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Acute Lymphoblastic Leukaemia (ALL) in Children PowerPoint Presentation

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Acute Lymphoblastic Leukaemia (ALL) in Children Presentation Transcript

Slide 1 - Chi Kong Li, MBBS, MD Chief, Division of Haem/Onc/BMT Lady Pao Children Cancer Centre Prince of Wales Hospital The Chinese University of Hong Kong Acute Lymphoblastic Leukaemia (ALL) in Children:what do we learn from the clinical trials BTG2013
Slide 2 - Paediatric ALL Commonest childhood malignancy 25% of all childhood cancer Incidence: 3-4 cases per 100,000 children 30-40 new cases per year in Hong Kong 6,600 – 8,800 new cases per year in China (222 million children <15 yr)
Slide 3 - ppt slide no 3 content not found
Slide 4 - Overall survival probability by treatment era for patients enrolled onto Children's Oncology Group trials in 1990-1994, 1995-1999, and 2000-2005. Hunger S P et al. JCO 2012;30:1663-1669 1990 to 1999, 84% of death occurred within 5 year of diagnosis, only 1% > 10 year 83.7% 90.4% 80.1% 83.9%; COG
Slide 5 - Moricke, A. et al. Blood 2008;111:4477-4489 Germany BFM 95 Study EFS compared with historical result improvement of EFS over the years: from 71.7% to 79.6%
Slide 6 - Improvement of Event free survival by chemo: HKALL 93 (UK based) vs HKALL 97 (BFM based) HKALL97 HKALL 93 Li CK et al. Hong Kong Med J. 2006 Feb;12(1):33-9, Hematol Oncol 2003; 21:1-9
Slide 7 - How to improve the cure rate? Understand the genetic basis of ALL, Discover effective anti-leukaemia agents Learn to use the anti-leukaemia drugs properly and wisely through large scale randomized studies Avoid agents/therapy with significant late complications Tailor the treatment intensity best suit the patient (individualized treatment)
Slide 8 - Genetic basis ALL is NOT a single disease Heterogeneity in genetic basis with great variability in prognosis, treatment response Large clinical trials define the importance of various genetic basis
Slide 9 - Estimated frequency of specific genotypes in childhood ALL. Pui C et al. Blood 2012;120:1165-1174
Slide 10 - Characteristics and Clinical Outcomes of Selected Subtypes of Childhood ALL: Treatment implications
Slide 11 - Temporary remission in acute leukaemia in children produced by folinic acid antagonist, 4-aminopteroyl-glutamic acid (Aminopterin) Farber S, Diamond LK, Mercer RD, Sylvester RF, Wolff JA New England J Medicine 1948, 238:787. Effective Anti-Leukaemia Agents
Slide 12 - 5-year survival < 10% in the 1960s 20% in early 1970s to 60% in late 70s Further improve to 77% in 1985 -1994 ~90% in 2000s New anti-leukaemia drugs introduced in 1970s
Slide 13 - Early studies in 1980s: No new drugs!
Slide 14 - 1990s chemotherapy protocols Induction: VCR, L-asp, Dexa/Pred, +/- Daunorubicin Early Intensification: Cyclophosphamide, Ara-C, 6MP Consolidation: Methotrexate, 2g or 5 g or escalating MTX 100mg, + 6MP Delayed intensification: VCR, L-asp, Dexa, DNR, Cyclophosphamide, Ara-C Maintenance: 6MP. MTX, +/- pulse VCR/steroid
Slide 15 - Why is there significant improvement in survival? Basically no new drugs in past 3 decades
Slide 16 - Proper use of chemotherapy Multi-center large scale clinical trials Randomised studies to test hypothesis Applying drugs of different combination at different dosage at different timing According to patient biological characteristics and initial response to treatment
Slide 17 - Overall survival probability by treatment era for patients enrolled onto Children's Oncology Group trials in 1990-1994, 1995-1999, and 2000-2005. Hunger S P et al. JCO 2012;30:1663-1669 1990 to 1999, 84% of death occurred within 5 year of diagnosis, only 1% > 10 year 83.7% 90.4% 80.1% 83.9%; COG
Slide 18 - Moricke, A. et al. Blood 2008;111:4477-4489 BFM 95 Study EFS compared with historical result improvement of EFS over the years: from 71.7% to 79.6%
Slide 19 - Randomized studies with sig results CCG-105: Intermediate Risk (<10 years) Delayed intensification (DI) vs no DI, 625 p’ts recruited, DI showed sig survival benefit: 10-year EFS 74% vs 60% UKALL 97: Induction : Dexamethasone 6.5mg vs Pred 40 mg (also same steroid during maintenance) 1621 p’ts recruited Dexa reduced CNS relapse 2.5% vs 5.0% (p=0.007) EFS also improved 84.2% vs 75.6% (p=0.0007)
Slide 20 - Matloub, Y. et al. Blood 2006;108:1165-1173 randomized study testing intrathecal therapy: MTX versus triple IT (MTX/Ara-C/steroid) CCG 1952 (1996-2000)
Slide 21 - Treatment intensity according to biological characteristics and early treatment response Precise stratification: age, WBC, genetics Early treatment response: 7 days steroid response Bone marrow blast % : Day 7, Day 15, Day 30 by morphology Detection of very low level residual leukaemia cells in first 3 months: Minimal Residual Disease monitoring (1 in 10-4)
Slide 22 - Minimal Residual Disease detection in paed ALL:Real-time Quantitative PCR, or Flow cytometry
Slide 23 - Conter, V. et al. Blood 2010;115:3206-3214 Event-free survival (A) and cumulative incidence of relapse (B) according to PCR-MRD classification in pB-ALL patients 3184 patients treated in the AIEOP-BFM-ALL 2000 trial. Stratified into 3 risk groups according to MRD on day 33 and 84 marrow as detected by q-PCR
Slide 24 - Basso, G. et al. J Clin Oncol; 27:5168-5174 2009 (A) Event-free survival (EFS) and (B) cumulative incidence of relapse 815 patients treated in the AIEOP-BFM-ALL 2000 trial. Stratified into 3 risk groups according to MRD on day 15 marrow as detected by flow cytometry
Slide 25 - Avoid late sequelae High chance of long term survival Avoid agents predispose to second malignancy: Etoposide not used in non-High Risk patients Cranial irradiation for CNS prophylaxis nearly stopped for all patients Limit dose of anthracycline to prevent late cardiac toxicity
Slide 26 - New Drugs For very resistant diseases Difficult to conduct clinical trials: Small number of patients Need multi-national collaboration study Pharmaceutical industry may not be interested National grant or NGO sponsors
Slide 27 - Schultz, K. R. et al. J Clin Oncol; 27:5175-5181 2009 Early event-free survival in Philadelphia chromosome-positive acute lymphoblastic leukemia patients treated with imatinib
Slide 28 - Effect of imatinib given post induction on the outcome of children with Philadelphia chromosome-positive acute lymphoblastic leukemia (EsPhALL): a randomized, open-label, intergroup study Lancet Oncology, 2012, August 14. Biondi A et al.
Slide 29 - Can the approach of pediatric trials applicable to adults? Young adults similar to adolescents in biological features US Children Cancer Group studies included older age children and adolescents 5 year overall survival of > 15 years old in different era: P=0.0025
Slide 30 - Success of childhood ALL High recruitment rate, > 90% eligible patients treated according to research protocols Collaborative studies, national or international, included large number of patients Conducted serial clinical trials based on results of earlier studies Randomised clinical studies to test hypothesis Scientific research to understand genetics, pharmacogenetics and target therapy
 

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