Myelofibrosis (MF) is a chronic blood cancer characterized by the accumulation of scar tissue within the bone marrow, the soft tissue responsible for creating blood cells. This fibrotic process disrupts the body’s ability to produce normal red blood cells, white blood cells, and platelets. The body attempts to compensate by making blood cells in other organs, such as the spleen and liver, leading to their enlargement. Treatment for myelofibrosis is highly personalized, focusing on the patient’s individual disease characteristics, symptoms, and overall risk profile. The management strategy ranges from careful observation to systemic drug therapies aimed at controlling the disease and its complications, and in select cases, a potentially curative procedure.
Determining the Treatment Path
The initial step in managing myelofibrosis involves a thorough assessment of the disease’s aggressiveness and the patient’s expected survival. This process, known as risk stratification, is fundamental in determining whether to simply observe the patient or initiate active intervention. Physicians use validated scoring systems to categorize patients, integrating laboratory values, patient age, and genetic markers.
The Dynamic International Prognostic Scoring System (DIPSS-plus) and the newer Mutation-Enhanced International Prognostic Score System (MIPSS70) are commonly employed tools. These systems assign points for factors like advanced age, low hemoglobin levels, high white blood cell counts, the presence of circulating blasts, and specific high-risk gene mutations such as ASXL1.
Patients classified as low-risk or intermediate-1 who are experiencing minimal symptoms often receive a recommendation for “watchful waiting” or active surveillance. This approach avoids unnecessary treatment side effects while monitoring for disease progression. Conversely, patients who fall into the intermediate-2 or high-risk categories, particularly those with a predicted survival of five years or less, require prompt therapeutic intervention to control the disease, manage symptoms, and potentially alter the long-term course of their condition.
Targeted Disease-Modifying Therapies
Systemic drug therapies are the standard of care for most symptomatic patients who are not immediate candidates for a curative procedure. The primary goal of these agents is to modify the underlying disease process, most notably by reducing the size of the enlarged spleen (splenomegaly) and alleviating debilitating constitutional symptoms. These symptoms, which include drenching night sweats, fevers, itching (pruritus), and unintentional weight loss, are often driven by excessive inflammatory signaling molecules called cytokines.
The central class of drugs used for this purpose is the Janus Kinase (JAK) inhibitors, which target the overactive signaling pathway responsible for driving myelofibrosis. Ruxolitinib works by selectively inhibiting JAK1 and JAK2, leading to a profound reduction in cytokine levels and often significant shrinkage of the spleen and improvement in patient-reported symptoms.
Other approved JAK inhibitors offer alternative options, particularly for patients who have not responded adequately to or cannot tolerate ruxolitinib.
Alternative JAK Inhibitors
Fedratinib is a potent inhibitor of JAK2 and FLT3, commonly used for intermediate-2 or high-risk patients who have failed prior ruxolitinib treatment. Pacritinib is uniquely suited for patients with very low platelet counts (severe thrombocytopenia), as it demonstrates efficacy without causing further significant platelet suppression. Momelotinib is distinct because it also inhibits Activin A receptor type 1 (ACVR1), which helps regulate iron metabolism, offering the dual benefit of symptom control and improved anemia. Older, non-JAK-inhibitor therapies like hydroxyurea or pegylated interferon may still be used for patients with low-risk disease or specific blood count issues.
Managing Anemia and Symptomatic Complications
While systemic therapies target the core disease, specific supportive treatments are often necessary to manage the major complications of myelofibrosis, particularly anemia. Anemia, a low red blood cell count, causes severe fatigue and weakness, often requiring regular blood transfusions. The need for frequent transfusions significantly impacts a patient’s quality of life and is an independent poor prognostic factor.
Management of anemia begins with addressing nutritional deficiencies and often includes the use of erythropoiesis-stimulating agents (ESAs). ESAs are synthetic versions of a hormone that prompts the bone marrow to produce more red blood cells, but they are generally only effective in a subset of patients with relatively low natural erythropoietin levels. For other patients, anabolic steroids like danazol may be utilized to help increase hemoglobin levels.
Newer pharmacologic agents are becoming available to target anemia more effectively. Luspatercept, an erythroid maturation agent, works by regulating the late stages of red blood cell production and has shown promise in reducing transfusion dependence. Furthermore, the selection of a JAK inhibitor like momelotinib can directly address anemia due to its unique mechanism of action on iron regulation. Beyond anemia, non-drug methods are sometimes needed to relieve pressure and discomfort from an extremely enlarged spleen, including localized splenic radiation or, less commonly, a surgical splenectomy.
The Curative Approach: Allogeneic Stem Cell Transplant
Allogeneic Hematopoietic Stem Cell Transplantation (ASCT) is the only currently available treatment with the potential to cure myelofibrosis. This procedure involves replacing the patient’s diseased blood-forming stem cells with healthy stem cells from a matched donor. Because of the inherent risks, ASCT is generally reserved for younger patients, typically under the age of 70, who have high-risk disease features or who have failed prior systemic therapies.
The decision to proceed with ASCT is complex, balancing the potential for cure against the significant risks of the procedure itself. The main complications include non-relapse mortality, which is the risk of death from the transplant itself, and graft-versus-host disease (GvHD). GvHD occurs when the donor’s immune cells recognize the patient’s body as foreign and attack various organs, which can range from mild to life-threatening.
Patient selection is guided by prognostic scores and overall physical condition, with candidates ideally having a good performance status and an expected survival of less than five years without the transplant. Finding a suitable donor, such as a matched sibling or an unrelated donor from a registry, is an absolute prerequisite. If a patient has a significantly enlarged spleen, it may be reduced in size with JAK inhibitors or removed surgically prior to the transplant to improve outcomes. Post-transplant, patients require careful monitoring for signs of relapse or GvHD.