Chronic Myeloproliferative Neoplasms (MPN) Ph-negative 2018-11-17 Chronic Myeloproliferative Neoplasms (MPN) Ph-negative Marta Sobas Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation 1

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

MPN Ph (-) epidemiology Median age: 60-65 y.o. 1. Titmarsh GJ, et al. Am J Hematol. 2014;89:581-587. 2. Sant M, et al. Blood. 2010;116:3724-3734. Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation

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 .

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

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 ??

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

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

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

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

Essenthial thrombocythemia - clinics 1. Asimptomatic – very often 2. Increase numer of platelets in rutinary morphology 2. Thrombosis or hemorhages - sometimes 3. Splenomegaly – no or slight Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation

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

Treatment Low risk of thrombosis (<60 u.o. with no previous history of thrombosis): aspirin (75 mg daily) only In case of platelets > 1000-1500/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

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

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

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

Increased leucocytosis and thrombocytosis is possible Increased Hgb and Htc Increased leucocytosis and thrombocytosis is possible C.Rend.Soc.Biol.44:384-388 (1892) Bone marrow: Panmyelopoesis

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

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

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

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

Prognostic scores in MF 2018-11-17 Prognostic scores in MF IPSS, Cervantes et al, Blood 2009;113:2895-901 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;115:1703-8 Gangat N et al, J Clin Oncol 2011;29:392-7 Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation 22 22

Ruxolitinib (JAK1/JAK2 inhibitor) – inhibition of JAK-STAT pathway: 2018-11-17 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