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Leukaemia

Hematopoiesis Leukaemia
Acute Chronic
Develops & Progress quickly Progress slowly than Acute
Need to be treated as soon as May not require treatment for a
diagnosed long time after diagnosed
Affects very immature blood cells
Prevent from maturing properly
Types
Acute (No maturation Chronic (Maturation
beyond blast) beyond blast)
Lymphocytic ALL (T-ALL, B-ALL) CLL
(B/T Lineage) (Acute Lymphoblastic) (Chronic Ly mphoblastic)
Myeloid – AML CML
Granulocytes (Acute Myeloid) (Chronic Myeloid)
Erythroids
Monocytes
Myeloid Maturation Platelets

Blood Cell Maturation

Chronic Myeloid Leukaemia Management (Chronic Phase)

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Acute Leukaemia

Definition Acute Myeloid Leukaemia Acute Lymphoblastic Le ukaemia

Heterogenous group of malignant disorders Cancer that affects immature blood
Characteristics cells on myeloid cell line
Uncontrolled clonal Causes Overproduction of abn ormal
Accumulation of blasts cells in BM (Bone Marrow) & body tissues blast cells which crowd BM & prevent
Sudden onset BM from making normal blood cells
If left untreated – fatal (weeks → months)
Incidence – 1.8/100,000 (Malaysia)

Classification
FAB WHO
Morphology Immunophenotyping
Cytochemical Cytogenetic
Immunophenotyping

FAB
Acute Myeloid Leukaemia Acute Lymphoblastic Le ukaemia Arise from malignant transformation Commonest within 2-10 y/o
M0 – Acute Nonlymphocytic (ANLL) L-1 of a myeloid precursor (Peak – 3-4 y/o)
M1 – Myeloiblastic (AML) L-2 Rare in childhood (10 -15%) Incidence ↓ with age
M2 – AML with differentiation L-3 (Burkitt’s) Incidence ↑ with age Secondary rise > 40 y/o
M3 – Promyeloicytic (APML) In children – most common malignant
M4 – Myelomonocytic (AMML, Naegeli) disease (50%)
M5a – Monoblastic (AMoL, Schiling) Specific Manifestation Specific Manifestation
M5b – AmoL with differentiation Hepatosplenomegaly Bone Pain, Arthritis
M6 – Erythroleukemia (Di Guglielmo) Lymphadenopathy Lymphadenopathy
M7 – Megakaryoblastic Gum Hypertrophy (M4/ M5) Hepatosplenomegaly
Skin deposits (M4/ M5) Mediastinal mass
Principles of Leukaemogenesis Renal damage (M5) Testicular swelling
A multistep process DIVC (M3) Meningeal syndrome
Neoplastic cell is a hematopoietic pluripotent cell/ Early progenitor cell
Dysregulation of cell growth Investigations
Proliferation of leukemic clone with blocked of differentiation at an early stage Full Blood Picture
Peripheral blood count
Acute Leukaemogenesis (Pathogenesis) • Anaemia – Normochromic, Nor mocytic
Epidemiological evidence Molecular evidence • Leukopenia (<1.0x10ଽ /L) or Leukocytosis (>200x10ଽ /L), Neutropenia
Hereditary Factors Genes • Thrombocytopenia (<10 x10ଽ /L)
• Fanconi’s anaemia • Genes involved in cell Morphology
• Down’s syndrome proliferation/ differentiation Myeloblast Lymphoblast
• Ataxia telangiectasia • Changes within genes to cause Blast size Large Small
Radiation, Chemical, Drugs malignant transformation Cytoplasm Moderate Scanty
Virus related Leukaemias Chromatin Fine, Lacy Dense
• Retrovirus – HTLV 1 & EBV Nucleoli Prominent Indistinct
Pre-existing blood disorders Auer-rods Present in 50% Never present
(Risk of developing AML)
• Myelodysplastic disorders
• Myelofibrosis
• Aplastic anaemia
• Paroxysmal nocturnal
haemoglobinuria
• Chronic Myeloid Leukaemia
(CML) Acute Myeloid Acute Lymphoblastic
Bone Marrow Aspiration
Pathophysiol ogy (Cause Morbidity, Mortality) Confirm Acute Leukaemia (Blast > 20%) (WHO Classi fication)
↓ Blood cell Invasion of Vital Organs Systemic disturbances Usually Hypercellular
Number & Function (vary according to by Metabolic
subtype) Imbalance Lab Diagnosis (Classify Type of Leukaemia)
Infection Hyperleukocytosis Due to disease/ Cytochemical staining
Impairment of ↑ Blood viscosity treatment AML ALL
phagocytic function & Brain, Liver, Eyes Hyponatremia Peroxidase +ve - ve
neutropenia Injudicious used of vasopressin-like Periodic Acid Schiff -ve +ve (block)
Haemorrhage packed cell transfusion substance by Acid Phos phatase +ve
Thrombocytopenia Hidden site relapse myeloblast (Focal positive) (T-ALL)
2° DIVC/ Liver disease Testes Hypokalemia due to Immunophenotyping
Anaemia Meninges lysozyme release by Identify antigens present on blast cells
Normochromic- myeloblast Determine lymphoid/ myeloid leukaemia
normocytic Hyperuricaemia – Differentiate T-ALL/ B-ALL
Due to ineffective spontaneous lysis of Monoclonal antibodies
erythropoiesis leukaemic blast release AML CD13, CD33
purines into plasma ALL B-ALL CD10, CD19, CD22
T-ALL CD3, CD7
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Lab Diagnosis (Prognostic value)

Cytogenetic
t(8;21) AML with maturation (M2)
t(15;17) AML-M3 (APML)
Inv 16 AML-M4
t(9;22) Chronic granulocytic leukaemia (Philadelphia chromosome)
t(8;14) B-ALL
Molecular test

Other Investigations
Biochemical s creening
Leukocyte count ↑ - Renal impairment, Hyperuricaemia
Chest radiography
Mediastinal mass – Present in up to 70% of patients with T-ALL
Lumbar puncture Gum Hypertrophy
Detect Leukemic cells in CSF (indicate involvement of CNS)
(Done in Acute Lymphoblastic Leukaemia)

Management
Supportive care
Central venous catheter inserted
Discussion with family – Disease, Diagnosis, Prognosis, Choices of Treatment
Blood Support
Platelet Concentrate – Bleeding Episodes, Platelet count <10x10ଽ /L with fever
Fresh Frozen Plasma (FFP) – Coagulation results abnormal
Packed Red Cell – Severe Anaemia (Caution: If white cell count is extremely ↑)
Prevention & Control Infection
Barriers
IV Antimicrobial agents if Fever/ Sign of Infection
Physiological & Social support

Cytotoxic Chemotherapy (Specific Treatment)

Aim
Induce Re mission
(absence of any clinical or conventional lab evidence of the disease)
Eliminate hidden leukemic cells
Anti-metabolites (Methotrexate, Cytosine arabinoside)
Action Side Effects
Inhibit Purine & Pyramidine synthesis Mouth ulcer
Incorporate into DNA Cerebellar toxicity
DNA binding (Dou norubicin )
Action Side Effects
Bind DNA Cardiac toxicity
Interfere with Mitosis Hair loss
Mitotic Inhibitors (Vincristine, Vinblastine)
Action Side Effects
Spindle damage Neuropathy
Interfere with Mitosis Hair loss
Corticosteroids
Inhibition/ enhance gene expression
Trans-retinoid aci d
Induce differentiation

Complications
Early Late
Nausea, Vomiting Cardiac – Arrhythmias, Cardiomyopathy
Mucositis, Hair loss, Neuropathy, Pulmonary – Fibrosis
Renal & Hepatic dysfunction Endocrine – Growth delay,
Myelosuppression Hypothyroidism, Gonadal dysfunction
Renal - ↓ GFR
Psychological – Intellectual dysfunction
2° malignancy
Cataracts

Poor Prognosti c Factors

AML ALL
Age > 60 y/o < 1 y/o
TWBC High > 50x10ଽ /L
CNS Present (rare) Present
Sex Male/ Female Male
Cytogenetic monosomy 5, 7 t(9;22)
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Chronic Myeloid Leukaemia

Definition Lab Features

Clonal malignant myeloproliferative disorder Peripheral Blood Film
Characteristic Anaemia
↑ Proliferation of Granulocytic cell line without loss differentiation Leukocytosis (Usually > 25x10ଽ /L,
Results in Freq >100x10ଽ /L)
↑ Myeloid cells, Erythoid cells, Platelets (in Peripheral blood) WBC Differential shows granulocytes
Myeloid hyperplasia in Bone Marrow in all stages of maturation
Originate in a single abnormal haemopoietic stem cell Basophilia
Incidence – 1/100,000 (UK) Thrombocytosis
Accounts for 7-1 5% of all leukaemia in adults
Median age – 53 y/o
All age groups can be affected (inclu ding children)
Myeloid cell CML AML Normal
Blasts ↑ ↑
Etiology
Promyelocytes ↑
Not clear, Little evidence of genetic factors linked to disease
Myelocytes ↑
↑ Incidence
Metamyelocytes ↑
Survivors of atomic disasters (Nagasaki & Hiroshima)
Post radiation therapy Bands ↑
Neutrophils ↑ ↓ ↑
Leukaemogenesis Bone Marrow
Hypercellular (↓ fat spaces)
Myeloid : Erythroid = 10 : 1 to 30 : 1 (Normal = 2 : 1)
Myelocyte predominant cell, Blasts less 10%
Megakaryocytes ↑ & Dysplastic
↑ Reticulin fibrosis in 30-40%
Neutrophil Alkaline Phosphatase (NAP) ↓
Serum B12 & Transcobalamin ↑
Serum Uric acid ↑
LDH ↑
Cytogenetic - Philadelphia chromosome

Phases
Accelerated Blastic
Median duration – 3.5-5 years before Resembles acute leukaemia
evolving into ↑ aggressive phases Diagnosis requires >30% blast in
Philadelphia (Ph) chromosome (acquired cytogenetic anomaly) Clinical marrow
Characterized in all Leukemic cells in CML ↑ Splenomegaly refractory to chemo 2/3 transform to Myeloid Blastic
90-95% of CML patients have Ph chromosome ↑ Chemotherapy requirement phase
Reciprocal translocation of chromosomes 22 & 9 Lab features 1/3 transform to Lymphoid Blastic
BCR (Breakpoint Cluster Region) Blasts > 15% in blood phase
Gene on chrom. 22 fused to ABL (Ableson leukemia virus) on gene on chrom. 9 Blast & promyelocyte > 30% in blood Survival
Ph chromosome found on Basophil 20% in blood 9 months (lymphoid )
Myeloid, Monocytic, Erythroid, Megakaryocytic, B-cells, T-cells (sometimes) Thrombocytopenia 3 months (myeloid)
CML derived from pluripotent stem cell Cytogenic – Clonal evolution
BCR-ABL has ↑ activity in Tyrosine Kinase activity
BCR-ABL protein transform Hematopoietic cells Principles of Treatment
(so that their growth & survival become independent of cytokines) Relieve symptoms – Hyperleukocytosis, Splenomegaly, Thrombocytosis
BCR-ABL protects Hematopoietic cells from Apoptosis (programmed cell death) Hydration
Chemotherapy (Bulsu phan, Hydroxyurea)
Clinical Control & Prolong Chroni c phase (non-curative)
Disease is Biphasic, Triphasic (sometimes) α interferon & Chemotherapy
40% asymptomatic Imatinib mesylate
Chronic phase Chemotherapy (Hydroxyurea)
Splenomegaly (often massive) Eradicate Malignant Clone (curative)
Hypermetabolism Allogeneic transplantation
Weight loss α interferon
Anorexia Imatinib mesylate/ STI 571 (Thyrosine kinase inhibitor)
Lassitude
Night sweats Chemotherapy
Anaemia Haematological remissions – 80% for both drugs
Pallor Disease progression not altered
Dyspnoea Persistence of Ph chromosome containing clone
Tachycardia Busul phan Hydroxyurea
Abnormal Platelet function Alkylating agent, Preferred in older Inhibit enzyme Ribonucleotide
Bruising patients (not transplant candidate) reductase
Epistaxis (nosebleed) Side Effects Fewer Side Effects
Menorrhagia (abnormally heavy menstrual at regular intervals) Prolonged Myelosuppression
Hyperleukocytosis Pulmonary fibrosis
Thrombosis Skin pigmentation
↑ Purine breakdown – Gout Infertility
Visual disturbances Recombinant α-Interferon
Priapism Prolong chronic phase & ↑ s urvival
Haematological & cytogenetic remission
General Management Side Effects – Flu like symptoms, Fever & Chills, Anorexia, Depression
Discuss with family
Disease, Diagnosis, Prognosis, Choice of Treament (Cytotoxic drug, BM Prognosis
transplant), Side Effects Median survival – 3.5 years (range 2-8 years)
Interferon + Chemotherapy = 6 years
Transplant = 5+ years