Myeloproliferative Neoplasms: Definition, Diagnosis, and Treatment

What Are Myeloproliferative Neoplasms?

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by excessive production of one or more mature myeloid cell lineages in the bone marrow, leading to elevated blood cell counts, thrombotic complications, and potential transformation to acute leukemia. 1

The WHO classification includes several distinct entities 1:

Chronic myeloid leukemia (CML) - BCR-ABL1 positive
Polycythemia vera (PV) - excess red blood cells
Essential thrombocythemia (ET) - excess platelets
Primary myelofibrosis (PMF) - bone marrow fibrosis with extramedullary hematopoiesis
Chronic neutrophilic leukemia (CNL)
Chronic eosinophilic leukemia
Mastocytosis

These disorders arise from acquired driver mutations (most commonly JAK2, CALR, or MPL) and share common features including thrombotic risk, potential for leukemic transformation, and variable survival ranging from years to decades. 2, 3

Diagnostic Approach

Initial Clinical Evaluation

Obtain a focused history addressing 4:

Prior chemotherapy, radiation, or radioiodine exposure
Occupational/hobby chemical exposures
Complete medication history
Alcohol intake and smoking habits
Bleeding, bruising, or thrombotic events
Infection history
Family history of blood disorders

Laboratory Testing Algorithm

Step 1: Complete Blood Count with Differential 4

Identify which cell line(s) are elevated (erythrocytosis, thrombocytosis, leukocytosis)
Quantify circulating blasts if present

Step 2: Comprehensive Blood Panel 4

RBC indices, reticulocyte count
Iron studies, vitamin B12, folate levels
LDH, bilirubin, haptoglobin
Hepatitis B and C testing
Viral studies as indicated

Step 3: Peripheral Blood Smear Examination 5

Mandatory for MDS/MPN diagnosis - count at least 200 cells using May-Grünwald-Giemsa staining 5
Look for dysplastic features:
- Erythroid: anisocytosis, poikilocytosis, basophilic stippling 5
- Myeloid: pseudo-Pelger-Huët cells (bilobed nuclei), hypogranulation 5
- Megakaryocytic: giant platelets, platelet anisocytosis 5
Enumerate blasts (≥1% circulating blasts is significant) 5

Critical Caveat: Peripheral smear alone is insufficient—it must be combined with bone marrow examination and molecular testing. 5

Bone Marrow Examination (Mandatory)

Bone marrow aspirate and biopsy are required for all suspected MPNs to establish diagnosis, assess dysplasia, and rule out disease progression. 4, 6

What to evaluate 6:

Cellularity: hypercellular marrow is typical
Morphologic dysplasia: >10% of cells in affected lineage must show dysplastic features 5
Fibrosis grading: essential for distinguishing ET from early PMF 6
Blast percentage: <30% for chronic MPNs; ≥30% indicates acute leukemia 7
Megakaryocyte morphology and clustering: helps differentiate ET from early PMF 6

Bone marrow biopsy is particularly critical for distinguishing true ET from early-stage PMF (which can present with thrombocytosis), as these have vastly different prognoses and progression risks. 6

Molecular and Cytogenetic Testing

Step 4: BCR-ABL1 Testing (First Priority) 1

Exclude CML in all MPN cases - perform chromosome analysis with FISH for BCR-ABL1
If BCR-ABL1 negative and CML still suspected, proceed to RT-PCR 1

Step 5: Driver Mutation Analysis (Diagnostic) 1

JAK2 V617F mutation - present in ~95% of PV, 50-60% of ET and PMF 1, 3
CALR mutations - found in JAK2-negative ET and PMF 1
MPL mutations - less common, seen in ET and PMF 1

These mutations are considered diagnostic and are mandatory in the workup of BCR-ABL1-negative MPNs. 1

Step 6: Cytogenetic Analysis 1, 4

Chromosome banding studies for prognostic stratification
Karyotype is included in DIPSSPlus scoring for PMF prognosis 1
FISH if standard cytogenetics fail 4, 5

Step 7: Additional Molecular Studies (Recommended) 4, 5

Flow cytometry immunophenotyping 4
Mutation analysis for prognostic markers (TP53, SF3B1) 5
Single nucleotide polymorphism array if indicated 4

Step 8: Tyrosine Kinase Fusion Screening (If Eosinophilia Present) 1

Exclude FIP1L1-PDGFRA, PDGFRB, FGFR1, and PCM1-JAK2 rearrangements by FISH or RT-PCR 1
These fusions have variable responsiveness to targeted therapies (e.g., imatinib for PDGFRA/B) 1

When to Repeat Bone Marrow Examination

Repeat bone marrow biopsy is indicated when 4:

Initial findings are inconclusive or show only subtle dysplasia
Only unilineage dysplasia with normal karyotype
Monitoring for disease progression to myelofibrosis or acute leukemia
Before initiating cytoreductive therapy 1

For mild cytopenia with minimal dysplasia and normal karyotype, observe for 6 months before confirming MDS/MPN diagnosis. 4, 5

Treatment Approach

Risk Stratification Framework

Treatment decisions are based on disease subtype, risk category, and specific complications. 1

Polycythemia Vera Treatment Algorithm

Low-Risk PV (Age <60 years, no prior thrombosis) 1:

Phlebotomy to maintain hematocrit <45% (may individualize to 42% for women) 1
Aspirin 81-100 mg daily for vascular symptoms 1
Manage cardiovascular risk factors aggressively 1
Monitor every 3-6 months for thrombosis, bleeding, or disease progression 1

Indications to Initiate Cytoreductive Therapy in Low-Risk PV 1:

New thrombosis or major bleeding
Frequent phlebotomy need with poor tolerance
Symptomatic or progressive splenomegaly
Symptomatic thrombocytosis
Progressive leukocytosis
Progressive disease-related symptoms (pruritus, night sweats, fatigue)
Disease progression to myelofibrosis or acute leukemia

High-Risk PV (Age ≥60 years or prior thrombosis history): Cytoreductive therapy is indicated at diagnosis. 1

Essential Thrombocythemia and Primary Myelofibrosis

Treatment should be guided by risk stratification systems (IPSET for ET, DIPSSPlus for PMF) and evaluated at centers with hematologic expertise. 1

Key treatment goals across all MPNs 3:

Reduce thrombotic and hemorrhagic complications
Control symptoms and improve quality of life
Prevent or delay progression to myelofibrosis or acute leukemia
Achieve molecular remission when possible

Chronic Myeloid Leukemia (BCR-ABL1 Positive)

CML requires tyrosine kinase inhibitor (TKI) therapy as first-line treatment. 1

Monitoring response to TKI therapy 1:

Cytogenetic monitoring at 3,6, and 12 months until complete cytogenetic response (CCyR) achieved
Analyze at least 20 metaphases for disease monitoring 1
Once CCyR achieved, can switch to FISH or RQ-PCR for follow-up 1
Use peripheral blood samples for treatment response monitoring 1
More frequent monitoring needed if additional chromosomal abnormalities present at diagnosis 1

Critical monitoring caveat: Watch for new clonal abnormalities in Ph-negative cells during follow-up, particularly deletions of 7q or monosomy 7, as 2-10% of CML patients develop MDS/AML in Ph-negative clones. 1

Myeloid/Lymphoid Neoplasms with Tyrosine Kinase Fusions

For disorders with PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 rearrangements, targeted therapy with appropriate tyrosine kinase inhibitors may be effective. 1

Common Diagnostic Pitfalls

Mistaking early PMF for ET: Bone marrow biopsy with fibrosis grading is essential, as early PMF can present with thrombocytosis but has worse prognosis. 6
Relying solely on peripheral smear: Always combine with bone marrow examination and molecular testing. 5
Missing cryptic BCR-ABL1 rearrangements: If chromosome analysis is normal but CML suspected, perform FISH and RT-PCR. 1
Overlooking reactive causes: Rule out infections, nutritional deficiencies, and non-hematopoietic tumors before diagnosing MPN. 1
Inadequate blast enumeration: Count at least 200 cells on peripheral smear and accurately quantify blasts in bone marrow. 5
Premature MDS/MPN diagnosis: When dysplasia is subtle with mild cytopenia and normal karyotype, observe for 6 months before confirming diagnosis. 4, 5

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