Acute Lymphoblastic Leukemia An Overview Aziza Shad, MD

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

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

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;2002:100400 and 100526

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

Morphology and Immunophenotype Making the diagnosis: Morphology and Immunophenotype

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

Leukemia is a Bone Marrow Diagnosis!

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

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%

Acute Lymphoid Leukemia Incidence by Age

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 (1986-1994). 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

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)

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

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

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

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

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

Immunophenotype Side-scatter CD10 CD19 CD45 CD138 CD22

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

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?

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

Years of Diagnosis Number of Children 80 60 40 20 100 1995-97 1,299 1993-95 1,585 1989-93 3,402 % Survival 1983-89 3,711 1978-83 2,984 1975-78 1,313 1972-75 936 1970-72 499 1968-70 402 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, 1968-1997. Bleyer A, Hather N, Personal Communication

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

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

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

Prognostic Variables Clinical and Lab Variables: Age: 1-9 yrs Best outcome 5 yr EFS 88% 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

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

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

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

Prognostic Variables Cytogenetics: Favorable Prognosis Poor 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

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

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

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

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

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

Treatment Consolidation: Delayed Intensification: Intensified CNS therapy Delayed Intensification: improves outcome Anthracyclines, Cyclophosphamide

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

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

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

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%

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

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