ACUTE LEUKEMIA

ACUTE LEUKEMIA OBJECTIVE

Define acute leukemia Classify leukemia Understand the pathogenesis Understand the pathophysiology Able to list down the laboratory investigations required for diagnosis Understand the basic management of leukemia patients

Leukemia

Incidence of leukemia of all types; 10/100 000 per annum, of which just under half are cases of acute leukaemia. Classification : Acute M:F 3:2 Acute lymphoblastic leukemia (T-ALL & B-ALL) Acute myeloid leukemia Chronic Chronic myeloid leukemia M:F 1.3:1 Chronic lymphocytic leukemia M:F 2:1

Acute Leukemia

Define : heterogenous group of malignant disorders which is characterised by uncontrolled clonal and accumulation of blasts cells in the bone marrow and body tissues Sudden onset

If left untreated is fatal within a few weeks or months

Acut MyeloidLeukemia/Morphological classification- FAB(French,American,British)
Acute nonlymphocytic (ANLL) % Adult cases M0 Minimally differentiated AML 5% - 10% Negative or < 3% blasts stain for MPO ,PAS and NSE blasts are negative for B and T lymphoid antigens, platelet glycoproteins and erythroid glycophorin A. Myeloid antigens : CD13, CD33 and CD11b are positive.  M1 Myeloblastic without maturation 10 - 20% >90% cells are myeloblasts 3% of blasts stain for MPO +8 frequently seen

FAB –AML cont. M2 AML with maturation 30 - 40% 30% - 90% are myeloblasts ~ 15% with t(8:21)

FAB FOR AML con.

FAB-AML-cont.
M4 Acute Myelomonocytic Leukemia 10-15% Increased incidence of CNS involvement Monocytes and promonocytes 20% - 80%M4 with eosinophilia ((M4-Eo), assoc with del/inv 16q – marrow eosinophil from 6% - 35%,

FAB-AML-cont.

M5a Acute Monoblastic Leukemia 10-15% M5b Acute monoblastic Leukemia with differentiation <5% Often associated with infiltration into gums/skin Weakness, bleeding and diffuse erythematous skin rash

FAB-AML-cont.

M6 Erythroleukemia (Di Guglielmo) <5% 50% or more of all nucleated marrow cells are erythroid precursors, and 30% or more of the remaining nonerythroid cells are myeloblasts (if <30% then myelodysplasia)

FAB-AML-cont.

M7 Acute Megakaryoblastic Leukemia <5% Associated with fibrosis (confirm origin with platelet peroxidase + electron microscopy or MAb to vWF or glycoproteins

FAB- Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) L-1 85% L-2 14% L-3 (Burkitt’s) 1% childhood

L1
L2
L3

Acute Leukemogenesis

Develop as a result of a genetic alteration within single cell in the bone marrowa)Epidemiological evidence :1. Hereditary Factors· Fanconi’s anaemia· Down’s syndrome· Ataxia telangiectasia


Acute Leukemogenesis

Acute Leukemogenesis

Acute Leukaemogenesis

Pathophysiology

Acute leukemia cause morbidity and mortality through :- Deficiency in blood cell number and function Invasion of vital organs Systemic disturbances by metabolic imbalance

Pathophysiology

A. Deficiency in blood cell number or function Infection - Most common cause of death - Due to impairment of phagocytic function and neutropenia Hemorrhage - Due to thrombocytopenia or 2o DIVC or liver disease Anaemia - normochromic-normocytic - severity of anaemia reflects severity of disease - Due to ineffective erythropoiesis

Pathophysiology

Invasion of vital organs- vary according to subtype i.Hyperleukocytosis -cause increase in blood viscosity-Predispose to microthrombi or acute bleeding-Organ involve : brain, lung, eyes-Injudicious used packed cell transfusion precipitate hyperviscosityLeucostatic tumour-Rare-blast cell lodge in vascular system forming macroscopic pseudotumour – erode vessel wall cause bleedingHidden site relapse-testes and meninges

Pathophysiology

Metabolic imbalance Due to disease or treatment - Hyponatremia vasopressin-like subst. by myeloblast - Hypokalemia due to lysozyme release by myeloblast - Hyperuricaemia- lysis of leukemic blast release purines into plasma

Acute Lymphoblastic Leukaemia

Cancer of the blood affecting the white blood cell known as LYMPHOCYTES. Commonest in the age 2-10 years Peak at 3-4 years. Incidence decreases with age, and a secondary rise after 40 years. In children - most common malignant disease 85% of childhood leukaemia


Acute Lymphoblastic Leukemia
Specific manifestation : *bone pain, arthritis *lymphadenopathy *hepatosplenomegaly *mediastinal mass *testicular swelling *meningeal syndrome

Acute Myeloid Leukemia

Arise from the malignant transformation of a myeloid precursor Rare in childhood (10%-15%) The incidence increases with age 80% in adults Most frequent leukemia in neonate

Acute Myeloid Leukemia

Specific manifestation : - Gum hypertrophy Hepatosplenomegaly Skins deposit Lymphadenopathy Renal damage DIVC(Disseminated Intravascular Coagulation)

Investigations

Investigations

Acute lymphoblastic leukemia

Acute myeloid leukemia

Investigations

ALL(Lymphoblast) Blast size : small Cytoplasm: Scant Chromatin: Dense Nucleoli : Indistinct Auer-rods: Never present
AML (Myeloblast) Large Moderate Fine, Lacy Prominent Present in 50%

Investigations

2. Bone marrow aspiration and trephine biopsy confirm acute leukaemia (blast>20%) usually hypercellular

Investigations

3. Cytochemical staining a) Peroxidase :- * negative ALL * positive AML

Positive for myeloblast

Investigations
b)Periodic acid schiff *Positive ALL (block) * Negative AML

Block positive in ALL

Investigations
c)Acid phosphatase : focal positive (T-ALL)

Investigations

Investigations

Investigations

5. Cytogenetics and molecular studies detect abnormalities within the leukaemic clone diagnostic or prognostic value E.g : the Philadelphia chromosome : the product of a translocation between chromosomes 9 and 22 confers a very poor prognosis in ALL

Investigations

COMMON CHROMOSOME ABNORMALITIES ASSOCIATED WITH ACUTE LEUKEMIA t(8;21) AML with maturation (M2) t(15;17) AML-M3(APML) Inv 16 AML-M4 t(9;22) Chronic granulocytic leukemia t(8;14) B-ALL

Others Investigations

DIAGNOSISSPECIFIC THERAPY
NO
YES
RELAPSE

Management

Supportive care 1. Central venous catheter inserted to : facilitate blood product adminstration of chemotherapy and antibiotics frequent blood sampling

Management

2. Blood support :- platelet concentrate for bleeding episodes or if the platelet count is <10x109/l with fever fresh frozen plasma if the coagulation screen results are abnormal packed red cell for severe anaemia (caution : if white cell count is extremely high)

Blood products : 

Transfusion of whole blood, even when fresh is only useful to replace blood loss . 3 important points should be remembered when indicating blood transfusion 1-For pt presenting with high WBC count, should not be given blood before WBC count is reduced. 2-For pts on IV drips, diuretics will be required to cover blood transfusion. 3-Large volumes of blood will result in platelet dilution

Management

Prevention and control of infection barrier nursed Intravenous antimicrobial agents if there is a fever or sign of infection

Prophylaxis of infection

1-protective isolation in the form of single room. 2-Insertion of a central venous line (Hickman line) 3-Gut decontamination a typical regimen combines colistin + ciprofloxacin and fluconazole with oral amphotericin and betadine mouth-washes. Children neomycin instead of ciprofloxacin

Prophylaxis for infection (Cont.)

4-Measures to reduce the number of pathogenic organism in the skin by using solution or creams of chlorhexidene and antiseptic soaps. Oral hygiene, clean food, avoid fresh salads, fresh fruits. Antifungal lozenges, &Tb prophylaxsis INH 5-Growth factor. G-CSF, GM-CSF from 6 days after the end of chemotherapy until WBC count > 1.0x109/L .

INFECTIONS

In febrile neutropenic patients the most common pathogenic organisms : Gram negative (Klebsiella and enterobacter spp. Pseudomonas, E. coli, proteus) originate from patient own gut bacterial flora. - Gram positive organism , staph. epidermidis, staph. aureus & streptococcus (Flora of skin and mucous membrane). -Fungal infections : candida albicans, Aspergellus.

Treatment of Established infection

Any consistent ( > 4 hrs) elevation in temp. to 38.0oC or more requires immediate blood culture and institution of broad spectrum antibiotic.

Treatment of Established infection(cont)

Third generation cephalosporin (ceftazidime) Penicillin with extended spectrum (piperacillin or azlocillin) Carbapenems (meropenem, imipenem) Monobactam (Aztroneam)

Treatment of Established infection (cont)

In Acute Llymphoblastic Leukaemia pts are susceptible to pneumocystis carenii(jirovecii) causing severe pneumomia. Treatment: high dose co-trimoxazole initially IV then change to oral treatment. 4.Physiological and social support

Drugs commonly used in the treatment of acute leukaemia

Specific treatment

Cytotoxic chemotherapy

Anti-metabolites Methotrexate Cytosine arabinoside Act: inhibit purine & pyrimidine synt or incorp into DNA S/E : mouth ulcer, cerebellar toxicity DNA binding Daunorubicin Act : bind DNA and interfere with mitosis S/E : Cardiac toxicity, hair loss

Cytotoxic chemotherapy

Mitotic inhibitors Vincristine Vinblastine Act : Spindle damage, interfere with mitosis S/E : Neuropathy, Hair loss Others Corticosteroid Act : inhibition or enhance gene expression Trans-retinoic acid Act : induces differentiation ATRA (all trans retinoic acid) in acute promyelocytic leukaemia, which has greatly reduced induction deaths from bleeding in this good-risk leukaemia.

Complications of cytotoxic drug

Early side effects nausea and vomiting mucositis, hair loss, neuropathy, and renal and hepatic dysfunction myelosuppression



Complications
Late effects Cardiac–Arrhythmias, cardiomyopathy Pulmonary–Fibrosis Endocrine–Growth delay, hypothyroidism, gonadal dysfunction Renal–Reduced GFR Psychological–Intellectual dysfunction, Second malignancy Cataracts

Outcome in adult acute leukaemia