Baseline Serum Ferritin Differentially Predicts W24 Transfusion Independence Response for Momelotinib and Ruxolitinib in Patients with Myelofibrosis
Authors: Oh Stephen T. , Gerds Aaron T. , Mesa Ruben A. , Gupta Vikas , Huang Mei , Ro Sunhee , Strouse Bryan , Klencke Barbara Jane , Verstovsek Srdan 
Published: November 2021

Abstract

Introduction
Myelofibrosis (MF) typically presents with constitutional symptoms, splenomegaly, and anemia with the degree of anemia and transfusion dependency being among the most important predictors of poor overall survival (OS). Momelotinib (MMB) is a differentiated JAK1, JAK2 inhibitor with potent activity against ACVR1/ALK2, a critical regulator of hepcidin production and iron metabolism.
MMB has demonstrated clinical activity against all 3 of these hallmark features of MF in the SIMPLIFY Ph 3 studies including SIMPLIFY-1 (S1) in the JAK inhibitor (JAKi) naïve setting compared directly to ruxolitinib (RUX) and in the previously JAKi experienced patients (SIMPLIFY-2 [S2]) in comparison to best available therapy (BAT) which was predominately RUX. MMB has also demonstrated robust OS in the JAKi naïve population (S1) and JAKi experienced population (S2) (Verstovsek et al. ASH 2020). Critically, patients randomized to MMB who maintain or achieve transfusion independence (TI) by Week 24 (W24) had better OS, further suggesting that MMB's anemia benefits positively impact long term outcomes in patients with MF (Mesa et al. EHA 2021).
Increased hepcidin and ferritin are associated with dysregulated iron metabolism and inflammation, both of which have previously been shown to be strong negative prognostic factors for OS in patients with MF at the time of first referral (Pardanani et al. 2013). A Ph 2 translational biology study previously demonstrated MMB acutely and chronically suppresses elevated levels of hepcidin and restores iron homeostasis in transfusion dependent patients who achieve a W24 TI-response (TI-R; Oh et al. 2020). Interestingly, several baseline factors, such as hepcidin, ferritin and CRP from this study suggested a potential threshold of W24 TI-R for patients treated with MMB, warranting further exploration.
Methods
Based on the findings from the Ph 2 translational biology study we retrospectively analyzed the relationship between serum ferritin, hepcidin and CRP and the W24 TI-R rates for patients randomized to MMB and RUX in S1 using generalized linear regression models where the degree of predictiveness measured by the interaction between treatment and the biomarkers as continuous or categorical variables using various cutoffs were examined. These findings were then independently confirmed in the previously RUX treated patients from S2.
Results
These analyses identified pre-treatment serum ferritin level as the most predictive biomarker for the treatment effect of MMB vs RUX on W24 TI-R rate in S1. The TI-R treatment effect of MMB vs RUX was significantly greater (p=0.0051) in the ≥90ng/mL cohort (62% vs 35% respectively, with response ratio [RR]=1.8) than in the &lt;90ng/mL cohort (79% and 73%, RR=1.1). This trend was also observed in the S2 study, where TI-R treatment effect of MMB vs BAT/RUX was greater in the ≥90ng/mL cohort (41% vs 11%, RR=3.8) than in the &lt;90ng/mL cohort (57% and 50%, RR=1.1) although the interaction was marginally significant (p=0.0707) potentially due to the smaller sample size.
Data also demonstrated a significant increase in serum ferritin for RUX vs MMB at W24 vs baseline (RUX mean ferritin change +226.1ng/mL vs MMB +13.8ng/mL, p=0.0003), irrespective of baseline ferritin.
Conclusion
Ferritin is a well-established and easily measured clinical biomarker that is associated with both iron metabolism and uncontrolled inflammation. Prior analyses demonstrate patients randomized to MMB who achieve a W24 TI-R have increased OS compared to non-TI responders. These new analyses expand on these findings, demonstrating that the MMB vs RUX treatment effect is greater in baseline serum ferritin ≥90ng/mL vs &lt;90ng/mL in JAKi naïve and in RUX-experienced patients. Further, data presented here show JAKi naïve patients in S1 randomized to RUX have significantly elevated ferritin levels by W24 when compared to MMB. These data suggest the possibility that, in contrast to RUX, treatment with MMB may have the capacity to attenuate ferritin elevation in a manner that corresponds to achievement of TI-R. The mechanistic explanation for these observations requires further investigation. These data additionally suggest serum ferritin may become an important biomarker to help inform therapy selection in the front line as well as potentially guide the transition to MMB in the post-RUX setting. This association should be examined prospectively in future MMB trials.
Figure 1 Figure 1.

Disclosures
Oh: Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Celgene Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Membership on an entity's Board of Directors or advisory committees; PharamaEssentia: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees. Gerds: PharmaEssentia Corporation: Consultancy; CTI BioPharma: Research Funding; Sierra Oncology: Consultancy; AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Constellation: Consultancy; Novartis: Consultancy. Mesa: CTI: Research Funding; Pharma: Consultancy; Incyte Corporation: Consultancy, Research Funding; Abbvie: Research Funding; AOP: Consultancy; Constellation Pharmaceuticals: Consultancy, Research Funding; Samus: Research Funding; Celgene: Research Funding; Gilead: Research Funding; Promedior: Research Funding; La Jolla Pharma: Consultancy; Sierra Oncology: Consultancy, Research Funding; CTI: Research Funding; Novartis: Consultancy; Genentech: Research Funding. Gupta: Pfizer: Consultancy; Roche: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation Pharma: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding. Huang: Sierra Oncology: Current Employment; BioMarin: Ended employment in the past 24 months. Ro: Sierra Oncology: Current Employment; BeiGene: Ended employment in the past 24 months. Strouse: Sierra Oncology: Current Employment. Klencke: Sierra Oncology: Current Employment, Current equity holder in publicly-traded company. Verstovsek: Blueprint Medicines Corp: Research Funding; Roche: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; Ital Pharma: Research Funding; Protagonist Therapeutics: Research Funding; Incyte Corporation: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Sierra Oncology: Consultancy, Research Funding; Promedior: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.