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The chronic 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:
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.[3,4,5] 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.[6,7,8,9,10,11] Researchers are pursuing specific targeting of this aberrant protein as well as new targets based on next-generation sequencing of the genome. 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.[13,14,15]
Leukemic transformation from Philadelphia chromosome–negative myeloproliferative neoplasms is defined as having 20% or greater myeloblasts in the blood or marrow (MPN-blast phase) and having no standard approach and a poor prognosis (3- to 5-month median survival). Allogeneic stem cell transplantation has resulted in anecdotal long-term survivors, but this approach is often not feasible in older patients with comorbid conditions or lack of initial response to leukemic induction therapy.
Refer to the PDQ summary on Chronic Myelogenous Leukemia Treatment for more information.
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.
Other confirmatory findings no longer required for diagnosis include the following:[2,3,4]
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.[6,7,8] Age older than 65 years, leukocytosis, and a history of vascular events (bleeding or thrombosis) are associated with a poor prognosis.[6,9,10]
The primary therapy for p. vera includes intermittent, chronic phlebotomy to maintain the hematocrit below 45%; this recommendation was confirmed in a randomized, prospective trial, which demonstrated lower rates of cardiovascular death and major thrombosis using this hematocrit target.[11,12] 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:
(Refer to the PDQ summary on Oral Complications of Chemotherapy and Head/Neck Radiation for more information.)
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.[2,16,17]
Patients who required therapy with hydroxyurea but had either an inadequate response or unacceptable side effects were randomly assigned to receive ruxolitinib or standard therapy (interferon, chlorambucil, or busulfan). Ruxolitinib provided better control of hematocrit (60% vs. 20%, P < .001), reduction of spleen volume (38% vs. 1%, P < .001) and reduction of symptom score by 50% (49% vs. 5%, P < .001).[Level of evidence: 1iiDiv]
Patients with p. vera and no splenomegaly in whom hydroxyurea failed were studied in a randomized prospective trial of 173 participants. Patients were randomly assigned to receive ruxolitinib (the JAK2 inhibitor) versus best available therapy (such as interferon, higher doses of hydroxyurea, or no treatment). Hematocrit control was achieved in 62% of ruxolitinib-treated patients versus 19% of controls (hazard ratio, 7.28; 95% confidence interval [CI], 3.43‒15.45, P < .001).[Level of evidence: 1iiDiv]
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, 0.03–1.14). A retrospective review of 105 patients who underwent surgery documented that 8% of them had thromboembolisms and 7% of them had major hemorrhages with previous cytoreduction by phlebotomy and postoperative subcutaneous heparin in one half of the patients.
Guidelines based on anecdotal reports have been developed for the management of pregnant patients with p. vera.
Treatment options include the following:
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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:
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.[6,7]
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:
(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.
The median survival is 3.5 years to 5.5 years, but patients younger than 55 years have a median survival of 11 years.[6,7] The major causes of death include the following:
Fatal and nonfatal thrombosis was associated with age older 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.
Prognostic factors include the following:[16,17,18,19,20]
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.[21,22] International prognostic scoring systems incorporate the aforementioned prognostic factors.[21,23]
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.[15,24]
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:[7,25,26,27]
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 (5 years in COMFORT-I and in COMFORT-II) showed a survival benefit (statistically significant only for COMFORT-I) among ruxolitinib-treated patients compared with control patients (COMFORT-I hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.50–0.96, P = .025; and COMFORT-II HR, 0.67; 95% CI, 0.44–1.02, P = .06).[38,39][Level of evidence: 1iiA] Clinical benefits were observed across a wide variety of clinical subgroups.[40,41] Discontinuation of ruxolitinib results in a rapid worsening of splenomegaly and the recurrence of systemic symptoms.[36,37,42] Ruxolitinib does not reverse bone marrow fibrosis or induce histologic or cytogenetic remissions. Aggressive B-cell lymphomas have occurred among patients treated with ruxolitinib when a preexisting clonal B-cell population was identified at diagnosis in conjunction with myelofibrosis.
Painful splenomegaly can be treated temporarily with ruxolitinib, hydroxyurea, thalidomide, lenalidomide, cladribine, or radiation therapy, but sometimes requires splenectomy.[27,44,45] 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).[7,44]
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.[49,50] Favorable responses to thalidomide and lenalidomide have been reported in about 20% to 60% of patients.[25,26,27,51,52,53][Level of evidence: 3iiiDiv]
A more aggressive approach involves allogeneic peripheral stem cell or bone marrow transplantation when a suitable donor is available.[54,55,56,57,58,59] 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.[57,60] Detection of the JAK2 mutation after transplantation is associated with a worse prognosis.
The proposed revised World Health Organization (WHO) criteria for the diagnosis of essential thrombocythemia requires the following criteria:
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.[2,3,4] Patients with prefibrotic primary myelofibrosis may also have a higher tendency to bleed, which can be exacerbated by low-dose aspirin.
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.[2,13,14,15] Similar to the other myeloproliferative syndromes, conversion to acute leukemia is found in a small percentage of patients (<10%) with long-term follow-up.
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.
These 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. Unlike results for p. vera or myelofibrosis, ruxolitinib was not helpful for patients resistant to hydroxyurea.
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.[27,28]
CNL is a rare chronic myeloproliferative neoplasm of unknown etiology, characterized by sustained peripheral blood neutrophilia (>25 × 109 /L) and hepatosplenomegaly.[1,2] The bone marrow is hypercellular. No significant dysplasia is in any of the cell lineages, and bone marrow fibrosis is uncommon.[1,2] 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).[1,3,4,5] 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.[6,7,8] 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:[1,2]
No single or specific cytogenetic or molecular genetic abnormality has been identified in CEL.
(Refer to the PDQ summaries on Hot Flashes and Night Sweats; Fatigue; Cardiopulmonary Syndromes; Cancer Pain; Pruritus; and Gastrointestinal Complications for information on many of the symptoms listed above.)
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.[3,4]
Treatment of HES has included the following:[5,6]
Case reports suggest symptomatic responses to imatinib mesylate for patients with HES who have not responded to conventional options.[6,7,8][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.[6,9][Level of evidence: 3iiiDiv] HES with the FIP1L1-PDGFR alpha fusion tyrosine kinase translocation has been shown to respond to low-dose imatinib mesylate.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Added ruxolitinib as a treatment option.
This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic myeloproliferative neoplasms. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
Board members review recently published articles each month to determine whether an article should:
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Levels of Evidence
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PDQ® Adult Treatment Editorial Board. PDQ Chronic Myeloproliferative Neoplasms Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/myeloproliferative/hp/chronic-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389291]
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Last Revised: 2019-09-12
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