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

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

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)

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

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

CML with Philadelphia Chromosome

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

Clinical Presentation of Ph+ CML

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.

Imatinib Mechanism of Action

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

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

Survival Rates for Stem Cell Transplantation

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

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

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

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

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

JAK2V617F and STAT Pathways

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

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

JAK2 and Other Mutations in MPN

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

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

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

Cytokines Play a Key Role in Myelofibrosis

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

Clinical Relevance of the Progressive Pathology of Myelofibrosis

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

Risk Stratification in Myelofibrosis

Burden of Disease: Symptoms of Myelofibrosis

Examining the causes of mortality in PMF

Diagnosing PPV-MF or PET-MF

Geyer and Mesa, ASH 2014

  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)

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