely to achieve a spleen response. However, in the case of FEDR therapy, it remains unclear whether spleen size prior to treatment initiation affects the extent of spleen response and reduction in symptoms.

This study assessed a subset of patients with enlarged spleens at baseline from the phase 3 JAKARTA (FEDR 400 mg/day starting dose in patients who discontinued RUX) and phase 2 JAKARTA2 (placebo, FEDR 400 mg/day or 500 mg/day in patients without prior JAK inhibitor exposure) trials. Observations from these investigations revealed that 6 cycles of FEDR improved spleen volume and severity of MF-specific symptoms compared with baseline in MF patients with or without previous treatment with RUX. Patients were divided according to the median spleen size (mSS; greater than mSS vs less than mSS) at baseline in each study and assessed for changes in spleen volume compared with baseline post-FEDR initiation. In this analysis, data are reported for patients who received 400 mg/day FEDR in continuous 28-day treatment cycles and had documented spleen volume or total symptom score (TSS) at baseline and were also assessed for spleen response and TSS at the end of cycle (EOC) 6.

In the JAKARTA cohort (n = 96), median palpable spleen size at baseline was 16 cm (range, 5-40). At EOC 6, median spleen volume reduction (SVR) was –38% (95% confidence interval [CI], –43% to –31%) in the “less than mSS” group, and –40% (95% CI, –40% to –28%) in the “greater than mSS” group. Median changes in TSS were similar in the “less than mSS” (–49%, n = 37) and “greater than mSS” (–51%, n = 34) groups. There were more pronounced changes for itching and pain under ribs–left side in the “less than mSS” group and for night sweats in the “more than mSS” group. Similar rates of reduction were observed in both groups for all other symptoms.

In the JAKARTA2 cohort (n = 97), median palpable spleen size at baseline was 18 cm (range, 5-36). At EOC 6, median SVR from baseline was –35% (95% CI, –40% to –29%) for patients with “less than mSS” at baseline and –30% (95% CI, –37% to –17%) for patients with “greater than mSS.” Median changes in TSS were lower in patients with “less than mSS” (–36%) compared with the “greater than mSS” group (–49%). Except for pruritus, patients with “greater than mSS” at baseline had similar or higher reductions in all other symptoms (night sweats, early satiety, pain under ribs–left side, abdominal discomfort, and bone/muscle pain) compared with patients with “less than mSS.”

Despite higher spleen volume and TSS in the “greater than mSS” group at baseline, responses to FEDR were similar in both trials. These data indicate that baseline spleen size does not correlate to spleen response or symptom reduction in response to FEDR treatment.

Source: Kiladjian J-J, Tefferi A, Passamonti F, et al. Spleen and symptom responses with fedratinib (FEDR) in patients with myelofibrosis (MF) and substantial splenomegaly. American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 2576.

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