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

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

5. Maslak, P. ASH Image Bank 2004;2004:101200
Diagnosis?
Acute Leukemia
(most likely ALL)
Maslak, P. ASH Image Bank 2004;2004:101200 4

6. Morphology and Immunophenotype
Making the diagnosis:
Morphology and Immunophenotype

7. Morphologic classification – French American British (FAB) subtypes
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 5

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 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 %
for some sub-groups, the cure rate is close to 90%, for others, it is < 20%

11. Acute Lymphoid Leukemia Incidence by Age

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
ALL is the most common form of leukemia in children. There are approximately 2,000 children in the United States aged 14 and younger diagnosed with ALL each year.1
The peak incidence of ALL is reported among children in the United States between ages 2 and 3. In this group, there were more than 80 new cases per million per year ( ). ALL affects substantially more white children than black children. Among children less than 5 years old, whites are affected more than twice as much as blacks. ALL is more common in boys than girls at all ages.2
The overall 5-year survival rate for ALL is between 75% and 80%. Factors that affect survival include age at diagnosis, with a poorer prognosis for infants and children over age 15. The poor prognosis in these age groups is related to unfavorable chromosomal abnormalities: rearrangement of the MLL gene in infants and the increased relative frequency of Philadelphia chromosome-positive ALL and T-cell ALL in adolescents.2

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. Clinical Presentation
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 8

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
Side-scatter
CD10
CD19
CD45
CD138
CD22

21. Molecular genetics Favorable risk High 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. Years of
Diagnosis
Number of
Children 80 60 40 20
100
1,299
1,585
3,402 %
Survival
3,711
2,984
1,313
936
499
402 2 4 6 8 10
Total Number of
Patients Treated:
16,131
Years after Study Entry
Legend: Survival of CCG Patients with Newly-Diagnosed Acute Lymphoblastic Leukemia, 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 features
Leukemia cells characteristics
Response to initial therapy

28. Prognostic Variables Clinical and Lab Variables: Age:
1-9 yrs Best outcome 5 yr EFS 88%
10-15 yrs %
>15 yrs %
< 12 mths %
< 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:
Precursor B ALL: CD19, CD10 (cALLa), HLA-DR
80%- 85% of ALL
80% CD10 positive
Early pre-B (no sIg or cyIg)
Pre-B (cy Ig)
B-cell (sIg) 3% (FAB L3, CMYC gene trans)
Mature 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

32. Prognostic Variables Cytogenetics: Favorable Prognosis Poor Prognosis
High Hyperdiploidy: 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. Response to Initial Therapy:
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
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: Delayed Intensification:
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
VCR/Prednisone pulses improved EFS
Dexamethasone in 1-9 yr SR patients showed fewer CNS relapses and improved EFS compared to Prednisone
Use of Dexamethasone in Adolescents: Risk of Aseptic Necrosis and bone fractures

41. Treatment T-cell ALL: Infant ALL: Philadelphia +ve ALL:
Intensified chemotherapy protocols
Pilot 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