1. October 2014
Myeloproliferative Neoplasms Angela Fleischman Division of hematology/Oncology

2. MPN are clonal disorders of the hematopoietic stem cell
Essential Thrombocythemia (ET)
Polycythemia Vera
(PV)
Myelofibrosis (MF)
Platelets
Marrow Fibrosis
Red Cells
Hematopoietic stem cell (HSC)
JAK2V617F mutation
CALR mutation

3. MPN are clonal disorders of the hematopoietic stem cell
Polycythemia Vera
(PV)
Red Cells
Hematopoietic stem cell (HSC)
JAK2V617F mutation

4. MPN are clonal disorders of the hematopoietic stem cell
Essential Thrombocythemia (ET)
Platelets
Hematopoietic stem cell (HSC)
JAK2V617F mutation

5. MPN are clonal disorders of the hematopoietic stem cell
Myelofibrosis (MF)
Marrow Fibrosis
Hematopoietic stem cell (HSC)
JAK2V617F mutation

6. Molecular Defects in Classical MPNs
JAK2 mutations (PV 96%, ET 30-50%, PMF 50%, Blast phase MPN 50%
CALR (calreticulin) (25%-35% of patients with ET and PMF, 67-88% among JAK2 negative patients)
BCR-ABL (CML 100%)
Others:
MPL mutations
TET2 mutations
ASXL1 mutations
CBL mutations
IDH1/2 mutations
IKZF1 mutations
LNK mutations

7. Activation of EPO-Receptor (Normal)
JAK2 P
JAK2 P
Stat5 P
Stat5 P
Gene Transcription X

8. Activation of EPO-Receptor (JAK2V617F)
Stat5 P
Stat5 P
Gene Transcription
CHANGE JAK2 SHAPE AND COLOR X

9. Patient R.M. 59 yo man with 6 month history of itchy skin, headache
CBC reveals WBC Hct 60% Plt 600K
Exam: obese, reddish skin, spleen tip felt, otherwise normal
PMH: none
SH: smokes
FH: father died of leukemia

10. Patient R.M. 59 yo man with 6 month history of itchy skin, headache
CBC reveals WBC Hct 60% Plt 600K
Exam: obese, reddish skin, spleen tip felt, otherwise normal
PMH: none
SH: smokes
FH: father died of leukemia
REFERRED TO HEMATOLOGY
WHAT DO YOU DO NEXT?

11. Patient R.M. Serum Epo is low
JAK2V617F mutation is present (allele burden 45%)
Bone marrow biopsy shows hypercellular marrow, trilineage myeloproliferation, no increased fibrosis

12. Patient R.M. Serum Epo is low
JAK2V617F mutation is present (allele burden 45%)
Bone marrow biopsy shows hypercellular marrow, trilineage myeloproliferation, no increased fibrosis
DIAGNOSIS?

13. Patient R.M. Serum Epo is low
JAK2V617F mutation is present (allele burden 45%)
Bone marrow biopsy shows hypercellular marrow, trilineage myeloproliferation, no increased fibrosis
DIAGNOSIS?
Polycythemia Vera

14. Patient R.M. Serum Epo is low
JAK2V617F mutation is present (allele burden 45%)
Bone marrow biopsy shows hypercellular marrow, trilineage myeloproliferation, no increased fibrosis
DIAGNOSIS?
Polycythemia Vera
TREATMENT?

15. Patient R.M. Serum Epo is low
JAK2V617F mutation is present (allele burden 45%)
Bone marrow biopsy shows hypercellular marrow, trilineage myeloproliferation, no increased fibrosis
DIAGNOSIS?
Polycythemia Vera
TREATMENT?
ASA (81mg/day) and phlebotomize to Hct <45%
Encourage weight loss and smoking cessation

16. Polycythemia vera
Diagnosis
Standard Therapies

17. Who CRITERIA FOR Polycythemia vera
REQUIRES MEETING EITHER BOTH MAJOR CRITERIA AND ONE MINOR CRITERIA OR THE FIRST MAJOR CRITERIUM AND 2 MINOR CRITERIA
MAJOR CRITERIA:
HEMOGLOBIN > 18.5G/DL IN MEN, >16.5 G/DL IN WOMEN, OR EVIDENCE OF INCREASED RED CELL VOLUME
PRESENCE OF JAK2V617F MUTATION OR OTHER FUNCTIONALLY SIMILAR MUTATION (EG., EXON 12 MUTATION)
MINOR CRITERIA:
BM BIOPSY SHOWING HYPERCELLULARITY FOR AGE WITH TRILINEAGE MYELOPROLIFERATION
SERUM EPO BELOW REFERENCE RANGE
ENDOGENOUS ERYTHROID COLONY FORMATION IN VITRO

18. Therapeutic goals in pv
PREVENT THROMBOSIS
CONTROL DISEASE-RELATED SYMPTOMS

19. TREATMENT STRATEGIES
Reduction of CV risk factors Antiplatelet therapy (aspirin) ALL PATIENTS Phlebotomy (goal hct <45%) Cytoreduction (hydrea) HIGH RISK PATIENTS (age >60 or prior thrombosis)

20. Patient S.S.
65 yo woman found to have a plt count of 700K on 2 consecutive yearly exams
Reactive?
Primary (ET)?

21. Causes of thrombocytosis
Myeloid malignancy Essential thrombocythemia Polycythemia vera Primary myelofibrosis Chronic myeloid leukemia Refractory anemia with ringed sideroblasts and thrombocytosis Myelodysplatic syndrome assoicated with isolated del(5q) Reactive (secondary thrombocytosis Blood loss or iron deficiency Infection or inflammation Disseminated malignancy Drug effect (vincristine,epinephrine, ATRA) Hyposplenism or congenital absence of spleen Hemolytic anemia Familial thrombocytosis Mutations in TPO, MPL, JAK2V617I or unknown genes Spurious thrombocytosis Cryoglobulinemia Cytoplasmic fragmentation accompanying myeloid or lymphoid neoplasia Red cell fragmentation

22. Bone Marrow Biopsy
JAK2V617F not present

23. Essential thrombocythemia
Diagnosis
Standard Therapies

24. WHO Diagnostic criteria for ET
MUST MEET ALL 4 CRITERIA:
Sustained platelet count ≥450 x 109/L
Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes; no significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis
Not meeting WHO criteria for PV, PMF, CML, MDS or other myeloid neoplasm
Demonstration of JAK2 V617F or other clonal marker, or in the absence of a clonal marker, no evidence for reactive thrombocytosis

25. CALRETICULIN MUTATIONS IN MPN
In December groups identified calreticulin (protein designated CRT, gene designated CALR) in MPN
Present in >65% of ET and MF patients without JAK2V617F mutation
Does not occur in PV
Patients either have JAK2V617F or CALR NOT both
CRT is an ER chaperone protein and on the cell surface serves as an “eat me” signal for phagocytes

26. Treatment goals in ET
REDUCE RISK OF BLOOD CLOTS
RELIEVE SYMPTOMS

27. Blood clot Risk assessment in ET
High risk
No high-risk features
Low risk
Intermediate risk
Age > 60 y
Age < 40 y
Age y
Prior thrombosis
Platelets >1500 × 109/L
Aspirin +
cytoreductive agent
Aspirin alone
(and encourage to reduce cardiovascular risk factors as much as possible (smoking, weight, etc)

28. Choice of cytoreductive agent
Age group
First line
Second line
< 40 y
Interferon
Hydroxyurea
Anagrelide
40-75 y
> 75 y
Pipobroman
Busulphan
Radioactive phosphorus

29. PATient j.l.
73 yo man with 2 years of slowly progressive anemia, fatigue
Workup by PCP unrevealing, referred to hematology
CBC – WBC 9.5 (1% blasts), Hct 28%, Plt 150
Splenomegaly on exam
BM biopsy shows 4+ fibrosis, <5% blasts
JAK2V617F not detected

30. myelofibrosis
Diagnosis
Standard Therapies

31. Diagnostic criteria for pmf
MUST MEET ALL 3 MAJOR AND 2 MINOR CRITERIA
Major criteria:
Presence of megakaryocyte proliferation and atypia, usually accompanied by either reticulin or collagen fibrosis
Not meeting WHO criteria for polycythemia vera, BCR-ABL1–positive chronic myelogenous leukemia, myelodysplastic syndrome, or other myeloid disorders
Demonstration of JAK2 V617F or other clonal marker, or, in the absence of the above clonal markers, no evidence that bone marrow fibrosis is secondary to other causes
Minor criteria:
Leukoerythroblastosis (immature cells in blood)
Increase in serum lactate dehydrogenase level
Anemia
Palpable splenomegaly (enlarged spleen)

32. Dynamic international prognostic scoring system for mf (DIPSS)
Obtained at any time during follow-up
0 = Low
1-2 = Intermediate-1
3-4 = Intermediate-2
5-6 = High
Passamonti et al, Blood 2010

33. Causes of Death in PMF
Cervantes et al, Blood 2009.

34. Symptomatic Burden in MF
Constitutional
Symptoms
Splenomegaly
Myeloproliferation
Functioning
Percentage of patients reporting symptoms
Scherber et al, Blood 2011

35. Consequences of Increased Inflammation
HSC
exhaustion
Stress
hematopoiesis
Constitutional Symptoms
-weight loss
-fatigue
-fever

36. Management of pmf Treatment for anemia Treatment for splenomegaly
Erythropoietin (growth factor)
Corticosteroids
Androgens (danazol) +/- Prednisone
Thalidomide /lenalidomide+ Prednisone
Transfusions
Treatment for splenomegaly
Hydroxyurea
Splenectomy
Ruxolitinib

37. Ruxolitinib (JAKAFI)
Dual JAK1/JAK2 inhibitor FDA approved in Nov 2011 for: Intermediate or high-risk Myelofibrosis (=80-90% of MF patients) JAK2V617F NOT required

38. ruxolitinib WHAT IT DOES: Reduces spleen size Relieves symptoms
WHAT IT DOESN’T DO:
Improve anemia
Significantly reduce the JAK2V617F allele burden
WHAT IT MAY DO:
Retard progression of fibrosis
Extend lifespan

39. Treatment goals for mpn
Prevent thrombosis
Prevent hemorrhage
Alleviate constitutional symptoms
Minimize primary and iatrogenic disease progression
Improve QOL and survival

40. Questions?