1. Chronic Myeloproliferative Neoplasms (MPN) Ph-negative
Chronic Myeloproliferative Neoplasms (MPN) Ph-negative
Marta Sobas
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation 1

2. Myeloid disorders MPN Ph CML Ph (-) AML MDS Ph (+) PV ET MF Increased
Rare
Normal (<5%)
Mature cells
Dysplasia
Blasts
AML transformation
Decreased
Yes
<5% or 5-20%
Common
Sometimes
>=20% -
Ph (+) PV ET MF

3. MPN Ph (-) epidemiology
Median age: y.o.
1. Titmarsh GJ, et al. Am J Hematol. 2014;89:
2. Sant M, et al. Blood. 2010;116:
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation

4. MPN definition A clonal desease
Mutation
Polycythemia vera
(PV)
Essential thrombocythemia (ET)
Chronic myeloid leukemia
Primary myelofibrosis
(PMF)
MPN definition
A clonal desease
Origin: pluripotential haematopoietic stem cel (HSC)
Classified according to the predominant phenotypic expression of the MPN .

5. MPN definition Independece of numerous cytokines
DECODE
Independece of numerous cytokines
Increased and abnormal myelopoiesis
Evolution/transformation possible . PV ET
MF secondary
AML
PMF

6. MPN Ph(-) etiology Not known
In different subtypes of MPN Ph(-) – mutations JAK2V617F, JAK2-exon12, CALR, MPL appear with different frequencies
There are MPN Ph(-) with no JAK, CALR, MPL mutation (Triple Negative; TN) PV ET
PMF TN ??

7. MPN Ph(-) etiology What does JAK2 normally do?
It is a switch that tells blood cells to grow
Mutations JAK2, CALR, MPL: are not the origin of the MPN Ph(-)
These mutations induce constant (independent form cytocines) JAK-STAT activation and increased myelopoiesis
Erythropoietin independence
JAK2
Stat
Proliferation and survival P
Cell Membrane
Cell nucleus
The best characterized pathway for activation by JAKs are Stats
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation 7

8. Essential thrombocythemia
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation

9. Causes of thrombocythosis - diferentiation
Causes of Reactive Thrombocytosis
MPN with Thrombocytosis
Iron Deficiency
CML
Inflammatory Diseases PV
Malignancy MF
Chronic Infections ET
Drugs (vinca alcalods…)
Post-splenectomy (or functionally asplenic state)
Rebound thrombocythosis (following acute blood loss, post-splenectomy)
MDS (5q- Sd, Sideroblastic anemia)
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation

10. Platelets anisocytosis Alt. In granulation
Copyright © 2018 American Society of Hematology
Platelets anisocytosis
Alt. In granulation
Platelets agregations

11. Essenthial thrombocythemia - clinics
1. Asimptomatic – very often 2. Increase numer of platelets in rutinary morphology 2. Thrombosis or hemorhages - sometimes Splenomegaly – no or slight
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation

12. Diagnosis + YES Essential thrombocythemia suspected Bone marrow biopsy
Blood mutation screening
JAK2V617F+ (50-60%)
CALR (20-25%)
MPL (4%)
Triple-negative (15%)
Bone marrow biopsy
to confirm diagnosis
Excluded reactive thrombocythemia ?
YES +
Diagnosis
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation

13. Treatment
Low risk of thrombosis (<60 u.o. with no previous history of thrombosis): aspirin (75 mg daily) only
In case of platelets > /ul: aspirin should not be used; in this case cytoreduction should be evaluated
Patients with high risk of thrombosis (> 60 y.o. or history of previous thrombosis +/- cardiovascular risk factors): aspirin + cytoreduction (Hydroxyurea or Anagrelide or IFN)
Pregnancy: IFN +/- aspirin +/- heparin

14. Polycythemia vera
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation

15. Polycythemia
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation

16. Clinics of polycythemia vera
Thrombosis, microvascular hyperviscocity (headache, dissiness, skin redness, vision problems, abortions)
Tiredness
Pruritus (after warm water bath)
Splenomegaly: present (different sizes)
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation

17. Increased leucocytosis and thrombocytosis is possible
Increased Hgb and Htc
Increased leucocytosis and thrombocytosis is possible
C.Rend.Soc.Biol.44: (1892)
Bone marrow: Panmyelopoesis

18. JAK2V617F+ (95%), JAK2exon 12 hypercelularity, panmyelopoyesis
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation

19. Polycythemia vera - treatment
Age > 60 y.o. and/or history of thrombosis
LOW risk NO
HIGH risk
YES
Cytoreductuve treatment (Hydroxyurea, IFN….)
+ Aspirin
Htc < 45% +
Aspirin
Pregnancy: IFN +/- aspirin +/- heparin
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation

20. Primary and secondary myelofibrosis
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation

21. Clinics of myelofibrosis
Bone marrow fibrosis
Dacryocytes (tear drop poikilocytes)
Circulating blasts
Clinics of myelofibrosis

22. Prognostic scores in MF
Prognostic scores in MF
IPSS, Cervantes et al, Blood 2009;113:
Risk group
Points
Low
Intermediate-1 1
1-2
Intermediate-2 2
3-4
High
>=3
5-6
IPSS
DIPSS
DIPSS, Gangat N et al, J Clin Oncol 2011;29:392-7;
DIPSS plus, Passamonti et al, Blood 2010;115: Gangat N et al, J Clin Oncol 2011;29:392-7
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation 22 22

23. Ruxolitinib (JAK1/JAK2 inhibitor) – inhibition of JAK-STAT pathway:
8-11 years
2-4 years
Ruxolitinib (JAK1/JAK2 inhibitor) – inhibition of JAK-STAT pathway:
Decrease of splenomegaly
Deacrease of general symptoms
This is not cure for MPN Ph(-)
When you stop the treatment – all symptoms reapere
Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation 23