番茄社区

Myelofibrosis remains a rare disease, even though recent attention to the condition might suggest otherwise.

Annual ranged from 0.1 to 1.0 per 100,000. Prevalence has been difficult to measure, with some ranging from 2.5 to 5.7 per 100,000. in the U.S. are thought to be living with myelofibrosis, well below the generally of a rare disease (<200,000).

"I suspect that the incidence is actually higher than what we originally thought, not only because of the aging population, but more so because of increased recognition of the disease," said Aaron Gerds, MD, of the Cleveland Clinic.

The discovery of driver mutations in the JAK/STAT pathway and subsequent development of simple diagnostic tests contributed greatly to the increased recognition and appreciation of myelofibrosis, he continued. Then came the first disease-specific targeted agents -- JAK inhibitors. Ruxolitinib (Jakafi) in 2011 became the first drug specifically for myelofibrosis, which was followed by fedratinib (Inrebic), pacritinib (Vonjo), and momelotinib (Ojjaara).

"When you have a drug to treat a disease, you tend to find the disease more often," said Gerds. "There are a lot of examples of this over history -- BPDCN [blastic plasmacytoid dendritic cell neoplasm], for example. We thought that disease occurred in roughly 50 people a year in the United States. Once we had tagraxofusp (Elzonris) to treat that disease, it seems like it's everywhere."

A search of with the term myelofibrosis in the title shows an explosion of research following the approval of ruxolitinib, with 2,156 citations since 2012, doubling the number from the 12 years prior.

When former U.S. Senator and vice presidential candidate died earlier this year, recognition of myelofibrosis got another boost with the revelation that Lieberman had lived with the disease since 2018. News of a celebrity who has a particular disease often increases awareness of and interest in a disease, said Gary Schiller, MD, of the University of California Los Angeles.

Older age is a risk factor for myelofibrosis, an aging population has more clonal disorders of the bone marrow, but "it's hard to say" how much that has contributed to the increased recognition of myelofibrosis, he added.

Myelofibrosis Origins

Originating in the bone marrow, myelofibrosis is one of three disorders grouped under the broader diagnostic category of (MPNs), the other two being essential thrombocythemia (ET) and polycythemia vera (PV). All three conditions evolve from clonal hematopoietic stem cell disorders associated with JAK mutations and abnormal signaling in the JAK/STAT pathway. In general, MPNs, including myelofibrosis, exhibit considerable with respect to genetics, blood cell counts, presence or absence of dysplastic features and fibrosis, and disease evolution.

In myelofibrosis, bone marrow is , which increasingly constricts the marrow's ability to produce normal blood cells. accounts for 80-90% of all cases. The remaining cases arise from (secondary myelofibrosis), which is indistinguishable from primary myelofibrosis. In about 5-10% of cases, myelofibrosis transforms into .

The similar origins of the MPNs and their heterogeneity underscore the need for diagnostic accuracy.

"We really rely on our hematopathologists to make the diagnosis accurately, and the criteria by which they do so have really tightened," said James Rossetti, DO, of the University of Pittsburgh and Hillman Cancer Center. "If you have somebody who really sees a lot of hematological disease, they can help to make the distinction. Sometimes you can't [make the distinction] and they fall into a category that is unclassifiable MPN."

"Maybe it's a prefibrotic myelofibrosis," he continued, "which has different outcomes associated with it than does, for example, a true polycythemia vera. So the risk of misdiagnosing is that the prognostic model associated with the disease could have significant implications on what treatment you select."

Variety of Symptoms

The is about 65, and diagnosis before age 50 is uncommon. , but can vary depending on disease stage and extent of fibrosis. Survival has improved considerably since the introduction of effective targeted therapies.

Not uncommonly, any of a variety of symptoms associated with myelofibrosis could bring a patient to a primary care provider's clinic for assessment: fatigue, night sweats, changes in appetite, unexplained weight loss, fever, recurrent infections, and easy bruising, among others.

"Some patients have significant bone pain, sort of a deep, nagging pain, often in the long bones and in the areas where the marrow is produced," said Rossetti.

If a clinician orders a complete blood count, anemia will stand out in a patient with myelofibrosis, said Schiller. Anemia in the absence of iron deficiency should at least create suspicion of myelofibrosis, especially in an older patient.

"After anemia, it's a toss up," he said. "Some patients present with all the blood counts low -- leukopenia, anemia, thrombocytopenia. Then there are other patients who present with very high white counts. Another big clue, regardless of the white cell count, is the presence of early white blood cell forms, such as myelocytes, metamyelocytes. Rarely there might be a blast or two and often a basophil and eosinophil predominance, which is something distinct that should catch the eye of a primary care provider right away."

A hallmark clinical manifestation of myelofibrosis is splenomegaly, which reflects (EMH). EMH is associated with abnormal trafficking patterns of clonal hematopoietic cells resulting from dysregulated bone marrow.

"As your spleen enlarges it can cause discomfort in your abdomen and fullness in the stomach as the spleen pushes on the stomach, which lead to early satiety and even weight loss," said Gerds.

An accumulation of evidence pointing to myelofibrosis usually leads to mutation testing. From 50-60% of patients with myelofibrosis have . Another 25-35% have mutations in calreticulin (CALR), and 5-10% have mutations in the myeloproliferative leukemia (MPL) oncogene. As many as 80% patients have one or more other mutations, and some patients have no driver mutations. The presence or absence and the type of mutations have varying prognostic implications.

"Just testing for JAK2 is inadequate," said Rossetti. "We now do what's called myeloid NGS or next-generation sequencing, which looks at a host of potential mutations, which may be targets for treatment downstream, something that is known in other related diseases. We are starting to see hints that certain mutations might respond better to different agents."

Comment