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

*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

Increased Basophils

*Chronic Myeloid Leukemia…Entire Spectrum of WBC Precursors

*Myelofibrosis

*Nucleated RBCs.Myelofibrosis

*Myelofibrosis…Teardrop

* Essential Thrombocythemia…Increased Platelets

Increased Megakaryocytes

Myeloproliferative Disorders Differential Diagnosis..Tests Clinical presentation Routine CBC Bone marrow aspirate & biopsy Chromosome analysis

*Myeloproliferative Disorders Clinical Features CML –Dramatic increase in mature & immature myelocytes in the circulation –Abdominal discomfort from splenomegaly Myelofibrosis –Signs or symptoms of anemia –Splenomegaly can cause pain –Tear Drops & Nucleated RBCs ET –increased platelets can lead to platelet dysfunction P.Vera…vascular accidents

*Myeloproliferative Disorders Special Lab Studies *Leukocyte alkaline phosphatase(LAP) –Elevated in leukemoid reactions –Can have reduced levels in: Paroxysmal Nocturnal Hemoglobinuria Myelofibrosis Myelodysplastic syndromes CML

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

*Polycythemia Abnormally elevated Hemoglobin or Hematocrit Increased hematocrit can be from a reduced plasma volume (relative polycythemia) Detection & accurate diagnosis of Polycythemia because of the effect on whole blood viscosity

Blood Viscosity

*Erythroid Dependent RBCs

*Erythropoietin

*Class of Erythyrocytosis

*Diagnostic Criteria

Polycythemia vera -- Diagnostic Criteria (1960s-2007) Major –Increased RBC Mass, >92% sat, Splenomegaly Minor –>400,000 platelets, >12,000 WBC, Elevated leukocyte alkaline phosphatase, Elevated B12 level (>900pg/ml) or B-12 Binding Capacity (>2200pg/ml) Dx: 3 major, 2major/2minor

*Primary Polycythemia Vera Is a clonal disorder that is INDEPENDENT of Erythropoietin Other conditions that cause polycythemia that are erythropoietin DEPENDENT are not Primary Polycythemia vera

*Polycythemia Evaluation Erythropoietin assay – increased with hypoxia, high affinity hemoglobins, tumors & cysts JAK2 mutation Bone marrow shows panmyelosis Blood gas measurements eliminates patients with lung or heart disease (congenital heart disease & sleep apnea) Measure carbon monoxide (carboxyhemoglobin) Abnormal P50 --high affinity hemoglobinopathy RBC mass eliminates contracted plasma volume

*Erythrocytosis with Increased/Normal Erythropoietin Levels

Erythrocytosis & Erythropoeitin

High Hemoglobin Affinity…Abnormal P 50

P 50 Changes

Normal Blood Volume Relationships RBCs are produced in response to hypoxia Normal Hemoglobin varies depending on the sex of the patient and at what altitude the patient is living Hgb varies in patients with lung disease or inherited defect in the hemoglobin- oxygen dissociation

Plasma volume has its own rules –dehydration will elevate hgb even though RBC mass is not increased Major increases in RBC mass are seen with Polycythemia vera COPD patients have compensated Hgb for chronic hypoxia Normal Blood Volume Relationships

*Polycythemia Clinical Features Vary depend on the disease process & rate of onset Expansion of RBC mass requires weeks or months of sustained increased RBC production Few complaints from patients with COPD, Hemoglobinopathy or P. vera because of slow rise unless Hgb > then HA, Malaise, Easy fatiguability

*Polycythemia Clinical Features Cyanosis in patients who are hypopoxic Pruritis almost continuously especially after a shower –secondary to mast cell proliferation Palpable splenomegaly

Polycythemia Laboratory Studies Hgb of 16/18 for women/men at sea level is upper limit of normal If hgb >20, RBC mass is almost certainly elevated Increased Hgb, WBC, Platelet count, basophilia & leukocyte alkaline phosphatase with pruritis, HA, malaise, & splenomegaly is virtually diagnostic Is probably a Stem Cell Disorder

Relative Polycythemia Dehydration Overuse of diuretics Cushing’s disease Pheochromocytoma Smoking & increased carboxyhemoglobin

Primary Polycythemia Vera Therapy Accurate diagnosis is essential Maintain Hgb of 15 –phlebotomy –chemotherapy -- hydroxyurea –radiotherapy with P 32* –Ruxolitinab…monoclonal aby..Anti-Jak2Aby NEJM Jan for intolerant of Hydroxyurea Hgb <15 decreases vascular complications of the disease

*Primary Polycythemia Vascular Events & Hemoglobin Range

*Secondary Erythrocytosis Increased RBC mass without evidence of changes in other hematopoietic cell lines Hypoxic Hemoglobinopathies Increased erythropoietin –Hydronephrosis, polycystic kidney disease, renal cysts, post-kidney transplant, benign & malignant renal tumors, uterine myomas, hepatomas, cerebellar hemangiomas, idiopathic epo overproduction, adrenal adenoma, over sensitive erythropoietin receptors

Increased Erythropoietin Production -- Evaluation CT of head, abdomen & pelvis Renal and liver function tests

*Secondary Erythrocytosis…Therapy Erythropoietin producing tumor --remove the tumor Hemoglobinopathy --phlebotomy for Hgb >22 Sleep apnea --Treat disease Stress Polycythemia --discontinue smoking, phlebotomy will improve HA & fatigue