ACUTE LYMPHOBLASTIC LEUKEMIA (ALL)

Definition Leukemia: Uncontrolled neoplastic

proliferation of hematopoietic cells in the bone marrow.

Acute: based on presentation i.e early onset, presents early and may die early.

First disseminated cancer shown to be curable and as such has represented the model malignancy for the principle of cancer diagnosis, prognosis and treatment.

Epidemiology

It is the second most common childhood cancer in Kenya after Burkitt lymphoma

Leukaemia account for about 20% of peadiatric malignancies in Kenya with ALL being 68% of this.

It has a striking peak incidence between 2-6years of age and occurs slightly more frequently in boys than in girls.

Etiology Etiology is unknown. Several genetic and environmental

factors are associated with childhood leukemia:

Genetic conditions: Down syndrome Turner syndrome Fanconi syndrome Neurofibromatosis Bloom syndrome Ataxia telangiectasia Diamond blackfan anaemia Severe combined immune deficiency Schwachman syndrome Paroxysmal nocturnal hamoglobinuna Kleinfelters syndrome Li freumeni syndrome

Environmental factors

Ionizing radiation Drugs Alkylating agents Nitrosourea Epipodophyllotoxin Benzene exposure Advanced maternal age

Pathogenesis

The classification of ALL depends on characterizing the malignant cell in the bone marrow to determine the morphology, phenotypic characteristics as measured by cell membrane markers, and cytogenetic and molecular genetic features.

Morphology alone is usually adequate for diagnosis, the others are for disease classification and prognosis and choice appropriate therapy

FAB classification L1 – Lymphoblast are predominantly small, with

little cytoplasm L2 – Larger and pleomorphic with increased

cytoplasm, irregular nuclear shape and prominent nucleoli

L3 – finely stippled and homogeneous nuclear chromatic, prominent nucleoli and deep blue cytoplasm with prominent vacuolization. Also known as Burkitt leukaemia – one of the most rapidly growing cancer in humans.

85% of ALL derived from progenitors of B celli and about 15% are derived from T cells and about 1% are derived from B cell (relatively mature)

Chromosomal abnormalities are found in most patients with ALL.

No staging system fro ALL

Clinical manifestations

Initial presentation is usually non-specific and has been present for a short while (4wks)

Anorexia Fatigue Irritability Low-grade fever Patients often have a history of an

upper respiratory tract infection in the proceeding 1-2 months. Some may have a skin rash.

Clinical manifestations For the few who present later, symptoms

are predominantly localised to the bones or joints, and may include joint swelling

There may also be abdominal discomfort. As the disease progresses, signs and

symptoms of bone marrow failure become obvious

Pallor and fatigue – anaemia Bruising and epistaxis –thrombocytopenia Fever – (neutropenia, malignancy) - 25%

may be due to and infection such as URTI or otitis media

On examination

Pallor Purpuric and petechial skin lesions Mucous membrane hemorrhage Lymphadenopathy Splenomegaly Hepatomegaly (less common) Tenderness on bone palpation Joint swelling and effusion

Rarely, sign of intracranial pressure, such as headache and vomiting, indicate leukaemic meningeal involvement - (Meningeal lymphomatosis) so have papilledema, cranial nerve palsies, seizures, nuchal rigidity.

Hyperviscosity syndrome may occur. Respiratory distress – usually related

to anaemia but may occur due to mediastinal mass of lymphoblasts. Seen typically in adolescent boys with T-cell ALL

Diagnosis

1) Diagnostic testsFull blood count Hb- anemia WBC counts. May be raised, normal

or decreased. Majority of patients have a WBC count of less than 10,000/mm3

Platelets – thrombocytopenia (some pts (¼) have level >100,000/mm3

Peripheral blood film Usually reported as atypical

lymphocytes. These are blasts in circulation

Bone Marrow Aspirate Leukemic lymphoblasts Occasionally BMA may be hypocellular

– do biopsy. ALL is diagnosed by bone marrow cells

being 25% lymphoblast

Other diagnostic tests

Cytochemical staining To differentiate from AMLType of leukemia

PAS Sudan black/ Peroxidase

Lysozyme esterase

ALL ++ - -

AML - +++ N

Cell markers (flow cytometry) To further classify into B cell, T cell or

Pre B Surface markers e.g. B cells: TdT, CD34, CD20, CD24, CD10. T cell: CD7, CD2, CD5. CD10 is also known as common ALL

antigen (CALLA) Good prognosis.Cytogenetics Chromosomal alterations e.g.

Translocations. Poor prognosis.

2. Tests for disease burden and spread

Chest x-ray – check for mediastinal mass.

CSF – Lymphoblasts and CSF leukocyte count increased.

Bone radiographs – may show altered medullary trabeculae, cortical defects or subepiphyseal bone resorption

Biochemistry- LDH levels.

3. Investigations for therapy or treatment.

LFTs U/E/C Septic screening

Differential diagnosis

Acute myeloblastic leukemia Subcutaneous nodules or

“blueberry muffin” lesions Infiltration of the gingiva and

parotid gland (uncommon) Signs and lab findings of DIC (esp.

acute promyelocytic leukemia) Discrete masses – chloromas or

granulocytic sarcomas

Other DDX Juvenile rheumatoid arthritis Rheumatic fever Infections mononucleosis Leukemoid cxn in fnfxns. Tb, Histoplasmosis,

granulomelons disease Pertussis Acute hemolytic syndrome Sickle cell disease Disease associated with BM failure.

Malignant – neuroblastoma, rhabdomyosarcona, Ewing sarcoma, retinoblatorw Non-Malignant – Aplastic anaemia

Treatment

Supportive Definitive; chemotherapy and

irradiation

Supportive care

Family and patient counselling. This include disease aetiology, treatment design and cost, treatment side effect (and associated complication) and prognosis

Screening and management of infections. Third generation cephalosporins singly or in combination with an aminoglycoside

Pain control. Start with NSAIDs – morphine is the ultimate (Addiction unwarranted if rx is of short period of time)

Anti-emetics; Use plasil (metochlopromide), Phenergan (promethazine) dexamethasone or Motilium singly or in combination. Ondansetron or tropisetron (5HT receptor antagonists) severe emesis either singly or in combination with dexamethasome or plasil

Haematological support; With exception of vincnistine, prednisone and L-asparaginars, all other cytotoxic drugs cause myelosuppression. Total neutrophil count below 100,/mm3 Hb <9g/dI, and platelet count <20000/mm3 – product transfusion before further chemotherapy.

Education rehabilitation – long duration of hospitalization

Nutritional support Management of metabolic

complication; Tumor lysis syndrome: Hypocalcaemia,Hyperuricemia (give allopunnol 10mg/kg/day (bd or TID) Maximum of 200mg TID) hyperkalemia and Hyperphosphatemia

Investigations before treatment

LFTs U/E/C Septic screening

Chemotherapy

Patients are divided into 1. low risks 2. high riskAccording to age, wbc count and

response to initial steroid therapy.

Risk groupsLow Risk High Risk

AGE 2-10YRS <2yrs and >10yrs

WBC COUNT

< 20,000/mm³

>20000/mm³

INITIAL RESPONSE TO STEROID THERAPY

Good (< 1000 blasts/mm³)

Poor (>1000 blasts/mm³)

Treatment is divided into :1. Remission induction2. Consolidation3. CNS prophylaxis4. Maintenance

Induction Start prednisone tabs 60mg/m2 (as TID)

after diagnosis and give for one week than assess total blast count. Allopurinol is commenced at least 24 hours before and IT cystosar (cytosine arabinoside) or methotraxate given during diagnostic LP.

Tabs prednisone-3 weeks then tail down. IV vincristine- 4 weeks IV adriamycin- 4 weeks(Omit adnamycin

in low risk disease) IT methotrexate or cytosar weekly for 4

weeks

If CNS disease is present, alternate IT methotrexate and cytostar weekly for total of 10 doses then monthly IT adding hydrocortisone for 6 months

Consolidation (Two courses 7-10 days apart)

IV cyclophosphamide -single dose IV cytosar- once daily for 4 days 6 mercaptopunne- once daily for 4

weeks Bone marrows aspirate to assess

remission status before commencement of maintenance therapy. If not in remission, repeat a third course of consolidation

Cranial irradiation

Maintenance

Monthly (2yrs) Vincristine 6 mercaptopurine Methotrexate Prednisone Doses of 6mp or MTX may be

adjusted upward or downwards to maintain leucocytes counts between 1500-3500

Maintenance

3 monthly (1 year) Adnamycin Cyclophosphomide

Relapse

Usually those with T cell type. The bone marrow is the most

common site of relapse, although almost any site can be affected.

Extramedullary sites, - Most common CNS and testes.

Treatment of testes- Testicular irradiation. chemo should be reinforced for patients who are still undergoing rx or reinstituted for those who have a relapse after treatment

Prognosis

Treatment is the single most important prognostics factor. The earlier the better.

Other than these are Age <2 - >10yrs, Initial leucocyte count - >20,000/mm³ poor prognosis.

CALLA good prognosis. Philadelphia chromosomes – poor

prognosis. And other translocatins- poor prognosis