Myeloproliferative Neoplasms 2015 Robert J Jacobson MD FACP

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 1

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 2

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) 3

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 4

Most CML Patients Are Diagnosed in the Chronic Phase 80% Blast Phase 10% 5

CML with Philadelphia Chromosome t (9; 22) 6

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 7

Clinical Presentation of Ph+ CML 8

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 2001 -2011. • Now 4 drugs, second generation tyrosine kinase inhibitors available to treat CML. • Drugs continue throughout life. 9

Imatinib Mechanism of Action 10

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 11

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

Survival Rates for Stem Cell Transplantation 13

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

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 15

Ph Negative MPN Majority of the patients have the gene mutation JAK 2 V 617 F • Polycythemia vera • Essential Thrombocythemia • Primary Myelofibrosis 16

Diagnosis of Polycythemia Vera Major Criteria 1. Hgb level > 18. 5 g/d. L in men, >16. 5 g/d. L in women 2. Presence of the JAK 2 V 617 F mutation (in 95% of patients) Minor Criteria 1. Bone marrow biopsy showing hypercellularity 2. Serum Epo level below normal range 3. Endogenous erythroid colony formation in vitro PV is likely if: A. Both major criteria and at least 1 minor criterion are met, or B. First major criterion and at least 2 minor criteria are met Epo = erythropoietin; Hgb = hemoglobin; JAK = Janus-associated kinase; PV= polycythemia vera 17

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

JAK 2 V 617 F and STAT Pathways 19

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) JAK 2 inhibitor • • • Hct = hematocrit; HU = hydroxyurea; IFNα = interferon- α 20

Essential Thrombocythemia • Elevated platelet count often in excess of 1 million/d. L, RBC and WBC normal • JAK 2 V 617 F 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 JAK 2 inhibitors • Patients can live >10 years 21

JAK 2 and Other Mutations in MPN 22

Myelofibrosis with Myeloid Metaplasia • JAK 2 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 23

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

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: JAK 2, CALR and MPL –Excessive production of cytokines –Increased JAK 1 signaling 25

Cytokines Play a Key Role in Myelofibrosis 26

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

Clinical Relevance of the Progressive Pathology of Myelofibrosis 28

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

Risk Stratification in Myelofibrosis 30

Burden of Disease: Symptoms of Myelofibrosis 31

Examining the causes of mortality in PMF 32

Diagnosing PPV-MF or PET-MF 33

Geyer and Mesa, ASH 2014 34

Myelofibrosis Status Agent ↓ ↓ ↑ Spleen Const. HB Sympt. Polycythemia Vera ↑ ↓ ↓ ↓ SURV Phleb Const. Vasc Sympt. Events Approved Ruxolintinib +++ (MF) (INCB 18424) Phase III (PV) Phase III (MF) Pacritnib+++ (SB 1518) +++ - ++ +++ Unk +++ - Unk Phase III (MF) Momelotinib +++ Phase II (CYT 387) (PV/ET) +++ - Unk Unk 35

Summary & Conclusions • Myeloproliferative neoplasms are characterized by distinct and specific genetic findings and clinical presentations • The translocation t(9: 22) and mutation JAK 2 V 617 F 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 36