Acute Lymphoblastic Leukemia:

Incidence
ALL is the most common malignancy in
children

1/3rd of all pediatric cancers

The annual incidence of ALL is about 30 cases

per million people
ALL accounts for 75-85% of acute
leukemias in children
 ALL

Sex: M> F (1.3:1)

Race: more frequently in Caucasians than in

African Americans

Age: peaks age 2-5 years

 Aetiology

Mostly unknown
Many environmental factors - exposure to
ionizing radiation and electromagnetic fields)
Post-chemo for other malignancies
Pesticides
Infectious agents
Papilloma virus—aggressive T-Cell leukaemia in
young adults
 Risk Factors
Single Gene Defects:
Fanconi's anaemia
NeurofibromatoisType 1
X-Linked Agammaglobulinaemia
Osteogenesis Imperfecta
PKU
Marfan's Syndrome, Achondroplasia
 Risk Factors

Chromosomal: -
Down, Turner
Immunedeficiency: -
Wiscott Aldrich, EBV
Identical Twin 20% chance < 5years
 Acute Lymphoblastic Leukemia:
Pathogenesis

A lymphoid progenitor cell becomes genetically

altered > dysregulated proliferation > clonal
expansion

Altered expression of genes > development of

abnormal B cells and T cells

Recent data : suggest that leukemia arises from

the stem cell
 ALL: Clinical features
S/S reflects bone marrow infiltration and
extramedullary disease
Features of BM failure: -
1. Anaemia—pallor, irritable, dec activity,
fatigue
2. Thrombocytopenia —bleeding mainly
superficial—petechiae, ecchymosis, DIC
3. Infections—dec functional WBC
neutropenia. —fever, localization not
present, quick dissemination
 ALL: Clinical features
RE System Infiltration
Lymphadenopathy
Hepatosplenomegaly

Involvement of other sites— CNS, Testes, Thymus, GIT,

Cardiac, Pulmonary, Ocular
Bone Pain
Weight loss
 ALL: Clinical features
CNS involvement
- headache, nausea, vomiting, lethargy,
irritability, nuchal rigidity, papilledema

Cranial nerves mostly involved – 7th ,3rd ,4th 6th

cranial nerves

Intracranial or spinal mass - leading to nerve

compression/ICSOL features
 C/F of Chronic leukemia
Common in CGL -Anemia, splenomegaly,
fatigue ,weight loss
Less common - Hemorrhagic Manifestations
(Bruising)
Occasional - Abdominal, bones, joints pain
Neurologic symptoms
Disturbance of vision or hearing
 Differential diagnosis: ALL
Acute Myelocytic Leukemia

Aplastic anemia

Juvenile Rheumatoid Arthritis

Lymphoma

ITP

Neuroblastoma
HSP
ITP
Menincococcal septicemia
 ALL: Investigations

Blood counts:
1. Hemoglobin -reduced (3-8gm/dl)
2. WBC-20,000-50,000/cumm.of blood.May
exceed 100,000/cumm
3. Platelets – Decreased
 ALL: Investigations

1. Blood film:
A) RBC-Microcyitc or normocytic, moderate to
marked anisopoikilocytosis, nucleated RBC
few
B) WBC-30-90% atypical or typical blast cells
C) Platelets – Decreased
- Reticulocytes count-Increased upto 5%
 Invasive
Lumbar puncture/CSF analysis
Bone marrow aspiration
- > 30% Blast cells
- FAB classification (L1, L2, L3)
is generally used
 Histologic Findings:
3 groups based on morphology.
– L1: Cells are usually small, with scant
cytoplasm and inconspicuous nucleoli.
accounts for 85% of cases of childhood
ALL

– L2: Cells are larger in size, with prominent

nucleoli, and abundant cytoplasm.
accounts for 14% of all childhood ALLs.
 Histologic Findings:

– L3: Cells are large and notable for

their deep cytoplasmic basophilia and
prominent cytoplasmic vacuolation
accounts for 1% of childhood
ALLs
 ALL: Investigations

Imaging studies
– CXR : mediastinal involvement
– Testicular sonography
 ALL: Investigations
Serum biochemistry
– Uric acid,
– Potassium,
– Phosphorus, and calcium,
– Lactate dehydrogenase (LDH)
– Coagulation studies can be helpful
 ALL: Investigations

Immunophenotyping
– B cell
Poor prognosis, L 3 type
Lymphomatous masses in abdomen
head & neck
– pre B cell, early pre B cell
Better prognosis , L 1 & 2
80 % of all childhood ALL
 ALL: Investigations
– T cell origin
Poorer prognosis
High WBC counts
CNS involvement
Cytogenetic analysis - PCR, southern blot

Chromosomal translocations / gene fusions

- BCR-ABL (t 9;22) > poor prognosis
– E2A-PBX1(t 1:19) > poor prognosis
– TEL-AML1 (t 12;21) > good prognosis
 Treatment : considerations
Based on risk stratification

Different protocols are used by different centers but phase of

treatment is same
Phases :
– Induction
– Consolidation
– Maintenance -interim maintenance
- delayed intensification
- continue maintenance

Duration

Treatment of relapse

Molecular targeted therapy

 Supportive Therapy

Transfusions—Packed cells, Platelets

Treat infections—do culture, IV Antibiotics
Counseling of family
Moral and financial support

Metabolic support—to prevent Tumour Lysis

syndrome—Alkalinize the Urine, Allopurinol
(100mg/M2)-24 hrs before starting atileukemic
therapy and continue for 14 days , IV Fluids
 MCP 841 protocol for ALL
Induction Consists of 3-4 drugs given for 6 weeks
Goal – achieve remission or <5% blasts in the bone marrow
Induction 1:
Prednisolone - PO Day 1-28
Vincristine - IV days 1,8,15,22 & 29 (weekly )
L Asparaginase - IM 10 doses days 2-20
Anthracycline (Daunorubicin) – 8,15,29
MTX – IT days 1,8,15,22
 Induction 2
6- Mercaptopurine –PO days 1-7 & 15-21
Cyclophosphamide – IV days 1 & 15
MTX – IT days 1,8,15 & 22
Cranial irradiation – 9 days
Repeat induction :
Same as Induction 1
Induces complete remission in more than 98%
of patients.
 Consolidation
To further reduce the leukemic cell burden
The drugs given at doses higher than those
used during induction, or the patient is given
different drugs
– 6-mercaptopurine (6-MP) –PO days 1-7 & days 15-
21
– Cyclophpsphamide – IV days 1&15
– Vincristine – IV days 1 & 15
– Cytosine arabinoside – S/C 12hrly x 6 doses day 1-
3 & day 15-17
 Maintenance
In interim maintenance, oral medications are administered
to maintain remission and allow the bone marrow to recover

This occurs for 4 weeks and is followed by delayed

intensification, which is aimed at treating any remaining
resistant leukemia cells

The last phase of treatment is continue maintenance

 Treatment Cont…
3. Maintanance – 6 cycles - aimed at treating any
remaining resistant leukemia cells
Prednisolone—1- 7 days every 4 weeks
Vincristine – IV every 4 weeks day 1
Daunorubicin— IV day 1
L- Asparaginase – IM day 1,3,5,7
6 – mercaptopurine – PO daily 3 wks out of every
4wk for total 12 wks begin on day 15
MTX – PO once a week missing every 4th for total of
12 wks begin on day 15
 Continue Maintenance
To maintain remission and allow the bone marrow to recover -This
consists of LPs with intrathecal MTX every 3 months, monthly
vincristine, daily 6-MP, and weekly MTX

Phase last-for 2-3 years

6 Mercaptopurine(6MP) PO, daily OD
MTX- PO, IV - weekly
Intrathecal MTX every 3 months,
IV Vincristine – monthly
Methylprednisolone -monthly
 Continue Maintenance
 Co-trimoxazole (900mg/M2 from beginning
of wk 5 to end of maintanance therapy

Bone Marrow Transplant with HLA matched

donor
 CNS preventive therapy
Triple IT therapy - IT Therapy Instead of
cranial irradiation
Methotrexate (mtx) + Cytosine Arabinoside
(Ara C) + Hydrocortisone Given every week
for 6 cycles
To treat patients with high-risk disease

Also improve the long-term survival of

patients with standard-risk disease
 High-risk patients:
Optimal treatment for patients with very high-risk
ALL has not been found.

Many institutions treat these patients with

allogeneic stem-cell transplantation (SCT) soon
after first remission is achieved.

For patients without a matched family donor,

transplantation of marrow from an unrelated donor
is a reasonable treatment option.
 Molecular targeted therapy
The best example is imatinib mesylate, a selective
BCR-ABL tyrosine kinase inhibitor.

Imatinib mesylate has demonstrated significant

anti-leukemic activity and is now a standard
frontline treatment for Ph-positive chronic myeloid
leukemia (CML).

Imatinib mesylate is also effective in Ph-positive

ALL, and combination regimens with imatinib
mesylate and conventional chemotherapy or SCT
have been evaluated in trials.
 Duration of therapy
B-cell ALL - 2 to 8 month course of intensive
therapy

B-precursor and T-cell ALL - 2-2.5 years of

continuation therapy

Most protocols - include a continuation phase

based on weekly parenteral MTX given with
daily oral 6-MP interrupted by monthly pulses
of vincristine and a glucocorticoid
 Complete Remission: -

Blood ANC > 1500

APC > 100,000
No Blast cells
Bone Marrow > 20% Cellularity
< 5% Blast cells
Relapse: -
Most common site—Bone Marrow
Most serious CNS, Testes
 Relapse
Relapsed ALL – resistant to exposed
chemotherapy drugs

Treatment of relapse is intensive and often

including SCT and new drugs. (e.g,
Clofarabine, Nelarabine )

The outcome of relapse is poor

Complications and treatment
Tumor lysis syndrome

Immediately admit patient who is neutropenic- IV

broad-spectrum antibiotics

Pneumocystis prophylaxis: All patients should be

on TMP-SMZ to prevent PCP.

Fungal prophylaxis: Patients should be given oral

nystatin or clotrimazole

Mouth care: chlorhexidine (Peridex) or antibacterial

enzymatic mouthwash (Biotene)4 times a day.
 Prognosis

More than 80% of children with ALL now can

be cured
Treatment failure in 20% children -unknown
 Prognosis
Criteria Standard Risk High Risk
Sex Female Male

Age 1-9 yrs <1yr or > 10yr

WBC < 50,000 >50,000

Ph Chromosome Absent Present

 Prognosis
Criteria Standard Risk High Risk

Adenopathy Negative Positive

Hepatosplenomegaly Absent or<3cm >3cm

Hb >10 gm < 7 gm

Platelets > 100,000 100,000

Poor response to initial ___ +++

presnisolone
 Prognosis
Criteria Standard Risk High Risk

LDH Normal Increased

Med mass Absent Present

Chr anomaly hyperdiploidy = t(9:22),t(4:11)

good prognosis - poor
Criteria Standard Risk High Risk

Response to induction 5% blast cells 25% 0n day

mass 14

Type of Blast cells L1 L 2,3

Septicemia No Yes
Criteria Standard Risk High Risk

T-cell ALL ___ +++

Type of Blast cells L1 L 2,3

CNS /Testes involvement No Yes

Septicemia No Yes
 Congenital Leukaemia

Onset : -within 1st month

Type—mostly Myeloid
Cl features—marked extramedullary involvement
Massive hepatosplenomegaly
Skin nodules
CNS involvement
Bl picture—marked Leukocytosis and
Thrombocytopenia
Prognosis: -Poor
 AML

20% of all Leukaemias

M>F
Clinical Features
As for ALL—
In addition:
Gum hypertrophy
Chloroma—localised mass of Leukaemic
cells- may herald Leukaemia. Seen in
Orbital/Epidural site
 Diagnosis
> 30% Blast cells in Marrow
Treatment:
Vigorous Induction: During induction patient
is very ill - 10% die.
Anthracyclines
Daunorubicin
Cytosine Arabinoside
Supportive care: - same as ALL
 Treatment:

Induction takes > 6weeks

CNS IT Therapy
BMT –Allogenic Stem Cell transplant with a
matched sibling –70% cure
Interleukin 2—to produce Immunomodulation
AML with Relapse—very poor prognosis.
 CML
3-5% of all Leukaemias
Juvenile Type < 5 yrs of age
M>F
Cl features: -
Suppurative lymphadenopathy
hepatosplenomegaly
Erythematous rash
Eczema
Purpura
Pulmonary infiltrates
 CML - Diagnosis:

Anaemia, dec platelets

WBC inc > 60,000
Inc monocytes/ granulocytes in BM
Hb F increased in > 50%
Only Trt: - BMT/ SCT—50% failure
Prognosis: - poor- Death within 9months
 CML
Adult Type: - More common
Ph Chromosome present
Older children: -lassitude, weight loss,
bone pain, inc in size of abdomen.
Blood: - WBC > 100,000
Platelets N or inc
Anaemia
BM hyperplasia
 CML
3 Phases—
1.Chronic—years-well controlled by
Chemotherapy
2.Accelerated – Months, decreased
response
3.Blast Crisis—days—
Myeloid—common does not respond to
treatment
Lymphoid –responds briefly to
treatment
 Treatment
Hydroxyurea 1500-3000 mg/m2 4-6
weekly
Busulphan
Alpha Interferon
Allogenic BMT/ SCT—80% survival if
Identical HLA matched sibling
Thank You