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Interpreting an Abnormal CBC

Nicholas A. Forward MD, MSc, FRCPC Assistant Professor Division of Dalhousie University [email protected]

Interpreting an Abnormal CBC – April 11, 2018

1 Disclosures • No conflicts of interest particularly relevant to this talk • Advisory Boards • Celgene • Co-/sub-investigator on a number therapeutic trials for various hematologic malignancies including , , myeloma

• Not discussing “off-label” medication use

Interpreting an Abnormal CBC – April 11, 2018 2 Lecture Objectives • 1. Understand normal cell production at a very broad level • 2. Develop an initial approach to working up CBC abnormalities • Cytopenias • “-Cytosis” • 3. Recognize concerning abnormalities • Recognize hematologic emergencies/red flags • When to refer and our local triage criteria

Interpreting an Abnormal CBC – April 11, 2018 3 Refresher- Normal Hematopoiesis

Normal bone marrow

Interpreting an Abnormal CBC – April 11, 2018 4 Refresher- Normal Hematopoiesis

Courtesy of Dr. Clinton Campbell, Hematopathology

Interpreting an Abnormal CBC – April 11, 2018 5 Refresher- Normal Hematopoiesis

Courtesy of Dr. Clinton Campbell, Hematopathology

Interpreting an Abnormal CBC – April 11, 2018 6 Refresher- The Peripheral Blood Smear

Courtesy of Dr. Clinton Campbell, Hematopathology

Interpreting an Abnormal CBC – April 11, 2018 7 Refresher – The bone marrow

Normal bone marrow

Interpreting an Abnormal CBC – April 11, 2018 8 Refresher- CBC Parameters Parameter Normal Range* Units WBC (White blood cells) 4.50-11.00 X 109 cells/L RBC (Red blood cells) 4.50-6.50 X 1012 cells/L Hgb (Hemoglobin) 140-180 g/L Hct (Hematocrit) 0.420-0.540 MCV (Mean corpuscular volume) 80.0-97.0 fL MCH (Mean corpuscular hemoglobin) 28.0-32.0 pg MCHC (Mean corpuscular hgb concentration) 315-350 g/L RDW (Red cell distribution width) 11.5-14.5 % Plt () 150-350 X 109 cells/L MPV (Mean plateler volume) 9.0-12.5 fL count 28.80-94.0 X 109 cells/L Reticulocyte percent 0.56-1.52 %

Interpreting an Abnormal CBC – April 11, 2018 *QEII lab, male patient 9 Refresher – CBC Parameters

Parameter Normal Range* Units (i.e. ANC, absolute count) 2.00-7.50 X 109 cells/L Myelocytes* - * - * - Blasts* - 1.50-4.00 X 109 cells/L 0.10-0.90 X 109 cells/L 0.00-0.50 X 109 cells/L 0.00-0.10 X 109 cells/L Immature fraction (“IG”) 0.00-0.09 X 109 cells/L *Neutrophil precursors, will only be reported on manual differential (generally abnormal) KEY MESSAGE: The absolute counts are more important/helpful than the percentage counts

Interpreting an Abnormal CBC – April 11, 2018 10 KEY MESSAGE: For WBC differential, focus on absolute counts, not percentages

Interpreting an Abnormal CBC – April 11, 2018 11 Cytopenias – Conceptual Overview

Courtesy of Dr. Clinton Campbell, Hematopathology

Interpreting an Abnormal CBC – April 11, 2018 12 Cytopenias • Conceptual definition: • Decreased quantity (absolute) of a given cell lineage due to the inability of body to support effective hematopoiesis • Imbalance of supply and demand • Technical definition: • Cell concentration below reference range for age and gender • Generally measured in cells/L

Interpreting an Abnormal CBC – April 11, 2018 13 Pancytopenia

• Pancytopenia = decrease below reference range (for age) of neutrophils, , and erythrocytes • Does not generally refer to lymphocytes, monocytes, other WBC lineages

Interpreting an Abnormal CBC – April 11, 2018 14 A conceptual approach to pancytopenia

Courtesy of Dr. Clinton Campbell, Hematopathology

Interpreting an Abnormal CBC – April 11, 2018 15 A conceptual approach to workup of pancytopenia

Courtesy of Dr. Clinton Campbell, Hematopathology

Interpreting an Abnormal CBC – April 11, 2018 16 • Reticulocyte count • Elevated (destruction, blood loss) • Decreased, “abnormally normal” for degree of anemia • (decreased production) • Reticulocyte index • Absolute reticulocyte count/maturation factor • Hct ≥ 0.35: 1.0 • 0.35> Hct ≥ 0.25: 1.5 • 0.25 > Hct ≥ 0.20: 2.0 • 0.20 > Hct: 2.5 • RI >0.02 = adequate marrow response; RI <0.02 = inadequate response

Interpreting an Abnormal CBC – April 11, 2018 17 Anemia – Kinetic approach

Increased reticsre Decreased reticsre

Easy! Bleeding or Hemolysis More difficult… Broader differential

• Source of bleeding? • Morphologic approach • Hemolysis workup • Size of cells (MCV) • LDH (increased) • Unconjugated Bilirubin (increased) • Haptoglobin (decreased) • DAT (autoimmune) Microcytic Normocytic Macrocytic • Peripheral smear • Specialized testing • Membrane defects • Hemoglobin electrophoresis • PNH screen (flow cytometry)

Interpreting an Abnormal CBC – April 11, 2018 18 Anemia -

Iron status • Ferritin* Normal, Low iron • %sat • (Reticulated hemoglobin)1 elevated iron (Soluable transferrin receptor)2

Iron deficiency anemia Acquired Chronic • Other clues: • Increased RDW • Reactive thrombocytosis Anemia of chronic Thalassemias • Decreased MCV disease/ • Normal or high RBC proportionate to (Hepcidin-mediated) count degree of anemia • Low MCV out of • , inflammation • Identify source proportion to anemia Heavy metal toxicity *Consider IDA if ferritin <100-200 particularly if Sideroblastic anemia concomitant inflammation (Lead, others – rare) • (congenital; very rare) 1. Mast et al. Am J Hematol. 2008;83:307 2. Mast et al. Clin Chem. 1998;44:45

Interpreting an Abnormal CBC – April 11, 2018 19 Anemia- Macrocytic • 6-MP/azathioprine • Hydroxyurea • Carbemazepine Rule out • Metformin medication effect • Isoniazid • Zidovudane • Trimethoprim B12, folate • Many others (MMA, homocysteine if borderline) • reviewed in Hesdorffer NEJM; 2015;373:1649 If normal…

Mild increased MCV Marked increased MCV (100-110 fL) Apparent macrocytosis (>110 fL)

• “Round macrocytes” • Clumps of cells • MDS • • Agglutination • Other marrow disorders • Liver disease • • EtOH effect • Hypothyroidism • Monoclonal protein • “Oval macrocytes” (SPEP) • MDS • Inflammation/Infection

Interpreting an Abnormal CBC – April 11, 2018 20 Anemia- Normocytic Normocytic

High retics Low/Normal retics

Renal insufficiency? (high creatinine, low EPO) Bleeding, hemolysis Early/concomitant B12/folate or iron deficiency? Hypothyroidism?

Anemia of inflammation/ Marrow failure Marrow infiltration “chronic disease” • Infection • (congenital) • Acute leukemia • , HIV, HepB/C, • MDS parvovirus, EBV, CMV etc. • Myelofibrosis • Inflammatory disorders • Aplastic anemia • Lymphoma • Malignancy • Pure red cell aplasia • Myeloma • Metastatic cancer Medication effect • Granulomatous diseases • Storage diseases • Fungal infection

Interpreting an Abnormal CBC – April 11, 2018 21 Example Case #1 • Asymptomatic 50 year old woman presenting with anemia on routine CBC • Hgb 101 g/L => 103 g/L 3 years ago • MCV 60.5 fL => 61.7 g/L 3 years ago • RBC 5.6 x 1012 cells/L • Peripheral smear: “Mild anemia with severe microcytosis, target cells”

• Likely diagnosis: • VOTE: • 1. Iron deficiency • 2. Thalassemia trait • 3. Anemia of chronic disease • 4. Lead poisoning

Interpreting an Abnormal CBC – April 11, 2018 22 Example Case #1 • Asymptomatic 40 year old woman presenting with anemia on routine CBC • Hgb 101 g/L => 103 g/L 3 years ago • MCV 60.5 fL => 61.7 g/L 3 years ago • RBC 5.6 x 1012 cells/L • Peripheral smear: “Mild anemia with severe microcytosis, target cells”

• Likely diagnosis: • VOTE: • 1. Iron deficiency • 2. Thalassemia trait => Hemoglobin electrophoresis confirms beta thalassemia trait • 3. Anemia of chronic disease • 4. Lead poisoning

Interpreting an Abnormal CBC – April 11, 2018 23 Example Case # 2 • 40 year old woman presenting with fatigue x several months • Hgb 45 g/L => 105 g/L 1 year ago • MCV 59.0 fL => MCV 80.0 fL 1 year ago • Peripheral smear: “Severe microcytic, with pencil cells” • No history of GI bleeding/menorrhagia; normal diet; no other symptoms • Likely diagnosis: • VOTE: 1. Iron deficiency 2. Thalassemia trait 3. Anemia of chronic disease 4. Lead poisoning

Interpreting an Abnormal CBC – April 11, 2018 24 Example Case # 2 • 40 year old woman presenting with fatigue x several months • Hgb 45 g/L => 105 g/L 1 year ago • MCV 59.0 fL => MCV 80.0 fL 1 year ago • Peripheral smear: “Severe microcytic, hypochromic anemia with pencil cells” • No history of GI bleeding/menorrhagia; normal diet; no other symptoms • Likely diagnosis: • VOTE: 1. Iron deficiency => Ferritin 3; responded to IV iron; diagnosed with celiac dz. 2. Thalassemia trait 3. Anemia of chronic disease 4. Lead poisoning

Interpreting an Abnormal CBC – April 11, 2018 25 Example case #3 • 53 year old male presenting with fatigue, back pain – no prior bloodwork • Hgb 88 g/L • MCV 104 g/L • Serum total protein 130 g/L (ULN 83) • Creatinine 117 umol/L • Peripheral smear: “Rouleaux present” • Likely diagnosis: • VOTE 1. B12 deficiency 2. Liver disease 3. Myeloma 4. MDS

Interpreting an Abnormal CBC – April 11, 2018 26 Example case #3 • 53 year old male presenting with fatigue, lower back pain – no prior bloodwork • Hgb 88 g/L • MCV 104 g/L • Serum total protein 130 g/L (ULN 83) • Creatinine 117 umol/L • Peripheral smear: “Rouleaux present” • Likely diagnosis: • VOTE 1. B12 deficiency 2. Liver disease 3. Myeloma => IgG 98 g/L, SPEP- monoclonal IgG kappa, marrow:50% plasma cells, skeletal survery => large lytic lesion left iliac bone 4. MDS Interpreting an Abnormal CBC – April 11, 2018 27 Anemia

KEY MESSAGE: Kinetic and morphologic approach can be used to narrow down etiology of anemia • Reticulocyte count and MCV

Interpreting an Abnormal CBC – April 11, 2018 28 Thrombocytopenia Thrombocytopenia

Increased Decreased production “Other” consumption/destruction • ITP • EtOH, other drugs • Splenic sequestration • Primary • Liver disease • Cirrhosis/portal HTN • Secondary • B12, folate deficiencies • Other causes of • Drug-induced • Infection splenomegaly • Quinine • HIV, HepB/C • Pseudothrombocytopenia • Antibiotics • EBV, CMV • Platelet clumping • GP IIb/IIIa inhibitors • H. pylori • EDTA artifact • Heparin (HITT) • Sepsis • Send in citrate tube • Thrombotic • Marrow problem • Send fresh draw, microangiopathies • MDS, aplastic glass tube, no (, anemia tourniquet etc. hemolysis +/- abN • Leukemia, coags) lymphoma, other • TTP/HUS marrow infiltration • DIC • Inherited disorder • HELLP syndrome Interpreting an Abnormal CBC – April 11, 2018 29 • Others Thrombocytopenia • Platelet thresholds • >100 => neurosurgery, other very high bleeding risk surgeries • >50 => most other surgical procedures • <20-30 => increased risk of spontaneous bleeding, would consider treatment for ITP patients • <10 => increased risk of spontaneous bleeding, would consider platelet transfusion even in absence of bleeding • Transfusion may not be effective in ITP; ?possible harm in TTP (however would still consider if actively bleeding)

Interpreting an Abnormal CBC – April 11, 2018 30 Example case #1 • Previously well 23 year old woman presents with mild fatigue, bruising, petechial x 2 days. No medications/supplements etc. • CBC normal except platelets =3 • No jaundice, adenopathy, splenomegaly, neurologic findings. • Creatinine, BiliT +D, INR, PTT, haptoglobin, LDH, DAT, Immunoglobulins, HIV, Hep B and C testing, beta-HCG all normal/negative • Peripheral smear: “Severe thrombocytopenia. No schisctocytes or spherocytes. Few large, immature platelets noted. • Diagnosis: • VOTE: 1. Immune thrombocytopenia (ITP) 2. MDS 3. Disseminated intravascular coagulation (DIC) 4. Thrombotic thrombocytopenia purpura (TTP)

Interpreting an Abnormal CBC – April 11, 2018 31 Example case #1 • Previously well 23 year old woman presents with mild fatigue, bruising, petechial rash x 2 days. No medications/supplements etc. • CBC normal except platelets =3 • Petechial rash, bruising, wet purpura. No jaundice, adenopathy, splenomegaly, neurologic findings. • Creatinine, BiliT +D, INR, PTT, haptoglobin, DAT, Immunoglobulins, HIV, Hep B and C testing, beta- HCG all normal/negative, beta-HC • Peripheral smear: “Severe thrombocytopenia. No schisctocytes or spherocytes. Few large, immature platelets noted. • Diagnosis: • VOTE: 1. Immune thrombocytopenia (ITP) => Sent to ED for IVIG and prednisone 2. MDS 3. Disseminated intravascular coagulation (DIC) 4. Thrombotic thrombocytopenia purpura (TTP)

Interpreting an Abnormal CBC – April 11, 2018 32 Example case #2 • Previously well 19 year old woman presents with moderate fatigue, bruising, petechial rash x 2 days. 3 day history of bloody diarrhea. No medications/supplements etc. • O/E: petechial rash, bruising, jaundice • CBC: Hgb 82, plt 28, WBC normal/normal diff. • Creatinine 435, BiliT 60.3, D 5.2, LDH 984 (ULN 230), haptoglobin <0.08, normal INR/PTT, beta- HCG negative • Peripheral smear: “Severe thrombocytopenia. Anemia with increased polychromasia, 6% schistocytes present. No blasts” • Likely Diagnosis: • VOTE: 1. Immune thrombocytopenia (ITP) 2. Thrombotic thrombocytopenia purpura/hemolytic uremic syndrome (TTP/HUS) 3. Disseminated intravascular coagulation (DIC) 4. Acute

Interpreting an Abnormal CBC – April 11, 2018 33 Example case #2 • Previously well 19 year old woman presents with moderate fatigue, bruising, petechial rash x 2 days. 3 day history of bloody diarrhea. No medications/supplements etc. • O/E: petechial rash, bruising, jaundice • CBC: Hgb 82, plt 28, WBC normal/normal diff. • Creatinine 435, BiliT 60.3, D 5.2, LDH 984 (ULN 230), haptoglobin <0.08, normal INR/PTT, beta- HCG negative • Peripheral smear: “Severe thrombocytopenia. Anemia with increased polychromasia, 6% schistocytes present. No blasts” • Likely Diagnosis: • VOTE: 1. Immune thrombocytopenia (ITP) 2. Thrombotic thrombocytopenia purpura/hemolytic uremic syndrome (TTP/HUS) => emergency plasma exchange, ADAMTS13 normal, Shiga-toxin producing E.coli (STEC) stool test positive consistent with HUS 3. Disseminated intravascular coagulation (DIC) 4. Interpreting an Abnormal CBC – April 11, 2018 34

• ANC of 1.0 -1.5 x 109 in absence of other cytopenias/findings may warrant investigation non-urgently. Reassuring if chronic/stable/isolated • ANC of 0.5 -1.0 x 109 more concerning, particularly if recurrent • ANC of <0.5 x 109 should be evaluated urgently particularly if new onset • If febrile treat as febrile neutropenia with broad spectrum (often IV) antibiotics (medical emergency)

Interpreting an Abnormal CBC – April 11, 2018 35 Neutropenia • Congenital • Cyclical, inherited marrow failure syndromes • “Benign ethnic neutropenia” – normal variant • Medications (non-exhaustive list) • Many culprits- most , rituximab, other monoclonal antibody therapies, antibiotics (macrolides, vanco, semi-synthetic penicillins, cephalosporins, TMP-SMX, others), anticonvulsants, 5- ASA, NSAIDs, methimazole, PTU, anti-arrythymics, clozapine, cocaine (levamisole), EtOH • B12, folate deficiency, ?iron deficiency • Infections- viral, sepsis • Inflammation- trauma/ICU, rheumatoid arthritis (Felty syndrome), autoimmune

Interpreting an Abnormal CBC – April 11, 2018 36 Neutropenia • Lymphoproliferative disorders • Any secondary to marrow infiltration (usually pancytopenic) • T-LGL leukemia and in particular (can be isolated) • Myeloid • Acute myeloid leukemia • MDS • Myelofibrosis • Other marrow failure syndromes • Aplastic anemia, PNH • Other marrow infiltrative processes (usually with pancytopenia) • Metastastic cancer, granulomatous diseases, storage diseases

Interpreting an Abnormal CBC – April 11, 2018 37 Example Case #1 • Previously well 50 year old male presents with “flu-like” illness, productive cough, fatigue x several weeks, no response to 2 courses of antibiotics. Drinks 4 rum and coke/day x years • CBC shows WBC 0.9, ANC 0.1 x 109, Hgb 78, MCV 90, Plt 32 • T 38.7, vitals otherwise stable. Otherwise normal exam. • Peripheral smear: Pancytopenia. Circulating blasts with Auer rods 23% • Likely diagnosis: • VOTE: 1. Acute lymphoblastic leukemia 2. Acute myeloid leukemia 3. Drug-induced neutropenia/pancytopenia 4. Alcohol-related marrow suppression

Interpreting an Abnormal CBC – April 11, 2018 38 Example Case #1 • Previously well 50 year old male presents with “flu-like” illness, productive cough, fatigue x several weeks, no response to 2 courses of antibiotics. Drinks 4 rum and coke/day x years • CBC shows WBC 0.9, ANC 0.1 x 109, Hgb 78, MCV 90, Plt 32 • T 38.7, vitals otherwise stable. Otherwise normal exam. • Peripheral smear: Pancytopenia. Circulating blasts with Auer rods 23% • Likely diagnosis: • VOTE: 1. Acute lymphoblastic leukemia 2. Acute myeloid leukemia => Discussed with hematologist on call. Admitted emergently and started on broad-spectrum antibiotics for febrile neutropenia. Confirmed by flow cytometry and bone marrow biopsy. Had PICC line, wall motion study and started within ~24 hours

3. Drug-induced neutropenia/pancytopeniaInterpreting an Abnormal CBC – April 11, 2018 39 4. Alcohol-related marrow suppression Blast cell with (see arrow) ASH Image Bank ID: 1294

Interpreting an Abnormal CBC – April 11, 2018 40 Definitions Disease Oversimplified definition Detailed Description Leukemia Cancer of the white blood cells • Acute (immature cells = “blasts”) • Chronic (mature cells) • Myeloid (AML, CML) • Lymphoid (ALL, CLL) • Can also be in nodes, spleen, marrow Lymphoma Cancer of the lymphocytes • • B cell Non Hodgkin Lymphoma • Non Hodgkin Lymphoma • Mostly mature cells • Can also be in blood, marrow, spleen, skin, and other organs Cancer of the bone and marrow • Involves the most differentiated form of lymphocytes (plasma cells) • Usually makes abnormal antibody protein (monoclonal protein) Myeloproliferative Proliferation of other blood cells Overproduction of: neoplasms • Platelets -- Essential thrombocytosis • Red Blood Cells -- Vera Myelodysplastic Faulty differentiation of 1 or more • Abnormal production of blood cells syndrome line • Bad cells accumulate in marrow (MDS) Interpreting an Abnormal CBC – April 11, 2018 41 (See abbreviation slide at end of presentation)

Interpreting an Abnormal CBC – April 11, 2018 42 AML- Aggressive Treatment

i.e. “3+7” Induction Chemotherapy (daunorubicin/cytarabine)

Consolidation

Good Risk Int./Poor Risk

i.e. HiDAC Consolidative Allogeneic Stem Cell (high-dose cytarabine) Chemotherapy Transplant

Interpreting an Abnormal CBC – April 11, 2018 43 AML – Less Fit/Older Patients • “Best Supportive Care” • Transfusions, antibiotics, etc. • Average survival ~3 months • Low-dose chemotherapy • Subcutaneous cytarabine (injection under skin) • Can provide partial remissions with good quality of life • 20-30% will benefit, average survival 1 year • Azacitidine • Overall survival 10-15 months depending on blast count

Interpreting an Abnormal CBC – April 11, 2018 44 Myelodysplastic Syndromes

• “Pre-leukemia” • Malignant clonal stem cell disorders • Dysplastic and ineffective blood cell production • Cytopenias (low cell counts) • Cells don’t work properly • Risks • Progressive bone marrow failure • Progression to Acute Myeloid Leukemia

Interpreting an Abnormal CBC – April 11, 2018 45 MDS- Clinical Features and Diagnosis

• Clinical features • Complications of Cytopenias • Infections, symptoms of anemia, bleeding • Diagnosis • Peripheral Blood • Bone Marrow Biopsy • Cytogenetics • Molecular Testing

Cazzola.Blood .2013:122:4021

Interpreting an Abnormal CBC – April 11, 2018 46 MDS- Treatment

• Supportive care • Transfusions, antibiotics • Growth factors • Erythropoietin, G-CSF • Hypomethylating therapy (decitabine, azacytidine) • AML-like chemotherapy • Stem cell transplant • Investigations treatments (clinical trial)

Interpreting an Abnormal CBC – April 11, 2018 47 Classification of Lymphoid Malignancies

Lymphoid Malignancies

Lymphoma Myeloma Leukemia

Acute Chronic Lymphocytic Lymphocytic Leukemia Leukemia

Interpreting an Abnormal CBC – April 11, 2018 48 Too many cells - Thrombocytosis • Always consider reactive causes first • Iron deficiency • Trauma, burns, surgery • Infection • Malignancy • Post-splenectomy • Myeloproliferative disorders • Essential thrombocytosis • • • Chronic myeloid leukemia (can occasionally present with isolated thrombocytosis)

Interpreting an Abnormal CBC – April 11, 2018 49 Too many cells - Erythrocytosis • Appropriately increased EPO • Smoking • Chronic pulmonary disease • OSA • Obesity/hypoventilation syndrome • Cardiac shunts • Altitude • Inappropriately increased EPO • Renal cell carcinoma • Hepatocellular carcinoma • Pheochromocytoma • Fibroids

Interpreting an Abnormal CBC – April 11, 2018 50 Too many cells - Erythrocytosis • Apparent increased RBCs • Plasma volume contraction due to diuretics, other causes • Medications • Erythropoeitin-stimulating agenets • Testosterone, androgeneic/anabolic • Acquired bone marrow disorders • Polycythemia vera (Jak2 v617F mutation positive in 90-95%) • Myelofibrosis • CML • Inherited • EPOR mutations, certain hemoglobinopathies, other mutations

Interpreting an Abnormal CBC – April 11, 2018 51 Too many cells - Erythrocytosis • When to be concerned: • Men: Hgb >165 (especially if >180) • Women: Hgb >160 • Suggested workup: • Evaluate for secondary causes, medications etc. • Consider EPO level (usually low in PV) • Consider peripheral blood molecular testing for JAK2 V617F

Interpreting an Abnormal CBC – April 11, 2018 52 Too many cells – WBCs (Neutrophils) • Secondary • Smoking • Physical stress • Infection • Heatstroke • Medications • Glucocorticoids, G-CSF therapy • Lithium, other medications • Solid organ malignancies • Post-splenectomy/Asplenia

Interpreting an Abnormal CBC – April 11, 2018 53 Too many cells – WBCs () • Primary • Myeloproliferative disorders • Chronic Myeloid leukemia (BCR-ABL testing is diagnostic, can be ordered on peripheral blood) • “left-shifted” , basophilia, eosinophilia • Chronic neutrophilic leukemia • Myelofibrosis, polycythemia vera > essential thrombocytosis • JAK2 V617F, calreticulin, MPL mutations • Inherited disorders • Down syndrome

Interpreting an Abnormal CBC – April 11, 2018 54 Example Case # 1 • 46 year old male presents after CBC shows elevated WBC count. On further history has had early satiety and LUQ discomfort for several months • WBC 45 x 109, ANC 39.7 x 109, Hgb 101, Plt 430 • O/E: spleen palpable one hand breadth below costal margin • Peripheral smear: “Neutrophilia with left-shift to myelocyte stage, increased basophils, eosinophils. No increase in blasts. Suspicious for CML” • What test will confirm the diagnosis? • VOTE: 1. JAK2 V617F 2. HFE C282Y 3. BCR-ABL 4. CT scan chest/abdo/pelvis

Interpreting an Abnormal CBC – April 11, 2018 55 Example Case # 1 • 46 year old male presents after CBC shows elevated WBC count. On further history has had early satiety and LUQ discomfort for several months • WBC 45 x 109, ANC 39.7 x 109, Hgb 101, Plt 430 • O/E: spleen palpable one hand breadth below costal margin • Peripheral smear: “Neutrophilia with left-shift to myelocyte stage, increased basophils, eosinophils. No increase in blasts. Suspicious for CML” • What test will confirm the diagnosis? • VOTE: 1. JAK2 V617F 2. HFE C282Y 3. BCR-ABL => Confirmed CML. Referred to hematology and had bone marrow test. Started on imatinib with excellent response. 4. CT scan chest/abdo/pelvis Interpreting an Abnormal CBC – April 11, 2018 56 Too many cells- WBC () • Secondary/Reactive: • Smoking (especially younger women) • Infections • Viral – EBV, CMV, HIV, others • Bacterial – Pertussis, TB, , bartonella, rickettsial • Drug-induced • Trauma/physical stress • Thymoma, rheumatoid arthritis • Hyperthyroidism • Non-hematologic malignancy • Post-splenectomy

Interpreting an Abnormal CBC – April 11, 2018 57 Too many cells- WBC (lymphocytosis) • Lymphoproliferative disorders • Monoclonal B cell lymphocytosis (pre-CLL) • Chronic lymphocytic leukemia • Other B cell NHLs • Mantle cell, splenic marginal zone lymphoma, , others • Acute lymphoblastic leukemia (usually would be reported as blasts) • T cell neoplasms • Mycosis fungoides/Sezary syndrome • T-LGL leukemia • Others

Interpreting an Abnormal CBC – April 11, 2018 58 Lymphocytosis- when to evaluate? • Mild lymphocytosis <7-10 x 109 cells/L in absence of cytopenias, adenopathy, splenomegaly, etc • Can repeat CBC in 6-8 weeks to confirm persistence, then consider evaluation or referral • Lymphocytosis with ALC 7-109 cells/L, or persistent lymphocytosis without a clear cause (or fevers/sweats/wt. loss/adenopathy/splenomegaly) • Reasonable to send hematology referral • Could send peripheral blood flow cytometry screen to evaluate for monotypic lymphoid population while awaiting consultation • Polytypic = unlikely a lymphoproliferative disorder • Lymph node biopsy can be helpful if adenopathy

Interpreting an Abnormal CBC – April 11, 2018 59 KEY MESSAGE: Consider reactive causes of elevated blood counts

Interpreting an Abnormal CBC – April 11, 2018 60 My doctor says I have leukemia. He says I don’t need treatment yet, But I gotta go see him every three months... My uncle had leukemia, and he got chemo right away!!!

You should get a second opinion!!

Interpreting an Abnormal CBC – April 11, 2018 61 Chronic Lymphocytic Leukemia – a few comments • Indolent (for many) mature B cell neoplasms • Analogous to Small Lymphocytic Lymphoma in the lymph nodes • Generally incurable (outside of allogeneic stem cell transplant) • count by itself generally not concerning • Many patients with WBC ~100+, personal record WBC >600 before requiring treatment • Lymphocyte-doubling time of <6 months soft-indication for treatment • Rarely treat based on this alone • Lymphocyte count commonly goes up with infection, surgery, etc. • Indications for treatment/re-evaluation include progressive cytopenias, symptomatic adenopathy or splenomegaly, “”, fatigue related to CLL

Interpreting an Abnormal CBC – April 11, 2018 62 KEY MESSAGE: For patients with CLL, indication for treatment is based on symptoms rather than specific lymphocyte count

Interpreting an Abnormal CBC – April 11, 2018 63 Interpreting an Abnormal CBC – April 11, 2018 64 Interpreting an Abnormal CBC

Nicholas A. Forward MD, MSc, FRCPC Assistant Professor QUESTIONS? Division of Hematology Dalhousie University [email protected]

Interpreting an Abnormal CBC – April 11, 2018

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