Myelofibrosis, Primary

Essentials of Diagnosis

• Striking splenomegaly

• Teardrop poikilocytosis on peripheral smear

• Leukoerythroblastic blood picture; giant abnormal platelets

• Initially, hypercellular bone marrow, then hypocellular bone marrow with reticulin or collagen fibrosis

General Considerations

• Primary myelofibrosis is a myeloproliferative disorder characterized by clonal hematopoiesis that is often but not always accompanied by JAK2, CALR or MPL mutations, bone marrow fibrosis, anemia, splenomegaly, and a leukoerythroblastic peripheral blood picture with teardrop poikilocytosis

• A myeloproliferative disorder, also known as myelofibrosis with myeloid metaplasia, agnogenic myeloid metaplasia, and idiopathic myelofibrosis

• Can also occur as a secondary process following other myeloproliferative disorders (see Polycythemia Vera and Essential Thrombocytosis)

• It is believed that bone marrow fibrosis occurs in response to increased secretion of platelet-derived growth factor (PDGF) and possibly other cytokines

• In response to the bone marrow fibrosis, extramedullary hematopoiesis takes place in the liver, spleen, and lymph nodes

• Abnormalities of JAK2 and MPL are involved in the pathogenesis

Symptoms and Signs

• Onset is usually insidious

• Develops in adults over age 50 years

• Most common presentations

  • Fatigue due to anemia

  • Abdominal fullness related to splenomegaly

• Uncommon presentations

  • Bleeding

  • Bone pain

• Splenomegaly

  • Almost invariably present

  • Commonly massive

• Liver is enlarged in > 50% of cases

• Later in the course of the disease

  • Splenomegaly may result in early satiety

  • Splenic infarction may occur

  • Progressive bone marrow failure takes place as it becomes increasingly more fibrotic

  • Progressive thrombocytopenia leads to bleeding

  • 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

Differential Diagnosis

• Severe infection, inflammation, or infiltrative bone marrow processes

• Metastatic carcinoma, Hodgkin lymphoma, and hairy cell leukemia

• Chronic myeloid leukemia (CML)

• Polycythemia vera

• Essential thrombocytosis

Laboratory Findings

• Anemia

• White blood count

  • Variable—either low, normal, or elevated

  • May be increased to 50,000/mcL

• Platelet count is variable

• Peripheral blood smear is dramatic, with significant poikilocytosis and numerous teardrop forms in the red cell line

• Nucleated red blood cells are present and the myeloid series is shifted, with immature forms including a small percentage of promyelocytes or myeloblasts

• Platelet morphology may be bizarre, and giant degranulated platelet forms (megakaryocyte fragments) may be seen

• The triad of teardrop poikilocytosis, leukoerythroblastic blood, and giant abnormal platelets is highly suggestive of myelofibrosis

• Bone marrow usually cannot be aspirated (dry tap), though early in the course of the disease it is hypercellular, with a marked increase in megakaryocytes

• Fibrosis at this stage is detected by a silver stain demonstrating increased reticulin fibers; later, marrow biopsy reveals more severe fibrosis, with eventual replacement of hematopoietic precursors by collagen

• There is no characteristic chromosomal abnormality

• JAK2 is mutated in ~65% of cases, and MPL and CALR are mutated in the majority of the remaining cases; 10% of cases are "triple-negative"

Medications

• Androgens, prednisone, and thalidomide can control anemia

• Lenalidomide and pomalidomide result in control of anemia in 25% and thrombocytopenia in ~58% of cases, without significant reduction in splenic size

• Hydroxyurea

  • Dosage: 500–1000 mg/day orally

  • First-line therapy for primary myelofibrosis–associated splenomegaly

  • Effective in reducing spleen size by half in about 40% of patients

• Both thalidomide and lenalidomide may improve splenomegaly and thrombocytopenia in some patients

• Lenalidomide and pomalidomide

  • Immunomodulatory medications

  • Result in control of anemia in 25% and thrombocytopenia in ~58% of cases

  • However, there is no significant reduction in splenic size

• Ruxolitinib

  • A JAK2 inhibitor

  • Reduces spleen size and improves constitutional symptoms

  • However, does not induce complete clinical or cytogenetic remissions or significantly affect JAK2/CALR/MPL mutant allele burden

  • May lead to an overall survival benefit in patients with intermediate- or high-risk disease

  • Can exacerbate cytopenias

• Fedratinib

  • Newer selective JAK2 inhibitor

  • Can lead to sustained reduction in spleen size and improvement in disease-associated symptoms for patients with advanced stage myelofibrosis

  • However, it carries a significant risk of serious and fatal encephalopathy, including Wernicke encephalopathy

  • Providers should regularly assess thiamine levels in all patients

Therapeutic Procedures

• 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

• Splenectomy

  • Not routinely performed

  • Indications include drug-refractory splenic enlargement causing recurrent painful episodes, severe thrombocytopenia, or an unacceptable transfusion requirement

• 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

• The only potentially curative option is allogeneic stem cell transplantation

Complications

• Perioperative complications can occur in 28% of the patients and include infections, abdominal vein thrombosis, and bleeding

Prognosis

• Median survival from time of diagnosis is ~5 years

• The Dynamic International Prognostic Scoring System is associated with overall survival

• Therapies with biologic agents and the application of reduced-intensity allogeneic stem cell transplantation appear to offer the possibility of improving the outcome for many patients

• End-stage myelofibrosis is characterized by generalized asthenia, liver failure, and bleeding from thrombocytopenia, with some cases terminating in acute myeloid leukemia

When to Refer

• Patients should be referred to a hematologist

When to Admit

• Admission is not usually necessary