Treating Anemic Patients With Myelofibrosis in the New Janus Kinase Inhibitor Era: Current Evidence and Real-world Implications

Anemia is a prevalent and burdensome clinical manifestation of myelofibrosis (MF) with a complex etiology. Most MF patients are anemic within 1 year of diagnosis, and nearly all become dependent on red blood cell transfusions over time.¹ Anemia is associated with a reduced health-related quality of life (HRQoL) and shortened survival.² Moreover, anemia and transfusion dependence are independent negative prognostic indicators incorporated into standard clinical MF risk scoring systems.³ While specific subsets of patients with MF may derive temporary anemia benefit from androgens (eg, danazol), corticosteroids (eg, prednisone), immunomodulators (eg, pomalidomide), or erythropoiesis-stimulating agents, the vast majority of patients will not achieve a prolonged response.² The Janus kinase inhibitor (JAKi) ruxolitinib has been a decade-long standard of care for patients with intermediate- and high-risk MF due to its efficacy in reducing spleen size and improving disease-related symptoms; however, ruxolitinib is myelosuppressive and associated with dose-dependent worsening of anemia.⁴ More recently, the JAKi fedratinib and pacritinib have each been approved for the treatment of MF, having demonstrated spleen and symptom improvements compared with placebo or best available therapy.^{5, 6} Like ruxolitinib, new-onset or worsening anemia is commonly reported with fedratinib treatment,⁵ whereas pacritinib is relatively nonmyelosuppressive.⁶ Notably, the investigational agent momelotinib is the first and only JAKi to also target the iron regulator activin A receptor type 1/activin receptor-like kinase-2 (ACVR1/ALK2), addressing the unmet need of anemia in MF patients in addition to the traditional treatment goals of JAK inhibition: reducing splenomegaly and symptom burden.²

Due to the lack of comparative information among these expanding treatment options, a systematic literature review and network meta-analysis (NMA) of 7 randomized controlled trials of JAKi in patients with MF (noted in Table 1) by Sureau et al evaluated the relative efficacy and tolerability of treatments, including endpoints of reduced spleen volume and adverse events due to hematologic toxicity, among others.⁷ This NMA demonstrated that ruxolitinib, momelotinib, and fedratinib were comparably efficacious in reducing spleen volume (with ruxolitinib and momelotinib providing significant improvements in achieving ≥35% spleen volume reduction at 24 weeks compared with pacritinib), while momelotinib was associated with significantly less grade 3/4 anemia compared with ruxolitinib, fedratinib, or pacritinib.⁷ However, this analysis did not include real-world studies, examine anemia-related benefits among treatments (such as decreased transfusion need), or evaluate the differential impact of therapies on the HRQoL and economic burden associated with anemia and transfusions in MF.

To address this, we conducted an expanded targeted literature review within the MEDLINE, Embase, Cochrane, NHS Economic Evaluation, and Health Technology Assessment databases to identify articles published between January 2011 and February 2021 reporting treatment outcomes of phase 2 and phase 3 clinical trials and real-world studies in MF in the United States, United Kingdom, France, Germany, Italy, or Spain, with at least 25 patients per arm or cohort. Both approved (ie, ruxolitinib, fedratinib, pacritinib) and investigational (ie, momelotinib, as well as the telomerase inhibitor imetelstat and the transforming growth factor beta trap luspatercept) MF treatments were assessed. A total of 52 publications were identified, including 29 real-world studies and 23 records covering 16 clinical trials (Table 1). No published study of luspatercept met the inclusion criteria.

A detailed review of the 15 clinical trial publications that reported anemia- or transfusion-related outcomes in MF confirmed that momelotinib not only had the lowest grade 3/4 anemia rates among JAKi but also showed the greatest improvement in transfusion independence rates (Table 1). Specifically, reported rates of treatment-emergent grade 3/4 anemia ranged from 6% to 14% for momelotinib, 20% to 42% for ruxolitinib, 38% to 60% for fedratinib, 7% to 27% for pacritinib, and 30% for imetelstat. Overall, the proportion of transfusion-independent patients from baseline to week 24 or end of the treatment period decreased by 13% to 21% for ruxolitinib, decreased by 9% for fedratinib, remained stable with a 1% increase for pacritinib, and ranged from a 2% decrease to a 12% increase for momelotinib. Notably, momelotinib-treated patients experienced a higher rate of transfusion independence at week 24 compared with those treated with ruxolitinib in the head-to-head phase 3 SIMPLIFY-1 trial (66.5% versus 49.3%, nominal P < 0.001) and those treated with best available therapy (88.5% ruxolitinib) in SIMPLIFY-2 (43% versus 21%, nominal P = 0.0012).^{8, 9} Further, momelotinib-treated patients experienced lower rates of transfusion dependence at week 24 than ruxolitinib-treated patients in SIMPLIFY-1 (30.2% versus 40.1%, nominal P = 0.019), where the median rate of transfusion was 0 units/month with momelotinib compared with 0.4 units/months with ruxolitinib (nominal P < 0.001).⁸

Our targeted literature review also identified a growing body of real-world evidence demonstrating the substantial clinical burden associated with anemia and transfusions among patients with MF. Specifically, we identified 29 real-world reports of anemia- and transfusion-related outcomes (Table 1), including 14 studies conducted in the US (9 single-center studies, 3 database analyses, and 2 chart reviews), 14 conducted in Europe (11 multicenter, 2 single-center, and 1 registry study), and 1 conducted globally (multicenter registry study). Rates of anemia and transfusion dependence varied widely across the 24 real-world studies that directly reported it; among these MF populations, 5% to 93.3% of patients were anemic and 7% to 62% were transfusion dependent. Reported rates of ruxolitinib treatment modification due to anemia ranged from 8% to 36%, and rates of ruxolitinib discontinuation due to anemia ranged from 5% to 33%.

Additionally, we identified 5 real-world studies and 1 pooled clinical trial analysis that evaluated the association between anemia and overall survival in patients with MF, which include a range of treatments (Table 2). Among these, 5 of the 6 studies demonstrated an association between anemia and shortened overall survival (univariate hazard ratio range: 1.20–3.28; multivariate hazard ratio range: 1.27–1.92), and a similar trend was observed in the sixth study (Table 2), consistent with the known negative prognostic value of anemia in MF.³

Although the substantial clinical burden associated with anemia and transfusion dependence has been well documented in patients with MF, our review sought to quantify the impact of anemia and transfusions on HRQoL and economic outcomes in this specific patient population. Overall, we found that data from adequately sized MF patient populations is lacking in these areas. An investigation from the Nordic MPN Study Group found that transfusion-dependent patients with MF had significantly worse QoL scores than nontransfusion dependent patients; however, this study did not meet our review inclusion criteria for sample size per cohort, and it did not address economic implications.¹⁰ In patients with myelodysplastic syndromes, myeloid neoplasms with many features in common with MF including anemia, transfusion burden is associated with significant HRQoL and economic burden, with transfusion-dependent patients incurring 53% higher total costs over 2 years.¹¹ Future investigation is needed to quantify the full HRQoL and economic impact attributable to anemia and transfusion dependence in MF to assess the true value of current therapies as well as emerging treatments that have the potential to address all key hallmarks of MF, including anemia, splenomegaly, and symptoms.

Consistent with findings from Sureau et al,⁷ our expanded targeted literature review corroborates the inadequacy of ruxolitinib in addressing the unmet need among anemic patients with MF in real-world clinical practice. Anemic MF patients receiving ruxolitinib may require dose reductions, treatment interruptions, or early treatment discontinuation, which can reduce treatment efficacy, or red blood cell transfusions throughout the course of therapy. Furthermore, nearly 50% of MF patients treated with ruxolitinib require add-on agents to treat anemia, such as androgens, corticosteroids, or erythropoiesis-stimulating agents.¹² Despite the use of supportive measures, the median duration of ruxolitinib treatment in the real-world setting is shorter than in clinical trials.¹³ While the reasons for this short duration of treatment may be multifaceted, evidence suggests that adverse events (including anemia) and loss of treatment response are important contributing factors.¹³

The emergence of treatment options that directly address anemia in addition to the other key hallmarks of MF may lead to improved patient outcomes. Momelotinib inhibition of ACVR1/ALK2 in addition to JAK1 and JAK2 leads to decreased hepcidin, the master regulator of iron metabolism that is elevated in MF patients, and subsequent increased serum iron availability for erythropoiesis.¹⁴ Momelotinib may be a valuable first- or second-line JAKi option for anemic patients with MF, as its ability to reduce rates of anemia and transfusion dependence in addition to spleen volume and symptoms has been demonstrated in phase 3 trials and further confirmed by Sureau et al.⁷ In addition, several combination therapies are in advanced clinical development that have demonstrated clinical activity against anemia and other key hallmarks of MF, including ruxolitinib plus luspatercept, an activin receptor IIB ligand trap/erythroid maturation agent, ruxolitinib plus pelabresib, a bromodomain and extra-terminal protein (BET) inhibitor, and ruxolitinib plus navitoclax, a antiapoptotic B-cell lymphoma protein (BCL-X_L, BCL-2, BCL-w) inhibitor.¹⁵ Studies to address the substantial evidence gap identified in our targeted literature review surrounding quantification of the HRQoL and economic burden of anemia and transfusions in MF will be imperative to assessing therapeutic value among the growing number of currently available and new agents entering the MF treatment landscape.

AUTHOR CONTRIBUTIONS

JS and BK designed the study. JS conducted the search. ATG, PB, GH, AK, LMN, JS, BK, and CH analyzed the data and interpreted the findings. LMN wrote and edited the manuscript with input from ATG, PB, GH, AK, JS, BK, and CH.

DISCLOSURES

Aaron T. Gerds has served as a consultant for Celgene/Bristol Myers Squibb, Pfizer, Kartos Therapeutics, Promedior, and CTI BioPharma; Prithviraj Bose has received research support from Incyte, Bristol Myers Squibb, CTI BioPharma, Constellation/Morphosys, Kartos, Blueprint Medicines, Cogent, Pfizer, Astellas, NS Pharma and Promedior, and honoraria from Incyte, Bristol Myers Squibb, CTI BioPharma, Sierra Oncology, Abbvie, Constellation/Morphosys, Karyopharm, Pharma Essentia, Blueprint Medicines and Novartis; Gabriela S. Hobbs served as a consultant for Celgene/Bristol Myers Squibb, Pfizer, Blueprint Medicines, Incyte, Novartis, Abbvie, Keros and Pharmaxis; Andrew T. Kuykendall has received clinical research funding from Sierra Oncology, Constellation/Morphosys, and Celgene/Bristol Myers Squibb and has served on advisory boards for CTI Biopharma, Novartis, Abbvie, Celgene/Bristol Myers Squibb, Constellation/Morphosys, and Imago Biosciences; Lynn M. Neilson and Barbara Klencke are employees of Sierra Oncology; Jinlin Song is an employee of Analysis Group; and Claire Harrison has received clinical research funding from Novartis, Constellation, and Bristol Myers Squibb, and has served on advisory boards and as a speaker for Novartis, Celgene/Bristol Myers Squibb, CTI BioPharma, Gilead Sciences, Shire, Roche, Janssen, Promedior, Geron, AOP, Galecto, Sierra Oncology, Constellation, and Keros, and is Deputy Editor in Chief of HemaSphere.

SOURCES OF FUNDING

Momelotinib is sponsored by Sierra Oncology. The targeted literature search was performed by Analysis Group, which was sponsored by Sierra Oncology.

DATA AVAILABILITY STATEMENT

All data generated or analyzed during this study are included in this published article.