1. Myeloproliferative Neoplasms 2015
Robert J. Jacobson MD, FACP , FRCP(C). Florida Cancer Specialists Affiliate Professor of Biological Sciences Charles E. Schmidt School of Medicine Florida Atlantic University, Boca Raton, FL

2. Stem Cells and Hematopoietic Differentiation
Hematopoietic stem cells capable of
Self-renewal
Differentiation
Differentiation and proliferation controlled by molecular signals
Contact with stromal cells in bone marrow
Growth factors

3. Myeloproliferative Neoplasms (MPN)
- Clonal Hematopoietic stem cell diseases
- Overproduction of terminally differentiated cells of the myeloid lineage
Ph+ Chronic Myeloid Leukemia (CML)
Polycythemia Vera (P. Vera)
Essential Thrombocythemia (ET)
Primary Myelofibrosis (PMF)

4. CML Epidemiology and Etiology
In the US, there were 4,870 cases in 2010 and an expected 5,430 cases in 2012
15% of all adult leukemias
Incidence increases significantly with age
– Median age: ~ 67 years
– Prevalence increasing due to current therapy
– Most patients present in CP
Majority of CML-related deaths due to progression to AP/BC
– 50% of CML patients are asymptomatic at diagnosis
Risk factors
– Radiation exposure

5. Most CML Patients Are Diagnosed in the Chronic Phase
Blast Phase 10%

6. CML with Philadelphia Chromosome

7. CML Pathogenesis: Philadelphia (Ph) Chromosome
CML first cancer demonstrated to have underlying genetic abnormality
Associated with Ph chromosome
Result of translocation between chromosomes 9 and 22
Detected in approx. 95% of patients with CML

8. Clinical Presentation of Ph+ CML

9. Treatment of CML
Imatinib (Gleevec), developed by Dr. Brian Druker at Oregon Health & Sciences University and Novartis pharmaceutical company in mid-1990.
Also found to be effective in other blood cancers and GIST by inhibiting different TK proteins.
World-wide sales now $28 billion in the 10 years from
Now 4 drugs, second generation tyrosine kinase inhibitors available to treat CML.
Drugs continue throughout life.

10. Imatinib Mechanism of Action

11. Treatment of CML
4 Targeted drugs which block the action of tyrosine kinase (TKIs):
Imatinib (Gleevec)
Dastinib (Sprycel)
Nilotinib (Tasigna)
Bosutinib (Bosulif)
Side Effects
Skin rash
Fluid retention
Diarrhea
Vascular thrombosis
Omacetaxine (Synribo) or Homoharringtonine (alkaloid) approved use when 2 TKIs have failed

12. Event-Free Survival and Survival Without AP/BC on First-Line Imatinib

13. Survival Rates for Stem Cell Transplantation

14. ‘Inverted Iceberg’ Schematic of CML burden and reduction over time.

15. CML Treatment Cessation of TKIs
If relapse occurs, it develops within the first 6 months after the treatment stopped
About 40%—50% of patients have no recurrence if their initial leukemic burden was low and they had been on treatment for a long duration (> 10 years)
Ongoing studies investigating second generation TKIs e.g. nilotinib and achieving more rapid MMR > 4 – 5 logs
Current recommendation is to continue with TKI treatment for life
Patients may not be able to tolerate TKI and alternative drug chosen

16. Ph Negative MPN
Majority of the patients have the gene mutation JAK2V617F
Polycythemia vera
Essential Thrombocythemia
Primary Myelofibrosis

17. Diagnosis of Polycythemia Vera
Major Criteria
Hgb level > 18.5 g/dL in men, >16.5 g/dL in women
Presence of the JAK2V617F mutation (in 95% of patients)
Minor Criteria
Bone marrow biopsy showing hypercellularity
Serum Epo level below normal range
Endogenous erythroid colony formation in vitro
PV is likely if:
Both major criteria and at least 1 minor criterion are met, or
First major criterion and at least 2 minor criteria are met
Epo = erythropoietin; Hgb = hemoglobin; JAK = Janus-associated kinase; PV= polycythemia vera

18. Clinical Features of P. Vera
Fever, weight loss
Pruritis
Plethoric facies
Cyanosed digits
Splenomegaly
Thrombotic events
Transformation to leukemia
Myelofibrosis

19. JAK2V617F and STAT Pathways

20. Treatment of Polycythemia Vera (PV)
Control and maintain Hct levels <45%
Manage disease-related complications of PV
Phlebotomy to maintain Hct levels <45%
Low-dose aspirin in appropriate patients
Hydroxyurea or IFNα as first-line cytoreductive therapy at any age
Patients with inadequate response to or intolerance of HU use Ruxolitinib (Jakifi) JAK2 inhibitor
Hct = hematocrit; HU = hydroxyurea; IFNα = interferon- α

21. Essential Thrombocythemia
Elevated platelet count often in excess of 1 million/dL, RBC and WBC normal
JAK2V617F mutation in 50% of patients
Thrombosis/hemorrhagic complications
Splenomegaly can develop, especially if transformation to Myelofibrosis (MF)
Low dose aspirin, anegrelide, hydroxyurea used
Clinical trials underway with JAK2 inhibitors
Patients can live >10 years

22. JAK2 and Other Mutations in MPN

23. Myelofibrosis with Myeloid Metaplasia
JAK2 mutation in 60% of patients
Myelofibrosis is a clonal hematologic malignancy with reactive marrow fibrosis
Primary myelofibrosis, or PMF, entered the scientific discourse in 1879 with varied nomenclature
–Agnogenic myeloid metaplasia
–Myeloid metaplasia with myelofibrosis
–Chronic idiopathic myelofibrosis
Patients with an antecedent diagnosis of PV or ET are diagnosed with PPV-MF or PET-MF

24. Peripheral Blood and Bone Marrow in Myelofibrosis
Red blood cells, tear-drop shape
A leukoerythroblastic blood smear
Reticulin stain of marrow
Bone marrow fibrosis

25. Understanding Myelofibrosis
Myelofibrosis can be risk stratified by: low risk intermediate risk 1 & 2  high risk
–Bone marrow fibrosis
–Symptom burden
–Splenomegaly
–Cytopenias
Although the exact cause of myelofibrosis is unknown, multiple mechanisms are key features of the disease
–Genetic mutations: JAK2, CALR and MPL
–Excessive production of cytokines
–Increased JAK1 signaling

26. Cytokines Play a Key Role in Myelofibrosis

27. Overactive JAK-STAT Signaling is Present in all Patients with Myelofibrosis

28. Clinical Relevance of the Progressive Pathology of Myelofibrosis

29. Diagnosing primary Myelofibrosis: All major criteria plus ≥2 minor WHO criteria are required for diagnosis

30. Risk Stratification in Myelofibrosis

31. Burden of Disease: Symptoms of Myelofibrosis

32. Examining the causes of mortality in PMF

33. Diagnosing PPV-MF or PET-MF

34. Geyer and Mesa, ASH 2014

35. Myelofibrosis
Polycythemia Vera
Status
Agent
↓ Spleen
↓ Const. Sympt.
↑ HB
↑ SURV
↓ Phleb
↓ Vasc
Events
Approved (MF)
Phase III (PV)
Ruxolintinib (INCB18424)
+++ - ++
Unk
Phase III (MF)
Pacritnib- (SB1518)
Phase III (MF) Phase II (PV/ET)
Momelotinib (CYT387)

36. Summary & Conclusions
Myeloproliferative neoplasms are characterized by distinct and specific genetic findings and clinical presentations
The translocation t(9:22) and mutation JAK2V617F are responsible for the abnormal clonal production of cells derived from the myeloid lineage
Therapies are now available directed against the specific tyrosine kinases (BCR-ABL) or genetic pathways (JAK-STAT) that cause the uncontrolled marrow cellular growth