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Anemia is a key driver of fatigue and quality-of-life in patients with myelofibrosis, and has a negative impact on prognosis.

Fatigue is the most frequently reported symptom in patients with myelofibrosis, based on a global myeloproliferative neoplasm landmark survey, and it is also the symptom that patients would most like to have resolved.1 Although patients with myelofibrosis may present with fatigue when they have a normal hemoglobin, anemia is a key driver of fatigue and quality-of-life in patients with myelofibrosis.2 In addition to fatigue, anemia contributes to an increased burden on health care resources (due to the necessity of red blood cell transfusions) and has a negative impact on prognosis (Figure 1).2-7 Abdulraheem Yacoub, MD, Associate Professor of Medicine and Clinical Director of Ambulatory Hematology Clinics at The University of Kansas Cancer Center, Westwood, Kansas, explained that in addition to anemia being one of the minor diagnostic criteria for myelofibrosis,8 “almost all patients with myelofibrosis will develop some degree of anemia during their disease course.” A study conducted in 2018 showed that 86% of patients with newly diagnosed primary myelofibrosis present with hemoglobin below the lower normal limit, with 14% of patients presenting with moderate anemia (hemoglobin ≥ 8 and < 10 g/dL), and 37% of patients presenting with severe anemia (hemoglobin < 8 g/dL or transfusion-dependence).9

Figure 1. Anemia in Myelofibrosis: Key Facts

Multiple models have been proposed to risk-stratify patients with myelofibrosis, guide treatment decisions, and predict the risk of disease progression and death.10 Regardless of which model is used, “it seems to be consistent among all prognostic models that if the patient’s hemoglobin is below 10 g/dL, it definitely is a worse prognostic feature” explained Dr. Yacoub.

Current Treatment Options for Myelofibrosis

Disease risk scoring and presence of symptoms are used to guide treatment selection in patients with myelofibrosis.10 The only curative therapy for myelofibrosis is allogeneic stem cell transplant (allo-HCT). This treatment is associated with high transplantation-related morbidity and mortality; thus, timing and use of this strategy is individualized.10 Patients with higher-risk disease should be evaluated for allo-HCT10,11; however, Srdan Verstovsek, MD, Professor of Medicine at The University of Texas MD Anderson Cancer Center, Houston, Texas, noted that “evaluation for allo-HCT is not usually my first approach; it is usually my last approach.” Asymptomatic patients with lower-risk disease can be managed by observation, and lower-risk patients with symptoms receive therapy directed at managing the symptoms they have.

Dr. Verstovsek explained that the current primary goal of therapy in myelofibrosis is “quality-of-life improvement and elimination of systemic symptoms.” Improving the overall survival is also emerging as the primary or secondary endpoint in clinical trials and is considered the holy grail of treatment for myelofibrosis.12

Disease Management Strategies for Myelofibrosis-Related Anemia

Based on the National Comprehensive Cancer Network (NCCN) Guidelines for myelofibrosis, patients with lower-risk disease whose only symptoms are related to anemia can be managed with erythropoiesis stimulating agents (ESAs) if the serum erythropoietin is < 500 mU/mL.10 Dr. Verstovsek noted that ESA therapy may have better chance of benefitting patients if the erythropoietin level is “< 125 mU/mL, as evidenced in clinical studies.”13,14 The use of ESAs in patients with myelofibrosis is limited due to inefficacy in transfusion-dependent patients and the potential to exacerbate splenomegaly or increase the risk for thrombosis.2,11 Patients who are unlikely to respond to an ESA are typically managed with androgens (eg, danazol) or an immunomodulatory agent (lenalidomide or thalidomide) combined with prednisone.2,11 Dr. Verstovsek noted that “patients who are anemic and do not have general systemic symptoms are not very common; approximately 10% to 15% of patients comprise this cohort. Most of the time, patients have both systemic symptoms or splenomegaly and anemia at the same time.”

Patients who have lower-risk disease with splenomegaly or constitutional symptoms have the option of treatment with ruxolitinib. In patients with myelofibrosis-related anemia, where splenomegaly cannot be managed with approved or investigational treatments, splenectomy may be considered as a last resort. However, splenectomy carries a significant risk of complications in this population.2

Patients with higher-risk myelofibrosis are managed with Janus kinase (JAK) inhibitors.10 Ruxolitinib improves constitutional symptoms, reduces splenomegaly, and improves quality-of-life and overall survival in patients with myelofibrosis.15-20 Fedratinib reduces splenomegaly and symptom burden in patients with myelofibrosis and has shown possible improvement in progression-free survival.21-23 Recent phase III clinical trials showed that pacritinib reduced splenomegaly and symptoms in patients with myelofibrosis and thrombocytopenia (baseline platelet count < 100 × 109/L); the results of the phase III clinical trial PERSIST-2 (ClinicalTrials.gov identifier NCT02055781) led to regulatory approval of pacritinib for patients with platelet counts < 50 × 109/L.24,25

JAK Inhibitors and Anemia

Dr. Yacoub highlighted that “the classic dilemma in myelofibrosis is that many of the active therapies, particularly ruxolitinib, which is a first-line therapy in this disease, can result in significant improvement in constitutional symptoms, splenomegaly, and cachexia, but could result in worsening of anemia.” Grade 3 or higher anemia was observed in 43% of the patients receiving fedratinib in the JAKARTA study and 45% of the patients receiving ruxolitinib in the COMFORT-II study.17,22

A combined analysis of the COMFORT-I and COMFORT-II studies showed that 61% of patients who did not have baseline anemia developed anemia during treatment with ruxolitinib, and 69% patients who had baseline anemia experienced worsening of anemia with ruxolitinib.26 Notably, improved survival associated with ruxolitinib was observed in patients with anemia at baseline and among those without anemia at baseline. In addition, development of new or worsening anemia while on ruxolitinib did not affect overall survival.26 Real-world evidence of ruxolitinib treatment in patients with baseline anemia along with data on ruxolitinib in the COMFORT-II study and fedratinib in the JAKARTA study showed low discontinuation rates (< 1%) of JAK inhibitors due to anemia.17,21,27 In a real-world study, the discontinuation rate of ruxolitinib in myelofibrosis patients with and without baseline anemia was 10.5%.28 While JAK inhibitors may induce or worsen anemia in patients with myelofibrosis, “anemia is not a contraindication for JAK inhibitor use,” emphasized Dr. Verstovsek. He noted that based on his experience, “anemia measurements, after initial worsening, improve after about 4 to 6 months.”

Dr. Yacoub and Dr. Verstovsek agreed that their “clinical experience matches with the published data from the COMFORT studies in which patients who were treated with ruxolitinib experienced significant improvement in symptom burden and quality-of-life despite worsening anemia.” In a post hoc analysis of the COMFORT-II study, compared with best supportive care, patients receiving ruxolitinib experienced improvements in overall quality-of-life and fatigue as early as week 8, despite the high rate of anemia in the trial.29 Dr. Yacoub explained that “we do need to support our patients a lot more closely at the beginning; we need to run lab tests frequently. JAK inhibitors (ruxolitinib, fedratinib) may increase the severity of the anemia and/or certain patients may require transfusions in the short term, but this can be mitigated with supportive care measures as well as red blood cell transfusions.”

JAK inhibitors … may increase the severity of the anemia and/or certain patients may require transfusions in the short term, but this can be mitigated with supportive care measures as well as red blood cell transfusions. Abdulraheem Yacoub, MD

Strategies to manage anemia in patients receiving JAK inhibitors include red blood cell transfusions, addition of an ESA,14 danazol,30,31 luspatercept,32 or an immunomodulatory agent (thalidomide or lenalidomide)33-38 (Figure 2). Dr. Yacoub noted, “Myelofibrosis is a chronic disease. Patients might need and benefit from an ESA; unfortunately, the benefit can be short-lived and then they might need to move on to alternative agents such as danazol, thalidomide, or luspatercept, or other options that become available in the future. Most patients will need more than one therapy in addition to transfusion support.”   Preliminary evidence supports addition of luspatercept (1 mg/kg subcutaneously every 3 weeks, titrated every 6 weeks to a maximum of 1.75 mg/kg every 3 weeks) to ruxolitinib to manage anemia.32 Further evaluation of luspatercept in combination with ruxolitinib is ongoing in the pivotal phase III INDEPENDENCE study in anemic patients with myelofibrosis (NCT04717414). Other strategies to mitigate anemia with ruxolitinib include gradually titrating the dose of ruxolitinib using the REALISE dosing strategy.39 Based on the REALISE dosing strategy, ruxolitinib is administered as 10 mg orally twice daily for 12 weeks. Then, based on platelet counts and efficacy, ruxolitinib may be titrated up to 25 mg twice daily over 8 weeks.

Figure 2. Management of Anemia in Patients Receiving JAK Inhibitors for Myelofibrosis

A Marathon, Not a Sprint

“I always like to explore the therapy for myelofibrosis as a marathon,” explained Dr. Yacoub. “This is not a quick win. Rather, it is a strategic therapy in which you would like to achieve results and then build on them. One strategy is to start with a lower dose of ruxolitinib and allow patients to benefit from that, and then keep challenging them with dose escalation and dose titration over time until we get to the optimum dose and the maximum tolerated dose from which patients can get the most benefit.”

It is safe to say that avoiding or delaying JAK inhibitor therapy due to baseline anemia is unnecessary. Srdan Verstovsek, MD

Dr. Verstovsek underscored that “it is safe to say that avoiding or delaying JAK inhibitor therapy due to baseline anemia is unnecessary.” Patients benefit from and tolerate ruxolitinib with a low discontinuation rate due to anemia. Multiple strategies are available to mitigate anemia in patients with myelofibrosis, though current options have limited efficacy and durability of response. “The future is a lot more promising for patients because there are studies being designed specifically to tackle anemia in myelofibrosis. Patients with myelofibrosis are hopefully going to enjoy the benefit of additional agents in the future once those studies are complete” said Dr. Yacoub.

Disclosure

Dr. Verstovsek has served in a consulting or advisory role for Celgene, Constellation Pharmaceuticals, Incyte, Novartis, and Sierra; and has received research funding from AbbVie, Celgene, Constellation Pharmaceuticals, Galecto Biotech, Geron, Incyte, Kartos Therapeutics, PharmaEssentia, Protagonist Therapeutics, Sierra Oncology, and Telios Pharma.

Dr. Yacoub has served in a consulting or advisory role for AbbVie, Acceleron Pharma, CTI BioPharma Corp, Gilead Sciences, Incyte, Notab, Novartis, Pfizer, Pharmaessentia, and Servier.

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