MD2B - Myeloproliferative Disorders
Paul Aridgides, MD, Upstate Medical University
Neha Vapiwala, MD, Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 30, 2008
The term "myeloproliferative disorders" was first coined by William Dameshek in 1951.
This heterogeneous group consists of four diseases, all featuring chronic, acquired, monoclonal proliferation of either pluripotential or more differentiated hematopoietic stem cells. The four types of myeloproliferative disorders are named for the predominant cell type involved, and are frequently associated with biochemical and chromosomal abnormalities, as discussed below. Recently shared mutations have been discovered that provide a molecular link between these disorders and provide further insight into the genetic events resulting in “myeloproliferation.”
Chronic Myelocytic Leukemia (CML)
Characterized by severe granulocytosis (with higher than average proportion of immature cells), anemia, thrombocytosis and splenomegaly.
Epidemiology, Etiology and Pathogenesis 
- Incidence is 1.6/100,000 population, occurs predominantly in the middle-aged, and is slightly more common in males (1.4 to 1)
- Associated with ionizing radiation exposure.
- Progenitor cell involved gives rise to granulocytes (neutrophils, eosinophils, basophils), monocytes, erythrocytes, platelets and possibly some B- and T- lymphocytes
- Pathognomonic “Philadelphia chromosome (Ph)” 9;22 translocation, present in >90% patients, results in the formation of the BCR-ABL fusion protein
- BCR-ABL has constitutive tyrosine kinase activity which results in continuous cell replication and growth
- In the chronic phase, additional molecular and chromosomal abnormalities are acquired as a consequence of increased marrow proliferation; over years hematopoietic differentiation is impaired and acute leukemia (blast crisis) develops.
- History: Fatigue, hypermetabolic symptoms, abdominal discomfort and early satiety from splenomegaly, or asymptomatic and detected by routine blood tests
- Physical exam: Splenomegaly, sternal tenderness from marrow expansion
- Labs: WBC count (granulocytosis often >50,000 cells/mL) and differential (granulopoiesis and left shift) usually diagnostic, anemia, and thrombocytosis. 
- Peripheral smear shows granulocytes, with a predominance of mature cells and late precursors (polyps, bands, metamyelocytes, myelocytes) but few primitive cells; also see eosinophils and basophils.
- Molecular testing confirms diagnosis with detection of Ph chromosome, BCR-ABL protein, or BCR-ABL mRNA in peripheral blood or bone marrow. 
- Chronic Phase: First 1-5 years are usually asymptomatic and very amenable to achieving remission with targeted therapy.
- Accelerated Phase: Increasing WBC immaturity, difficulty in controlling WBC counts, anemia, worsening splenomegaly, fever.
- "Blast Crisis:" Medullary/acute leukemia or extra-medullary/ "chloromas", with patient survival measured in months at this stage.
Treatment – both treatment and prognosis are dependent on disease phase
- Imatinib, approved in 2001, is a molecular inhibitor of BCR-ABL. It has revolutionized CML treatment and serves as a model for molecular targeted therapy; however similar successes have yet to be seen in other malignancies. 
- Chronic Phase: imatinib is first-line therapy with excellent rates of remission. After 5 years of imatinib as initial therapy, 98% of patients had hematological remission, 87% had complete cytogenetic remission, 7% had progression to accelerated/blast phase, and overall survival was 89%. 
- Accelerated/Blast Crisis: high-dose imatinib, with median survival increased from 2-3 months to 7.5 months. 
- Imatinib Failure: options include allogeneic stem-cell transplantation if young (potentially curative in 40-60%) and imatinib or dasatinib (targeted inhibitors of imatinib-resistant BCR-ABL mutants). 
- Cytogenetic and molecular response after imatinib should be monitored by FISH and RT-PCR. A combination cytogenetic and molecular response is strongly predictive of long-term treatment success. 
Polycythemia Vera (PV)
Characterized monoclonal proliferation of trilineage, with disproportionate expansion of RBCs and platelets, leading to a clinical picture of hyperviscosity, hemorrhage and thrombosis.
Epidemiology, Etiology and Pathogenesis 
- Incidence is 5/ 1,000,000 population, usually middle-aged to older patients.
- Mutations in the JAK2 tyrosine kinase are found in nearly all (>95%) and are believed to be central to pathogenesis
- JAK2 mutations activate the JAK-STAT pathway, resulting in cytokine-independent growth and transformation of hematopoietic progenitor cells.
- Erythroid cells undergo transformation through interactions between the erythropoietin receptor and the constitutively active JAK2 kinase mutant protein
- History: Majority of cases are asymptomatic, but symptoms can include headaches, dizziness, visual changes, tinnitus, erythromelalgia, pruritis, gout, hemorrhagic events in 25% of patients (nose/GI bleeds) and thrombotic events in 33% (strokes, MI, hepatic vein thrombosis in 10%)
- Physical Exam: Plethoric, distended fundal veins, mild-moderate splenomegaly and hepatomegaly, hypertension
- Labs: Chronically elevated Hgb, elevated RBC mass (to exclude relative polycythemia), normal arterial oxygen saturation; thrombocytosis, leukocytosis, normal LAP score, elevated vitamin B12 level, hyperuricemia.
- Diagnosis (by major WHO criteria): Hgb >18.5males/16.5females, JAK2 mutation 
- Polycythemic Phase: 5-20 years, 10-20% patients die of thrombotic events and 5% die of hemorrhage.
- Stable Phase: RBC mass stabilizes
- Postpolycythemic Myeloid Metaplasia: 15-20% of cases, with anemia, leukoerythroblastic smear, leukopenia, thrombocytopenia, marrow fibrosis and massive hepatosplenomegaly
- Acute Leukemia/ AML: 1% of cases, therapy-resistant
- The primary goal of treatment is to decrease thrombotic complications (cardiac, PE, venous) while limiting treatment side effects (acute leukemia)
- Low thrombotic risk (age <60, no previous thrombosis)
- Phlebotomy (goal Hct<45) and Aspirin 
- In a randomized trial aspirin reduced major thrombotic events, however did not improve mortality. 
- High thrombotic risk (age >60, history of thrombosis):
- Myelosuppressive therapy (hydroxyurea)
- Hydroxyurea shown to decrease thrombotic complications. IFN-alpha is the agent of choice for younger patients (<40) and in pregnant women. [6,8]
- The leukemogenic potential of hydroxyurea as monotherapy is controversial: the majority of data indicate no increased risk of leukemia however no direct randomized comparison has been done.
Essential Thrombocytosis (ET)
Also features clonal trilineage hematopoiesis, but with prominent megakaryocytic hyperplasia, increased platelet counts and risk for thrombosis.
Epidemiology, Etiology and Pathogenesis
- 6,000 new cases per year in the US (less common than PV)
- Median age at diagnosis is 60 years old, more common in females 2:1 
- Associated with iron deficiency, chronic inflammatory disease, solid tumors, splenectomy)
- JAK2 mutations are found in 41-72% of ET resulting in clonal hematopoeisis. Pathogenesis, including myeloproliferation in JAK2 negative patients, is incompletely understood. 
- History: Most are asymptomatic, but can present with nosebleeds, bruises, macrovascular or microvascular obstruction
- Physical Exam: Mild, palpable splenomegaly in 50%
- Labs: Platelets > 100,000, mild anemia, leukocytosis below 50,000, normal or elevated LAP score, hyperuricemia less common, pseudohyperkalemia
- Peripheral smear shows abnormal platelet morphology, with large, small, bizarre and agranular forms on peripheral smear, but absent or minimal collagen fibrosis of the marrow
- Diagnosis (by Major WHO Criteria): plt >450,000, bone marrow biopsy, JAK2 mutation 
- Majority have normal expectancy
- Thrombotic risk increased with advance age, leukocytosis, and JAK2 mutation [10, 11]
- Hemorrhagic risk highest with platelet count >1,500,000 
- Rare myelofibrosis (4%) and AML (2%) in an Italian cohort (15-year risk) 
- Many require no therapy (young, no previous thrombosis)
- Cytoreductive therapy in high risk (age >65, thrombotic event, CV risk factors), options include hydroxyurea, anagrelide, and IFN-alpha.
- Hydroxyurea has emerged as treatment of choice due to proven efficacy (reduction of thrombosis in randomized prospective trials), good tolerability, and minimal leukemogenic potential. 
- Aspirin is useful for relief of pain, neurologic, and ocular symptoms of microvascular ischemia. Combination Aspirin + cytoreductive therapy is often prescribed in high risk patients, but prospective studies have not been done.
Myelofibrosis/ Myeloid Metaplasia (MMM)
The rarest of the myeloproliferative disorders, MMM is characterized by a triad of: 1) leukoerythroblastic peripheral blood smear, 2) extramedullary hematopoiesis and 3) collagen fibrosis of the marrow. This increase in marrow fibroblasts is a polyclonal response to ineffective megakaryocyte production and subsequent release of fibrogenic growth factors. These factors lead to fibroblast proliferation, collagen secretion and collagenase activity. The extramedullary hematopoiesis usually occurs in the liver and spleen, probably from progenitor cells that have landed in these organs after leaking out from the damaged marrow.
Epidemiology, Etiology and Pathogenesis
- Rare, usually presents in late middle-aged patients
- No specific chromosomal or molecular genetic abnormality, although karyotypes are abnormal in one-third of patients
- History: Majority present symptomatically with weight loss, fatigue, dyspnea from anemia, early satiety and abdominal discomfort from splenomegaly
- Physical exam: 100% with splenomegaly, 66% with hepatomegaly
- Labs: Modest leukocytosis with a few myeloblasts, mild anemia, variable platelet count, hyperuricemia, elevated or normal LAP score (but low in 10%)
- Peripheral smear shows "teardrop" RBC's, nucleated RBC's, immature granulocytes, large platelets and megakaryocyte fragments
- Marrow aspiration yields "dry tap" and biopsy shows marked megakaryocytic hyperplasia, bizarre-looking cells, and marked reticulin and collagen fibrosis
- Radiographic studies: plain bone x-rays with osteosclerosis in 50% of cases
- Diagnosis (Major WHO criteria): bone marrow biopsy, not meeting criteria for other MPDs, clonal marker (JAK2, MPL) 
- plus minor criteria (2) - leukoerythroblastosis, serum LAD, splenomegaly, anemia
Natural Course 
- Usually indolent (median survival of 5 years) and variable.
- Poorest survival in >60yo, hemoglobin <10, WBC <4,000 or WBC >30,0000 
- Eventually develop multifactorial anemia, massive splenomegaly with infarctions, compression, portal hypertension, thrombosis (40%), symptomatic tumors from extramedullary hematopoiesis, transformation to acute leukemia (5%)
- No therapy initially, otherwise direct therapy to symptoms and complications as follows:
- Painful splenomegaly: Splenic irradiation or splenectomy (up to 30% mortality rate from post-operative portal vein thrombosis or sepsis) [17,18]
- Hypermetabolism and thrombosis: Hydroxyurea or alpha-interferon (30-50% hematologic response rates) . Low dose thalidomide + prednisone being explored (70% hematologic response in a small study). 
- Thrombosis: Aspirin controversial as in ET
- Symptomatic extramedullary tumors: Radiation therapy
- Potential curative approach for younger patients involves allogeneic peripheral stem cell or bone marrow transplantation if a suitable sibling donor is available with 30% treatment related mortality and 50% 5 year survival.
1. Schiffer, CA: BCR-ABL Tyrosine Kinase Inhibitors for Chronic Myelogenous Leukemia. New England Journal of Medicine 357:258-265, 2007.
2. Hehlmann R, Hochlaus A, Baccarani M: Chronic Myeloid Leukemia. Lancet 370:342-350, 2007.
3. Druker BJ, Guilhot F, O’Brien SG et al: Five-Year Follow-up of Patients Receiving Imatinib for Chronic Myeloid Leukemia. New England Journal of Medicine 355:2408-17, 2006.
4. Levine RL, Pardanani A, Tefferi A et al: Role of JAK2 in the Pathogenesis and Therapy of myeloproliferative disorders. Nature Reviews Cancer 7:673-683, 2007.
5. Tefferi A, Thiele J, Orazi A et al: Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: recommendations from an ad hoc international expert panel. Blood 110:1092-1097, 2007.
6. Finazzi G and Barbui T: How I treat patients with polycythemia vera. Blood 109:5104-11, 2007.
7. Landolfi R, Marchioli R, Kutti J, et al: Efficacy and Safety of Low-Dose Aspirin in Polycythemia Vera. New England Journal of Medicine 350:114-24, 2004.
8. Campbell PJ, Green AR, et al: Management of Polycythemia Vera and Essential Thrombocythemia. Hematology Am Soc Hematol Educ Program 201-8, 2005.
9. Briere JB: Essential Thrombocythemia. Orphanet J Rare Dis 2:3, 2007.
10. Tefferi A: JAK2 Mutations and Clinical Practice in Myeloproliferative Neoplasms. Cancer J 12:366-371, 2007.
11. Kittur J, Knudson RA, Lasho TL, et al: Clinical Correlates of JAK2V617F Allele Burden in Essential Thrombocythemia. Cancer 109:2279-84, 2007.
12. Passamonti F, Rumi E, Pungolino E et al: Life Expectancy and Prognostic Factors for Survival in Patients with Polycythemia Vera and Essential Thrombocythemia. Am J Med 117:755-761, 2004.
13. Harrison CN, Campbell PJ, Buck G et al: Hydroxyurea Compared with Anagrelide in High-Risk Essential Thrombocythemia. New England Journal of Medicine 353:33-45, 2005.
14. Barosi G: Myelofibrosis with Myeloid Metaplasia: Diagnostic Definition and Prognostic Classification for Clinical Studies and Treatment Guidelines. Journal of Clinical Oncology 17(9):2954-2970, 1999.
15. Hoffman R and RondelliD: Biology and Treatment of Primary Myelofibrosis. Hematology Am Soc Hematol Educ Program 346-54, 2007.
16. Cervantes F, Mesa R, and Barosi G: New and Old Treatment Modalities in Primary Myelofibrosis. Cancer J 13:377-383, 2007.
17. Barosi G, Ambrosetti A, Buratti A, et al.: Splenectomy for Patients with Myelofibrosis with Myeloid Metaplasia: Pretreatment Variables and Outcome Prediction. Leukemia 7(2): 200-206, 1993.
18. Benbassat J, Gilon D, Penchas S: The Choice between Splenectomy and Medical Treatment in Patients with Advanced Agnogenic Myeloid Metaplasia. American Journal of Hematology 33(2): 128-135, 1990.
19. Gilbert HS: Long term treatment of myeloproliferative disease with interferon-alfa-2b: feasibility and efficacy. Cancer 83(6):1205-1213, 1998.
20. Giles FJ, Cooper MA, Silverman L et al: A Phase 2 Trial of Combination Low-dose Thalidomide and Prednisone for the Treatment of Myelofibrosis with Myeloid Metaplasia. Blood 101:2534-2541, 2003.