2010 Childhood Leukaemia

7/27/2019 2010 Childhood Leukaemia

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A. Osei-Akoto

DCH,SMS-KNUST


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know what leukaemia is

Causes/risk factors/epidemiology

Diagnosis- clinical features/laboratory Prognostic factors

Treatment


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1. General considerations2. Epidemiology and risk factors

3. Clinical presentation

4. Laboratory diagnosis5. Prognostic factors

6. Principles of therapy


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Classified by morphology into LYMPHOCYTIC- cells of lymphoid lineage

NONLYMPHOCYTIC- cells of granulocyte,

monocyte, erythrocyte, or platelet lineage


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97% of all childhood leukaemias Rapidly fatal within weeks to a few months of

diagnosis if untreated; often curable withtreatment

Malignant cells are referred to as BLASTS


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ALL- Acute lymphocytic (lymphoblastic)leukaemia- large numbers of lymphoblasts inBM.

Most common paediatric neoplasm in theworld

80% of all childhood acute leukaemia


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ACUTE NONLYMPHOCYTIC LEUKAEMIA(ANLL)accounts for 20% of acute leukaemiain children


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3% of childhood leukaemias Patients survive for many months to years

even without treatment

Evolve into acute that is not curable Are of non-lymphocytic lineage

Cells are more mature and functional


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Syndromes associated with chromosomalabnormalities- number/stability

Immunodeficiency states Identical twins- 70% risk (if one develops it in

1styr of life); Twins-risk is 2x that in general population if

one develops it between age 5-7yrs Intense treatment for solid tumors eg

Hodgkins, Wilms


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Congenital marrow failure states-Schwachman-Diamond syndrome, Diamond-Blackfan syndrome

Other environmental factors


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Similar clinical features for all the leukaemiasbcos of disruption of Bone marrow function.

Differ in specific clinical and lab features

Marked variation in response to therapy andin prognosis


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BONE MARROW FAILURE- Leukaemic cells in place of normal

haemopoietic elements results in decreasedproduction of rbcs, wbcs, platelets----Aplastic anaemia


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Anaemia- develops slowly1. pallor

2. Irritability

3. Decreased activity- easy fatiguability


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Bleeding tendencies-a. usually due to thrombocytopenia

i. Petechiae and ecchymosis in the skin

ii. Mucosal bleeding, such as epistaxis ormaelena

b. Associated DIC may lead to severe life-threatening bleed- eg in CNS


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Infection due to lack of adequate neutrophils- Fever is the usual symptom/sign

- Localised signs may be absent

- Infection quickly spreads-bacteremia andsepsis


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RES infiltration1. lymphadenopathy- common and may be

massive

2. Hepatosplenomegaly-massive or minimal


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Bone and/or joint pain-expansion of marrow cavity or destruction ofcortical bone by cells


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Involvement of sanctuary sites esp inrecurrence of disease

- CNSdiffuse meningeal irritation

- Testis- unilateral or bilateral enlargement outof proportion to childs sexual development.


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Peripheral blood:normal CBC does notrule out leukaemia

1. Normochromic, normocytic anemia withlow retic count

2. Thrombocytopenia is common3. Neutropenia: low (20,000

in 1/34.Blast cells is common


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BM aspiration- confirmation of diagnosisGold standard for diagnosis- presence of>25% blast cells


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COUNSELLING OF PATIENT and/orPARENTS (FAMILY) IS KEY BEFORESTARTING THERAPY


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SUPPORTIVE CARE1. Transfusional support- often necessary

a. pRbc used for correcting anaemia

b. Platelet concentrates for thrombocytopeniac. Granulocytes rarely needed


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Treatment of infections- very essentialIf fever is present take appropriate Cultures and

start iv broad-spectrum antibiotics Metabolic support- essential to prevent

Tumor Lysis Syndrome:Hyperuricemia, hyperkalaemia,hyperphosphatemia

NEUTROPENIC FEVERH/w


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Treatment of hyperviscosity- EBT andleukopheresis lowers high wbc counts

Treatment of compressive symptoms:

large collection of cells in anteriorMediastinum may produce compressivesymptoms- superior vena cava syndromeetc.

Treatment is by chemotherapy andradiotherapy


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Remission induction- 4 weeks

Objective: successful cytoreduction

Evidence: normal haematopoiesis,


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Consolidation : 14-28weeks1. Kill additional leukaemic cells

2. Prevent relapse within CNS- with therapydirected at the CNS


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Maintenance- longest phase- 2-3yrs1. Continuation of remission

2. Additional cytoreduction for cure


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Discontinuation of therapyPatients who remain in remission throughout

maintenance phase


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Read on the various agents-- action

- side effects


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ALL is a malignant disease; immaturelymphoid cells accumulate in the bonemarrow and replace normal haemopoieticelements.

The malignant cells are released intoperipheral blood, and may spread toinfiltrate all organ systems.

The normal lymphoblast conc. in bonemarrow is 5%.

25% occupancy of BM by lymphoblastconfirms diagnosis of Leukaemia


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Most common childhood cancer; accountsfor 33% of paediatric malignancies

ALL reps about 75% of childhood leukaemias;AML about 20%; 5% CML hardly seen in

children


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ALL is most common type of childhoodleukaemia

More common in whites than blacks

Boys > girls

Peak incidence in 2-6 year old age group


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ALL : 6 (2009), 3 (2010)

BURKITTS : 57 (2009), 72 (2010)

WILMS : 12 (2010) NEUROBLASTOMA: 4 (2010)


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CAUSE IS UNKNOWN The immature lymphoid cells of ALL come

from lymphoid precursor cells in the BMwhich give rise to mature B and T

lymphocytes.

The malignant cells come from clonalproliferation from a single stem or progenitorcell


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Oncogenes/proto-oncogenes : activationof these is thought to trigger eventsleading to leukaemogenesis

1. Chromosome translocation andrearrangements

2. Point mutations

3. Inactivation

4. amplification


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Hereditary- increased incidence in1. Down syndrome- 20-30 fold risk

2. Blooms syndrome

3. Fanconi syndrome/anemia

4. Wiskott-Aldrich syndrome

5. Klinefelter syndrome

6. Ataxia-telangiectasia


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ChemicalsChronic exposure to benzene, akylatingagents eg chlorambucil etc.

Radiation especially to the marrow

Survivors in Japan after atomic bomb,Children of mothers who receive xray during

pregnancy; of fathers who work in nuclearplants;

patients given extended field irradiation


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Predisposing haematological diseases-Hodgkins, multiple myeloma, CML,myeloproliferative diseases

Viruses- eg EBV


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Morphology FAB1. L1(complete) lymphoblast: small with

scanty cytoplasm, inconspicuous nucleoli.Most common type

1. L2 lymphoblasts: larger with abundantcytoplasm, one or more nucleoli. Lesscommon

2. L3- large, deeply basophilic and

vacuolated cytoplasm and prominentnucleoli.


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Immunohistochemistry classification1. Non-T, non-B-cell ALL 84% of cells

a. CALLA-negative early pre-B-cell ALL

b. CALLA-positive ALL

2. B-cell ALL 1%

3. T-cell ALL 15%


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Hepatosplenomegaly 70% Fever 40-60%

Lymphadenopathy 25-50%

Bleeding 25-50%

Bone/joint pain 25-40%

Fatigue 30%

Anorexia 20-35%


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Leukocyte count (mm3)1. < 10,000 45-55%

2. 10,000-50,000 30-35%

3. >50,000 20% Hb (gm/dl)

1. 10 25%


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Platelet count (mm3)1. 100,000 25%


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Factor Favorable unfavorable

WBC 10,000

Age 2-10 yrs 110 yrs

Immunotype CALLA+ CALLA-

Morphology L1 L2, L3

Chromosomes Normal Translocations:

DNA content N/hyperdiploid Hypodiploid,haploid

Bulky disease Absent present

Sex Female male


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A febrile illness (long duration) associatedwith adenopathy

Any disease assoc. with BM failure eg aplasticanaemia

Infectious mononucleosis Infiltration of BM- tumors: neuroblastoma,

rhabdomyosarcoma, Ewing sarcoma,retinoblastoma


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Remission induction: 4-6 weeksSuccessful in 95-98% of children

At least 3 drugs are given- prednisolone,vincristine (oncovin), Methotrexate,Adriamycin /Asparaginase


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Consolidation 14-28 weekscontinuoussystemic therapy

IT methotrexate cranial irradiation is givenfor CNS prophylaxis


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Maintenancetherapy : 2-3yrsDaily oral 6-mercaptopurine(6MP), weekly oral

methotrexate + periodic reinducton pulsesof prednisolone and vincristine


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Continuous complete remission mostcommon outcome

Relapses still occur in 30-40% of patients.Can occur in the

1. Bone marrow- the most common site forrelapse

2. CNS3. Testes- becoming the most common site

of extramedullary relapse


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ALL treatment use lower doses ofchemotherapy over a longer period of time(usually 2 to 3 years)


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vincristine (Oncovin)

daunorubicin, also known as daunomycin(Cerubidine)

doxorubicin (Adriamycin) cytarabine, also known as cytosine

arabinoside or ara-C (Cytosar)

L-asparaginase (Elspar), PEG-L-asparaginase (pegaspargase, Oncaspar)

6-mercaptopurine (Purinethol


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6-thioguanine methotrexate

cyclophosphamide (Cytoxan)

prednisone (numerous brand names)

dexamethasone (Decadron, other


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vincristine (Oncovin) doxorubicin (Adriamycin)

methotrexate

cyclophosphamide (Cytoxan)

prednisone

Dexamethasone

Allopurinol


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Refer to Child Health Treatment Guidelines Regimen induction for patients age


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Remission Rapid early responders

Late early responders

Relapse

Minimal Residual disease

Cure

Read


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Chemotherapy drugs work by attackingcells that are dividing quickly (cancer cells)

cells in the bone marrow, the mucosa of

the mouth and intestines, and the hairfollicles, also divide quickly and are alsoaffected

The side effects depend on type, dose of

drugs, and the length of time they aretaken


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hair loss

mouth sores

loss of appetite

diarrhea nausea and vomiting

increased risk of infections

Bleeding tendencies Fatigue

TLS- tumour lysis syndrome


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Learning disabilities especially in youngchildren

Transient somnolence syndrome

Fatal leucoencephalopathy

Brain tumours


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Bone marrow or peripheral blood stem celltransplant is the answer

Blood-forming stem cells used for atransplant are obtained either from the blood

(for a peripheral blood stem cell transplant,or PBSCT) or from the bone marrow (for abone marrow transplant, or BMT)


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Allogeneic stem cell transplant:

the blood-forming stem cells are generallydonated from another person

The donor's tissue type (also known as theHLA type) should be identical to thepatient's tissue type

Usually the donor is a brother or sister.Commonest method employed.


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Autologous stem cell transplant:

the patient's own stem cells are removedfrom his or her bone marrow (bonemarrow stem cells) or bloodstream

(peripheral blood stem cells, PBSCs).

Cells are frozenand stored during

treatment; purging is done and cells arethen re-infused into the child's blood aftertreatment.


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ANLL AML


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Write short notes on Acute lymphocyticleukaemia (ALL) under the following:

a. Epidemiology and risk factors

b. Clinical presentation

c. Laboratory diagnosis

d. Prognostic factors

e. Principles of therapy


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Nelson textbook of pediatrics- 18thedition NMS pediatrics 3rdedition Pediatric secrets 2ndedition Essential haematology 3rdedition-

Hoffbrand and Pettit Lecture notes on haematology-Huges-Jones, Wickramasinghe

Manual of Pediatric Hematology and

oncology -3rdedition by Lanzkowsky

Documents

2010 Childhood Leukaemia