This document discusses the diagnostic approach and classification of myeloproliferative neoplasms according to the 2008 WHO criteria. It describes the differential diagnosis and clinical features of polycythemia vera, essential thrombocythemia, and primary myelofibrosis. It discusses diagnostic criteria, disease course, prognosis, and treatment approaches for these chronic myeloproliferative disorders.

1. Diagnostic Approach to
Myeloproliferative Neoplasms

2. 2008 WHO Classification Scheme for Myeloid Neoplasms
Acute Acute Myeloid Leukemia Chronic Myelomonocytic Leukemia
Atypical Chronic Myeloid Leukemia
Juvenile Myelomonocytic Leukemia
Myelodysplastic Syndromes MDS/MPN, unclassifiable
Chronic Myelogenous Leukemia
MDS/MPN
Polycythemia Vera
Essential Thrombocythemia
Primary Myelofibrosis
Chronic Myeloproliferative Neoplasms Chronic Neutrophilic Leukemia
Chronic Eosinophilic Leukemia, NOS
Hypereosinophilic Syndrome
Mast Cell Disease
MPNs, unclassifiable
Myeloid neoplasms associated with
Myeloproliferative neoplasms
PDGFRA rearrangement
associated with eosinophilia and
Myeloid neoplasms associated with
abnormalities of PDGFRA,
PDGFRB rearrangement
PDGFRB, or FGFR1
Myeloid neoplasms associated with
FGFR1 rearrangement (EMS)

3. • A 55 year-old man presents for routine
evaluation
• CBC reveals erythrocytosis with mild
leukocytosis and thrombocytosis:

4. What is your differential diagnosis?
• Relative erythrocytosis
– Secondary to decreased plasma volume
– Hemoglobin > 18.5 gm/dL (males) or > 16.5 gm/dL (females)
diagnostic for absolute erythrocytosis
– Otherwise, measure RBC mass
• Absolute erythrocytosis
– Polycythemia vera
– Secondary erythrocytosis

5. Differential diagnosis of erythrocytosis

6. Polycythemia vera – clinical features
• May be incidental finding of high Hgb/HCT
• Non-specific complaints: HA, weakness, dizziness, excessive sweating
• Pruritus
– Typically after hot bath/shower or rubbing of skin
– Presumed 2/2 mast cell degranulation –
histamine, prostaglandins, etc...(unproven)
– Consistent with finding that ASA can relieve pruritus in some patients
• Erythromelalgia/acral paresthesias
– Burning pain/parasthesias in hands/feet accompanied by erythema, pallor, or
cyanosis
– Thought to be 2/2 microthrombi; associated with thrombocytosis
– Responds dramatically to ASA or reduction of plt count to normal

7. Polycythemia vera – clinical features
• Thrombosis (venous or arterial)
– Risk factors include age, h/o prior thrombosis, leukocytosis
• Extreme thrombocytosis and CV risk factors may also be risk factors
(controversial)
– Suspect PV in patients with unusual sites of thrombosis, e.g. Budd-Chiari, portal,
splenic, or mesenteric vein thrombosis, particularly in women < 45
– Transient visual disturbances (e.g. amaurosis fugax, migraine)
• Splenomegaly +/- hepatomegaly

8. Diagnostic approach to erythrocytosis

9. Polycythemia Vera
Diagnostic Criteria

10. Polycythemia Vera
Course and Prognosis
• Median survival is ~ 14 years
• Chronic phase may last for years
• Progression to:
– Myelofibrosis (~10% at 10 years)
– AML (1-5% at 10 years)
• Thrombosis major source of morbidity and mortality

11. Polycythemia Vera
Treatment
• Low dose aspirin indicated for all patients
• Phlebotomy: Goal to Hct < 45 (< 42 in females)
• Myelosuppression (usually hydroxyurea)
– Typically used in patients at high risk for thrombosis (age > 60 or
prior h/o thrombosis)
• Alpha-interferon (younger high-risk patients)

12. • A 66 year-old woman presents with
headaches and recurrent TIA symptoms
• CBC reveals thrombocytosis:

13. Differential Diagnosis of Thrombocytosis
• Reactive (secondary) thrombocytosis
– Infection/inflammation
– Iron deficiency
– Chronicity of thrombocytosis helpful
• Primary thrombocytosis
– Essential thrombocythemia
– (masked) polycythemia vera
– Need to exclude CML (BCR-ABL)

14. Essential Thrombocythemia
Clinical Features
• Chronic thrombocytosis (often extreme, > 1 x 106/µL)
• Many patients are asymptomatic
• Vasomotor symptoms: headaches, syncope, visual disturbances, atypical
chest pain, erythromelalgia (typically ASA-responsive)
• Thrombosis major cause of morbidity and mortality
– Both arterial and venous; unusual sites
– No clear association with platelet count
• Paradoxical increase in bleeding complications
– Risk factors/associations:
• Extreme thrombocytosis > 1 million (controversial)
• Use of ASA > 325 mg/day or other NSAIDs
• Acquired VWD
• Splenomegaly

15. Essential Thrombocythemia
Diagnostic Criteria
• Platelet count ≥ 450,000
• JAK2 V617F+ OR no evidence of reactive thrombocytosis
• Not meeting WHO criteria for other MPNs (e.g PV, CML)
• Megakaryocyte proliferation with large and mature morphology;
no or little granulocyte or erythroid proliferation
- ALL FOUR CRITERIA ARE “REQUIRED”

16. Essential Thrombocythemia
 Bone marrow: Hypercellularity with marked
megakaryocytic hyperplasia

17. Essential Thrombocythemia
Course and Treatment
• Survival curves near age-matched controls
– Thrombosis major cause of morbidity and mortality
– Progression to myelofibrosis in ~5% and AML in ~1-5%
• Low dose aspirin indicated for all patients without history of
bleeding
• Myelosuppresive therapy for high-risk patients (age > 60 OR
h/o thrombosis)
– Hydroxyurea, anagrelide
• Treatment based on platelet count alone is controversial

21. • A 57 year-old man presents with
fatigue, anorexia, and night sweats
• He also complains of abdominal discomfort
and early satiety
• CBC reveals pancytopenia with an abnormal
peripheral smear
Seg 35, bands 20, metamyelocytes 10, myelocytes 8, promyelocytes 4, blasts 3, teardrop
RBCs, nRBCs

22. Primary Myelofibrosis
Differential Diagnosis
• Reactive myelofibrosis
– Marrow infiltration with cancer
– Infections (mycobacterial or fungus)
– Myelodysplasia
• Other MPNs
• Work-up
– Bone marrow biopsy
– Genetic testing for JAK2 V617F and BCR-ABL

23. Primary myelofibrosis – clinical features
• Severe fatigue, weight loss, fevers, night sweats
• Splenomegaly, often massive
– LUQ discomfort/pain, early satiety
• Hepatomegaly
– Portal HTN related to HSMG – ascites, varices, UGIB
– Portal vein thrombosis
• Extramedullary hematopoiesis
– Foci can occur in almost any organ
• Cytopenias (but can also have leukocytosis, thrombocytosis)
• Leukoerythroblastic reaction

24. Leukoerythroblastic Reaction
Triad:
• Tear drop RBC
• Nucleated RBC
• Immature myeloid cells
Associated with marrow
infiltration
• Myelofibrosis
• Cancer
• Certain infections

25. Primary Myelofibrosis: Diagnostic Criteria

26. Primary Myelofibrosis
 Bone marrow: Megakaryocytic hyperplasia with marked
fibrosis

27. Primary Myelofibrosis
Course and Prognosis
• Median survival of only 3 years
• Bone marrow failure
– Progressive cytopenias
– RBC transfusion dependence
– Susceptibility to infections
– Hemorrhage
• Evolution to AML

28. Primary Myelofibrosis
Course and Prognosis
DIPSS:
• Age >65 years: 1 point
• Leukocyte count >25,000/microL: 1 point
• Hemoglobin <10 g/dL: 2 points
• Circulating blast cells ≥1 percent: 1 point
• Presence of constitutional symptoms: 1 point
DIPSS category Points DIPSS-plus DIPSS-plus
points category
Low-risk 0 0 0
Intermediate-1 1-2 1 1
Intermediate-2 3-4 2 2-3
High-risk 5-6 3 4-6
Unfavorable karyotype 1
Platelets < 10,000/microL 1
RBC transfusion-dependence 1

29. Primary Myelofibrosis
Course and Prognosis

30. Primary myelofibrosis – treatment
• Supportive care
– Transfusions
– ESAs – not generally effective in PMF
• Hydroxyurea
– Can be effective in controlling leukocytosis and/or thrombocytosis
– Can ameliorate splenomegaly
– Myelosuppression Is limiting factor
• Splenectomy
– Indicated for severe symptoms related to SMG
– May be helpful for improving anemia and/or thrombocytopenia
• Splenic irradiation
– Considered for poor surgical candidates
– Benefits are transient (3-6 months)
• BMT
– Not an option for many patients

31. Primary myelofibrosis – treatment
• Well tolerated – initial study with higher doses of thalidomide poorly tolerated
• 28% with ongoing response
– Durable treatment response for anemia and thrombocytopenia, not SMG

33. JAK2 inhibitors in MPNs
Grade 3/4 Grade 3/4
thrombocytopenia anemia
INCB018424 20% 23%
TG101348 24% 35%
CYT387 27% 7%
Anemia response by IWG
INCB018424 8%
TG101348 0%
CYT387 50%