Approach To The Highs And Lows Of White Cell Counts – The What, Why and How ! Dr Ng Chin Hin Consultant Haematologist National University Cancer Institute 11-MAR-2017
Approach to high WBC count
My approach • Look at the differential count – especially the manual differential count • Check if other cell lines are affected. – Low Hb or high Hb – Low Plt or high Plt • History: – Recent history of bleeding – Recent infection – Recent surgery – Recent chemotherapy, GCSF? – Any constitutional Sx? Fever, LOA/LOW, fatigue • Physical examination – liver, spleen, LN
How Do We Approach High WBC ?
36 yrs old male, p/w with 4 days history of cough and fever. O/e: crackles were heard over the right lung. Reactive neutrophilia – Monitor FBC weekly to two weekly. It secondary to infection should normalise over 2-4 weeks if the underlying infection is treated Clues: adequately. • Mainly neutrophilia • Mild left shift • May be a/w thrombocytosis • Toxic changes reported in Neu
Other causes of reactive neutrophilia • Recovering from chemotherapy, especially after administration of G-CSF Haemolysis • • Bleeding Chronic wound •
58 yrs old female, presented with abdominal discomfort and progressive lethargy over the past 3 months. O/e: Pale, Splenomegaly (10 cm) Refer patient urgently to NUH via EMD Chronic Myeloid Leukemia Clues: • Marked neutrophilia with prominent left shift – mainly myelocytes, not so much of metamyelocytes • Basophilia • Eosinophilia • Thrombocytosis • Splenomegaly !
Diagnosis of CML Demonstrating the presence of the t(9;22) or its gene product is absolutely essential in diagnosing a patient with CML Bcr-Abl cDNA Bcr Abl
Chronic / Accelerated / Blast Phase Baccarani et al, Blood 2013
Treatment of CML Tyrosine Kinase Inhibitor (TKi) – 1 st Generation: Glivec (Imatinib) – 2 nd Generation: Tagsina (Nilotinib), Sprycel (Dasatinib), Bosulif (Bosutinib), Iclusig (Ponatinib) Quintas-Cardama et al. Mayo Clin Proc 2006; 81(7):973-988
71 yrs old female, p/w recurrent fever, night sweat, LOA/LOW. o/e: moderate pallor, splenomegaly (5cm) Chronic Lymphoproliferative Disorders: • Chronic Lymphocytic Leukemia • Splenic Marginal Zone Lymphoma • Mantle Cell Lymphoma • Hairy Cell Leukemia • Follicular Lymphoma Clues: • Marked Lymphocytosis • May be associated with anemia and thrombocytopenia • Splenomegaly
Chronic Lymphocytic Leukemia • Progressive accumulation of functionally incompetent lymphocytes, which are monoclonal in origin. More common in the West – incidence: 4-6 per 100,000 • per year. Asian incidence: 0.5-1.0 per 100,000 per year. • Disease of the elderly. Median age: 70 yrs Presentation: • – Mostly asymptomatic. 25% of CLL found on routine FBC. – LN swelling: 50-90% – Splenomegaly: 25-55% – 10% with “ B ” Sx: Unintentional weigh loss >10% over 3 months, fever, drenching night sweat, extreme fatigue – Recurrent infection – Anaemia: related to disease load or secondary to autoimmune haemolytic anaemia
Diagnosis of CLL Absolute lymphocytosis > 5x10 -9 /L • Immunophenotyping: • – Expression of B cell associated antigens including CD19, CD20, and CD23. Expression of CD20 is usually weak. – Expression of CD5, a T cell associated antigen. – Low levels of surface membrane immunoglobulin (ie, SmIg weak). – Presence of Kappa or Lambda light chain restriction – needed to confirm clonality. BMA or trephine biopsy – not needed for diagnosis • FISH study – CLL panel – could identify good vs adverse • risk groups based on genetic abnormalities. – Low risk: del13q14 – High risk: TP53 abnormalities
Staging Median Survival: Stage 0 – 150 months Stage I – 101 months Stage II – 71 months Stages III and IV – 19 months
Treatment of CLL Treat only when symptomatic – symptomatic anaemia, “ B ” Sx, LN • enlargement with compression over vital organ, etc Chlorambucil – elderly • • Fludarabine/Cyclophosphamide/Ritux • Bendamustine/Ritux Allogeneic stem cell transplant – very high risk patient – p53 • abnormality
60 yrs old Malay gentleman, p/w sudden onset of left hypochondriac pain which was worsen on deep inspiration. O/e: Splenomegaly (6cm), and tender to palpation. Chronic Myelomonocytic Leukemia Clues: • Marked neutrophilia • Marked monocytosis • Splenomegaly
Presentation • Median age: 65-75 yrs Mostly asymptomatic • • Splenomegaly with or without spenic infarct (pain) Hepatomegaly • • Lymphadenopathy • Symptomatic anemia
Treatment • Mainly supportive – blood transfusion, hydroxyurea for cytoreduction • Low intensity chemotherapy – azacytidine • Curative: allogeneic stem cell transplant in younger patients (<65 yrs old)
27 yrs old Indonesian lady, p/w recurrent fever and progressive lethargy. o/e: gum hypertrophy Acute Monocytic Leukemia Clues: • High WBC with increased blast • Gum hypertrophy • Elevated LDH
20 yrs old boy, c/o chest tightness and persistent cough for past 2 weeks. He also noted easy bruising. Acute Lymphocytic Leukemia (T-ALL) Clues: Raised WBC with increased Blast, mediastinal mass, elevated LDH
Common presentation of Acute Leukemia • Bleeding Sx: Easy bruising, epistaxis, gum bleeding • Recurrent or prolonged fever • Easy fatigue • Lymphadenopathy • Splenomegaly / Hepatomegaly • Mediastinal mass
Common lab findings LDH is almost always elevated – due to high turn over of • leukemic blasts • Anemia and thrombocytopenia are common WBC is usually elevated, but can be within normal range • or even leukopenia – so pay attention to the differential count ! DIC - acute promyelocytic leukemia. • Tumorlysis – elevated UA, renal impairment, • hypocalcemia, hyperphosphatemia, hyperkalemia, elevated LDH – more common in acute lymphoblastic leukemia than acute myeloblastic leukemia
Acute Leukemia AML ALL Non- APML B-ALL T-ALL APML
Diagnosis of AML • Bone marrow aspirate and trephine: – Smear: morphological Dx (M0-M7) – Histology (trephine): immunohistochemistry – MPO, CD34, CD117 – Cytogenetic (Karyotype): risk stratification and prognosis. For examples: t(8;21), inv(16), t(15;17) are good risk, while monosomy 7, complex cytogenetics, t(6;9), inv(3) are very poor risk – Molecular study: risk stratification and prognostic. For examples: bialleilic CEBPA mutations, NPM1 mutation are good risk, while FLT3-ITD mutation, TP53, RUNX1 mutations are poor risk – Flow cytometry (immunophenotyping): determine lineage, describe baseline leukemia associated phenotypes for subsequent MRD monitoring
ELN 2017 Risk Stratification
Treatment of AML • Induction Consolidation • Induction: – Non-APML: Standard 3+7 (3 days of anthracycline plus 7 days of continuous Cytarabine infusion) – APML: ATRA/ATO with or without Anthracycline • Consolidation: – Favorable/Good risk: Chemotherapy alone (usually 3 cycles of high dose Ara-C) – Intermediate risk: Mostly allogeneic SCT, those unfit would be consolidated with chemotherapy (HIDAC) – Adverse risk: Allogeneic SCT
Diagnosis of ALL • Rarer than AML in adults • NUH: AML (40-50 cases), ALL (12-15 cases) • B-ALL vs T-ALL • Bone marrow aspirate / trephine: – Morphology – Cytogenetics – Molecular baseline MRD: IgvH and TCR
Risk Stratification of ALL • High risk: – Hypodiploidy – t(4;11) and other MLL rearrangement – t(9;22) – iAMP21 – IKZF1 deletion – TP53 mutation – Bcr-abl-like B-ALL – ETPALL – Complex cytogenetic – High WBC: B-ALL>30k, T-ALL>100k • Standard risk: those without high risk features
Treatment - ALL • Age < 30 years: MASPORE Protocol (Paediatric-inspired protocol) • Age > 30 years: HyperCVAD Protocol • Ph+ B-ALL: TKi + HyperCVAD • CD20+ B-ALL: Rituximab + HyperCVAD • Allogeneic SCT: high risk features, high MRD
56 yrs old female, p/w abdominal discomfort and feeling easy fatigue. o/e: splenomegaly (12cm) PRIMARY MYELOFIBROSIS Clues: • Leukoerythroblastic picture in PBF (presence of immature granulocytes and nucleated red cells) • Thrombocytosis – dysplastic platelet (anisocytosis, giant platelets, agranular platelet) • Tear-drop cells • Splenomegaly (massive)
Common presentation of MF • Abdominal discomfort – due to massive splenomegaly. If acutely painful – likely due to splenic infarct • Constitutional Sx : low grade temp, LOA, LOW, excessive sweating, fatigue
Lab findings - MF Elevated WBC and platelet – common. Thrombocytosis • can be quite severe (>1000k) • A/w Jak2 mutation (50%), CALR mutation (20-25%) • LDH is often elevated Typical tear-drop cells and leukoerythroblastic picture on • PBF 1-2% blasts on PBF is common but if % increasing • blast transformation
Diagnosis - MF • PBF – leukoerythroblastic picture and tear-drop cells • BMA/Trephine – abnormal megakaryocytes, increase reticulin staining on trephine • Can be idiopathic (primary) or secondary – post PV or ET myelofibrosis
Prognosis • Using D-IPSS to risk stratify: Age >65, constitutional Sx, WBC > 25k, Hb <10g, Peripheral blast ≥1% Passamonti et al, Blood 2010
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