1. Treatment of Acute Leukemia in Children Hyo Seop Ahn, MD Professor Emeritus, Seoul National University College of Medicine Department of Pediatrics Bundang Seoul National University Hospital Cancer Center Feb. 22, 2014

3. 1.Treatment of Acute Lymphoblastic Leukemia 2.Multi-center Study in Korea

4. Acute leukemia Neoplasm of leukocyte precursors Variable block in differentiation, uncontrolled proliferation Adults: relapse very common Children: relapsed acute leukemia still leading cause of cancer death Few targeted agents Need novel therapeutic approaches Need comprehensive understanding of the genetic lesions causing leukemia, and treatment failure

5. Acute leukemia in childhood cancer

6. Increased Risk of Developing Leukemia Down ( trisomy 21) Bloom ( chromosomal breakage syndrome) Fanconi ( chromosomal breakage syndrome) Klinefelter (extra X; XXY) Ataxia telangiectasia (ATM gene)

7. Genetic classification of acute lymphoblastic leukemia T-lineage Hyperdiploidy >50 chromosomes 25% TEL-AML1 t(12;21) 22% Hypodiploidy <45 chromosomes 1% Others 22% E2A-PBX1 t(1;19) 5% HOX11 0.7% TAL1 7% HOX11L2 2.5% LYL1 1.5% MLL rearrangements 8% BCR-ABL t(9;22) 3% B-lineage MLL-ENL 0.3% Pui N Engl J Med 2004;350:1535 MYC t(8;14), t(2;8),t(8;22) 2%

8. Immunophenotype by Flow cytometry Confirm diagnosis and provides MRD information Definition of lineage  B-lineage: CD10, 19, 20, 22, & Tdt+  T-ALL: CD10, 2, 5, 7, intracellular CD3 & Tdt+  AML: CD38, 33, 13, 15, 4+, Tdt-  B-ALL: CD20, 22, 38, & SIg+, CD10-

9. Classification of ALL tel-aml

10. Genotype Correlates with Outcome Children ’ s Oncology Group

11. History of ALL Treatment 50% of those treated with supportive care died within 4 months Steroids, MTX, 6-MP: 8 to 12 months remission “Total Therapy” study was initiated in 1962 with studies I-III producing a 17% EFS Cure was first accomplished in St. Jude Total Study V (1967-1968)

12. Treatment of ALL in SNUCH 1955 : ACTH 1956 : Cortisone, 6MP 1959 : PD ± 6MP 1967 : L-ASP 1968 : MTX 1971 : VCR → PD, VCR ± 6MP 1976 : PD, VCR, L-ASP Standard therapy in standard risk ALL

13. The survival rate was increased after mid 1980 in SNUH.

14. Components of Therapy Induction CNS prophylaxis/Consolidation Delayed Intensification Maintenance Therapy

15. Delayed Intensification Norton Simon Hypothesis: Cells remaining post-induction are relatively/absolutely resistant; a late intensification using new agents may be beneficial

16. Prognostic Factors at Diagnosis initial WBC/uL 50,000 10,000 Low Intermediate High 1yr10yrage2yr Induction regimen for Standard (low + intermediate) risk group: 3 drugs (PD, VCR, L-Asp) High risk group: 4 drugs (PD, VCR, L-Asp + Anthracycline)

17. Delayed intensification Initial WBC Reversal of outcomes in CCG study (during 1983 - 1988) Adding delayed intensification (reinduction + reconsolidation) improved EFS delayed intensificationinductionconsolidationmaintenance CCG 105 for intermediate risk (10,000/uL < WBC < 50,000/uL) EFS: 74% inductionconsolidationmaintenance CCG 104 for low risk (WBC <10,000/uL) EFS: 62%

18. Double delayed intensification Initial WBC Reversal of outcomes in CCG study (during 1988 - 1995) Adding delayed intensification (reinduction + reconsolidation) doubly also improved EFS -> combine low risk and intermediate risk to standard risk DIinductionconsolidationmaintenance CCG 1891 for intermediate risk (10,000/uL < WBC < 50,000/uL) EFS: 83% inductionconsolidationmaintenance CCG 1881 for low risk (WBC <10,000/uL) EFS: 79% DI

19. Philadelphia positive ALL Arico M. N Eng J Med 2000, 342; 998 Development of treatment modality esp. transplantation improve the result of Philadelphia positive childhood ALL

20. Response related Prognostic Factors Initial response to chemotherapy CCG 1882 study Induction Early response: D7 BM Standard BFM BM blast <25% EFS: 76% EFS: 79% Augmentation of chemotherapy intensity increased the EFS of poor early responder. Augmented BFM BM blast >25%

21. Cure Rate of Childhood ALL - Improvement of cure rate is owing to the development of chemotherapy by multicenter clinical trials of large study groups based on prognostic factors. - To improve the current results in plateau, further development of treatment is needed with the reduction of toxicity for better life. Quality of life Further development

22. Radiation Therapy in Leukemia CNS leukemia High risk group: Slow early responder (SER); M3 marrow (>25% blast) on d7 Chloroma Testicular leukemia (at Dx;No, at relapse;Yes)

23. Complications -Late effects Cardiomyopathy Osteonecrosis Endocrine–growth delay, hypothyroidism, gonadal dysfunction Renal–reduced GFR Psychological–intellectual dysfunction Second malignancy Cataract

24. Multicenter study to establish proper treatment of high risk acute lymphoblastic leukemia in children in Korea 12 Institutions in 2005 26 Institutions in 2013 Supported by Ministry of Public Health and Welfare

25. Current Problem and Development of Treatment in Childhood ALL Standard riskHigh riskVery high risk 80-90% Cure Nationwide Std Thx Improvement of QOL 50-70% Cure Increase cure rate Decrese side reaction <50% Cure Relapse: Main cause of Tx failure 20% Cure

26. EFS of high risk ALL in Korea (EFS=76.9%) EFS 66.2% Age 10-14 yr, multi-center reviewHigh risk ALL SNUCH WBC > 50,000, 5yr SR: 65% KSPHO multi-center retrospective review, 2002. EFS 76.9%

27. Prospective multi-center trial for HR-ALL in Korea Object: To improve Childhood HR ALL(expected SR: 70~75% 5Yr EFS). Elegibility –Age: 1 ~ 21 yr –Dx: HR B-Precursor ALL, T cell ALL, Previous steroid treated ALL Treatment Arm –RER (Rapid early responder) and SER (Slow early responder) according to day 7 BM response

28. The 1st Subject Multi-center study of newly diagnosed high risk ALL in children

29. The 1st Subject Multi-center study of newly diagnosed high risk ALL in children Registration 201.9% : 210/104 Rimission rate: 92.9% (195/210) EFS: 79.8% (n=210) OS: 84.9% (n=210) 무사건 생존율 : 78.8% (210 명 )

30. The 2nd Subject Multi-center study of very high risk ALL in children Very high risk (SCT) 1. Philadelphia positive 2. Hypodiploidy 3. t(4;11) 4. Initial WBC > 200,000/uL 5. First induction failure

31. The 2nd Subject Multi-center study of very high risk ALL in children As of Dec. 2009 Enrolled Pts;39 - 3Yr OS 58.8% (n=39) -3Yr EFS 47.7%(n=39) Registration 158.9% (62/39) 명 ) N=39

32. The 3rd Subject Multi-center study of relapsed ALL in children

33. The 3rd Subject Multi-center study of relapsed ALL in children Registration 194% : 70/36 Complete Remission Rate : 75% 5Yr OS : 32.7% N=70

34. New concepts in ALL Patient gender age race pharmacogenetics Leukemic blast cytogenetic/ploidy immunologic subtype myeloid antigen expression gene expression profile new molecular factors Treatment chemotherapy Disease-leukemia initial WBC platelet count mediastinal mass in vivo response minimal residual disease ex vivo response toxicity & complication

35. Minimal Residual Disease Methods - controversy FACS: surface marker PCR: Ig or Tc receptor gene rearrangement Marshall GM. J Clin Oncol 2003; 21, 704 MRD after 1 month of tx correlate strongly with poor survival in children with ALL

36. Pharmacogenomic Chemotherapy same dosage Optimal - cure Sub-optimal - relapse Supra-optimal - toxic complication Drug metabolism enzymes Drug transporters Drug targets Genetic polymorphism Individualized tailoring therapy

37. Pharmacogenetics of chemotherapeutic drug CYP3A4: cytochrome P4503A4 CYP3A5: cytochrome P4503A5 MDR1: p-glycoprotein VDR: vitamin D receptor GSTs: glutathione S transferases UGT1A1: UDP-glucuronosyltransferase 1A1 TPMT: thiopurine S-methyltransferase MTHFR: methylenetetrahydrofolate reductase TYMS: thymidylate synthetase RFC: reduced folate carrier NR3C1: glucocorticoid receptor Rocha JC. Blood 2005; 105, 4752 Ching-Hon Pui, MD St. Jude Children’s Hospital

38. MD Hyo Seop Ahn Hee Young Shin Kyung Duk Park Hyoung Jin Kang Hery Kim Ji Won Lee Nurse Practitioner Eun Sun Song Hwa Jin Kim Nam Hee Kim Research Lab Hoy Jeong Kim Young Hwa Woo Mi Kyung Jang