AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Myeloproliferative diseases (MPDs) are a heterogenous group of disorders characterized by cellular proliferation of one or more hematologic cell lines in the peripheral blood, distinct from acute leukemia.

According to the French-American-British (FAB) classification, chronic myeloproliferative diseases consist of 4 diseases: chronic myelogenous leukemia (CML); polycythemia vera (PV); essential thrombocythemia (ET); and agnogenic myeloid metaplasia (AMM), which is also known as myelofibrosis (MF). In 2002, the World Health Organization (WHO) proposed an alternate classification schema for these diseases, adding chronic neutrophilic leukemia (CNL) and chronic eosinophilic leukemia (CEL)/hypereosinophilic syndrome (HES).¹ For a comparison of these classification systems, see the table below.

A related disorder, systemic mastocytosis (SM), has many features in common with the myeloproliferative diseases and is considered by some authors to belong to this group. In some patients, conditions overlap, and clear categorization may be difficult. Myeloproliferative disease may evolve into one of the other myeloproliferative conditions, transform to acute leukemia, or both.

Comparison of FAB and WHO Classifications of Chronic Myeloproliferative Diseases.

Some evidence indicates that myeloproliferative diseases arise from malignant transformation of a single stem cell. Involvement of erythropoiesis, neutrophilopoiesis, eosinophilopoiesis, basophilopoiesis, monocytopoiesis, and thrombopoiesis occurs in the chronic phase of chronic myelogenous leukemia. Some evidence also indicates that lymphocytes are derived from primordial malignant cells. This is based on observations that a single isoenzyme for glucose-6-phosphate dehydrogenase (G-6-PD) is present in some T and B lymphocytes in women with chronic myelogenous leukemia who are heterozygous for isoenzymes A and B.

See CME available on Chronic Myeloproliferative Disorders and Advances in the Treatment of Chronic Myeloid Leukemia.

Pathophysiology

Data from G-6-PD studies, cytogenetic analyses, and molecular methods have established the clonal origin of myeloproliferative diseases; this clonality potentially occurs at different stem cell levels. An attribute common to these disorders appears to be an acquired activating mutation in the gene coding for various tyrosine kinases.

In chronic myelogenous leukemia, the tyrosine kinase activity of the bcr-abl hybrid gene is increased. In polycythemia vera, essential thrombocythemia, and myelofibrosis, the prevalent genetic lesion appears to be a valine to phenylalanine substitution at amino acid position 617 (V617F) within the Janus kinase 2 (JAK2) gene.^{2, 3} This produces hypersensitivity to erythropoietin. At least in myelofibrosis patients the leukemic transformation is probably not related to JAK-2 (V617F) mutation status.⁴ Systemic mastocytosis has been linked with the D816 mutation of the KIT gene. The FIP1L1-PDGFR mutation has been identified in a subgroup of people with systemic mastocytosis with eosinophilia (SM-eos).

Frequency

United States

Approximately 4300 new cases of chronic myelogenous leukemia are diagnosed in the United States every year, accounting for more than half of myeloproliferative disease cases. The incidence of polycythemia vera in the United States is approximately 5-17 cases per 1 million population per year. True incidences of essential thrombocythemia and myelofibrosis are not known because epidemiological studies on these disorders are inadequate.

International

The incidence of polycythemia vera is 0.02-2.8 per 100,000 per year; Japan has the lowest incidence. Essential thrombocythemia has an incidence of 0.1-1.5 per 100,000 per year. Myelofibrosis has an international incidence of 0.4-0.9 per 100,000 per year.

Mortality/Morbidity

In the United States, 2,400 deaths every year are secondary to chronic myelogenous leukemia. Exact mortality and morbidity rates of other myeloproliferative diseases are unknown.

Race

Chronic myelogenous leukemia appears to affect all races with approximately equal frequency. The incidences of polycythemia vera, essential thrombocythemia, and myelofibrosis were tenfold higher among Ashkenazi Jews in northern Israel than in persons of Arabic descent in the region.

Sex

The female-to-male ratio is 1:1.4.

Age

Most cases encountered in clinical practice are in patients aged 40-60 years. Myeloproliferative diseases are uncommon in people younger than 20 years and are rare in childhood.

CLINICAL

Section 3 of 11  

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History

• Easy fatigability
• Anorexia, weight loss
• Abdominal discomfort and early satiety secondary to splenomegaly is more common in chronic myelogenous leukemia and agnogenic myeloid metaplasia.
• Easy bruising, bleeding, and/or symptoms of thrombosis
• Swollen, painful joint(s) secondary to gouty arthritis secondary to hyperuricemia
• Priapism, tinnitus, or stupor from leukostasis
• Left upper quadrant and left shoulder pain as a consequence of splenic infarction and perisplenitis
• In many patients, abnormal blood counts are noted on a blood test performed for other reasons.

Physical

• Pallor, except in patients with polycythemia vera
• Plethora secondary to polycythemia
• Petechiae and/or ecchymosis
• Palpable spleen and/or liver
• Occasionally, syndrome of fever accompanied by painful maculopapular violaceous lesions on trunk, arms, legs, and face, which is called acute febrile neutrophilic dermatosis or Sweet syndrome

Causes

As with other malignant disorders, the precise cause of myeloproliferative disease is unknown. The etiology is complex, incompletely understood, and likely a multistep process involving more than one gene.

DIFFERENTIALS

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Other Problems to be Considered

Leukemoid reaction

WORKUP

Section 5 of 11  

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• Follow-up
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Lab Studies

• CBC counts and differential counts with microscopic examination of the peripheral smear
• Leukocyte alkaline phosphatase (LAP) score (to differentiate chronic myelogenous leukemia from other causes of leukocytosis)
• Polymerase chain reaction (PCR) or fluorescent in-situ hybridization (FISH) run on peripheral blood can detect bcr-abl gene rearrangement. This helps differentiate chronic myelogenous leukemia from other myeloproliferative diseases.
• Red blood cell mass study (true vs spurious polycythemia)
• Serum uric acid level

Imaging Studies

• Although not routinely required, a liver spleen scan may occasionally be helpful to assess the size of these organs in the diagnosis of difficult cases.

Other Tests

• Molecular test to detect bcr-abl gene when suspicious for chronic myelogenous leukemia and cytogenetically negative for Philadelphia chromosome
• PCR testing on bone marrow for JAK2 is available for suspected cases of polycythemia vera, essential thrombocythemia, or myelofibrosis.

Procedures

• Bone marrow aspiration and biopsy with cytogenetic studies are required in most, but not all, patients. Cytogenetic studies detect presence or absence of the Philadelphia chromosome and help to differentiate these disorders from myelodysplastic syndrome.

Histologic Findings

Bone marrow histology shows hypercellularity in most of these disorders. In the case of myelofibrosis, bone marrow fibrosis is demonstrated on the reticulin stain. Bone marrow fibrosis is also detected in the spent phase of chronic myelogenous leukemia and polycythemia vera.

TREATMENT

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Medical Care

• Treatment of chronic myelogenous leukemia (CML):  
• • Hematopoietic stem cell transplantation can be considered in young patients with chronic myelogenous leukemia in chronic phase if a human leukocyte antigen (HLA)-matched donor is available.
  • Imatinib mesylate (Gleevec), a bcr-abl–specific tyrosine kinase inhibitor, is approved for use in Philadelphia chromosome–positive chronic myelogenous leukemia patients in chronic phase. In one study at 18 months, the complete response rate was 76.2% and the major cytogenetic response rate was 87.1%. Imatinib is also indicated for chronic myelogenous leukemia in blast crisis, accelerated phase, or in chronic phase after interferon alfa therapy failure. This is the treatment of choice for most patients.⁶
  • Interferon alfa, usually administered as a subcutaneous daily injection in a dose of 5 million U, produces hematologic and molecular remissions in some patients with chronic myelogenous leukemia. In these patients, evidence shows that it prolongs survival. Several patients who achieved molecular remissions have survived for more than 10 years.
  • Addition of low-dose cytosine arabinoside to interferon alfa has been reported to achieve higher remission rates.
  • Patients with chronic myelogenous leukemia who are intolerant of interferon alfa therapy can be treated with hydroxyurea.
  • Dasatinib (Sprycel)  is indicated for the treatment of adults patients with chronic myeloid leukemia in chronic, accelerated, or myeloid or lymphoid blast phase who are resistant or intolerant to prior therapy including imatinib.
  • Nilotinib (Tasigna) is a kinase inhibitor indicated for the treatment of chronic phase and accelerated phase Philadelphia chromosome-positive chronic myelogenous leukemia in adult patients resistant to or intolerant to prior therapy including imatinib.
  • When the disease progresses to the blast phase, it is treated as acute leukemia, though the outcome is usually grave.
• Treatment of polycythemia vera (PV): Treatment is palliative. Young (<40 y), asymptomatic patients with polycythemia vera can be considered for therapeutic phlebotomies alone to maintain hematocrit level at less than 45%.
• • High-risk patients with systemic symptoms, history of thrombosis or bleeding, or high rate of phlebotomies or patients older than 69 years are best treated with myelosuppressive therapy in the form of hydroxyurea.⁷
  • An alternative therapy in older patients is radioactive phosphorous (32P), but this is unsuitable for younger patients because of the potential for causing secondary leukemia.
• Treatment of essential thrombocythemia (ET): Treatment of essential thrombocythemia is meant to relieve symptoms and to prevent complications because no curative modality is available at present. The aim of treatment is to maintain the platelet count within the reference range. This usually can be achieved by hydroxyurea or anagrelide.
• Treatment of myelofibrosis (MF): No curative treatment is available at the present time. 
• • Asymptomatic patients can be monitored clinically until symptomatic. Hydroxyurea is useful to suppress the number of circulating cells.
  • Patients with painful, massively enlarged spleens refractory to myelosuppressive therapy are occasionally treated with radiation therapy, but they may ultimately require splenectomy.
  • A few recent reports have shown that allogeneic bone marrow transplantation may be effective in some cases.
  • Two case reports suggest that oral bisphosphonates may be beneficial in decreasing bone marrow fibrosis associated with this illness.

Surgical Care

Splenectomy is occasionally required in myelofibrosis for symptomatic relief of pain associated with the massive splenomegaly refractory to medical management.

Consultations

• Surgical consultation for permanent central venous access device placement may be required for patients in whom repeated blood draws, blood transfusions, and/or chemotherapy is anticipated.
• A radiation oncologist may need to be involved in selected cases, when splenic radiation is considered appropriate.

Diet

Massive splenomegaly is usually associated with epigastric and left upper quadrant discomfort and early satiety. Patients with these symptoms are encouraged to eat frequent, small meals rather than 3 large meals.

Activity

Individuals with myeloproliferative diseases are not encouraged to restrict their daily activities, but they are encouraged to refrain from physical activities that might expose them to abdominal trauma because massively enlarged spleens are likely to rupture, sometimes in response to minimal trauma.

MEDICATION

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The goals of pharmacotherapy are to reduce morbidity and to prevent complications.

Drug Category: Interferons

Interferons are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha-, beta-, and gamma-interferons may be given topically, systemically, and intralesionally.

Drug Category: Antimetabolites

Antimetabolites inhibit cell growth and proliferation.

Drug Name	Anagrelide (Agrylin)
Description	Reduces elevated platelet count in patients with essential thrombocythemia and polycythemia vera.
Adult Dose	0.5 mg PO qid (1 mg PO bid)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Initially monitor platelet count twice weekly; perform periodic hepatic and renal function tests; vasodilation, tachycardia, palpitations, and CHF may develop

Drug Category: Tyrosine kinase inhibitors

These agents inhibit the activity of bcr-abl tyrosine kinase, resulting in decreased proliferation and increased apoptosis in Ph-positive cell lines.

Drug Name	Dasatinib (Sprycel)
Description	Multiple tyrosine kinase inhibitor. Inhibits growth of cell lines overexpressing BCR/ABL. Orphan drug indicated for chronic myeloid leukemia (CML) in individuals resistant to or intolerant of prior therapy (eg, imatinib [Gleevec]). Has been able to overcome imatinib resistance resulting from BCR/ABL kinase domain mutations.
Adult Dose	70 mg PO bid; continue until disease progression or no longer tolerated Chronic-phase CML: Escalate dose to 90 mg PO bid Advanced-phase CML: May increase to 100 mg PO bid Coadministration with CYP3A4 inhibitors: 20-40 mg PO qd Coadministration with CYP3A4 inducers: May need to increase dose If clinically viable, an alternate medication with no or minimal enzyme inhibition or induction is recommended
Pediatric Dose	Not established
Contraindications	None known
Interactions	CYP450 3A4 substrate and inhibitor; CYP3A4 inhibitors (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) may increase serum concentrations; CYP3A4 inducers (eg, dexamethasone, phenytoin, rifampin, phenobarbital, carbamazepine, St. John's wort) may decrease serum concentrations coadministration with antacids or other drugs that decrease gastric pH (eg, H2 blockers [famotidine], proton pump inhibitors [omeprazole]) may decrease AUC and Cmax; may increase plasma levels of CYP3A4 substrates (eg, alfentanil, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, ergot alkaloids, simvastatin)
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Adverse effects include fluid retention (including pleural effusion), bleeding, diarrhea, rash, pyrexia, infections, headache, fatigue, and nausea; frequently causes anemia, neutropenia, or thrombocytopenia; because of extensive liver metabolism, caution in patients with hepatic impairment (may need to decrease dose); swallow tab whole, do not crush or cut

Drug Name	Nilotinib (Tasigna)
Description	Inhibits BCR/ABL kinase. In vitro, inhibits BCR/ABL–mediated proliferation of murine leukemic cell lines and human cell lines derived from Philadelphia chromosome–positive chronic myeloid leukemia. Under the conditions of the assays, was able to overcome imatinib resistance resulting from BCR/ABL kinase mutations in 32 of 33 mutations tested. In vivo, shown to reduce tumor size in a murine BCR/ABL xenograft model. Indicated for Philadelphia chromosome–positive chronic myeloid leukemia in adults whose disease has progressed or who cannot tolerate other therapies that include imatinib.
Adult Dose	400 mg PO bid 1 h ac or 2 h pc with water only; administer about 12 h apart; swallow whole (do not chew or crush)
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; long QT syndrome; uncorrected hypokalemia or hypomagnesemia
Interactions	CYP3A4, CYP2C8, CYP2C9, and CYP2D6 inhibitor; CYP2B6, CYP2C8, and CYP2C9 inducer; coadministration with other drugs known to prolong QT interval (eg, class III antiarrhythmics [amiodarone, dofetilide, sotalol], tricyclic antidepressants, verapamil, erythromycin, moxifloxacin, thioridazine) increases risk of life-threatening arrhythmias and sudden death; avoid coadministration with strong CYP3A4 inhibitors (eg, grapefruit, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole), which may increase serum levels, thereby increasing QT interval; avoid coadministration with strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John's wort)
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	May prolong QT interval, leading to life-threatening arrhythmias and possible sudden death; this risk is lowered by taking without food, avoiding grapefruit products, and confirming that potassium and magnesium levels are within normal limits; if QTc >480 milliseconds, withhold and analyze concurrent medications, serum potassium levels, and magnesium levels (reduce dose according to prescribing information); food increases bioavailability, thus administer on empty stomach to avoid elevated serum levels and toxicity; common adverse effects include myelosuppression (obtain CBC count q2wk for 2 mo, then monthly), rash, headache, nausea, and itching; may cause hepatic toxicity, edema, and pancreatitis; females of childbearing potential should use effective contraception; caution in liver impairment; withhold drug with ANC <1 X 109/L, platelet count <50 X 109/L, or serum lipase, amylase, bilirubin, or hepatic transaminase levels > grade 3

FOLLOW-UP

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Complications

• Patients are at risk of both thrombotic and hemorrhagic events. 
• • Thrombotic and hemorrhagic events are particularly common in polycythemia vera (PV) and essential thrombocythemia (ET). Thrombosis is the cause of death in 30-40% of patients.
  • A particularly serious thrombotic event that may be associated with polycythemia vera is Budd-Chiari syndrome, which is due to hepatic venous or inferior venal caval thrombosis.
• Patients are at risk of developing secondary acute leukemia from their underlying disorder as well as their treatment.

MISCELLANEOUS

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Medical/Legal Pitfalls

When suspecting polycythemia in patients with iron deficiency, replenish iron before conducting red blood cell mass studies; otherwise, some cases of true polycythemia may be missed.

MULTIMEDIA

Section 10 of 11  

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Media file 1:  Peripheral smear of a patient with chronic myelogenous leukemia (CML) shows leukocytosis with extreme left shift and basophilia.
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Media file 2:  Peripheral smear of a patient with chronic myelogenous leukemia (CML) in blastic phase shows several blasts.
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Media file 3:  Peripheral smear of a patient with essential thrombocythemia (ET) shows markedly increased number of platelets. Some of the platelets are giant (arrow).
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Media file 4:  Peripheral smear of a patient with agnogenic myeloid metaplasia (myelofibrosis) shows leukoerythroblastosis. This photomicrograph also shows giant platelets.
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Media type:  Photo

Media file 5:  Photomicrograph of a peripheral smear of a patient with agnogenic myeloid metaplasia (myelofibrosis) shows findings of leukoerythroblastosis, giant platelets, and few teardrop cells.
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Media type:  Photo

REFERENCES

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1. Vardiman JW. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood. 2002;100:2299-2300. [Medline]. [Full Text].
2. Baxter EJ, Scott LM, Campbell PJ. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. Mar 19-25 2005;365(9464):1054-61. [Medline].
3. James C, Ugo V, Le Couedic JP. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature. Apr 28 2005;434(7037):1144-8. [Medline].
4. Mesa RA, Powell H, Lasho T, Dewald G, McClure R, Tefferi A. JAK2(V617) and leukemic transformation in myelofirbrosis with myeloid metaplasia. Leuk Res. 2006/11;30 (11):1457-60.
5. Donato NJ, Talpaz M. Clinical use of tyrosine kinase inhibitors: therapy for chronic myelogenous leukemia and other cancers. Clin Cancer Res. Aug 2000;6(8):2965-6. [Medline].
6. O'Brien SG, Guilhot F, Larson RA. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. Mar 13 2003;348(11):994-1004. [Medline].
7. Kaplan ME, Mack K, Goldberg JD. Long-term management of polycythemia vera with hydroxyurea: a progress report. Semin Hematol. Jul 1986;23(3):167-71. [Medline].
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9. Faderl S, Kantarjian HM, Talpaz M. New treatment approaches for chronic myelogenous leukemia. Semin Oncol. Oct 2000;27(5):578-86. [Medline].
10. Froom P, Elmalah I, Braester A. Clodronate in myelofibrosis: a case report. Am J Med Sci. Feb 2002;323(2):115-6. [Medline].
11. Johansson P, Kutti J, Andreasson B. Trends in the incidence of chronic Philadelphia chromosome negative (Ph-) myeloproliferative disorders in the city of Goteborg, Sweden, during 1983-99. J Intern Med. Aug 2004;256(2):161-5.
12. Kralovics R, Passamonti F, Buser AS. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med. Apr 28 2005;352(17):1779-90. [Medline].
13. Kutti J, Ridell B. Epidemiology of the myeloproliferative disorders: essential thrombocythaemia, polycythaemia vera and idiopathic myelofibrosis. Pathol Biol (Paris). Mar 2001;49(2):164-6. [Medline].
14. Levine RL, Wadleigh M, Cools J. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell. Apr 2005;7(4):387-97. [Medline].
15. O'Brien S, Tefferi A, Valent P. Chronic myelogenous leukemia and myeloproliferative disease. Hematology (Am Soc Hematol Educ Program). 2004;146-62.
16. Pardanani A, Brockman SR, Paternoster SF. FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia. Blood. Nov 15 2004;104(10):3038-45. [Medline]. [Full Text].
17. Staerk J, Kallin A, Demoulin JB. JAK1 and Tyk2 Activation by the Homologous Polycythemia Vera JAK2 V617F Mutation:CROSS-TALK WITH IGF1 RECEPTOR. J Biol Chem. Dec 23 2005;280(51):41893-9.
18. Tefferi A, Solberg LA, Silverstein MN. A clinical update in polycythemia vera and essential thrombocythemia. Am J Med. Aug 1 2000;109(2):141-9. [Medline].

Article Last Updated: Feb 13, 2008