Thrombocythemia Mark D. Browning, M.D. February 24, 2016

Elevated Platelet Count > 450,000 Normal Platelet Count –150, ,000 Causes of Elevated Platelet Count –Reactive –Tumors, Infection, Iron Deficiency –Stress –Splenectomy –Vincristine –Autoimmune Diseases, Other Myeloprolif. Dis –*Essential Thrombocythemia..Jak2 Aby+/- 2005

*Myeloproliferative Disorders Morphology

*Chromosome 9 …JAK2 Mutation

Myeloproliferative Class prior to JAK2 Mutation Era

*Diagnosis of Essential Thrombocythemia Mutation Negative

*Diagnosis of Essential Thrombocythemia+Mutation

Accumulation of DNA Damaged Cells

*Primary Thrombocythemia -- Essential Thrombocythemia **>450,000 platelets/ul in the absence of any other cause **Diagnosis of exclusion **Any cause of reactive thrombocytosis must be considered

*Reactive Thrombocythemia Iron deficiency Chronic inflammatory disorders Chronic infectious diseases Malignancy Other stem cell disorders such as Polycythemia vera, Chronic myelocytic leukemia, & idiopathic myelofibrosis

*Clinical History Thrombocythemia 79 yo male referred from family physician for evaluation of elevated platelet count No complaints & USAF Retired He denies arthritis, infection, cancer, TIAs, CVAs and family history of blood problems Platelet count increased from 250k, to 500k to 910k over the last 3 years

*Clinical History…Thrombocythemia Laboratory Information (R/O Iron, Inflammation & Tumor) Ferritin = 380 WNL Erythropoietin = 5.9 WNL (4.2-28) ESR = 1 Rheumatoid factor = 7.9 CT Abdomen/pelvis normal except for diverticulosis JAK2 Mutation + V617F

Essential Thrombocythemia Clinical Aspects 6,000 people in USA diagnosed/year Life expectancy is not effected F:M preponderance 2:1 Median age is 60 20% of patients <40 1/3 asymptomatic 2/3 vasomotor or thrombohemorrhagic complications

*Essential Thrombocythemia Vasomotor Symptoms Headache, light-headedness, syncope, atypical chest pain, *acral parasthesia, visual disturbances, livedo reticularis, *erythromelalgia (burning pain of the hands or feet associated with erythema and warmth) –events can be controlled with ASA –some are resistant & need cytoreductive therapy

*Essential Thrombocythemia Hypercoagulable Venous & arterial thrombotic events Distal vessel thromboses Strokes Coronary artery occlusions Budd-Chiari syndrome or skin necrosis Vasomotor symptoms: HA, dizziness, parasthesias, & acrocyanosis

Clonal disorder proven by G6PD isoenzyme studies Overlaps with other MPD, 50% of patients have leukocytosis &/or anemia Most detected on routine CBC Most are asymptomatic Very high platelet counts --bleed or hypercoagulable Primary Thrombocythemia

*Essential Thrombocythemia Laboratory Studies CBC distinguishes CML, P.Vera & Myelofibrosis –WBCs & RBCs are not markedly elevated –No teardrops or nucleated RBCs Normo/hypercellular marrow –Megakaryocytes should be increased & No Fibrosis Iron studies to exclude Iron deficiency ESR to exclude an inflammatory state JAK2 +/- & no 9/22 translocation

Increased # of Platelets

Increased Megakaryocytes

Essential Thrombocythemia Thrombosis & Hemorrhage Major thrombosis 4 to 7% Studies vary –Thrombosis 9-22% –Hemorrhage 8-14%

Essential Thrombocythemia Disease Transformation P. Vera - 2.7% Myelofibrosis - 4% Acute myeloid leukemia 1.4%

Essential Thrombocythemia Management Indiscriminate use of harmful agents is not warranted Make diagnosis accurately Evaluate for risk factors Treat patient according to each risk group

Essential Thrombocythemia Risk Stratification Low Risk –<60, No hx of thrombosis, Platelets <1.5M, no cardiovascular risk factors (smoking,obesity) High Risk –>60, Previous hx of thrombosis Intermediate Risk –neither high nor low risk

Essential Thrombocythemia Management Low-Risk –incidence of thrombosis is 1.9/100 patient years & not much different than the 1.5/100 patient years for age matched controls –No intervention

Essential Thrombocythemia Management Intermediate-Risk Patients Low-dose ASA

Essential Thrombocythemia High-Risk Study with median f/u of 27 months 3.6% risk of thrombosis if platelets <400,000 24% risk of thrombosis of platelets >400,000 and not controlled Supports cytoreductive therapy Hydroxyurea, Anagrelide, Interferon, P-32

Myelofibrosis Mark D. Browning, M.D Oncology/Hematology Associates February 24, 2016

Myelofibrosis Can present de novo Can be a secondary manifestation of: –CML –Polycythemia vera –Essential Thrombocythemia G6PD isoenzymes & cytogenetics show it is a clonal malignancy involving all hematopoietic cell lineages

*Myelofibrosis *Marrow fibrosis is its most distinguishing feature The malignant chain is a malignant stem cell line, especially megakaryocytes Its most distinguishing feature is: –Fibrosis –Fibroblasts & reticuloendothelial cells are reacting to the malignant stem cell line

Myeloproliferative Disorders Morphology CML – uncontrolled myeloid line –Ph chr + P. Vera –uncontrolled RBC line Essential thrombocythemia – uncontrolled megakaryocyte line Myelofibrosis --- excess fibrous tissue in marrow

Myelofibrosis Clinical Manifestation Non-specific symptoms & signs –Fatigue –Malaise –Abdominal distention & abdominal pain –*Marked splenomegaly results from extramedullary hematopoiesis –Dragging sensation in the abdomen, LUQ pain & early satiety

Myelofibrosis Clinical Manifestaions Less prone to splenic infarction than patients with CML Patients with rapidly progressive, acute myelofibrosis, can complain of bone pain & tenderness, especially over the sternum

Myelofibrosis Laboratory Studies CBC distinguishes Myelofibrosis from CML Normochromic, normocytic anemia with prominent anisocytosis & poikilocytosis **NUCLEATED RED BLOOD CELLS & TEARDROPS in peripheral smear –Characteristic suggesting extramedullary hematopoiesis in the spleen Giant platelets & dysplastic leukocytes (Pelger- Huet anomaly)

*Nucleated Red Blood Cells

*Teardrop RBC

Myelofibrosis Laboratory Studies Moderate increased WBC (not like CML) Disease progression, WBCs fall to subnormal levels secondary to poor production or increased destruction by the spleen Platelets may be any number at presentation –Falls to low levels or can increase dramatically after treatment Thrombocytosis after splenectomy

Myelofibrosis Laboratory Studies Diagnosis **Definitive diagnosis depends on fibrosis in the marrow biopsy **Marrow is difficult or impossible to aspirate & core biopsy is required **Biopsy can show variable distortions of marrow structure ranging from complete fibrous replacement to patchy losses of hematopoietic and fat cells

*Marrow Fibrosis

*Myelofibrosis Diagnosis Immature & abnormal megakaryocytes are frequent *Increases in reticulin & collagen can vary depending on the severity & progression of the disease process

Myelofibrosis Can develop as a secondary manifestation of CML, Polycythemia vera & Essential Thrombocythemia Proliferating megakaryocytes is a prominent component –Suggests key role of Megakaryocyte & platelet growth factor in stimulating the fibrosis Need to inspect the marrow for nests of malignant cells

Myelofibrosis Differential Diagnosis T & B cell lymphomas Hairy-cell leukemia Miliary tuberculosis CML

*Myelofibrosis Laboratory Studies Chromosomal abnormalities are frequent…only predominant karyotype…JAK2 mutation noted in 2005 Other labs follow other Myeloproliferative Disorders: –Increased Uric acid & LDH

Myelofibrosis Disease Course Protracted course Median survival is 5 to 8 years Is a disorder of older patients, death may be from natural causes -1/3 or less will die of complications resulting from their hematopoietic disorder -Unlike CML, <10% progress to acute leukemia

*Myelofibrosis Risk Factors(7) > 60 years of age Hepatomegaly Weight loss Anemia (Hgb <10) Leukocytosis (WBC > 30,000) Leukopenia (WBC < 4,000) Thrombocytopenia (<150,000) Survival 2 risk factors Survival 8-10 years if < 2 risk factors

Myelofibrosis Therapy Ruxolitinab…monoclonal approved 2011 –Weekly Rx & Improvement in splenomegaly –Anti-Jak2Aby Allogenic stem cell transplant –5 year survival rate of 47% Androgen therapy –Improves anemia in 25% of patients –Need monitoring of LFTs & prostate screening Hydroxyurea…decreases spleen size, controls platlet & WBC counts Splenectomy or splenic irradiation

Myelofibrosis Therapy