Primary myelofibrosis (also known as agnogenic myeloid metaplasia, chronic idiopathic myelofibrosis, myelosclerosis with myeloid metaplasia, and idiopathic myelofibrosis) is characterized by splenomegaly, immature peripheral blood granulocytes and erythrocytes, and teardrop-shaped red blood cells. In its early phase, the disease is characterized by elevated numbers of CD34-positive cells in the marrow, while the later phases involve marrow fibrosis with decreasing CD34 cells in the marrow and a corresponding increase in splenic and liver engorgement with CD34 cells.
As distinguished from chronic myelogenous leukemia (CML), primary myelofibrosis usually presents as follows:
- A white blood cell count smaller than 30,000/mm3.
- Prominent teardrops on peripheral smear.
- Normocellular or hypocellular marrow with moderate to marked fibrosis.
- An absence of the Philadelphia chromosome or the BCR/ABL translocation.
- Frequent positivity for the JAK2 mutation.
In addition to the clonal proliferation of a multipotent hematopoietic progenitor cell, an event common to all chronic myeloproliferative neoplasms, myeloid metaplasia is characterized by colonization of extramedullary sites such as the spleen or liver.[3,4]
Most patients are older than 60 years at diagnosis, and 33% of patients are asymptomatic at presentation. Splenomegaly, sometimes massive, is a characteristic finding.
- Splenic pain.
- Early satiety.
- Bone pain.
- Night sweats.
- Weight loss.
The proposed World Health Organization criteria for the diagnosis of primary myelofibrosis requires all three major criteria and two minor criteria.
- Presence of megakaryocyte proliferation and atypia, usually accompanied by either reticulin and/or collagen fibrosis; or, in the absence of significant reticulin fibrosis, the megakaryocyte changes must be accompanied by increased bone marrow cellularity characterized by granulocytic proliferation and often decreased erythropoiesis (so-called prefibrotic cellular-phase disease).
- Not meeting criteria for polycythemia vera (p. vera), CML, myelodysplastic syndrome, or other myeloid neoplasm.
- Demonstration of JAK2 617V greater than F or other clonal marker; or, in the absence of a clonal marker, no evidence of bone marrow fibrosis caused by an underlying inflammatory disease or another neoplastic disease. About 60% of patients with primary myelofibrosis carry a JAK2 mutation, and about 5% to 10% of the patients have activating mutations in the thrombopoietin receptor gene, MPL. Almost 90% of the patients without JAK2 or MPL carry a somatic mutation of the calreticulin gene, which is associated with a more indolent clinical course than is seen with JAK2 or MPL mutations.[6,7]
- Increased serum level of lactate dehydrogenase.
- Palpable splenomegaly.
- Progressive marrow failure.
- Transformation to acute nonlymphoblastic leukemia.
- Thrombohemorrhagic events.
- Heart failure.
- Portal hypertension.
Fatal and nonfatal thrombosis was associated with age more than 60 years and JAK2 617V positivity in a multivariable analysis of 707 patients followed from 1973 to 2008. Bone marrow examination including cytogenetic testing may exclude other causes of myelophthisis, such as CML, myelodysplastic syndrome, metastatic cancer, lymphomas, and plasma cell disorders. In acute myelofibrosis, patients present with pancytopenia but no splenomegaly or peripheral blood myelophthisis. Peripheral blood or marrow monocytosis is suggestive for myelodysplasia in this setting.
There is no staging system for this disease.
- Age 65 years or older.
- Anemia (hemoglobin <10 g/dL).
- Constitutional symptoms: fever, night sweats, or weight loss.
- Leukocytosis (white blood cell count >25 × 109/L).
- Circulating blasts of at least 1%.
Patients without any of the adverse features, excluding age, have a median survival of more than 10 to 15 years, but the presence of any two of the adverse features lowers the median survival to less than 4 years.[15,16] International prognostic scoring systems incorporate the aforementioned prognostic factors.[15,17]
Karyotype abnormalities can also affect prognosis. In a retrospective series, the 13q and 20q deletions and trisomy 9 correlated with improved survival and no leukemia transformation in comparison with the worse prognosis with trisomy 8, complex karyotype, -7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement.[9,18]
Asymptomatic low-risk patients (based on the aforementioned prognostic systems) should be followed with a watchful waiting approach. The development of symptomatic anemia, marked leukocytosis, drenching night sweats, weight loss, fever, or symptomatic splenomegaly would warrant therapeutic intervention.
The profound anemia that develops in this disease usually requires red blood cell transfusion. Red blood cell survival is markedly decreased in some patients; this can sometimes be treated with glucocorticoids. Disease-associated anemia may occasionally respond to the following:[4,19-21]
- Erythropoietic growth factors. Erythropoietin and darbepoetin are less likely to help when patients are transfusion dependent or manifest a serum erythropoietin level greater than 125 U/L.[22,23]
- Prednisone (40–80 mg/day).
- Danazol (600 mg/day).
- Thalidomide (50 mg/day) ± prednisone. Patients on thalidomide require prophylaxis for avoiding thrombosis and careful monitoring for hematologic toxicity.
- Lenalidomide (10 mg/day) ± prednisone.[25-27] In the presence of del(5q), lenalidomide with or without prednisone, can reverse anemia and splenomegaly in most patients.[25-27] However, patients on lenalidomide require prophylaxis for avoiding thrombosis and careful monitoring for hematologic toxicity.
- Pomalidomide. Patients on pomalidomide require prophylaxis for avoiding thrombosis and careful monitoring for hematologic toxicity.
Ruxolitinib, an inhibitor of JAK1 and JAK2, can reduce the splenomegaly and debilitating symptoms of weight loss, fatigue, and night sweats for patients with JAK2-positive or JAK2-negative primary myelofibrosis, post–essential thrombocythemia myelofibrosis, or post–p. vera myelofibrosis.
In two prospective, randomized trials, 528 higher-risk patients were randomly assigned to ruxolitinib or to either placebo (COMFORT-I [NCT00952289]) or best available therapy (COMFORT-II [NCT00934544]). At 48 weeks, patients on ruxolitinib had a decrease of 30% to 40% in mean spleen volume compared with an increase of 7% to 8% in the control patients.[Level of evidence: 1iiDiv]; [Level of evidence: 1iDiv] Ruxolitinib also improved overall quality-of-life measures, with low toxic effects in both studies, but with no benefit in overall survival in the initial reports. Additional follow-up in both studies (1 year in COMFORT-I and 2 years in COMFORT-II) showed a survival benefit among ruxolitinib-treated patients compared with control patients (COMFORT-I hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.36–0.95; and COMFORT-II HR, 0.48; 95% CI, 0.28–0.85).[32,33][Level of evidence: 1iiA] Clinical benefits were observed across a wide variety of clinical subgroups.[34,35] Discontinuation of ruxolitinib results in a rapid worsening of splenomegaly and the recurrence of systemic symptoms.[30,31,36] Ruxolitinib does not reverse bone marrow fibrosis or induce histologic or cytogenetic remissions. More selective JAK inhibitors are currently being evaluated in clinical trials.[37,38]
Painful splenomegaly can be treated temporarily with ruxolitinib, hydroxyurea, thalidomide, lenalidomide, cladribine, or radiation therapy, but sometimes requires splenectomy.[21,39,40] The decision to perform splenectomy represents a weighing of the benefits (i.e., reduction of symptoms, decreased portal hypertension, and less need for red blood cell transfusions lasting for 1 to 2 years) versus the debits (i.e., postoperative mortality of 10% and morbidity of 30% caused by infection, bleeding, or thrombosis; no benefit for thrombocytopenia; and accelerated progression to the blast-crisis phase that was seen by some investigators but not others).[4,39]
After splenectomy, many physicians use anticoagulation therapy for 4 to 6 weeks to reduce portal vein thrombosis, and hydroxyurea can be utilized to reduce high platelet levels (>1 million). However, data from a retrospective review of 150 patients who underwent surgery provided documentation that 8% of the patients had a thromboembolism and 7% had a major hemorrhage with prior cytoreduction and postoperative subcutaneous heparin used in one-half of the patients.
Hydroxyurea is useful in patients with splenomegaly but may have a potential leukemogenic effect. In patients with thrombocytosis and hepatomegaly after splenectomy, cladribine has shown responses as an alternative to hydroxyurea. The use of interferon-alpha can result in hematologic responses, including reduction in spleen size in 30% to 50% of patients, though many patients do not tolerate this medication.[44,45] Favorable responses to thalidomide and lenalidomide have been reported in about 20% to 60% of patients.[19-21,46-48][Level of evidence: 3iiiDiv]
A response defined as 50% reduction of splenomegaly or development of transfusion independence was attained by one-third of 34 symptomatic patients using tipifarnib.[Level of evidence: 3iiiDiv] A more aggressive approach involves allogeneic peripheral stem cell or bone marrow transplantation when a suitable donor is available.[50-55] Allogeneic stem cell transplantation is the only potentially curative treatment available, but the associated morbidity and mortality limit its use to younger, high-risk patients.[53,56] Detection of the JAK2 mutation after transplantation is associated with a worse prognosis.
- Clinical trials involving other JAK2 inhibitors.
- Allogeneic peripheral stem cell or bone marrow transplantation.[51-55]
- Splenic radiation therapy or radiation to sites of symptomatic extramedullary hematopoiesis (e.g., large lymph nodes, cord compression).
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with primary myelofibrosis. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site.
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