Acute Lymphocytic Leukemia ( ALL ) , ,,,,

Acute Lymphocytic Leukemia

1. Acute Lymphoblastic Leukemia
An Overview
Aziza Shad, MD

2. Case 1
•History:
3yo boy presents to Emergency Department with a 5
day history of back pain and pain/difficulty walking
• On exam:
Febrile with pallor, bruising, petechiae, mild
hepatosplenomegaly
•Labs:
CBC: Hgb 6.0g, Hct 18.0, Plts 11k, WBC 13.6
(10p, 60l, 24 atypical lymphocytes, 6 blasts) ANC 136
CHEM: K normal, Uric acid 7.0 ↑, LDH 2200 ↑
•CXR:
Reported as normal

3. Peripheral smear
Maslak, P. ASH Image Bank 2004;2004:101159
Blasts with scant cytoplasm
and prominent nucleoli

4. Bone marrow aspirate and biopsy
•BMA: Blasts have a high nuclear to
cytoplasmic ratio and lack granules
in the cytoplasm
Maslak, P. ASH Image Bank 2002;2002:100400 and 100526
BMBx: Bone marrow
architecture is replaced by
monotonous population of
blasts

5. Diagnosis?

Acute Leukemia
(most likely ALL)
Maslak, P. ASH Image Bank 2004;2004:101200

6. Making the diagnosis:
Morphology and
Immunophenotype

7. Morphologic classification –
French American British (FAB) subtypes
L1 – 85%
Small, uniform cell size
Fine, homogeneous chromatin
Scant cytoplasm
Inconspicuous nucleoli
L2 – 14%
Large, heterogeneous cell size
Irregular, clefted nuclei
Variable amount of cytoplasm
Nucleoli usually visible
L3 – 1%
Large, homogeneous
cell size
Prominent vacuolization
Basophilic cytoplasm
Nucleoli usually visible

8. Leukemia is a Bone
Marrow Diagnosis!

9. Introduction
•Leukemia accounts for about a third of all
childhood cancers
•About 80% of children with leukemia have ALL
•17% have AML
•The remainder have rare forms of chronic
leukemia

10. Pediatric Acute Lymphoblastic
Leukemia
•Most common cancer of childhood
•Affects children from 0 -20 years
•Peak incidence is between 3 -6 years
•Untreated, life expectancy is days to weeks
•Modern risk-based therapy has brought the
cure rate up to 75 -85%
• for some sub-groups, the cure rate is close to
90%, for others, it is < 20%

11. Acute Lymphoid LeukemiaAcute Lymphoid Leukemia
Incidence by Age Incidence by Age
AGE IN YEARS

N
U
M
B
E
R

O
F

C
A
S
E
S
0
20
40
60
80
100
120
140
02468101214

12. Epidemiology of Pediatric ALL
•Most common form of childhood leukemia
•2,500-3,000 children annually in U.S. (3 per
100,000)
•Sibling relative risk is 2-4x
•Monozygotic twin concordance 25% - highest in
infancy, no increased risk after 7 years of age
– mechanism in monozygotic twins is shared in utero
circulation, with transfer of preleukemic from one twin
to the other

13. Pathophysiology
•Most cases – cause unknown
•Inherited genetic syndromes:
•Downs syndrome, Bloom’s syndrome, Nijmegen
breakage syndrome, ataxia telangiectasia
•Environmental exposures
Ionizing radiation, benzene, prior chemotherapy
•Other possible environmental influences
•High birth weight, parental tobacco/alcohol, maternal
diet, exposure to pesticides or solvents, prenatal
vitamins (protective)

14. •Symptoms directly related to marrow
infiltration
–Decreased WBC : fevers, infections
–Decreased RBC :signs and symptoms of anemia
–Decreased platelets: bruising, bleeding
–Marrow infiltration: bone pain, limp
–Extramedullary infiltration : lymphadenopathy,
hepatosplenomegaly, mediastinal mass
Clinical Presentation

15. Remember…
•A given case may have several symptoms or
only a few
•A normal CBC does not rule out leukemia!
•Back pain/limp in pediatrics is a red flag and
requires work-up
•Before treating any child with steroids for any
reason, stop and think about whether
leukemia is in the differential diagnosis

16. Differential Diagnosis
•Non Malignant conditions:
• Juvenile rheumatoid arthritis
• Infectious Mononucleosis
• ITP
• Pertussis and Parapertusis
• Aplastic Anemia
• Other viral illnesses

17. Differential Diagnosis
•Malignancies:
•Neuroblastoma
• Retinoblastoma
• Rhabomyosarcoma
•NHL
• Other small round blue cell tumors
•Hyper-eosinophilia, other aplastic presentations

18. Standard Work-up for ALL
•History and Physical Exam
•CBC, electrolytes, LDH, Uric acid
•Peripheral smear
•Chest X-Ray
•Bone marrow aspirate and biopsy with special stains
•Immunophenotyping ( flow cytometry)
•Cytogenetics
•Molecular diagnostics

20. Immunophenotype
CD138
C
D
1
0
CD22
C
D
1
9
S
id
e
-
s
c
a
t
t
e
r
CD45

21. Molecular genetics
•Favorable risk
–TEL-AML1 (ETV6-RUNX1) fusion,
t(12;21)
–Hyperdiploidy (esp triple trisomies –
chr 4, 10, 17; or double trisomies –
chr 4, 10)
•High risk
–Philadelphia chromosome, t(9;22)
–MLL rearrangement (11q23)
–Hypodiploidy (<44 chromosomes)
fusion signal

22. Back to our patient…
•Received hydration, PRBC and platelet
transfusions, tumor lysis lab monitoring and
prophylaxis (allopurinol)
•Consented to start induction chemotherapy
•Bone pain and fevers resolve within a few
days, discharged home to follow up for
ongoing outpatient chemotherapy
•What is his prognosis?

23. Cure Rates
•Over the last 50 years, survival rates for childhood
cancer have risen from 10% to almost 80%
•Remarkable progress has been made in the past
decade in the treatment and understanding of
leukemia
•Collaborative clinical trials implementing risk-
stratified therapy have dramatically improved cure
rates in ALL
•Outcome in ALL has gone from a 6-month median
survival to an 80% overall cure rate

24. 1975-78
1972-75
0 2 4 86 10
80
60
40
20
100
Years after Study Entry
%
S
u
r
v
i
v
a
l
1989-93
1983-89
1978-83
1970-72
1968-70
3,402
3,711
2,984
1,313
936
499
402
Years of
Diagnosis
Number of
Children
16,131
Total Number of
Patients Treated:
1993-951,585
1995-971,299
Legend: Survival of CCG Patients with Newly-Diagnosed Acute Lymphoblastic
Leukemia, 1968-1997. Bleyer A, Hather N, Personal Communication

25. Prognostic Factors in Childhood ALL
•Age
•WBC count at presentation
•Immunophenotype
•Recurrent chromosomal abnormalities
•Response to initial therapy
•These prognostic factors have been used to stratify
therapy following induction remission
•Gene expression analysis
•Pharmacogenomics

26. Risk adapted therapy for Pediatric ALL
•Standard, high or very-high risk groups
–Patients with ‘high risk’ features get intensified
chemotherapy
–Patients with ‘very-high risk’ features are
candidates for BMT
–‘Low risk’ group being studied – reduced intensity
treatment

27. Prognostic Factors in Childhood ALL
•Clinical and Lab featuresClinical and Lab features
•Leukemia cells characteristics
•Response to initial therapy

28. Prognostic Variables
•Clinical and Lab Variables:
•Age:
–1-9 yrs Best outcome5 yr EFS88%
–10-15 yrs 73%
–>15 yrs 69%
–< 12 mths 44%
–< 6 mths poor outcome
•Infants: Poor outcome
–MLL gene, Increased WBC, CNS Leukemia
–CD10 Negative
–Poor initial response
Pui et
al, Lancet 2008

29. Prognostic Variables
•Clinical and Lab Variables:
•WBC Count at Presentation:
–Increasing WBC confer a poor outcome especially in
patients with Precursor B-cell ALL
–T-cell ALL patients with WBC > 100k have a higher risk of
CNS relapse

30. Prognostic Variables
•Leukemic Cell Characteristics:
•Immunophenotype:Immunophenotype:
•Precursor B ALL: CD19, CD10 (cALLa), HLA-DRPrecursor B ALL: CD19, CD10 (cALLa), HLA-DR
80%- 85% of ALL80%- 85% of ALL
80% CD10 positive80% CD10 positive
•Early pre-B (no sIg or cyIg) Early pre-B (no sIg or cyIg)
•Pre-B (cy Ig)Pre-B (cy Ig)
•B-cell (sIg) 3% (FAB L3, CMYC gene trans)B-cell (sIg) 3% (FAB L3, CMYC gene trans)
Mature B-cell phenotype no longer confers a poor prognosisMature B-cell phenotype no longer confers a poor prognosis

31. Prognostic Variables
•Leukemic Cell Characteristics:
•Immunophenotype:
•T- Cell ALL : CD2, CD7, CD5, CD3
Males, Older Age, High WBC, Mediastinal mass
12 % of ALL
T-cell phenotype no longer confers a poor prognosis T-cell phenotype no longer confers a poor prognosis

32. Prognostic Variables
•Cytogenetics:
•Favorable Prognosis
–High Hyperdiploidy: 51 -65 chromosomes/cell
or DNA index > 1.16
–Trisomies 4, 10, 17
–TEL/AML1 t(12;21)
•Poor Prognosis
–Hypoploidy:< 44 chromosomes
–Philadelphia chromosome
–T(4;11) with MLL-AF4 fusion

33. Prognostic Variables
•Response to Initial Therapy:
–Day 7 and Day 14 BM responses
Rapid response is favorable
Current COG protocols
–Peripheral blood response to steroids
Day 7 (blasts< 1000/ul) GR is favorable
BFM protocols

34. EARLY RESPONSE TO THERAPY
•Rapidity of response to initial
chemotherapy is a significant predictor
of long-term outcome

35. Treatment
•Induction of Remission (4 -6 weeks)
•Consolidation ( 4 -8 weeks)
•Interim Maintenance (8 weeks)
•Delayed Intensification (8 weeks)
•Maintenance (2 -3 years)

36. Treatment
•Induction of Remission
Standard or Low Risk
Dexamethasone
Vincristine
L Asparaginase
High Risk
Dexamethasone/Prednisone
Vincristine
L Asparaginase
Anthracyclines (Daunomycin)

37. Treatment
•Induction of Remission
Dexamethasone Low Risk
Less CNS and BM relapses
Better EFS
Use in Adolescents Aseptic Necrosis
Use in High Risk Infections

38. Treatment
•Consolidation:
–Intensified CNS therapy
• Delayed Intensification:
– improves outcome
– Anthracyclines, Cyclophosphamide

39. Treatment
•Maintenance Therapy:
–Daily oral 6MP and weekly oral MTX
–Severe hematopoietic toxicity with
Thiopurine S Methyl Tranferase
deficiency
–CNS prophylactic therapy

40. Treatment
Maintenance Therapy:
– VCR + Prednisone/ Dexamethasone Pulses
1.VCR/Prednisone pulses improved EFS
2.Dexamethasone in 1-9 yr SR patients showed fewer CNS
relapses and improved EFS compared to Prednisone
3.Use of Dexamethasone in Adolescents: Risk of Aseptic
Necrosis and bone fractures

41. Treatment
•T-cell ALL:
Intensified chemotherapy protocolsIntensified chemotherapy protocols
Pilot trials with ARA-GPilot trials with ARA-G
•Infant ALL:
Intensive chemotherapy protocols
•Philadelphia +ve ALL:
BMT from matched related or MUD
Imatinib

42. Relapsed ALL
•Timing of Relapse:
Early Relapse: Survival < 10-20%
[ Relapse on therapy or 6 months off ]
Late Relapse: Survival 30-40% (chemotherapy)
[ Relapse 12 months off therapy]
T-cell ALL: Survival < 20%

43. Treatment of Relapsed ALL
•Bone Marrow Transplantation:
Early Relapse
High Tumor Load (>10,000 blasts/ul)
•Chemotherapy

44. Conclusions
•ALL is the commonest leukemia of childhood
•Minimal evaluation should include a good
H&P, peripheral smear and bone marrow
exam
•Simple treatment protocols utilizing common
agents used for ALL treatment should be used
initially
•Treatment modifications should be based on
institutional experience and results