Primary myelofibrosis

Primary myelofibrosis is a myeloproliferative disorder char­acterized by clonal hematopoiesis that is often but not always accompanied by JAK2, CALR, or MPL mutation; bone mar­row fibrosis; anemia; splenomegaly; and a leukoerythroblas­tic peripheral blood picture with teardrop poikilocytosis. Myelofibrosis can also occur as a secondary process follow­ing the other myeloproliferative disorders (eg, polycythemia vera, essential thrombocytosis). It is believed that fibrosis occurs in response to increased secretion of platelet-derived growth factor (PDGF) and possibly other cytokines.

“Primary myelofibrosis (PMF) is a rare bone marrow disorder that is characterized by abnormalities in blood cell production (hematopoiesis) and scarring (formation of fibrous tissue) within the bone marrow. Bone marrow is the soft, spongy tissue that fills the center of most bones. Bone marrow contains specialized cells called hematopoietic stem cells that grow and eventually develop into one of the three main types of blood cells: red blood cells, white blood cells or platelets. In primary myelofibrosis, a change in the DNA of a single hematopoietic stem cell causes the abnormal cell to continually reproduce itself. Eventually, these abnormal cells crowd out normal, healthy cells in the marrow and, along with scarring within the marrow, disrupt the production of red and white blood cells and platelets

In response to bone marrow fibrosis, extramedullary hemato­poiesis takes place in the liver, spleen, and lymph nodes. In these sites, mesenchymal cells responsible for fetal hemato­poiesis can be reactivated.

According to the 2016 WHO classification, “prefibrotic” primary myelofibrosis is distin­guished from “overtly fibrotic” primary myelofibrosis; the former might mimic essential thrombocytosis in its presen­tation and it is prognostically relevant to distinguish the two.

Signs and symptoms

Primary myelofibrosis develops in adults over age 50 years and is usually insidious in onset. Patients most commonly present with fatigue due to anemia or abdominal fullness related to splenomegaly. Uncommon presentations include bleeding and bone pain. On examination, splenomegaly is almost invariably present and is commonly massive. The liver is enlarged in more than 50% of cases.

Later in the course of the disease, progressive bone marrow failure takes place as it becomes increasingly more fibrotic. Progressive thrombocytopenia leads to bleeding. The spleen continues to enlarge, which leads to early sati­ety. Painful episodes of splenic infarction may occur. The patient becomes cachectic and may experience severe bone pain, especially in the upper legs. Hematopoiesis in the liver leads to portal hypertension with ascites, esophageal varices, and occasionally transverse myelitis caused by myelopoiesis in the epidural space.

Treatment

Observation with supportive care is a reasonable treat­ment strategy for asymptomatic patients with low or inter­mediate-1 Dynamic International Prognostic Scoring system (DIPSS)-plus risk disease, especially in the absence of high-risk mutations. Anemic patients are supported with transfusion.

Anemia can also be controlled with androgens, prednisone, thalidomide, or lenalidomide. First-line therapy for myelofibrosis-associated spleno­megaly is hydroxyurea 500–1000 mg/day orally, which is effective in reducing spleen size by half in approximately 40% of patients. Both thalidomide and lenalidomide may improve splenomegaly and thrombocytopenia in some patients.

Splenectomy is not routinely performed but is indicated for medication-refractory splenic enlargement causing recurrent painful episodes, severe thrombocyto­penia, or an unacceptable transfusion requirement. Peri­operative complications can occur in 28% of patients and include infections, abdominal vein thrombosis, and bleeding. Radiation therapy has a role for painful sites of extramedullary hematopoiesis, pulmonary hypertension, or severe bone pain.

Transjugular intrahepatic portosys­temic shunt might also be considered to alleviate symp­toms of portal hypertension.

Patients with DIPSS-plus high or intermediate-2 risk disease, or those patients harboring high-risk mutations such as ASXL1 or SRSF2, should be considered for alloge­neic stem cell transplant, which is currently the only potentially curative treatment modality in this disease. Nontransplant candidates may be treated with JAK2 inhibitors or immunomodulatory agents for symptom control.

Ruxolitinib, the first JAK2 inhibitor to be FDA approved, results in reduction of spleen size and improve­ment of constitutional symptoms, but does not induce complete clinical or cytogenetic remissions or signifi­cantly affect JAK2/CALR/MPL mutant allele burden. Moreover, ruxolitinib can exacerbate cytopenias.

The immunomodulatory medications lenalidomide and pomalidomide result in control of anemia in 25% and thrombocytopenia in ~58% of cases, without significant reduction in splenic size.