Fedratinib Induces Spleen Responses in Patients with Myeloproliferative Neoplasm-Associated Intermediate- or High-Risk Myelofibrosis (MF) Previously Exposed to Ruxolitinib (RUX), Regardless of Reason for Discontinuing RUX
Authors: Harrison Claire N , Schaap Nicolaas , Vannucchi Alessandro M , Kiladjian Jean-Jacques , Jourdan Eric , Silver Richard T. , Schouten Harry C , Passamonti Francesco , Zweegman Sonja , Talpaz Moshe , Verstovsek Srdan , Rose Shelonitda , Shen Juan , Berry Tymara , Brownstein Carrie , Mesa Ruben A 
Published: November 2019

Background: Treatment (Tx) options for patients (pts) with MF are limited following RUX failure. Fedratinib (FEDR) is an oral, selective inhibitor of JAK2. The phase II JAKARTA2 study of FEDR in pts with MF previously treated with RUX was initiated shortly after RUX was approved, and at the time there were no well-established criteria for RUX failure. Pt eligibility for JAKARTA2 was determined per investigator assessment. JAKARTA2 findings were originally reported using a last-observation-carried-forward (LOCF) analysis method in the "Per Protocol" population (pts with a baseline [BL] and ≥1 post-BL spleen assessment) (Harrison, Lancet Haematol,2017). Since JAKARTA2 was conducted, clinical experience with RUX has better informed criteria for RUX failure.
Objective: To evaluate FEDR safety and efficacy using intention-to-treat (ITT) analyses for all pts enrolled in JAKARTA2 (ITT Population), and for a subgroup of pts who met more stringent definitions for RUX relapsed, refractory, or intolerant ("Stringent Criteria Cohort") than used in the original analysis.
Methods: Adult pts with intermediate- or high-risk primary, post-polycythemia vera, or post-essential thrombocythemia MF, platelet counts ≥50 × 109/L, and ECOG PS scores 0-2 were enrolled. Pts were assessed by investigators to be RUX-resistant after receiving ≥14 days of prior RUX therapy, or RUX-intolerant due to toxicity following any duration of RUX exposure.
The Stringent Criteria Cohort comprised pts who met the following criteria for RUX relapsed, refractory or intolerant: relapsed/refractory required ≥3 mo of prior RUX Tx with an initial response followed by spleen regrowth or suboptimal response; RUX intolerance required ≥28 days of RUX Tx with development of RBC transfusion requirement or grade ≥3 cytopenias, hematoma, or hemorrhage.
Initial FEDR dose was 400 mg/day in 28-day cycles. The primary endpoint was spleen volume response rate (SVRR); ie, the proportion of pts who achieved a ≥35% spleen volume reduction from BL to end of cycle 6 (EOC6). LOCF analysis was not used; pts missing an EOC6 spleen volume measure were deemed nonresponders.
Results: In the ITT Population (N=97), median age was 67 yrs (range 38-83) and 55% of pts had primary MF. Outcomes of prior RUX therapy are shown in the Table. In the ITT Population, 64 pts (66%) were resistant and 32 (33%) were intolerant to RUX per investigators. Median BL spleen volume was 2894 mL (~14× normal). Median prior RUX exposure was 11.7 mo in RUX-resistant pts and 7.0 mo in RUX-intolerant pts. Median duration of FEDR Tx on-study was 24.4 weeks. SVRR at EOC6 in the ITT Population was 31% (95%CI 22, 41), with similar rates between RUX-resistant pts (33% [22, 46]) and RUX-intolerant pts (28% [14, 47]). All but 1 pt with EOC6 data (n=51) had some degree of spleen volume reduction (Figure).
The Stringent Criteria Cohort included 79/97 pts (81%) who met stringent definitions of RUX relapsed (n=18, 23%), refractory (n=47, 60%), or intolerant (n=14, 18%) (Table), with median prior RUX exposures of 11.8, 11.4, and 8.7 mo, respectively. Median duration of FEDR Tx was 24.3 weeks. SVRR in the Stringent Criteria Cohort overall was 30% (95%CI 21, 42). SVRR in RUX relapsed, refractory, and intolerant pts was 28% (95%CI 10, 54), 32% (19, 47), and 29% (8, 58), respectively. All pts with available assessments (n=41) had spleen volume reductions from BL at EOC6 (Figure).
In the Stringent Criteria Cohort, adverse events (AEs) were reported with generally similar frequency among RUX relapsed, refractory, and intolerant pts, with rates of grade 3-4 anemia of 44%, 49%, and 29%, respectively; and grade 3-4 thrombocytopenia of 28%, 19%, and 14%. Proportions of RUX relapsed, refractory, or intolerant pts who discontinued FEDR Tx due to an AE were 22%, 17%, and 29%, respectively.
Conclusion: Tx with FEDR in JAKARTA2 pts, who had substantial prior exposure to RUX, was associated with a robust spleen response rate, similar to or higher than rates seen with other JAK inhibitors when used as front-line Tx for MF (Harrison, NEJM, 2012; Mesa, Lancet Haematol, 2017; Mesa, JCO, 2017). About one-third of pts in JAKARTA2 achieved a spleen volume response and most pts had some degree of spleen volume reduction during FEDR Tx, regardless of whether they were relapsed, refractory, or intolerant to RUX. Long-term FEDR Tx in pts previously exposed to RUX is currently under study in 2 ongoing phase III studies (NCT03755518, NCT03952039).

Disclosures
Harrison: Shire: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Promedior: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte: Speakers Bureau; AOP: Honoraria; Roche: Honoraria; Janssen: Speakers Bureau; Sierra Oncology: Honoraria; Gilead: Speakers Bureau; CTI: Speakers Bureau. Schaap:Novartis: Consultancy; Celgene: Consultancy. Vannucchi:ITALFARMACO: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Celgene: Consultancy; AOP Orphan: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Jourdan:Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schouten:Novartis: Honoraria; Sanofi: Honoraria; Gilead: Honoraria; Alexion: Honoraria, Other: Travel expenses. Passamonti:Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Talpaz:Novartis: Research Funding; Samus: Research Funding; Janssen: Research Funding; CTI: Research Funding; Stemline: Research Funding; Gilead: Research Funding; Constellation: Research Funding; NS Pharma: Research Funding; Incyte: Research Funding; BMS: Consultancy; Celgene: Consultancy, Other: Travel; Asana: Research Funding; Promedior: Research Funding. Verstovsek:Incyte: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Rose:Celgene Corporation: Employment, Equity Ownership. Shen:Celgene: Employment, Equity Ownership. Berry:Celgene: Employment, Equity Ownership. Brownstein:Celgene: Employment, Equity Ownership. Mesa:Gilead Sciences: Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; CTI: Research Funding; AbbVie: Research Funding; Genotech: Research Funding; Incyte: Other: travel, accommodations, expenses, Research Funding; Galena Biopharma: Consultancy; NS Pharma: Research Funding; LaJolla: Consultancy; Samus: Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; Shire: Honoraria; Baxalta: Consultancy; Sierra Oncology: Consultancy; Celgene Corporation: Research Funding; Promedior: Research Funding; Genentech: Consultancy; PharmaEssentia: Research Funding.