acute leukemia

Fifthstage

Medicine
Lec-14
د.محمد

3/4/2017

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

Incidence of leukaemia 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 Leukaemia:

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

FAB Acute Myeloid Leukemia:

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 arepositive.


M1 Myeloblastic without maturation 10 - 20%
>90% cells are myeloblasts
3% of blasts stain for MPO
+8 frequently seen

M2 AML with maturation 30 - 40%

30% - 90% are myeloblasts ~ 15% with t(8:21)

M3 Acute Promyelocytic Leukemia (APML) 10-15%

marrow cells hypergranularpromeyelocytes
Auer rods/ faggot cells may be seen
Classical-Hypergranular, 80% leukopaenic
Variant-Hypogranular, leukocytosis
Granules contain procoagulants (thromboplastin-like) - massive DIC t(15:17) is diagnostic

M4 AcuteMyelomonocytic Leukemia 10-15%

Incresed incidence of CNS involvement Monocytes and promonocytes 20% - 80%
M4 with eosinophilia ((M4-Eo), assoc with del/inv 16q
marrow eosinophil from 6% - 35%,

M5a Acute Monoblastic Leukemia 10-15%

M5b AMoL with differentiation <5%
Often asso with infiltration into gums/skin
Weakness, bleeding and diffuse erythematous skin rash

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)

M7 Acute Megakaryoblastic Leukemia <5%

Assoc with fibrosis
(confirm origin with platelet peroxidase + electron microscopy or MAb to vWF or glycoproteins

Acute Leukaemogenesis:

Develop as a result of a genetic alteration within single cell in the bone marrow
a)Epidemiological evidence:
Hereditary FactorsFanconi’sanaemia, Down’s syndrome, Ataxia telangiectasia
Radiation, Chemicals and Drugs
Virus related LeukemiasRetrovirus :- HTLV 1 & EBV
b)Molecular Evidence:
Oncogenes :
Gene that code for proteins involved in cell proliferation or differentiation
Tumour Suppressor Genes :
Changes within oncogene or suppressor genes are necessary to cause malignant transformation.
Oncogene can be activated by :
chromosomal translocation
point mutations
inactivation
In general, several genes have to be altered to effect neoplastic transformation.


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

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
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 of packed cell transfusion precipitate hyperviscosity
Leucostatictumour
Rare
blast cell lodge in vascular system forming macroscopic pseudotumour – erode vessel wall cause bleeding
Hidden site relapse
testes and meninges


Metabolic imbalance
Due to disease or treatment
Hyponatremia vasopressin-like subst. by myeloblast
Hypokalemia due to lysozyme release by myeloblast
Hyperuricaemia- spont 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 decreaseswith age, and a secondary rise after40 years.
In children - most common malignant disease
85% of childhood leukaemia

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

Specific manifestation :

Gum hypertrophy
Hepatosplenomegaly
Skins deposit
Lymphadenopathy
Renal damage
DIVC

Investigations:

1. Full blood count
reduced haemoglobinnormochromic, normocytic anaemia,
WBC <1.0x109/l to >200x109/l, neutropenia and blast cells
Thrombocytopenia<10x109/l).

2. Bone marrow aspiration and trephine biopsy

confirm acute leukaemia (blast > 20%)
usually hypercellular

3. Cytochemical staining

a) Peroxidase :-
* negative ALL
* positive AML
b)Periodic acid schiff
*Positive ALL (block)
* Negative AML
c)Acid phosphatase :
focal positive
(T-ALL)


4.Immunophenotyping
· identify antigens present on the blast cells
determinewhether the leukaemia is lymphoid or myeloid(especially important when cytochemical markers are negative or equivocal. E.g : AML-MO)
differentiate T-ALL and B-ALL
Certain antigens have prognostic significance
Rare cases of biphenotypic where both myeloid and lymphoid antigen are expressed
Able to identify the subtype of leukemia. E.g : AML-M7 has a specific surface marker of CD61 etc.
Monoclonal antibodies(McAb) are recognised under a cluster of differentiation(CD). MONOCLONAL ANTIBODIES USED FOR CHARACTERISATION OF ALL AND AML. Monoclonal antibodiesAML : CD13, CD33ALL : B-ALL CD10, CD 19, CD22
T-ALL CD3, CD7

5. Cytogenetics and molecular studies

detect abnormalitieswithin the leukaemic clone
diagnostic or prognosticvalue
E.g : the Philadelphia chromosome: the product of a translocation between chromosomes 9 and 22
confers a very poor prognosis in ALL
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


6.Biochemical screening
leucocytecount very high - renal impairmentand hyperuricaemia

7. Chest radiography

mediastinal mass - present in up to 70% of patients with T -ALL
In childhood ALL bone lesions may also seen.

8.Lumbar puncture

initial staging inv. to detect leukaemic cells in thecerebrospinal fluid, indicating involvement of the CNS

Management:

Supportive care
1. Central venous catheter insertedto :
facilitate blood product
adm. of chemotherapyand antibiotics
frequent blood sampling
2. Blood support :-
platelet con.for bleeding episodes or if the platelet count is <10x109/l with fever
fresh frozen plasma if the coagulation screen resultsare abnormal
packed red cell for severe anaemia (caution : if white cell count isextremely 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, over 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

3. Prevention and control infection

barriernursed
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
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.
Third generation cephalosporin (ceftazidime)
Penicillin with extended spectrum (piperacillin or azlocillin)
Carbapenems (meropenem, imipenem)
Monobactam (Aztroneam)
In Acute LlymphoblasticLeukaemia 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:

Used of cytotoxic chemotherapy.
Aim :
To induce remission
(absence of any clinical or conventional laboratory evidence of the disease)
To eliminate the hidden leukemic cells

Cytotoxic chemotherapy:

Anti-metabolites
Methotrexate
Cytosine arabinoside
Act: inhibit purine & pyrimidine synt or incorp into DNA
S/E : mouth ulcer, cerebellar toxicity
DNA binding
Dounorubicin
Act : bind DNA and interfere with mitosis
S/E : Cardiac toxicity, hair loss
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 promyelocyticleukaemia, which hasgreatly reduced induction deaths from bleeding in this good-risk leukaemia.


Complications of cytotoxic drug:
Early side effects
nausea and vomiting
mucositis, hair loss, neuropathy, andrenal and hepatic dysfunction
myelosuppression
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: