Acute Lymphoblastic Leukemia

Incidence

Acute lymphoblastic leukemia (ALL) is the commonest childhood cancer. It constitutes one fourth to one third of all paediatric malignancies and 75% of all leukemias. In India,each year over 4000 children < 15 years of age will develop ALL. Indonesia with 200 millions people >2000childrens

Epidemiology

Age peak age of developing ALL is 4-5 years with the most frequent age range being 2 6 years. Boy are more frequently affected than girls (1,2:1) World wide, frequency, age distribution, and subtypes of ALL show striking geographic difference that could reflect variability in genetic susceptibility, environmental factor, or both.

Etiology

Childhood ALL, as with most other cancers remain a diseases with few proven etiology factor. Genetic and immunology factors. High incidence ALL amongst identical twins (inheritance); amongst patients with Blooms syndrome and Fanconi anemia (genetic, faulty DNA repair); Downs and Klinefelters syndrome (genetic); Environment factors : radiation (atomic bomb); benzene, pesticides and herbicides. Viral infection: Epstein-Barr virus (ALL L3; Burkit limphoma); HTLV I and II (adult T cell and hairy cell leukemia) and HIV (non Hodgkins lymphoma).

Morphologic classification (Frence-American-British)

Cytologic Features Cell size Nuclear chromatin L1 Small cell predominant Homogenous in any one case L2 Large,heterogenous in size Variable, heterogenous in any one case Irregular , clefting and indentation common One or more present, often large Variable, often moderate Variable, deep in some L3 Large and homogenous Finely stippled and homogeneous Regular oval to round Prominent,one or more Moderately abundant Very deep

Nuclear shape

Regular, occasional clefting or indentation

Not visible or small and inconspicuous Scanty Slight or

Nucleoli

Amount cytoplasm Basophilic cytoplasm

Immunologic subclasses of ALL

Type Antigen Expression Frequency (%)
57 22 Early pre B cCD22,CD79a,CD19, CD22,clg(mu),slg Pre - B Clg+ (mu)

Transitional Clg+(mu),slg+,slgpre - B (kappa), slg- (lambda) B-Cell Slg+,slg-(kappa), or slg+ (lambda) T - Cell cCD3+, CD17+,CD5+, or CD2+

4
2

15

Clinical features
The clinical features reflect underlying marrow failure including manifestation: Anemia: fatigue, irritability, pallor Trombocytopenia (petecchiae;purpura, bleeding) Neutropenia (fever, sepsis) Extra medullary diseases manifestation: Lymphadenopathy (50%); hepatosplenomegaly (68%); bone (28%); and joint paints (leukemic infiltrate of joint) CNS leukemia: raised intracranial pressure; headache; vomiting, neck stiffness, papilloedema; and/or focal neurologic symptooms like cranial nerve palsies.

Differential Diagnosis

Non Malignant conditions: - Juvenile rheumatoid arthritis - Infectious mononucleosis - Idiopathic Thrombocytopenic Purpura - Aplastic anemia - Acute infectious lymphocytosis Malignant conditions: - Neuroblastoma - Retinoblastoma - Rhabdomyosarcoma Unusual presentation: - Hyereosinopilic sndrome

Diagnosis

Bone marrow aspirate smear: 30% or more blast in marrow is diagnostic of acute leukemia. The distinction between ALL and AML is made by morphology of blast in the marrow and the characteristic pattern of staining with cytochemical stain FAB Classificaation * Immunobiology studies (phenotypes)

Essential Laboratory Work-up

Hb,

total and differential WBC count Bone marrow aspirate Chest X- ray (mediastinal mass) Uric acd and electrolyte: Na;K;Ca;PO4 LDH/LFT/KFT Diagnostic spinal tap

Prognostic factors
There are number of prognostic parameters which could help tailor the intensity of treatment. Some of these are: - WBC count at diagnosis - Age at diagnosis - Rapidity of leukemic cytoreduction during the early period of treatment - Cytogenetics [t(8;14),t(4;11),t(1;19) unfavourable; t(12;21) favourable - Ploidi (DNA index>1,1,, favourable) - Mediastinal mass (unfavourable) - CNS disease at presenation (UNFAVOURABLE)

Treatment: Supportive care and specific therapy

Supportive care:
Improvement in supportive care has contributes a great deal to improvement in survival of ALL and is the backbone of ALL treatment. Infection in induction therapy need to be treated urgently with high generation broad spectrum antibiotics. Bleeding and anemia need appropriate blood product support in the form of packed red cell and platelet transfusions. Another complication that is likely to occur immediately after start of induction therapy patients with high WBC counts is hyperuricemia

Treatment (contd) Specific therapy:

The specific approach to a patient differs somewhat depending upon the risk categorization, however the four main components of therapy remain the same. These include : Induction; CNS prophylaxis, consolidation and maintenance therapy.

Induction: aim therapy is induction of remission. Drug combination most frequently used ; Vincristine, L Asparaginase with or without Daunorubicine.
CNS prophylaxis: methotrexate intrathecal Consolidation: use same drugs as in induction and call it Reinduction treatment

Maintenance.(under guidance of the paediatric oncologist)

When to refer
1.

2.

Immediately after suspecting acute leukemia either clinically or by laboratory parameters. Early referral by the paediatrician can avoid many disease related potentially life threatening conditions like severe infection, bleeding and metabolic problem.

Treatment for relapse

Side of relapse in ALL: bone marrow; CNS; testes. Patients who develop hematologic relapse on therapy or shortly thereafter allogeneic haematopoietic stem cell transplantation is the treatment of choice. Autologous transplantation offers no substantial advantage over chemotherapy as post induction treatment.

Late sequelae

Few complications are as devastating as a second cancer, especially brain tumors or acute myeloid leukemia. Treatment with antracycline cardiomyopathy Cranial irradiation: brain tumors;neuropsychological deficit. endocrine dysfunction resulting in obesity short stature; precocious puberty osteoporosis Complication are seen in girls more then boys