The Chronic Myeloproliferative Neoplasms (MPN) consist of chronic myelogenous leukemia, polycythemia vera (p. vera), primary myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, and chronic eosinophilic leukemia. All of these disorders involve dysregulation at the multipotent hematopoietic stem cell (CD34), with one or more of the following shared features:
• Overproduction of one or several blood elements with dominance of a transformed clone.
• Hypercellular marrow/marrow fibrosis.
• Cytogenetic abnormalities.
• Thrombotic and/or hemorrhagic diatheses.
• Extramedullary hematopoiesis (liver/spleen).
• Transformation to acute leukemia.
• Overlapping clinical features.
Chronic MPN usually occur sporadically; however, familial clusters of MPN have been reported. These familial clusters include autosomal-dominant inheritance and autosomal-recessive inheritance.
Patients with p. vera and essential thrombocythemia have marked increases of red blood cell and platelet production, respectively. Treatment is directed at reducing the excessive numbers of blood cells. Both p. vera and essential thrombocythemia can develop a spent phase late in their courses that resembles primary myelofibrosis with cytopenias and marrow hypoplasia and fibrosis.
A specific point mutation in one copy of the Janus kinase 2 gene (JAK2), a cytoplasmic tyrosine kinase, on chromosome 9, which causes increased proliferation and survival of hematopoietic precursors in vitro, has been identified in most patients with p. vera, essential thrombocythemia, and idiopathic myelofibrosis. Researchers are pursuing specific targeting of this aberrant protein.
Other somatic activating mutations have been identified, including the myeloproliferative leukemia (MPL) exon 10 and the calreticulin (CALR) gene in patients with essential thrombocythemia and primary myelofibrosis.
The proposed revised World Health Organization criteria for the diagnosis of polycythemia vera (p. vera) requires two major criteria and one minor criterion or the first major criterion together with two minor criteria.
1.Hemoglobin of more than 18.5 g/dL in men, 16.5 g/dL in women, or elevated red cell mass greater than 25% above mean normal predicted value.
2.Presence of JAK2 V617F or other functionally similar mutations, such as the exon 12 mutation of JAK2.
1. Bone marrow biopsy showing hypercellularity with prominent erythroid, granulocytic, and megakaryocytic proliferation.
2. Serum erythropoietin level below normal range.
3. Endogenous erythroid colony formation in vitro.
Other confirmatory findings no longer required for diagnosis include the following:
• Oxygen saturation with arterial blood gas greater than 92%.
• Thrombocytosis (>400,000 platelets/mm3).
• Leukocytosis (>12,000/mm3).
• Leukocyte alkaline phosphatase (>100 units in the absence of fever or infection).
There is no staging system for this disease.
Patients have an increased risk of cardiovascular and thrombotic events and transformation to acute myelogenous leukemia or primary myelofibrosis. Age older than 65 years, leukocytosis, and a history of vascular events (bleeding or thrombosis) are associated with a poor prognosis.
The primary therapy for p. vera includes intermittent, chronic phlebotomy to maintain the hematocrit below 45%, and this recommendation has been confirmed in a randomized, prospective trial, which demonstrated lower rates of cardiovascular death and major thrombosis using this hematocrit target. The target level for women may need to be lower (e.g., hematocrit <40%), but there are no empiric data to confirm this recommendation.
Complications of phlebotomy include the following:
• Progressive and sometimes extreme thrombocytosis and symptomatology related to chronic iron deficiency, including pica, angular stomatitis, and glossitis.
• Dysphagia that is the result of esophageal webs (very rare).
• Possibly muscle weakness.
In addition, progressive splenomegaly or pruritus not controllable by antihistamines may persist despite control of the hematocrit by phlebotomy. (Refer to the PDQ summary on Pruritus for more information.) If phlebotomy becomes impractical, hydroxyurea or interferon-alpha can be added to control the disease.
The Polycythemia Vera Study Group randomly assigned more than 400 patients to phlebotomy (target hematocrit <45), radioisotope phosphorous 32 (32P) (2.7 mg/m2 administered intravenously every 12 weeks as needed), or chlorambucil (10 mg administered by mouth daily for 6 weeks, then given daily on alternate months).
The median survival for the phlebotomy group (13.9 years) and the radioisotope 32P group (11.8 years) was significantly better than that of the chlorambucil group (8.9 years), primarily because of excessive late deaths from leukemia or other hematologic malignancies.[Level of evidence: 1iiA] Because of these concerns, many clinicians use hydroxyurea for patients who require cytoreductive therapy that is caused by massive splenomegaly, a high phlebotomy requirement, or excessive thrombocytosis.
In a pooled analysis of 16 different trials, interferon-alpha therapy resulted in avoidance of phlebotomy in 50% of patients, with 80% of patients experiencing marked reduction of splenomegaly.[Level of evidence: 3iiiDiv] Interferon posed problems of cost, side effects, and parenteral route of administration, but no cases of acute leukemia were seen in this analysis. When patients are poorly compliant with phlebotomy or issues of massive splenomegaly, leukocytosis, or thrombocytosis supervene, treatment with interferon or pegylated interferon is considered for patients younger than 50 years (who are more likely to tolerate the side effects and benefit from a lack of transformation to leukemia), while hydroxyurea is considered for patients older than 50 years.
In a Cochrane review of two randomized studies of 630 patients with no clear indication or contraindication for aspirin, those receiving 100 mg of aspirin versus placebo had reduction of fatal thrombotic events, but this benefit was not statistically significant (odds ratio, 0.20; 95% CI, .03–1.14). A retrospective review of 105 patients who underwent surgery documented 8% thromboembolism and 7% major hemorrhage with prior cytoreduction by phlebotomy and postoperative subcutaneous heparin in one half of the patients.
Treatment options include the following:
2. Hydroxyurea (alone or with phlebotomy).
3. Interferon-alpha and pegylated interferon-alpha.
4. Rarely, chlorambucil or busulfan may be required, especially if interferon or hydroxyurea are not tolerated, as is often seen in patients older than 70 years.
5. Low-dose aspirin (≤100 mg) daily, unless contraindicated by major bleeding or gastric intolerance.
Guidelines based on anecdotal reports have been developed for the management of pregnant patients with p. vera.
(McMullin MF, Bareford D, Campbell P, et al.: Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol 130 (2): 174-95, 2005. [PUBMED Abstract]) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=16029446&dopt=Abstract
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, the myeloproliferative leukemia (MPL) mutation, or the calreticulin (CALR) gene mutation (identifying 70% of patients).
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.
Most patients are older than 60 years at diagnosis, and 33% of patients are asymptomatic at presentation. Splenomegaly, sometimes massive, is a characteristic finding.
Symptoms include the following:
• Splenic pain.
• Early satiety.
• Bone pain.
• Night sweats.
• Weight loss.
(Refer to the PDQ summaries on Cancer Pain; Fatigue; Hot Flashes and Night Sweats; and Nutrition for information on many of the symptoms listed above.)
The proposed World Health Organization criteria for the diagnosis of primary myelofibrosis requires all three major criteria and two minor criteria.
1. 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).
2. Not meeting criteria for polycythemia vera (p. vera), CML, myelodysplastic syndrome, or other myeloid neoplasm.
3. Demonstration of JAK2 V617F 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. More than half of the patients without JAK2 or MPL carry a somatic mutation of the CALR gene, which is associated with a more indolent clinical course than is seen with JAK2 or MPL mutations.
2.Increased serum level of lactate dehydrogenase.
The median survival is 3.5 years to 5.5 years, but patients younger than 55 years have a median survival of 11 years. The major causes of death include the following:
• 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 V617F 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.
Prognostic factors include the following:
• 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. International prognostic scoring systems incorporate the aforementioned prognostic factors.
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.
Asymptomatic low-risk patients (based on the aforementioned prognostic systems) should be monitored 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:
• 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.
• Prednisone (40–80 mg/day).
• Danazol (600 mg/day).
• Thalidomide (50 mg/day) with or without prednisone. Patients on thalidomide require prophylaxis for avoiding thrombosis and careful monitoring for hematologic toxicity.
• Lenalidomide (10 mg/day) with or without prednisone. In the presence of del(5q), lenalidomide with or without prednisone, can reverse anemia and splenomegaly in most patients. 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).[Level of evidence: 1iiA] Clinical benefits were observed across a wide variety of clinical subgroups. Discontinuation of ruxolitinib results in a rapid worsening of splenomegaly and the recurrence of systemic symptoms. Ruxolitinib does not reverse bone marrow fibrosis or induce histologic or cytogenetic remissions. More selective JAK inhibitors are currently being evaluated in clinical trials.
Painful splenomegaly can be treated temporarily with ruxolitinib, hydroxyurea, thalidomide, lenalidomide, cladribine, or radiation therapy, but sometimes requires splenectomy. 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).
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. Favorable responses to thalidomide and lenalidomide have been reported in about 20% to 60% of patients.[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. 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. Detection of the JAK2 mutation after transplantation is associated with a worse prognosis.
Treatment options include the following:
2. Clinical trials involving other JAK2 inhibitors.
4. Allogeneic peripheral stem cell or bone marrow transplantation.
9. Splenic radiation therapy or radiation to sites of symptomatic extramedullary hematopoiesis (e.g., large lymph nodes, cord compression).
The proposed revised World Health Organization (WHO) criteria for the diagnosis of essential thrombocythemia requires the following criteria:
1. Sustained platelet count of at least 450 × 109/L.
2. Bone marrow biopsy showing predominant proliferation of enlarged mature megakaryocytes; no significant increase of granulocytic or erythroid precursors. This finding distinguishes essential thrombocythemia from another entity with thrombocytosis, namely prefibrotic primary myelofibrosis, which is identified by increased granulocytic or erythroid precursors, atypical megakaryocytes, and increased bone marrow cellularity.
Patients with prefibrotic primary myelofibrosis have a worse survival than patients with essential thrombocythemia because of an increased progression to myelofibrosis and increased progression to acute myelogenous leukemia. Patients with prefibrotic primary myelofibrosis may also have a higher tendency to bleed, which can be exacerbated by low-dose aspirin.
3. Not meeting criteria for polycythemia vera (p. vera), primary myelofibrosis, chronic myelogenous leukemia, myelodysplastic syndrome, or other myeloid neoplasm.
4. Demonstration of JAK2 V617F mutation or myeloproliferative leukemia (MPL) exon 10 mutation. In the absence of a clonal marker, there must be no evidence for reactive thrombocytosis. In particular, with a decreased serum ferritin, there must be no increase in hemoglobin level to p. vera range with iron replacement therapy. In the presence of a JAK2 or MPL mutation and exclusion of other myeloproliferative or myelodysplastic features, a bone marrow aspirate/biopsy may not be mandatory for a diagnosis. About 60% of patients with essential thrombocythemia carry a JAK2 mutation, and about 5% to 10% of the patients have activating mutations in the thrombopoietin receptor gene, MPL. About 70% of the patients without JAK2 or MPL carry a somatic mutation of the CALR gene, which is associated with a more indolent clinical course than is seen with JAK2 or MPL mutations.
Patients older than 60 years or those with a previous thrombotic episode or with leukocytosis have as much as a 25% chance of developing cerebral, cardiac, or peripheral arterial thromboses and, less often, a chance of developing a pulmonary embolism or deep venous thrombosis. Similar to the other myeloproliferative syndromes, conversion to acute leukemia is found in a small percentage of patients (<10%) with long-term follow-up.
There is no staging system for this disease.
Untreated essential thrombocythemia means that a patient is newly diagnosed and has had no previous treatment except supportive care.
Controversy is considerable regarding whether asymptomatic patients with essential thrombocythemia require treatment. In a case-controlled, observational study of 65 low-risk patients (age <60 years, platelet count <1,500 × 109/L, and no history of thrombosis or hemorrhage) with a median follow-up of 4.1 years, the thrombotic risk of 1.91 cases per 100 patient years and hemorrhagic risk of 1.12 cases per 100 patient years was not increased any more than in the normal controls.
1. A randomized trial of patients with essential thrombocythemia and a high risk of thrombosis compared treatment with hydroxyurea titrated to attain a platelet count below 600,000/mm3 with a control group that received no therapy. Hydroxyurea was found to be effective in preventing thrombotic episodes (4% vs. 24%).[Level of evidence: 1iiDiv] A retrospective analysis of this trial found that antiplatelet drugs had no significant influence on the outcome. Resistance to hydroxyurea is defined as a platelet count of greater than 600,000/μL after 3 months of at least 2 g per day of hydroxyurea or a platelet count greater than 400,000/µL and a white blood count of less than 2,500/µL or a hemoglobin less than 10 g/dL at any dose of hydroxyurea.
2. A prospective, randomized trial in the United Kingdom (UK) of 809 patients compared hydroxyurea plus aspirin with anagrelide plus aspirin. Although the platelet-lowering effect was equivalent, the anagrelide group had significantly more thrombotic and hemorrhagic events (hazard ratio [HR], 1.57; P = .03) and more myelofibrosis (HR, 2.92; P = .01). No differences were seen for subsequent myelodysplasia or acute leukemia in this trial.[Level of evidence: 1iiD]
3. Another prospective, randomized trial also compared hydroxyurea and anagrelide in 259 previously untreated and high-risk patients. In this central European trial, the diagnosis of essential thrombocythemia was made by the WHO recommendations, not by the Polycythemia Vera Study Group criteria as in the UK study. This means that patients with leukocytosis and a diagnosis of early prefibrotic myelofibrosis (both groups with much higher rates of thrombosis) were excluded from the central European trial. In this analysis, there were no differences in outcome for thrombotic or hemorrhagic events.[Level of evidence: 1iiD]
These three randomized, prospective trials establish the efficacy and safety for the use of hydroxyurea for patients with high-risk essential thrombocythemia (age >60 years + platelet count >1,000 × 109/L or >1,500 × 109/L). For patients diagnosed by WHO standards (excluding patients with leukocytosis and prefibrotic myelofibrosis by bone marrow biopsy), anagrelide represents a reasonable alternative therapy. The addition of aspirin to cytoreductive therapies like hydroxyurea or anagrelide remains controversial, but a retrospective anecdotal report suggested reduction in thrombosis for patients older than 60 years.
Many clinicians use hydroxyurea or platelet apheresis prior to elective surgery to reduce the platelet count and to prevent postoperative thromboembolism. No prospective or randomized trials document the value of this approach.
Among low-risk patients (defined as age ≤60 years with no prior thrombotic episodes), a retrospective review of 300 patients showed benefit for antiplatelet agents in reducing venous thrombosis in JAK2-positive cases and in reducing arterial thrombosis in patients with cardiovascular risk factors. Balancing the risks and benefits of aspirin for low-risk patients can be difficult. In an extrapolation of the data from trials of p. vera, low-dose aspirin to prevent vascular events has been suggested, but there are no data from clinical trials to address this issue.
Treatment options include the following:
1. No treatment, unless complications develop, if patients are asymptomatic, younger than 60 years, and have a platelet count of less than 1,500 × 109/L.
3. Interferon-alpha or pegylated interferon-alpha.
CNL is a rare chronic myeloproliferative neoplasm of unknown etiology, characterized by sustained peripheral blood neutrophilia (>25 × 109/L) and hepatosplenomegaly.
The bone marrow is hypercellular. No significant dysplasia is in any of the cell lineages, and bone marrow fibrosis is uncommon.
Cytogenetic studies are normal in nearly 90% of the patients. In the remaining patients, clonal karyotypic abnormalities may include +8, +9, del (20q) and del (11q). There is no Philadelphia chromosome or BCR/ABL fusion gene.
CNL is a slowly progressive disorder, and the survival of patients is variable, ranging from 6 months to more than 20 years.
Until the last few years, the treatment of CNL focused on disease control rather than cure.
Once the disease progressed to a more aggressive leukemia, there was typically little chance of obtaining a long-lasting remission because of the older age of most patients as well as the acquisition of multiple poor prognostic cytogenetic abnormalities.
Allogeneic bone marrow transplantation represents a potentially curative treatment modality in the management of this disorder.
Varying success has been reported with the use of traditional chemotherapies including hydroxyurea and interferon.
CEL is a chronic myeloproliferative neoplasm of unknown etiology in which a clonal proliferation of eosinophilic precursors results in persistently increased numbers of eosinophils in the blood, bone marrow, and peripheral tissues.
In CEL, the eosinophil count is greater than or equal to 1.5 × 109/L in the blood.
To make a diagnosis of CEL, there should be evidence for clonality of the eosinophils or an increase in blasts in the blood or bone marrow.
In many cases, however, it is impossible to prove clonality of the eosinophils, in which case, if there is no increase in blast cells, the diagnosis of idiopathic hypereosinophilic syndrome (HES) is preferred.
Because of the difficulty in distinguishing CEL from HES, the true incidence of these diseases is unknown, although they are rare.
In about 10% of patients, eosinophilia is detected incidentally. In others, the constitutional symptoms found include the following:
• Muscle pains.
No single or specific cytogenetic or molecular genetic abnormality has been identified in CEL.
The optimal treatment of CEL remains uncertain, partially on account of the rare incidence of this chronic myeloproliferative neoplasm and the variable clinical course, which can range from cases with decades of stable disease to cases with rapid progression to acute leukemia.
Case reports suggest that treatment options include bone marrow transplantation and interferon-alpha.
Treatment of HES has included the following:
• Chemotherapeutic agents such as hydroxyurea, cyclophosphamide, and vincristine.
Case reports suggest symptomatic responses to imatinib mesylate for patients with HES who have not responded to conventional options.[Level of evidence: 3iiiDiv]
Imatinib mesylate acts as an inhibitor of a novel fusion tyrosine kinase, FIP1L1-PDGFR alpha fusion tyrosine kinase, which results as a consequence of interstitial chromosomal deletion.[Level of evidence: 3iiiDiv]
HES with the FIP1L1-PDGFR alpha fusion tyrosine kinase translocation has been shown to respond to low-dose imatinib mesylate.