Acute Lukemia pdf - د. خالد نافع

Fifth stage

Medicine

(Hematology)

Lec-

د.خالد نافع

27/10/2016

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

o Acute lymphoblastic leukemia (T-ALL & B-ALL)
o Acute myeloid leukemia



Chronic

o Chronic myeloid leukemia M:F 1.3: 1
o 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 are positive.

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 hypergranular promeyelocytes



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 Acute Myelomonocytic Leukemia 10-15%



Incresed incidence of CNS involvement Monocytes and promonocytes 20% - 80%



M4 with eosinophilia ((M4-Eo), associated 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,



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 Factors  Fanconi’s anaemia, Down’s syndrome, Ataxia telangiectasia



Radiation, Chemicals and Drugs



Virus related Leukemias  Retrovirus :- HTLV 1 & EBV

b) Molecular Evidence:



Oncogenes :

o Gene that code for proteins involved in cell proliferation or differentiation



Tumour Suppressor Genes :

o Changes within oncogene or suppressor genes are necessary to cause malignant

transformation.



Oncogene can be activated by :

o  chromosomal translocation
o  point mutations
o  inactivation



In general, several genes have to be altered to effect neoplastic transformation.

Pathophysiology:



Acute leukemia cause morbidity and mortality through :-

o  Deficiency in blood cell number and function
o  Invasion of vital organs
o  Systemic disturbances by metabolic imbalance

Deficiency in blood cell number or function

Infection

o Most common cause of death
o Due to impairment of phagocytic function and neutropenia

ii.

Hemorrhage

o Due to thrombocytopenia or 2o DIVC or liver disease

iii.

Anaemia

o  normochromic-normocytic
o  severity of anaemia reflects severity of disease
o  Due to ineffective erythropoiesis

B. Invasion of vital organs

o vary according to subtype

i.Hyperleukocytosis

o  cause increase in blood viscosity
o  Predispose to microthrombi or acute bleeding
o  Organ involve : brain, lung, eyes
o  Injudicious used of packed cell transfusion precipitate     hyperviscosity

ii.

Leucostatic tumour

o Rare
o blast cell lodge in vascular system forming macroscopic pseudotumour – erode

vessel wall cause bleeding

iii.

Hidden site relapse

o testes and meninges

C. Metabolic imbalance

o  Due to disease or treatment
o  Hyponatremia vasopressin-like subst. by myeloblast
o  Hypokalemia due to lysozyme release by myeloblast
o  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 decreases with age, and a secondary rise after 40 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 haemoglobin normochromic, normocytic anaemia,



WBC <1.0x10^9/l to >200x10^9/l, neutropenia and blast cells



Thrombocytopenia <10x10^9/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



determine whether 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 antibodies
AML :

CD13, CD33

ALL : B-ALL CD10, CD 19, CD22

T-ALL CD3, CD7

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

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



leucocyte count very high - renal impairment and 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 the cerebrospinal fluid, indicating
involvement of the CNS

Management:

Supportive care

1. Central venous catheter inserted

to :

o facilitate blood product
o adm. of chemotherapy

and antibiotics

o frequent blood sampling

2. Blood support :-

o  platelet con.  for bleeding episodes or if      the platelet count is <10x10^9/l with fever
o  fresh frozen plasma if the coagulation screen results are abnormal
o  packed red cell  for severe anaemia (caution : if white cell count is extremely high)

Blood products:

o Transfusion of whole blood, even when fresh is only useful to replace blood loss .
o 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

o barrier nursed
o 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 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:

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

o Methotrexate
o Cytosine arabinoside

 Act: inhibit purine & pyrimidine synt or incorp into DNA
 S/E : mouth ulcer, cerebellar toxicity



DNA binding

o Dounorubicin

 Act : bind DNA and interfere with mitosis
 S/E : Cardiac toxicity, hair loss



Mitotic inhibitors

o Vincristine
o Vinblastine

 Act : Spindle damage, interfere with mitosis
 S/E : Neuropathy, Hair loss



Others

o Corticosteroid

 Act : inhibition or enhance gene expression

o 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

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: