Myelofibrosis is a rare blood cancer in which scar tissue gradually replaces the spongy interior of your bone marrow, the factory where blood cells are made. As scarring progresses, your bone marrow loses its ability to produce healthy red blood cells, white blood cells, and platelets. This forces blood cell production to shift to other organs, particularly the spleen and liver, causing them to enlarge. Myelofibrosis affects roughly 1 to 2 people per 100,000 each year, with a median age at diagnosis of 68.
How Bone Marrow Scarring Develops
Myelofibrosis begins when a single blood-forming stem cell in the bone marrow acquires a genetic mutation and starts multiplying out of control. These abnormal cells flood the bone marrow with an excess of signaling molecules, including growth factors that stimulate the production of fibrous tissue. Over time, dense webs of scar tissue (reticulin and collagen fibers) accumulate, crowding out normal blood-producing cells and steadily worsening blood counts.
The key signaling pathway involved is called JAK-STAT, a communication system that tells blood stem cells when to grow, divide, and mature. In myelofibrosis, mutations lock this pathway into an “always on” position, making cells hypersensitive to growth signals. The result is unchecked cell proliferation and a chronic inflammatory state that drives the scarring forward.
The Genetic Mutations Behind It
About 60 to 65% of people with myelofibrosis carry a mutation in the JAK2 gene, specifically a change known as V617F. Another 20 to 25% have a mutation in CALR, and about 5% have a mutation in MPL. All three mutations activate the same JAK-STAT signaling pathway, just through slightly different mechanisms. The remaining patients, sometimes called “triple-negative” because they lack all three driver mutations, often carry mutations in other genes involved in regulating how DNA is read and repaired.
These mutations are almost always acquired during a person’s lifetime rather than inherited. Having one doesn’t guarantee myelofibrosis will develop, but when it does, identifying which mutation is present helps doctors predict how the disease will behave and choose treatment.
Primary vs. Secondary Myelofibrosis
When myelofibrosis arises on its own, it’s called primary myelofibrosis. But roughly a third of cases develop as a complication of two other blood cancers: polycythemia vera (which overproduces red blood cells) and essential thrombocythemia (which overproduces platelets). These secondary forms are referred to as post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. The transformation typically happens 7 to 20 years after the original diagnosis.
Regardless of origin, all forms of myelofibrosis share the same core features: progressive bone marrow scarring, declining blood counts, enlarged spleen, and debilitating symptoms. The distinction matters mainly because the starting point and disease trajectory can differ, which affects prognosis and treatment decisions.
Symptoms and How They Feel
Many people with early-stage myelofibrosis have no symptoms at all and are diagnosed through routine blood tests that show abnormal counts. As the disease progresses, symptoms fall into two broad categories: those caused by low blood counts and those caused by an enlarged spleen.
Anemia, or low red blood cell counts, is the most common problem. It causes persistent fatigue, weakness, and shortness of breath during everyday activities. Some people also develop low platelet counts, leading to easy bruising or bleeding, while others have abnormally high white blood cell counts early on before counts eventually drop.
The spleen, forced to take over blood cell production from the failing bone marrow, can swell dramatically. In one study, 85% of patients with an enlarged spleen reported pain or discomfort under the left rib cage, compared to 37% of those without spleen enlargement. Early satiety, the feeling of being full after eating only a small amount, affected 79% of patients with spleen enlargement versus 47% without. Night sweats, unintentional weight loss, fevers, and bone pain round out what doctors call “constitutional symptoms,” and they can be profoundly disruptive to daily life.
How Myelofibrosis Is Diagnosed
Diagnosis requires a bone marrow biopsy, a procedure where a small sample of bone and marrow is taken, usually from the hip bone. Pathologists examine the sample under a microscope looking for two hallmarks: abnormal-looking platelet-producing cells (megakaryocytes) and the degree of scarring. In early-stage disease, called pre-fibrotic myelofibrosis, scarring is minimal. In overt myelofibrosis, significant reticulin or collagen fibrosis is present.
Beyond the biopsy, diagnosis requires genetic testing for JAK2, CALR, or MPL mutations, or evidence of another clonal marker. Doctors also need to rule out other blood cancers that can look similar. At least one additional finding must be confirmed on two separate occasions: anemia, an elevated white blood cell count above 11,000 per microliter, a palpable spleen, elevated lactate dehydrogenase (an enzyme that rises with cell turnover), or the presence of immature red and white blood cells circulating in the bloodstream.
Predicting How the Disease Will Progress
Not everyone with myelofibrosis follows the same course. Some people live for many years with manageable symptoms, while others progress more rapidly. Doctors use scoring systems to estimate prognosis and guide treatment intensity. The most widely used is DIPSS Plus, which evaluates age over 65, hemoglobin below 10 g/dL, white blood cell count above 25,000, circulating immature blast cells, constitutional symptoms, platelet count below 100,000, unfavorable chromosomal changes, and transfusion dependence.
Based on these factors, patients are categorized into low, intermediate-1, intermediate-2, or high-risk groups. The risk category directly influences whether aggressive treatment like a stem cell transplant is recommended or whether a watch-and-wait approach with symptom management makes more sense.
Treatment With JAK Inhibitors
Four JAK inhibitor medications are currently approved by the FDA for myelofibrosis, and they represent the backbone of treatment. These oral drugs work by dialing down the overactive JAK-STAT signaling that drives the disease. They are particularly effective at shrinking the spleen and relieving constitutional symptoms like night sweats, weight loss, and fatigue.
Ruxolitinib, approved in 2011, was the first and remains the most widely used. It’s indicated for both higher-risk patients and lower-risk patients with a high symptom burden. Fedratinib, approved in 2019, provides an option for patients who don’t respond to or can’t tolerate ruxolitinib. Pacritinib, approved in 2022, fills an important niche for patients with very low platelet counts (below 50,000), a group that can’t safely take the other JAK inhibitors because those drugs further suppress platelet production. Momelotinib, the newest option approved in 2023, specifically targets anemia in addition to spleen and symptom control.
What makes momelotinib unique is that it blocks a protein involved in iron regulation in the liver. In myelofibrosis, the body inappropriately restricts iron availability, worsening anemia. By suppressing this signal, momelotinib frees up iron, raises hemoglobin levels, and can reduce or eliminate the need for blood transfusions. This is particularly valuable because ruxolitinib and fedratinib can actually worsen anemia as a side effect of how they work.
JAK inhibitors do not cure myelofibrosis. They control symptoms and improve quality of life, but the underlying bone marrow scarring generally persists.
Managing Anemia
Anemia is one of the most challenging aspects of myelofibrosis because it worsens over time and some treatments make it worse. Beyond momelotinib, several other approaches are used. Erythropoiesis-stimulating agents, which mimic the hormone that tells your body to make red blood cells, help some patients. Danazol, a synthetic hormone, produces anemia improvement in about 30% of patients, though responses typically last around five months and are less effective in people who already depend on transfusions.
Low-dose immunomodulatory drugs can reduce the need for transfusions without further suppressing blood counts. For many patients, regular red blood cell transfusions remain a necessary part of care, particularly as the disease advances.
Stem Cell Transplant as a Potential Cure
The only treatment that can potentially cure myelofibrosis is an allogeneic stem cell transplant, where a donor’s healthy stem cells replace the patient’s diseased bone marrow. Current guidelines recommend considering transplant for patients with intermediate or high-risk disease who are under 70. That said, age alone isn’t an automatic disqualifier. The number of transplants performed in patients 70 and older is steadily increasing as transplant techniques improve, and clinicians increasingly weigh overall fitness rather than a strict age cutoff.
Transplant carries significant risks, including graft-versus-host disease (where donor cells attack the recipient’s body), infections, and organ damage. Because of these risks, it’s generally reserved for patients whose disease is progressing and whose life expectancy without transplant is limited. For younger, otherwise healthy patients with aggressive disease, the potential for cure outweighs these risks. For older patients or those with lower-risk disease, the safer approach is usually long-term management with JAK inhibitors and supportive care.
Risk of Transformation to Acute Leukemia
One of the most serious concerns with myelofibrosis is the possibility that it transforms into acute myeloid leukemia, an aggressive blood cancer that is much harder to treat. This transformation occurs in a significant minority of patients and is more likely in those with high-risk genetic features. Monitoring for rising blast cells in the blood and bone marrow is a routine part of follow-up care, and a rising blast count is one of the signals that can prompt discussion about stem cell transplant timing.