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Acute Lymphoblastic Leukemia An Overview

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Presentation on theme: "Acute Lymphoblastic Leukemia An Overview"— Presentation transcript:

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

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

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