2. Introduction
• Leukemia is a neoplastic disorder of the hematopoetic
system, charecterised by aberrant or arrested
differentiation.
• Uncontrolled clonal proliferation and accumulation of
blasts cells in the bone marrow and body tissues.
• Acute leukemia
• Sudden onset
• Aggressive disease
• Poorly differentiated cells with many blasts
• If left untreated is fatal within a few weeks or months
4. ALL
• MC cancer in children
– 25% of childhood cancers
– 30-40 per million.
– 3950 new cases annually in US
– >2500 in children & adolescents
– Incidence gradually increasing.
• Peak age gp – 2-3 years.
– Median age – 10 yrs
– Males – 1.3 times
– Whites – more common
5. AML
• Disease of advancing age
– Median age 65 yrs
• 90% of all acute leukemias
– 25% of all leukemias
6. Etiology – acute leukemia
• Genetic – 10-15% esp ALL
– Syndromes of impaired DNA repair
• Fanconi’s anemia
• Ataxia telengectasia
• Bloom’s syndrome
– Li Fraumeni syndrome (germline p53 mutation)
– Inherited immunodeficiency – Wiskott-Akdrich syndrome
– Neurofibromatosis type I
– Down syndrome
• < 3 yrs – megakaryoblastic AML
• Older children – ALL
– Primary mediastinal germ cell tumors - megakaryoblastic AML
10. Classification - ALL
• Morphologic classification by FAB cooperative working
group
• L1
– Most common form in children (85%)
– Good prognosis
• L2
– Most common form in adults
– Same genetic abnormalities as L1
• L3
– Rarest form
– Identical to Burkitt’s lymphoma cells
– Mature B cell immunophenotype
12. • FAB classification – advantages
– Prognostic value . L1 better than L2. L3 has worst prognosis.
• criticism
– Does not correlate with immunophenotypic & cytogenetic
information.
– Subjective nature of classification
• Hence newer – immunophenotypic classification
– B cell
– T cell
13. • B cell ALL
– Express CD79a, CD19, HLA DR, CD10 antigen (cALLa) etc.
– 80-85% of childhood ALL
– 80% cALLa +, if negative – bad prognosis
• In infants, cALLa neg is assoc with 11q23 abnormalities & poor outcome.
– 3 types
– Some classifications – pro B cell group / transitional pre B group
Early pre B Pre B B cell
No surface or
cytoplasmic Ig
75% cases
Best prognosis
Cytoplasmic Ig
20-25%
Surface Ig
2%
L3 type
14. • T cell ALL
– Express CD3, CD7, CD2 or CD5
– Usually in a male, older age, with leukocytosis and mediastinal
mass.
– Prognosis bad, however with intensive therapy, has similar
outcome.
15. Clinical features
May present as
• Recurrent or severe infection.
• Pallor
• Bruising or petechiae
• Bone pain & limping gait.
• Lymphadenopathy – 50%
• Hepatosplenomegaly – 30-50%
• Extra medullary manifestations
16. – CNS
• 5% clinical symptoms
• Diffuse or focal neurological signs
• Raised ICP
• Seizures & nuchal rigidity
• Cranial N palsy – facial N
• Hypothalamic involvement
• Epidural infiltrate compressing the cord etc…
– Anterior mediastinal mass
• 10% cases
• Infiltration of thymus
• Usually T cell type
• Life threatening tracheobronchial / cardio vascular
compression – prompt chemo or XRT.
17. – Genito-urinary
• Clinical testicular involvement – rare
• Occult involvement – 21%, not clinically significant.
• Ovarian involvement – 30%
• Renal enlargement – leukemic infiltration/ hyperuricemia or
pyelonephritis.
– Bone and joint manifestations
• In 40 % - limp or painful bones
• Bone pain due to – direct leukemic infiltration of
periosteum, periosteal elevation, bone infarction, or
expansion of marrow cavity.
– Ocular manifestations
• In 33%
• Retinal haemorrhages – MC
• Ocular motor palsies & papilledema, indicate meningeal
leukemia – prompt XRT needed, if optic N involved.
18. Prognostic factors
• Age
• Strong prognostic factor
• Infants – high risk of Rx failure
– MLL gene rearrangement 11q23 common
– Associated with – high initial TC, CNS leukemia, cALLa –ve
• 1-9 years – best prognosis
• Adolescents better prognosis if Txed on pediatric & not adult
ALL protocols.
• WBC count at diagnosis
– > 50,000/μl – increased risk of treatment failure
19. • CNS status at diagnosis
– CNS 1 – CSF < 5 cells/μl & cytospin negative for blasts
– CNS 2 – CSF < 5 cells/μl & cytospin positive for blasts
– CNS 3 – CSF ≥ 5 cells/μl & cytospin positive for blasts
• ALL with CNS 2&3 are at higher risk for Tx failure both
within CNS & systemically
• Gender
– Girls, slightly better
– Boys, at increased risk of testicular, BM & CNS relapse.
• Morphology
– L1 – early pre B – good prognosis
– T cell - bad
20. • Cytogenetics
– Chromosome number
• Hyperdiploidy (> 50 chr or DNA index – 1.6) – good
– Seen in 25% B cell ALL, rare in T cell
• Trisomies 4, 10, 17 – good
• Hypodiploidy – treatment failure.
– Chromosome translocation
• TEL-AML1 t(12;21) in 25% B precursors – excellent
• Philadelphia chr t(9;22) – older pts with B precursors –
unfavourable
• MLL (11q23) gene involvement, usually infants - poor
21. • Early response to treatment
– Day 7 or 14 BM response
– Day 7 peripheral blood response
– Minimal residual disease by PCR at end of induction phase.
23. Treatment of ALL
• Over last 5 decades, dramatic improvement in the
prognosis.
• Single agents in 1950’s
• Combination agents in 1960’s
– Leukemia in CNS as initial site of relapse became
progressively more evident.
– Concept of pharmacological sanctuary - CNS
• Leukemic cells, even if subclinical, were present in CNS of all patients.
Protected from systemic chemotherapy by BBB.
• Radiation to CNS in 1970’s
– Pivotal step boosting long term DFS to > 50%
• Intensive therapy since 1980’s with good supportive care
– Complete remission > 95%
– Long term EFS > 80%
29. Remission induction
• Failure to achieve remission
– Less than 5%
– Use 2nd line agents – cytarabine, teniposide, daunomycin,
idarubicin.
– Ideally, after remission they should be considered for allogenic
stem cell transplantation
30. CNS treatment
• Initiated during induction therapy
• Definitive CNS Rx started immediately after induction.
– May be delayed by several months, if initial CSF is negative.
• Radiation therapy
– First modality, successfully used.
– 2400 – 1200 cGy to whole brain.
– Should be given to all patients with blasts in CSF.
• Intrathecal therapy
– IT MTx – induction and consolidation phases, along with radiation.
– IT MTx – induction, consolidation & continuation phases with intensive
systemic therapy, avoiding radiation in patients with low risk. (CCG study)
31. Intensification / consolidation
• Goal
– To further reduce the disease burden. (1010 blasts-at end of remission)
– Early studies – if no further Rx, most patients relapse with a median of
2-3 months.
– Designed to minimise the development of drug cross resistance.
– On some protocols, intensification delivered immediately after
remission – early intensification
Others – after a period of less intensive therapy – late intensification.
– Both low risk & the high risk groups benefit from these intensive cycle
of chemotherapy
– Anthracycline – doxo/dauno or high dose MTx
L- asparaginase, vincristine, steroids, cytarabine, endoxan
6 TG or 6 MP. Or various combinations of these.
– Various regimes exist, optimal treatment unknown.
32. Intensification / consolidation
• Examples
– PGI
• Early intensification (week 5-6)
– continue PDN for 1wk, taper off by day 44
– Vincristine – day 29, 63.
– Daunorubicin – 45mg/m2 IV day 29, 31
– Etoposide 100mg/m2 IV alternate day x 5 (29,31,33,35,37)
– Cytarabine 100mg/m2/dose BD IV –alternate day x 5
– 6TG – 60mg/m2 PO alternate day x 5
• CNS therapy (week 9-11), continuation phase (week 11-20)
• Late intensification ( week20-21) – instead of PDN – dexona
6mg/m2
• UK ALL group – both early & delayed intensification has
superior outcome than just one.
also three cycles better than two. –Eg- UK MRC ALL 97/01.
34. Continuation
• Less intensive therapy to complete at least 2 years.
• Weekly low dose MTx
daily oral 6 MP
± pulses of steroids + vincristine ( ? Benefit)
• How long ?
– Study by CCG – no significant benefit 5 yrs vs. 3 yrs.
– Study by UK ALL group – 2 yrs vs. 3 yrs – no significant survival
advantage.
– Boys however benefit from a more prolonged treatment.
– ? Even shorter duration with more intensive regime
• BFM group – 18 vs. 24 months – higher relapse
• Tokyo children’s cancer study group – only 12 mnth. – high relapse.
– Standard
• 2 years – female
• 3 years – male
35. Special subsets
• Philadelphia chromosome positive ALL
– t(9;22)(q34;q11)
– 5% of children, 20% adult ALL
– Dismal prognosis (EFS 0-25%)
– Allogenic stem cell transplantation may improve survival.
• Infants
– Poor prognosis & increased vulnerability to toxic effects of Rx.
– Biologically distinct form – MLL gene rearrangement.
– Very high dose cytarabine – may have a benefit.
– DFCI ALL protocol – early intensification with high dose cytarabine,
MTx and delayed cranial irradiation.
– EFS <40%.
36. Risk adapted therapy
• Goal
– “Treat away” adverse presenting features, so that cure rates are
similar to low risk disease
– Reduction in the use of elements with significant toxicity in low risk
disease.
High risk
• BCR/ABL +
• hypodiploidy (<44 chr)
• MLL gene rearrangement
Standard risk Intermediate risk
• Age >1 & < 10 yrs
• TLC < 50,000
• age > 10 yrs
• TLC > 50,000
• > 25% blasts on day 15 or
> 5% blasts on day 29 in BM
while on Rx.
37.
38.
39. Vincristine D1,8,15,22 & 29
Pred + Mtx + VCR + 6 MP
Dexa + VCR + Doxo + L Aspar +
Cyclo + TG + Ara-C
Pred + Mtx + VCR +
6 MP
Pred + Mtx + VCR + PEG L Aspar
Regimen A
Pred + L Aspar
Regimen B
Pred+ L Aspar + Dano
Pred + VCR
+ 6 MP
Pred + Mtx + VCR + 6 MP
Dexa + VCR + Doxo + L Aspar
+ Cyclo + TG + Ara-C
“Augmented BFM”
Cyclo + Ara-C + 6 MP +
VCR + PEG L Aspar
Pred + Mtx + VCR + PEG L Aspar
Regimen C
Pred+ L Aspar + Dano
Cyclo + Ara C
+ 6 MP
40. Adult ALL
• Poorer prognosis
• Increasing incidence of Philadelphia chr.(20%)
– Those who have CR – considered for allogenic BMT.
• Older age –itself poor prognosis.
• Poorer tolerance to intensive chemotherapy.
• 35-40% 2 year survival with aggressive treatment & best
supportive care.
• Young adults better treated with pediatric protocols.
41. Adult ALL
• PGI protocol (modified BFM)
• Induction
– Phase A (1-4 wks)
• PDN -60mg/m2 PO
• Vincristine -1.5 mg/m2 IV weekly
• Daunorubicin -30 mg/m2 IV weekly
• L-asparaginase -70,000 units/m2 IV twice weekly (2nd wk onwards)
• Endoxan -800mg/m2 IV day 1, 28
• BM examin for remission
– Phase B (5-9 wks)
• Endoxan IV wk 5, 7
• Cytarabine 75 mg/m2 -4 days/wk wk 5,6,7,8
• IT MTx – 12mg/m2 upto 15 – wkly
• XRT week 7 onwards.
43. • Maintanence phase
• T. 6 MP 75 mg/m2 daily
• T. MTx 25mg/m2 weekly
• Vincristine 1.5 mg/m2 monthly IV
• PDN 60 mg/m2 x 5days monthly
• IT MTx 3 monthly
– 2 years in females
– 3 years in males
• Relapse
• Ifosfamide 1.6- 4 gm/m2 D1-5
• Etoposide 100mg/m2 D1-5 max 2 cycles
• Maintain with D1-3 CCT for 1 year.
44. Cranial Irradiation.
• Indication
– Prophylactic
– Therapeutic
Prophylactic
• Early evidence
– Studies V & VI from SJCRH ( 1962-67)
• CSI to 24 Gy/16# - isolated CNS relapse 64% to 4%.
• 12 Gy not found useful.
• However, acute myelosuppression, late musculoskeletal
dysplasia.
– Study VI
• CSI vs. cranial XRT + IT MTx.
• Equivalent with 8 % risk of relapse.
– Study VII
• IV MTx & XRT in close proximity avoided.
• Oral MTx & 6 MP as maintenance decreased relapse.
45. – CCSG study 101
• 24 Gy CSI+ liver, spleen, gonads
• 24 Gy CSI
• 24 Gy cranial + IT MTx
• IT MTx
– Radiation definitely superior over IT MTx alone.
– Cranial RT + IT MTx superior to CSI
– CALGB studies
• In low risk ALL, CNS relapse rate is 5% regardless of CNS Rx.
• Recent trends
– In US, avoid XRT in all but high risk patients, avoiding long term
effects.
46. – CSSG trial – for low risk.
• Similar results if XRT substituted with IT MTx throughout
induction, consolidation & maintenance.
– CSSG 105 – intermediate risk.
• IT MTx with intensive CCT equivalent to
standard CCT with XRT.
• IT MTx alone with standard CCT – high CNS recurrence(20%).
– ALL high risk patients require XRT
• T cell ALL
• Counts > 1 lakh
Therapeutic
– All patients with CSF blasts + ( at diagnosis or relapse)
• Some exclude CSF -2 ( give more intense IT CCT), if TLC is normal.
47. • PGI
– All children were treated with XRT
• No strict risk stratification had been done.(? Are risk
factors same in indians)
• All children treated as high risk.
• Repeated lumbar puncture avoided. (infection )
• Bloody puncture at any time- relapse.
• New protocol (UK MRC ALL 97/01)
– Risk stratification, & no XRT for low risk patients.
– All adults with ALL
48. • Technique
– Volume: include all cranial meninges, including those
surrounding the optic nerve in the retro-orbit. And
extending down the spinal cord to level of L2.
– To keep lens dose to minimum.
– Immobilisation - supine position.
– Lateral opposed fields.
1. Rectangular field, with one edge running parellel to
Reid’s baseline
2. Using asymmetrical jaws & custom blocks, and keeping
the isocentre 15 mm behind the cornea, helps reduce
lens dose.
49. • Dose.
– Therapeutic – 2400 cGy /16#
– Prophylactic – 1800 cGy/12#
- 1200 cGy/8# with intensive CCT. (BFM-90 protocol)
– hyperfractionation ?
• The Dana Farber ALL consortium
• No definite advantage in relapse rates.
• Need for anesthesia twice daily.
50. Other roles of radiotherapy
• Testicular disease
– At presentation.
– At relapse.
Volume: both sides testis & spermatic cord upto the deep inguinal ring.
Positioning: supine
lead shield under scrotum to save perineum
penis taped against abdomen.
Field : direct anterior
Dose: 2400cGy/12#
51. Other roles of radiotherapy
• Retinal / optic nerve involvement.
– May present with mono-ocular blindness.
– Prompt Radiotherapy needed to salvage vision.
– Unilateral field or parallel opposed field
– 3x4 cm field, starting at the orbital rim
– If U/L – depth of 3 cm
– Dose: 2500 cGy/12#
• Severe bone pain.
– 1000 – 1500 cGy in 2-3 #
52. Other roles of radiotherapy
• Anterior mediastinal mass with severe dyspnoea
• Facial N palsy
• Treat from base of brain to peripheral extension over the
cheek.
• 2500 cGy
• Treat within 24 hrs – prompt restoration of motor power.
53. Follow up
• Monthly blood counts & clinical examination -2 years.
– Then at decreasing frequency.
• Most important clinical assessment: testis
• Routine bone marrow not indicated.
54. Relapse
Despite all this.
20-30 % relapse.
If EFS < 1 year, very bad prognosis.
• Bone marrow relapse
– Symptoms similar to initial presentation or on routine blood film.
– Confirm by bone marrow examination.
– Induction of remission – same regimen. 70-90% (Bcell)
– Maintaining remission
• Prolonged intensive CCT with CNS therapy.
Or
• High dose chemoradiotherapy & autologous/allogenic BMT.
55. • Standard CCT – 18% survival
• Intensive CCT – 30-40% ( very intensive-65%)
• Allogenic BMT – 25-60% (mortality 15-30%)
• Unrelated donor – 20-30%
• Autologous – 40-50% in good risk pts.
• Isolated CNS relapse -10%
– Headache, vomiting, raised ICP, FND, convulsions.
– CSF study. Look for relapse elsewhere – BM.
– 90% response with CNS directed therapy.
• IT MTx prolonged, with cranial XRT.
– They relapse later on in the BM.. Hence systemic CCT must.
56. • Isolated testicular relapse.
– Painless swelling of testicles.
– Biopsy B/L testis. Look for disease elsewhere.
– Systemic chemotherapy + testicular irradiation. ± CNS therapy.
• Relapses in other extra medullary sites
– Usually managed by local XRT & systemic therapy.
58. Summary
presentation
Investigative workup
& stabilisation
CSF study + day 1 IT
MTx
Induction + IT MTx
Bone marrow
Early intensification
CNS therapy (RT+ IT
MTX
continuation
Late intensification
continuation
2nd line agents –
BMT ideally
Follow up
BM relapse CNS relapse testicular
60. AML
• Disease of the elderly.
• Gradual improvement in survival, still majority patients
die from their disease.
• In older age group, the outcome remains frustratingly
disappointing.
61. Classification - FAB
• M0 - Minimally differentiated AML
– 5% cases.
– blasts are negative for B and T lymphoid antigens
– Negative or < 3% blasts stain for MPO, Sudan black and NSE
– Myeloid antigens : CD13, CD33 and CD11b are positive.
– Need to distinguish from ALL
62. • M1 Myeloblastic without maturation
– 10% cases.
– >90% myeloblasts.
– MPO & Sudan black >3%
– CD13,33,117
– Need to distinguish from ALL.
– Worse prognosis.
67. • M7 acute megakaryoblastic leukemia
– 3-5%
– >50% blasts of megakaryocytic lineage.
– Platelet peroxidase +
– MPO & Sudan black -ve
– Lytic bone lesions in children.
– Mediastinal germ cell tumors in male.
68. WHO classification
1. AML with recurrent cytogenetic translocation
• t(8;21)
• APML t(15;17)
• inv16
• 11q23 abnormality
2. AML with multilineage dysplasia
• With prior MDS
• Without prior MDS
3. AML, therapy related
• Alkylating agent related
• Epipodophyllotoxin related
• Other types
4. AML not otherwise categorized
Same as FAB classification.
69. Symptoms & signs
– Weakness – leading symptom
– Fever & bleeding manifestation more common than in
ALL
– LADenopathy, HSM, less common
– CNS involvement – rare.
– Gingival hypertrophy, skin nodules & pinkish patches –
M4&5
70. Prognostic factors
– Older age group – poor
– Cytogenetics
– Prior dysplasia / secondary AML
– High presenting TLC
– KPS
– Male sex.
Cytogenetic classification
Favourable intermediate unfavourable
t(15;17) +8, -Y, +6, del(12p) del 5q, del 7q
inv 16 normal t(8;21) with del 9q
t(8;21) without del 9q 21q, del 9q, t(6;9)
t(9;22)
complex karyotype
72. Non M3 - treatment
• Remission induction.
– Aim: cytoreduction to achieve CR
– CALGB trial 2 decades ago
• 3+7 induction regime.
• Daunorubicin 45mg/m2 D1-3 IV
Cytosine 100 mg/m2 BD D1-7 IV
• Marrow on day 14 ---60-75% CR
Other regimes
– Idarubicin vs. daunorubicin
– Mitoxantrone vs. daunorubicin
• Both found to have superior to daunorubicin.
• But with higher toxicity, and only in younger patients.
• Also unequal doses given.
73. – Higher dose cytarabine
• Higher response rate
• Too toxic
– Hence the standard for induction is the 3+7 regime.
• Consolidation
– 109 to 1010 cells still are circulating !!
– The options
• High dose chemotherapy
• Auto/ allo stem cell transplantation.
– High dose therapy
• Inj cytarabine 3gm/m2 BD D1, D3, D5.
• 3 consolidations.
74. • Stem cell transplantation
– Allogenic
• Limited to younger patients (<45 yrs)
• 50 – 55 % survive the procedure
• 15 % relapse
– Autologous
• Upto 60 years
• No GVleukemia effect.
• Leukemic cell reinfusion
– Comparing stem cell transplant with Chemotherapy.
• Significant impact in reducing relapse risk.
– In surviving patients !!
• No survival benefit.
75. • Maintanence ( optional)
– Tab 6 TG – 80mg BD D1-4
– Inj cytarabine 100mg/m2 SC on D5
– Continued for 6 months.
76. Older age group
• Unfavourable prognostic factors
• Inability to withstand intensive therapy.
• The decision to treat or not ?
• Lower doses of drugs.
• Inj cytosine 10mg/m2 SC 7-14 days
• Inj mitoxantrone 6mg/m2 IV D1-3
• T etoposide 100mg OD 7-14 days
• T 6 TG 40mg BD 7-14 days
– Assess monthly
77. M3 AML
• Induction
– ATRA + anthracycline ± cytarabine
• Cap ATRA 45 mg/m2 BD
• Daunorubicin – 50mg/m2 D1-3
• Consolidation
– Daunorubicin ± cytarabine
• Daunorubicin – 50mg/m2
• Cytarabine 100mg/m2 IV BD x 7 days ( if high risk)
• Maintenance
– ATRA ± low dose CCT
• ATRA 45 mg/m2/day BD x 15 days 3monthly
• T 6-MP 75 mg/m2 daily HS
• T MTx 20mg/m2 weekly.
Side effects of ATRA
Hyperleukocytosis
Retinoic acid syndrome
78. Newer approaches
• New chemotherapeutic drugs
• Clofarabine
• Arsenic trioxide
• Modulation of drug resistance -- PSC-833
• Sensitization
• Anti-angiogenesis
• Modulation of cell signaling
• Tipifarnib
• Immunotherapeutic
• Gemtuzumab Ozogamicin
79. SUPPORTIVE CARE
• Prevention & management of infections
– Antibiotics, antifungals
– Barrier nursing
• Support during bonemarrow aplasia period
– Blood products
– Management of DIC as in M3 AML
• Adequate hydration, allopurinol
• Management of metabolic complications
80. • Treat me to cure me ... I
want to have kids like me
to worry about...
• Ask me what is the
hardest part to me?
• Ask me what you can do
to help? But ask me in a
way I can understand...
• Treat me like you would
have wanted to be
treated way back when...
Cancer Treatment
… from the eyes of a child
81. Thank you for
wanting to
learn…and for
making a difference
in the lives of
children and young
adults
Photograph by K. Tartakoff
