At a Glance

Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (CMPN) characterized by a clonal proliferation of granulocytes and megakaryocytes and a propensity to develop marked fibrosis of the bone marrow. At early stages, patients present with leukocytosis and/or thrombocytosis, but most cases typically proceed to pancytopenia or even acute myeloid leukemia in 5-30% of patients.

In pre-fibrotic PMF, patients typically present with mild anemia, mild granulocytosis, and thrombocytosis. Splenomegaly is present in 10-20% at this stage of the disease. Night sweats, weight loss, and fever are reported by a minority of patients. In fact, in some studies, as many as 30% of patients are asymptomatic at presentation and are diagnosed as a consequence of routine blood work.

In fibrotic PMF, patients may present with a leukoerythroblastic peripheral smear that shows circulating nucleated red cells, markedly left-shifted myeloid elements, and teardrop red cells. There may even be a small percentage of myeloblasts in the peripheral blood. At this stage of the disease, patients often present with symptoms of bone marrow failure (fatigue, bleeding, and infections), as well as splenomegaly.

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What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Bone marrow biopsy with reticulin staining for fibrosis is essential in the diagnosis of PMF. Although fibrosis is the hallmark of fibrotic-phase PMF, it is not specific. The morphology of megakaryocytes in PMF is important in distinguishing PMF from other CMPN that can also present with fibrosis. PMF megakaryocytes are typically clustered and often show dark chromatin, bizarre nuclear lobation (hypolobation, “cloud-like” nuclei) with a wide range of sizes from small, naked megakaryocytes with hyperchromatic chromatin to large megakaryocytes with bulbous nuclei.

JAK2 mutation testing is recommended in diagnosing any of the CMPN. Approximately 50% of PMF cases have the JAK2V617F mutation, which can also be seen in most cases of polycythemia vera (PV) and in nearly 50% of essential thrombocythemia (ET).

Karyotype analysis is important in the diagnosis of PMF. As approximately one-half of all PMF cases are negative for JAK2 abnormalities, karyotypic abnormalities help confirm clonal hematopoiesis. Common cytogenetic changes in PMF include del(13q) and trisomy 9. Of note, these changes are not specific for PMF but support a diagnosis if other factors are present. Importantly, the presenting symptoms of chronic myelogenous leukemia (CML) with fibrosis can be similar to the presenting symptoms of PMF. If there is any suspicion for CML, fluorescence in situ hybridization (FISH) for the BCRABL rearrangement should be performed.

2008 World Health Organization (WHO) Diagnostic Criteria (3 Majors and 2 minors required)
Major Criteria

  • Megakaryocytic proliferation with characteristic atypia and fibrosis OR, in the absence of fibrosis, hypercellularity with atypical megakaryocytes and decreased erythropoiesis

  • Does not meet criteria for PV, CML, myelodysplasia (MDS), or other CMPN

  • Jak2 V617F or exon 12 mutation OR morphologic changes are primary

Minor criteria

  • Leukoerythroblastic smear

  • Increased Lactate Dehydrogenase (LDH)

  • Anemia

  • Splenomegaly

What Other Diseases Should Be Considered and How Do I Distinguish Between Them?

There can be significant overlap between prefibrotic PMF and any of the other CMPN. Key in the distinction is the lack of BCRABL rearrangement as detected by FISH. The presence of JAK2V617F is not specific for PMF but does help classify the disease as a CMPN.

ET and prefibrotic PMF can both present with markedly increased platelets, mild anemia, and mild leukocytosis, although PMF is more likely to present with a leukocytosis. PMF can be distinguished from ET in the bone marrow biopsy. PMF bone marrow typically shows hypercellularity, which is rare in ET bone marrows. PMF also shows myeloid hyperplasia and left-shifting, clustered megakaryocytes with atypical morphology, and, even in early stage, is more likely to show WHO grade 1 of 3 fibrosis.

PV typically presents with an increased hematocrit and hemoglobin. There is typically a panmyelosis in the bone marrow biopsy as opposed to a myeloid hyperplasia and megakaryocytic hyperplasia, as is seen in PMF.

CML with fibrosis must be excluded before a diagnosis of PMF is made, as the clinical presentation can be very similar. FISH for BCRABL is typically sufficient to diagnose CML.

Finally, the morphology of PMF megakaryocytes is distinct from both the large, multilobated megakaryocytes of ET and from the normal appearing megakaryocytes of PV and from the small, hypolobated megakaryocytes of CML. PMF megakaryocytes are often clustered and can range from large to small in size. The nuclear to cytoplasmic ratio is often increased, and the chromatin can be hyperchromatic or atypically clumped. The nucleus is atypically lobated with “cloud-like” or balloon shaped nuclei common. “Naked megakaryocytes” with hyperchromatic chromatin, bulbous nuclei, and very scant cytoplasm are common.

What Lab Results Are Absolutely Confirmatory?

There is no single lab result that is absolutely confirmatory for PMF. The diagnosis relies on the demonstration of characteristic bone marrow morphology in the presence of JAK2 mutation or other cytogenetic abnormalities (trisomy 9 or del(13q)). MDS, CML, and other CMPN must be excluded using karyotype, FISH, and bone marrow morphology.

What Confirmatory Tests Should I Request for My Clinical Dx? In addition, what follow-up tests might be useful?

JAK2V617F testing and bone marrow biopsy are central in establishing the diagnosis once FISH demonstrates there is no BCRABL fusion. Because PMF has a higher rate of transformation to AML than any other BCRABL-negative CMPN, regular follow-up with bone marrow biopsy is important. Even in cases that do not show transformation to acute myeloid leukemia (AML), survival in PMF patients is significantly shorter than that of PV and ET patients. The morbidity and mortality in PMF patients derives from their increased propensity for hemorrhage, anemia, and infection, as well as their increased rate of progression to AML.

What Is the Prognosis?

PMF patients have a worse prognosis than other BCRABL-negative CMPN patients. Transformation to AML occurs in 5-30% of patients, depending on the series. Hemorrhage and infection are also responsible for significant morbidity and mortality. In most studies, the mean survival of PMF patients is typically 30-50% shorter than that of ET or PV patients, on the order of 10 years versus 15-20 years.

International Prognostic Scoring System (IPSS) risk stratification is based on age, white blood cell (WBC), Hct, circulating blasts, constitutional symptoms, and has been modified to include platelet count, transfusion dependence, and karyotypic abnormalities by the International Working Group on Myeloproliferative Neoplasia. Increasing risk group stratification is strongly associated with shorter mean survival and, therefore, demands more aggressive therapy. Low-risk patients can be managed with observation and symptomatic therapy and graduate to androgens or thalidomide/lenalidomide and prednisone for anemia and hydroxyurea for splenomegaly. As risk increases, more aggressive therapy with experimental drugs or allogeneic transplantation may be indicated.

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