1. Treatment History of Leukemia in Korea
Hyo Seop Ahn, MD
Professor Emeritus
Seoul National University College of Medicine
Department of Pediatrics
Bundang Seoul National University Hospital Cancer Center
Feb. 22, 2015
The cure rate of acute lymphoblastic leukemia in children has dramatically improved over the past five decades from zero to approximately 80%. This improvement is mainly attributed to the development of chemotherapy by multicenter clinical trials of large study groups, based on a profound understanding of the biology of leukemia.

3. Treatment of Acute Lymphoblastic Leukemia in Children -Before 1983, after 1985

4. Acute leukemia Neoplasm of leukocyte precursors
Variable block in differentiation, uncontrolled proliferation
Relapsed acute leukemia still leading cause of cancer death
Few targeted agents
Need novel therapeutic approaches 4

5. Acute leukemia in childhood cancer -Annual report of the Central Cancer Registry in Korea

6. Presentation 1. BM failure (RBC, WBC, Platelet) 2
Presentation 1. BM failure (RBC, WBC, Platelet) 2. Hypermetabolism (Rapid production, destruction of leukemic cells) 3. Proliferation of leukemic cells

7. Evaluation for patients with leukemia
History taking & Physical examination
Laboratory examination
CBC, Tumor lysis labs
Bone marrow aspiration (Wright stain, Cytochemistry-PAS, Peroxidase, SBB, ANAE)
Bone marrow biopsy (1985.7)
Immunophenotype (1983.3)
Cytogenetics: FISH (1998), Classic chromosomal study
CSF cell count and Cytospin (1985)
Red color is the year of examination started in SNUH.

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. Cytogenetic Evaluation of ALL
Classic cytogenetics☎
Molecular cytogenetics☎
FISH or RT-PCR for translocations with a poor prognosis, t(9;22), t(4;11);
or good prognosis, t(12;21) or TEL/AML1

10. Classic cytogenetics☜

11. Classification of ALL
tel-aml

12. History of ALL Treatment
50% of those treated with supportive care died within 4 months
Steroids, 6-MP, MTX : 8 to 12 months remission
“Total Therapy” study was initiated in 1962 with studies I-III (PD+VCR & CS-RT 500 or 1,200 cGy) producing a 17% EFS.
Cure was first accomplished in St. Jude Total Study V ( ).

13. “Total Therapy” of ALL Study V (1967-1968)
CR rate = 88%

14. Treatment of ALL in SNUH(1)
1955 : ACTH
1956 : Cortisone, 6MP
1959 : PD ± 6MP
1967 : L-ASP
1968 : MTX
1st long-term survivor; diagnosed in 1965 and treated for 5.5yrs

15. Treatment of ALL in SNUH(2)
1971 : VCR → PD, VCR ± 6MP
1976 : PD, VCR, L-ASP – 3rd long-term survivor received standard therapy in SNUH
2nd long-term survivor; diagnosed in 1970 and treated for 5.5yrs

16. Treatment of ALL in SNUH (1976 ~ 1985.6)
Induction: PD, VCR, L-asp
Consolidation: C-RT, IT-MTX, 6MP
Maintenance: MTX(wkly), 6MP(daily) AND PD (2wks) + VCR (twice) pulse q 8wks, for 2y 6m (boys & girls) [Treated for 5.5yrs before 1976]

17. CSF cytospin; Autosmear CF-12 model, Sakura - after 1985 in SNUH
Shandon CytoSpin 4 (Thermo Fisher Scientific, Waltham, MA)
처음에는 Sakura 회사의 복수검사용으로 검사하다가 그 후 지금도 사용하는 Shandon Scientific Ltd. 제품으로 바꿈.
최근 발표자료에는 기계에 따라 발견율 차이가 있다[Shandon vs Wescor] (Shandon CytoSpin 4 (Thermo Fisher Scientific, Waltham, MA) to the Wescor Cytopro Rotor AC-060 (Wescor, Logan, UT).
Acta Cytol Mar-Apr;24(2): Comparison of cytocentrifugation and sedimentation techniques for CSF cytomorphology.
Am J Clin Pathol May;137(5): Detection of leukemic lymphoblasts in CSF is instrument-dependent.
Shandon, 600 rpm for 10 minutes with low acceleration; Wescor, 1,000 rpm for 5 minutes with high acceleration.

18. CNS Leukemia -initial relapse in the CNS was over 50% without prophylactic therapy
POG (n=381) : 2.8% at 5yr
IT triple therapy q 8wk
CCG104 (n=529) : 8% at 90mo
IT-MTX q 12wk
90mo = 7.5yr

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

20. UCLA period ( ~ )

21. Progress of CCG protocol (USA)
First study of new Tx for ALL : 1956
CCG-141 : ~
CCG-160 series : ~
CCG-100 series : 1983 ~
CCG-1880 series : 1988 ~
CCG-1900 series : 1990 ~

22. Prognostic Factors at Diagnosis
initial WBC/uL
50,000
10,000
Low
Intermediate
High
1yr
10yr
age
2yr
Standard (low + intermediate) risk group
High risk group

23. Induction chemotherapy of high risk ALL (before 1985 in SNUH)
Complete remission rate with PD, VCR and L-asp was 80%.

24. Induction chemotherapy
Standard risk
High risk
PD mg/m2
VCR mg/m2
L-ASP ,000 u/m2
IT Ara-C/MTX
CR rate >98%
PD mg/m2
VCR mg/m2
L-ASP ,000 u/m2
DNM mg/m2
IT Ara-C/MTX
CR rate >96%

25. CCG 160 series ( ~ ) Prof. H. Lee (Michael Reese Hospital and Medical Center, USA) gave me this protocol after his lecture – “Recent advance of treatment in childhood leukemia” (1982.7)
Induction: PD, VCR, L-asp (regardless of Px Gr)
IT-MTX on D0, 14, 28
Lymphoblast morphology (FAB L1, L2)
Immunophenotype
BM on d14
Prognosis group: Good, Average, Poor prognosis
Testis biopsy (boys) at 2 yrs of maintenance
Michael Reese Hospital & Medical Center, Chicago, IL

26. The survival rate of ALL has improved after adoption of CCG protocol
Annual No. of ALL (SNUH)
Annual new pts of ALL in Korea are about 240.

27. Changes after 1985 (1)
‘New Life for Children’ campaign for children with cancer, broadcasted on MBC TV – The first nationwide campaign that raised awareness and assistance for financially underprivileged patients (1990). 
The Korea Childhood Leukemia Foundation was established as the Childhood Leukemia Supporters’ Association in 1991 and was later licensed as a foundation in 2000 (Board Member, Chairman of Steering Committee, Korea Childhood Leukemia Foundation, now Executive Director). It is now a publicly recognized organization supporting children with cancer. 
Establishment of isolated in-patients’ ward solely for cancer patients (1994) 

28. Changes after 1985 (2)
School in the Children’s Hospital (1994), approved as an institute from the Ministry of Education (1999). 
First Stem Cell Transplantation (1996)
In 1996, a shelter for families of childhood cancer was built for the first time in Korea (Donated from Jeil Life Ltd). Currently, six shelters and two service centers are being operated in the country (Korea Childhood Leukemia Foundation; KCLF). 
Oncology Day Care Ward for out-patients (2008)

29. ‘New Life for Children’ campaign for children with cancer, broadcasted on MBC TV (2011)

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

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

32. Delayed intensification
Initial WBC
Reversal of outcomes in CCG study (during )
CCG 104 for low risk (WBC <10,000/uL)
induction
consolidation
maintenance
EFS: 62%
CCG 105 for intermediate risk (10,000/uL < WBC < 50,000/uL)
induction
consolidation
maintenance
delayed intensification
EFS: 74%
Adding delayed intensification (reinduction + reconsolidation)
improved EFS.

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

34. Cure Rate of Childhood ALL
Further development
Quality of life
- 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.

35. Multicenter study to establish proper treatment of high risk acute lymphoblastic leukemia in children in Korea (2005 ~ 2014)
12 Institutions in 2005
26 Institutions in 2013
Currently, second clinical trials for further improvement are underway since 2014.
Supported by Ministry of Public Health and Welfare
In Korea, the first nationwide multi-center clinical studies for high-risk, very high-risk and relapsed pediatric ALL was launched from 2005 to 2014 through the support by a grant from the National R&D Program for Cancer Control, Ministry for Health and Welfare. We were able to recruit clinicians from nationwide multi-centers and efforts to collaborate on a treatment protocol for pediatric ALL was initiated for the first time. Through this trial, the survival rates of pediatric ALL patients appeared to significantly improve. Currently, second clinical trials for further improvement are underway since 2014.

36. Childhood cancer survivors 1:1,000 young adults