Myeloproliferative Neoplasms

BASICS

DESCRIPTION

Myeloproliferative neoplasms (MPNs) are a group of diseases that share a common cell of origin in the pluripotent hematopoietic stem cell.
MPNs are characterized by proliferation of a specific stem cell lineage such as myeloid, erythroid, or megakaryocytic; resulting in granulocytosis, erythrocytosis, or thrombocytosis, respectively.
The "classic " MPNs include chronic myelogenous leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The World Health Organization (WHO) classification also includes chronic neutrophilic leukemia, chronic eosinophilic leukemia not otherwise specified (CEL-NOS), systemic mastocytosis, and myeloproliferative neoplasm unclassifiable. This topic focuses on the classic MPNs.
CML is characterized by the presence of Philadelphia-chromosome (reciprocal translocation between chromosomes 9 and 22 resulting in a BCR-ABL fusion gene). This results in an uninhibited proliferation of myeloid precursor stem cells resulting in granulocytosis and elevation of various granulocyte precursors.
The following three MPNs are characterized by varying degree of presence of JAK 2 mutation.
- PMF: MPN characterized by marrow fibrosis, extramedullary hematopoiesis, and splenomegaly
- ET: MPN characterized by a clonal proliferation of megakaryocytes, leading to thrombocytosis
- PV: MPN characterized by trilineage growth of hematopoietic stem cells with erythroid precursors predominating, leading to erythrocytosis

EPIDEMIOLOGY

Incidence

CML: 0.6 to 2.0/100,000/year; median age at diagnosis 66 years; male > female (1.6:1)
PMF: 0.5 to 1.5/100,000/year; median age at diagnosis 65 years; male = female
ET: 0.6 to 2.5/100,000/year; median age at diagnosis 60 years, second peak in younger patients at ~30 years; female > male (2:1)
PV: 1 to 2/100,000/year; male > female (1.3:1)

ETIOLOGY AND PATHOPHYSIOLOGY

CML: BCR-ABL1 gene leads to increased and unrestrained activity of the ABL tyrosine kinase resulting in an unchecked activation of downstream signaling pathways which have an antiapoptotic effect on the hematopoietic cells.
PMF: Progenitor hematopoietic stem cells undergo a clonal proliferation independent of growth factors likely due to activation of downstream intracellular pathways. The fibroblasts are nonclonal, and the increased fibrosis is likely driven by growth factors released by hematopoietic cells especially megakaryocytes.
ET: Thrombopoietin-induced megakaryocyte proliferation is uncontrolled due to a combination of increased sensitivity to thrombopoietin and decreased feedback regulation of the thrombopoietin levels which is usually inversely proportional to the platelet mass.
PV: Gain-of-function mutation (JAK2) leads to increased erythrocyte production due to a downstream activation of proteins involved in cell proliferation and resistance to apoptosis. The JAK2 tyrosine kinase is downstream of the erythropoietin receptor and thus its constitutive activation makes the hematopoietic progenitor cell independent of erythropoietin.

Genetics

Philadelphia chromosome (BCR-ABL1 gene): translocation and fusion of the BCR gene on chromosome 22 and the ABL gene on chromosome 9; seen in all patients with CML
JAK2 mutations: point mutations in the tyrosine kinase domain of JAK2, causing a substitution of phenylalanine for valine at position 617 (JAK2V617F); leading to unrestrained JAK2 activation with a deactivation of typical feedback mechanism
Seen in >95% of PV cases; 50% of ET and PMF cases
CALR mutation: Calreticulin (CALR) is an endoplasmic reticulum chaperone protein directing proper folding of proteins. This mutation may be seen in up to a third of patients of ET and PMF. These patients are seen to have a higher platelet count but lower risk of thrombosis.
Myeloproliferative leukemia virus (MPL) gene: Mutations found in 5 " 10% of patients with PMF and in 3 " 5% of those with ET. This encodes the thrombopoietin receptor MPL.
JAK2, CALR, and MPL mutations are mutually exclusive and together account for 85% of cases of ET and PMF.

RISK FACTORS

Rare familial cases have been reported.
CML: exposure to ionizing radiation

COMMONLY ASSOCIATED CONDITIONS

Progression to acute myeloid leukemia; most common with CML
Thrombosis/hemorrhage

DIAGNOSIS

HISTORY

Many MPN cases are found incidentally on routine blood work.
CML: Most patients are asymptomatic at time of diagnosis.
- Fatigue, malaise, weight loss, excessive perspiration, abdominal fullness, early satiety, bleeding episodes
PMF: Symptoms depend on the degree of anemia and splenomegaly.
- Fatigue, shortness of breath, early satiety, constitutional symptoms, cachexia, Budd-Chiari syndrome, splenic infarcts, osteosclerosis resulting in bone pains.
ET: characterized by thrombotic and hemorrhagic events
- Thrombotic events (deep vein thrombosis, pulmonary embolism, Budd-Chiari syndrome), microvascular occlusive events (digital ischemia, erythromelalgia), major/minor hemorrhagic events; headaches, dizziness, syncope, tingling, visual changes, transient ischemic attacks
PV: Symptoms are due to level of erythrocytosis and the resultant increased blood viscosity.
- Erythromelalgia, pruritus after hot baths, headaches, tinnitus, paresthesias, gout attacks

PHYSICAL EXAM

CML: splenomegaly, hepatomegaly
PMF: splenomegaly seen in nearly all patients, hepatomegaly, pallor
ET: possible petechiae, purpura, ecchymosis; splenomegaly
PV: cyanotic blush (lips, nose, ears, distal extremities), increased blood pressure, splenomegaly, epistaxis, ecchymosis

DIFFERENTIAL DIAGNOSIS

CML: leukemoid reaction (elevated LAP), juvenile myelomonocytic leukemia, chronic myelomonocytic leukemia (CMML), chronic eosinophilic leukemia, chronic neutrophilic leukemia
PMF: other MPNs, lymphoma, hairy cell leukemia; secondary myelofibrosis (malignant or nonmalignant)
ET: reactive thrombocytosis, CML, PV, PMF, and myelodysplastic syndromes
PV: hypoxic states (e.g., chronic obstructive pulmonary disease [COPD], anemia), renal cell carcinoma, Wilms tumor, hepatoma, polycystic kidney disease, exogenous androgens

DIAGNOSTIC TESTS & INTERPRETATION

CML: White blood cell count >10,000 109/L with differential showing increased mature and immature neutrophils and an increased percentage of myelocytes, metamyelocytes, and band forms; neutrophils have decreased leukocyte alkaline phosphatase; platelet count >600,000 109/L and a normochromic, normocytic anemia. Basophilia is common.
PMF (1)[A] (WHO criteria): Diagnosis requires meeting all three major criteria and two or more minor criteria:
- Major criteria: (i) megakaryocyte proliferation and atypia accompanied by either reticulin or collagen fibrosis; (ii) not meeting WHO criteria for CML, PV, MDS, or other myeloid neoplasm; (iii) demonstration of JAK2V617F or other clonal marker or absence of marker with no evidence of secondary marrow fibrosis
- Minor criteria: (i) leukoerythroblastosis, (ii) increased serum lactate dehydrogenase level, (iii) anemia, and (iv) palpable splenomegaly
ET (1)[A] (WHO criteria): Diagnosis requires meeting all four major criteria:
- Major criteria: (i) thrombocytosis with persistent platelet level ≥450 109/L; (ii) megakaryocyte proliferation with large and mature morphology; (iii) not meeting the WHO criteria for CML, PV, PMF, MDS, or other myeloid neoplasm; and (iv) demonstration of JAK2V617F or other clonal marker or absence of clonal marker with no evidence of reactive thrombocytosis
PV (1)[A] (WHO criteria): Diagnosis requires either both major criteria and one minor criterion or the first major criterion and two of the minor criteria:
- Major criteria: (i) hemoglobin >18.5 g/dL in men, >16.5 g/dL in women or other evidence of increased red cell volume and (ii) presence of JAK2V617F or other functionally similar mutation (e.g., JAK2 exon 12 mutation) (1)[B]
- Minor criteria: (i) bone marrow biopsy showing hypercellularity for age with trilineage myeloproliferation, (ii) low serum erythropoietin level, (iii) endogenous erythroid colony formation in vitro

Initial Tests (lab, imaging)
If clinical suspicion of MPN, obtain a CBC and peripheral blood smear; if suggestive, obtain bone marrow biopsy.

PMF: radiographic osteosclerosis in 25 " 66%

Diagnostic Procedures/Other

CML: diagnosis with identification of Philadelphia chromosome: Fluorescence in situ hybridization is more sensitive than karyotyping and is routinely used. Polymerase chain reaction (P210) is done at baseline to help monitor response to tyrosine kinase inhibitors.
- Bone marrow biopsy: increased cellularity and increased myeloid to erythroid ratio
PMF, ET, and PV: genotypic analysis and bone marrow biopsy as described in earlier WHO criteria; "dry tap " is common in PMF.
Risk stratification
- CML: three phases of CML
  - (i) Chronic phase (85% patients at diagnosis; <5% blast counts); (ii) accelerated phase (poorly controlled splenomegaly regardless of treatment, 10 " 19% blast counts, worsening anemia, basophil ≥20%); (iii) blast crisis (resembles acute myeloid or lymphoid leukemia, >20% blast counts)
- PMF: International Prognostic Scoring System (IPSS) at diagnosis and Dynamic IPSS (DIPSS-plus) throughout disease
  - IPSS: age >65 years, constitutional symptoms, hemoglobin <10 g/dL, leukocyte count >25 109, circulating blasts >1%
    - Low risk = 0 of above; intermediate-1 risk = 1 of above; intermediate-2 risk = 2 of above; high risk = ≥3 of above
  - DIPSS-plus: same 5 risk factors in the IPSS + the need for red cell transfusion, platelets <100 109/L and unfavorable karyotype
    - Low risk = 0 of above; intermediate-1 risk = 1 of above; intermediate-2 risk = 2 " 3 of above; high risk = ≥4 of above
- ET: low risk = age <40 years, no prior thromboembolic events, no cardiovascular risk factors, platelet count <1,500 109/L; intermediate risk = age 40 to 59 years, presence of cardiovascular risk factors, platelet count <1,500 109/L; high risk = age ≥60 years and/or prior thromboembolic or hemorrhagic episode and/or platelet count >1,500 109/L
- PV: low risk = age <60 years, no history of thrombosis/cardiovascular risk factors; intermediate risk = platelets >1,000 109/L and cardiovascular risk factors; high risk = age >60 years or a history of thrombosis

TREATMENT

GENERAL MEASURES

Low-dose aspirin for ET and PV

MEDICATION

First Line

CML
- Chronic phase: Imatinib mesylate (Gleevec): 400 mg/day, a tyrosine kinase inhibitor (TKI). Dasatinib and nilotinib are also approved for use in the first line (1).
- Accelerated or blast phase: Increase imatinib to 800 mg/day or switch to 2nd- or 3rd-generation TKIs like nilotinib and dasatinib.
- While awaiting confirmation of diagnosis, hydroxyurea can be used to lower the WBC count.
PMF: Main goal is symptomatic relief:
- Low and intermediate-1 risk: no drug therapy indicated, symptom-directed therapy
- Intermediate-2 and high risk: hydroxyurea or consider allogeneic SCT
- JAK2 inhibitor ruxolitinib is approved for intermediate or high-risk myelofibrosis. It is also approved for post-PV and post-ET myelofibrosis (2).
- Supportive treatment
  - Anemia: transfusions, erythropoiesis-stimulating agents, androgens, danazol, thalidomide, or lenalidomide
  - Splenomegaly: hydroxyurea, splenectomy, or IV cladribine for refractory cases
  - Thrombosis: hydroxyurea and low-dose aspirin
ET low and intermediate risk: "Watch and wait " + low-dose aspirin if microvascular disturbances are present and no contraindications; high risk: hydroxyurea 15 mg/kg/day in divided doses to reduce platelet count to <450 109/L (2).
PV
- Low and intermediate risk: phlebotomy and low-dose aspirin
- High risk (or those who do not tolerate phlebotomy): hydroxyurea 500 to 1,000 mg/day (2).

Second Line

CML: Only curable treatment is aSCT; reserved for accelerated/blast phase due to high rates of morbidity and mortality with aSCT
- 2nd-generation TKIs: dasatinib, nilotinib, and bosutinib; increasing evidence for improved, deeper responses with these medication resulting in use of 2nd-generation TKIs for first-line therapy. Ponatinib is a 3rd-generation TKI that has activity in cases of TKI resistance due to a T315I mutation for which all the other available TKIs are ineffective.
PMF: Only curable treatment is allogeneic SCT; reserved for intermediate-2 or high-risk patients
- If unresponsive to hydroxyurea, use pegylated interferon-α; tolerance may be an issue.
ET: If resistant/intolerant to hydroxyurea, use anagrelide.
- If resistant/intolerant to hydroxyurea or anagrelide, pregnant or age <40 years: Use interferon-α.
PV: if resistant or intolerant to hydroxyurea, can use ruxolitinib

ISSUES FOR REFERRAL

Patients with MPNs are usually referred to hematology/oncology.

SURGERY/OTHER PROCEDURES

May require splenectomy/palliative radiation for foci of extramedullary hematopoiesis

INPATIENT CONSIDERATIONS

Admission Criteria/Initial Stabilization
Severe cachexia; renal failure and hepatomegaly secondary to extramedullary hematopoiesis; massive splenomegaly requiring treatment; severe thrombotic/hemorrhagic episodes; anemia; tumor lysis syndrome
IV Fluids
Optimal hydration to prevent tumor lysis syndrome

ONGOING CARE

PROGNOSIS

CML: 10-year survival rate ~80% from time of diagnosis; 85% will die in blast crisis; 12- to 18-month median survival for accelerated phase; 3- to 6-month median survival for blast phase
PMF: worst prognosis of the MPNs; drug therapy does not modify disease course but treats the symptoms; median survival for IPSS low risk = 135 months, intermediate-1 risk = 95 months; intermediate-2 risk = 48 months; high risk = 27 months
PV: median survival often >10 years
ET: near-normal life expectancy

COMPLICATIONS

CML: blast crisis, transformation to acute leukemia, gout, or nephropathy due to hyperuricemia
PMF: 10% develop acute myeloid leukemia; anemia, massive hepatosplenomegaly, thrombohemorrhagic events, osteosclerosis, secondary gout, splenic infarcts, paraspinal/epidural extramedullary hematopoiesis
ET: <10% develop post-ET myelofibrosis, 2% develop acute myeloid leukemia; thrombohemorrhagic events
PV: 15 " 20% develop post-PV myelofibrosis, 5% develop leukemia; erythromelalgia, pruritus, secondary gout, headaches, vascular occlusive events

REFERENCES

11 Fava C, Rege-Cambrin G, Saglio G. The choice of first-line chronic myelogenous leukemia treatment. Ann Hematol. 2015;94(Suppl 2):S123 " S131.22 Geyer HL, Mesa RA. Therapy for myeloproliferative neoplasms: when, which agent, and how? Blood. 2014;124(24):3529 " 3537.

ADDITIONAL READING

Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895 " 2901.
Druker BJ, Guilhot F, O 'Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355(23):2408 " 2417.
Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372(5):426 " 435.
Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366(9):799 " 807.

CODES

ICD10

D47.1 Chronic myeloproliferative disease
C92.10 Chronic myeloid leukemia, BCR/ABL-positive, not having achieved remission
D45 Polycythemia vera
D47.3 Essential (hemorrhagic) thrombocythemia
C93.12 Chronic myelomonocytic leukemia, in relapse
D47.0 Histiocytic and mast cell tumors of uncertain behavior
C92.11 Chronic myeloid leukemia, BCR/ABL-positive, in remission
C93.11 Chronic myelomonocytic leukemia, in remission
D75.81 Myelofibrosis
C93.10 Chronic myelomonocytic leukemia not achieve remission
C92.12 Chronic myeloid leukemia, BCR/ABL-positive, in relapse

ICD9

238.79 Other lymphatic and hematopoietic tissues
205.10 Chronic myeloid leukemia, without mention of having achieved remission
238.4 Polycythemia vera
238.71 Essential thrombocythemia
238.76 Myelofibrosis with myeloid metaplasia
202.60 Malignant mast cell tumors, unspecified site, extranodal and solid organ sites

SNOMED

425333006 myeloproliferative disorder (disorder)
92818009 chronic myeloid leukemia, disease (disorder)
109992005 Polycythemia vera (disorder)
109994006 Essential thrombocythemia (disorder)
188733003 chronic eosinophilic leukemia (disorder)
307651005 Myelosclerosis with myeloid metaplasia
188734009 Chronic neutrophilic leukemia (disorder)
52967002 myelofibrosis (disorder)
397016004 Systemic mast cell disease (disorder)

CLINICAL PEARLS

Ruxolitinib has a role in amelioration of constitutional and splenomegaly-related symptoms in myelofibrosis.

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