The categories of myeloproliferative neoplasms (MPN) include:[1]
All of these disorders involve dysregulation at the multipotent hematopoietic stem cell, with one or more of the following shared features:
MPN usually occur sporadically; however, familial clusters of MPN have been reported. These familial clusters include autosomal-dominant inheritance and autosomal-recessive inheritance.[3] Patients with PV and ET have marked increases of red blood cell and platelet production. Treatment is directed at reducing the excessive numbers of blood cells. Both PV and ET can develop a spent phase during their courses that resembles PMF with cytopenias and marrow hypoplasia and fibrosis called post-PV/ET myelofibrosis.[4] A recurrent single nucleotide variant in one copy of the JAK2 gene, a cytoplasmic tyrosine kinase on chromosome 9, has been identified in most patients with PV, ET, and PMF.[5] Other single nucleotide variants were associated with genes encoding calreticulin (CALR) and the thrombopoietin receptor (MPL).[6,7]
There is no standard treatment approach for patients with progression from chronic-phase MPN to accelerated phase (blasts 10% to <20% in the peripheral blood or bone marrow) or blast phase (leukemic transformation, blasts ≥20% in the peripheral blood or bone marrow), and these patients have a poor prognosis (3- to 18-month median survival).[8] Allogeneic hematopoietic cell transplant has resulted in long-term survival, but this approach is often not feasible in older patients with comorbid conditions or lack of initial response to leukemic induction therapy.[9]
For information, see Chronic Myeloid Leukemia Treatment.
To establish a diagnosis of PV, the International Consensus Classification requires that the patient meet either all three major criteria or the first two major criteria with the minor criterion.[1]
Major Criteria
Minor Criterion
There is no staging system for this disease.
Patients have an increased risk of cardiovascular and thrombotic events [2] and leukemic transformation (blast-phase disease) or post-PV myelofibrosis.[3-5] Age older than 67 years, leukocytosis (≥15 × 109/L), a history of thrombosis, and the presence of pathogenic variants (SRSF2) are associated with a poor prognosis.[6]
The primary therapy for PV includes the use of phlebotomy or cytoreductive therapy to maintain the hematocrit below 45%. This approach was confirmed in a randomized prospective trial, which demonstrated lower rates of cardiovascular death and major thrombosis using this hematocrit target.[7]
Complications of phlebotomy include:
In addition, progressive splenomegaly and pruritus not controllable by antihistamines may persist despite control of the hematocrit by phlebotomy. For more information, see Pruritus.
If symptoms persist or phlebotomy is not tolerated, cytoreductive therapy can be added to control the disease.
Guidelines based on anecdotal reports have been developed for the management of pregnant patients with PV.[8]
Treatment options for PV include:
Early retrospective studies in patients with PV suggested a superior median survival with myelosuppressive therapy as opposed to either no treatment or treatment with phlebotomy alone. This observation was countered by concerns regarding the leukemogenicity of cytoreductive therapy. The Polycythemia Vera Study Group (PSVG) found that both chlorambucil and radioisotope phosphorous 32 can have leukemogenic potential and are detrimental to survival, but hydroxyurea does not have these effects.[9] Similarly, the leukemic potential of pipobroman and busulfan has been established.[17,18] The leukemogenic hazards of hydroxyurea are still being debated. In several large studies, no consistent association between exposure to hydroxyurea and leukemic transformation (blast-phase MPN) has been identified.
Evidence (frontline cytoreductive therapy):
Evidence (posthydroxyurea cytoreductive therapy):
No randomized trial has compared ruxolitinib with interferons in patients with PV who have previously received hydroxyurea.
After controlling hematocrit with phlebotomy or cytoreductive therapy, the second principle in treating PV is the use of antiplatelet agents to reduce the risk of thrombosis.
Evidence (antiplatelet therapy):
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To establish a diagnosis of ET, the revised World Health Organization (WHO) classification requires that the patient meet the following criteria:[1]
Patients with prefibrotic PMF have a worse survival than patients with ET because of an increased progression to myelofibrosis or acute myeloid leukemia.[2-4] Patients with prefibrotic PMF may also have a higher tendency to bleed, which can be exacerbated by low-dose aspirin.[5]
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.[2,13-15] Similar to the other myeloproliferative syndromes, conversion to acute leukemia is found in a small percentage of patients (<10%) with long-term follow-up. Patients younger than 40 years have a more indolent course, with fewer thrombotic events or transformation to acute leukemia.[16] A multivariable analysis in several cohorts that included almost 1,500 patients showed worse outcomes for men, with a hazard ratio (HR) of 1.5 (95% confidence interval [CI], 1.1‒2.5).[17]
There is no staging system for this disease.
Categorizing a patient as having untreated ET means that a patient is newly diagnosed and has had no previous treatment except supportive care.
Initiation of therapy for patients with asymptomatic ET is controversial.[18] 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 compared with normal controls.[19]
Treatment options for ET include:
Evidence (hydroxyurea):
These randomized prospective trials establish the efficacy and safety for the use of hydroxyurea for patients with high-risk ET (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.[32] In a phase II study (NCT01259856), 65 patients with ET who required therapy with hydroxyurea and had either an inadequate response or unacceptable side effects received pegylated interferon alfa-2a. The complete response rate was 43% and the partial response rate was 26%, with only a 14% discontinuation rate from side effects. Patients with a CALR variant had a significantly higher complete response rate than patients without a CALR variant (57% vs. 28%).[33][Level of evidence C3] Unlike results for PV or myelofibrosis, ruxolitinib was not helpful for patients resistant to hydroxyurea.[34]
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.[35] Balancing the risks and benefits of aspirin for low-risk patients can be difficult.[36] In an extrapolation of the data from trials of PV, low-dose aspirin to prevent vascular events has been suggested, but there are no data from clinical trials to address this issue.[37,38]
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PMF (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.[1] 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 myeloid leukemia (CML), PMF usually presents as follows:[2]
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. Patients younger than 40 years have a more indolent course, with fewer thrombotic events or transformation to acute leukemia.[8]
Symptoms of PMF include:
For more information about the symptoms listed above, see Fatigue, Hot Flashes and Night Sweats, and Nutrition in Cancer Care.
To establish a diagnosis of PMF, the World Health Organization classification requires that the patient meet all three major criteria and two minor criteria.[9]
Major Criteria
Minor Criteria
The major causes of death include:[13]
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.[16] Bone marrow examination including cytogenetic testing may exclude other causes of myelophthisis, such as CML, myelodysplastic syndrome, metastatic cancer, lymphomas, and plasma cell disorders.[7] 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:[17-21]
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.[22,23] International prognostic scoring systems incorporate the aforementioned prognostic factors.[22,24] Thrombocytopenia (platelet count <50 × 109/L) is a very poor prognostic factor for PMF and for myelofibrosis following thrombocythemia or PV.[25]
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.[16,26]
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 warrants 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:[7,27-29]
Treatment options for PMF include:
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 PMF, post–essential thrombocythemia myelofibrosis, or post-PV myelofibrosis.[55]
Evidence (cytoreductive therapy):
Discontinuation of ruxolitinib results in a rapid worsening of splenomegaly and the recurrence of systemic symptoms.[37-39] Ruxolitinib does not reverse bone marrow fibrosis or induce histological 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.[60]
Painful splenomegaly can be treated temporarily with ruxolitinib, hydroxyurea, thalidomide, lenalidomide, cladribine, or radiation therapy, but sometimes requires splenectomy.[29,50,61] 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).[7,50]
After splenectomy, many physicians use anticoagulation therapy for 4 to 6 weeks to reduce portal vein thrombosis. Hydroxyurea can be used to reduce high platelet levels (>1 million).[62] However, in a retrospective review of 150 patients who underwent surgery, 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.[63]
Hydroxyurea is useful in patients with splenomegaly but may have a leukemogenic effect.[7] In patients with thrombocytosis and hepatomegaly after splenectomy, cladribine may be an alternative to hydroxyurea.[52] The use of interferon alfa may result in hematological responses, including reduction in spleen size in 30% to 50% of patients, though many patients do not tolerate this medication.[53,54] Favorable responses to thalidomide and lenalidomide have been reported in about 20% to 60% of patients.[27-29,47-49][Level of evidence C3]
A more aggressive approach involves allogeneic peripheral stem cell or bone marrow transplant when a suitable donor is available.[41-46] Allogeneic stem cell transplant is the only potentially curative treatment available, but the associated morbidity and mortality limit its use to younger, high-risk patients.[44,64] Detection of a JAK2 variant after transplant is associated with a worse prognosis.[65]
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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 in patients with CNL. 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).[1,3-5] There is no Philadelphia chromosome or BCR::ABL fusion gene. CNL is a slowly progressive disorder, and the survival of patients ranges from 6 months to more than 20 years.
In the past, 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 transplant represents a potentially curative treatment modality for CNL.[6-8] Results vary with the use of traditional chemotherapies including hydroxyurea and interferon.[9]
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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.[1] 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. However, in many cases, 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:[1,2]
No single or specific cytogenetic or molecular genetic abnormality has been identified in CEL.
For more information about the symptoms listed above, see Hot Flashes and Night Sweats, Fatigue, Cardiopulmonary Syndromes, Pruritus, and Gastrointestinal Complications.
CEL is rare, and the optimal treatment remains uncertain. The clinical course 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 transplant and interferon alfa.[3,4]
Treatment of HES has included corticosteroids, chemotherapeutic agents (e.g., hydroxyurea, cyclophosphamide, or vincristine), and interferon alfa.[5,6]
Case reports suggest that patients with HES who have not responded to conventional options may have symptomatic responses to imatinib mesylate.[6-8][Level of evidence C3] Imatinib mesylate acts as an inhibitor of a novel FIP1L1::PDGFRA fusion tyrosine kinase, which results as a consequence of an interstitial chromosomal deletion.[6,9][Level of evidence C3] HES with the FIP1L1::PDGFRA fusion tyrosine kinase translocation has been shown to respond to low-dose imatinib mesylate.[9]
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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.
This summary was renamed from Chronic Myeloproliferative Neoplasms Treatment.
General Information About Myeloproliferative Neoplasms (MPN)
Added Arber et al. as reference 1.
Added Barosi et al. as reference 4.
Revised text to state that there is no standard treatment approach for patients with progression from chronic-phase MPN to accelerated or blast phase, and these patients have a poor prognosis (cited Mudireddy et al. as reference 8).
Treatment of Polycythemia Vera
This section was extensively revised.
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® Cancer Information for Health Professionals pages.
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of myeloproliferative neoplasms. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
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PDQ® Adult Treatment Editorial Board. PDQ Myeloproliferative Neoplasms Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/myeloproliferative/hp/myeloproliferative-neoplasms-treatment. Accessed <MM/DD/YYYY>. [PMID: 26389291]
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