1. CML in China Qian Jiang, MD Peking University People's Hospital, Peking University Institute of Hematology 2013-2-22

2. CML in China 江倩 北京大学 人民医院 北京大学 血液病研究所 2013-2-22

3. Outline Current status of CML in China TKI treatment for CML patients: experience from single center Transplant in the TKI era: experience from single center Therapeutic choices for CML patients based on financial constraints

4. Outline Current status of CML in China TKI treatment for CML patients: experience from single center Transplant in the TKI era: experience from single center Therapeutic choices for CML patients based on financial constraints

5. Incidence of CML Annual incidence: 0.4/100,000 population Median age at diagnosis: 40 years Male: Female = 1.4 - 2.3 : 1 Disease phase at diagnosis: - CP: 80% - 90% - AP and BP: 10% - 20% Kim DW, et al. Leuk Res. 2010;34:1459-71 Wang JX, et al. Zhonghua Xue Ye Xue Za Zhi. 2009;30:721-5.

6. National insurance coverage of CML therapies in China Hydroxyurea: fully covered Interferon: partial covered Transplant: partial covered, ￥ 30,0000- ￥ 500,000 Imatinib: not covered in the majority of regions - partial covered in a few provinces and cities - available through GIPAP, at least ￥ 70,000 each year Dasatinib & Nilotinib: not covered - available through access program, at least ￥ 90,000 each year

7. Treatment Patterns Asia CML Study Alliance (ACSA) developed a survey to assess current CML treatment patterns in the Asia-Pacific region between Nov 2008 and April 2009. Kim DW, et al. Leuk Res. 2010;34:1459-71

8. Number of patients who received imatinib treatment by year ECP LCP AP BP Data from CCF

9. Number of patients who received 2 nd generation TKIs treatment by year Nilotinib Dasatinib Dasatinib and nilotinib were approved as the second-line options after imatinib failure in China. Most patients received 2 nd generation TKIs in advanced phase. 2 nd TKIs were used as a first-line therapy only for clinical trials. Data from CCF & BMS

10. Case number Data from Chinese Hematopoietic Stem Cell Transplantation Register Group Transplantation is preferred for CML patients with TKI failure, inadvanced phase, or those who can not afford TKI treatment. Number of patients who underwent transplantat by year

11. Outline Current status of CML in China TKI treatment for CML patients: experience from single center Transplant in the TKI era: experience from single center Therapeutic choices for CML patients based on financial constraints

12. Imatinib therapy for newly diagnosed patients in chronic phase: response rates Estimated rate at 12 months at 48 months CCR n=172 86.0% 93.7% MMR n=165 34.1% 72.1% CMR n=165 12.2% 49.7% Median follow-up was 34 months (range, 4-118 months). Data from Peking University People's Hospital

13. Total n=172 Estimated rate at 48 months EFS event n=20 87.7% PFS AP/BP n=11 93.2% OS dead n=4 81.9% 98.8% (considering only CML related deaths) Median time to event was 9 months. Median time to AP/BP was 12 months. Median time to dead was 7 months. Probability of EFS, PFS and OS Imatinib therapy for newly diagnosed patients in chronic phase: EFS, PFS and OS Data from Peking University People's Hospital

14. Total n=56 At 10 years EFS event n=21 61.0% PFS AP/BP n=8 84.8% OS dead n=6 87.8% 90.1% (considering only CML related deaths) Imatinib therapy for interferon-failure patients in chronic phase: EFS, PFS and OS Probability of EFS, PFS and OS Months Data from Peking University People's Hospital

15. Imatinib versus nilotinib for newly diagnosed patients in chronic phase: CCR rate 28 27 27 31 31 30 P=0.003P=0.039 Data from Peking University People's Hospital

16. 3m 6m 12m P=0.055 P=0.027 P=0.003 BCR-ABL mRNA reduction Imatinib versus nilotinib for newly diagnosed patients in chronic phase: molecular response Data from Peking University People's Hospital

17. n=5 n=2 n=8 n=3 Imatinib versus nilotinib for newly diagnosed patients in chronic phase: event and progression The superior rate of responses has not yet translated into improvements in EFS, PFS and OS. Data from Peking University People's Hospital

18. Dasatinib as a second- or third-line therapy for imatinib-failure patients CP n=27 AP n=18 BP n=40 CP n=27 AP n=16 BP n=27 Data from Peking University People's Hospital

19. Outline Current status of CML in China TKI treatment for CML patients: experience from single center Transplant in the TKI era: experience from single center Therapeutic choices for CML patients based on financial constraints

20. Imatinib versus transplant for patients with CP CML <1 year after diagnosis: Flow chart of study 348 pts with CP CML <55 years old prospectively assigned to receive imatinib or an HLA-identical sibling transplant from April, 2001 to March, 2010. Jiang Q et al. ASH 2011 Abstract No. 162

21. Imatinib therapy was associated with better outcomes than transplant in patients with CP CML <1 year after diagnosis No 5-year TRM in the imatinib cohort compared to 17% in the transplant cohort. 5-year CIFs of progression were comparable in both cohorts. More MMR and CMR were in the transplant cohort. RR=3.62 (95% CI, 1.95–6.72) P<0.0001 RR=5.30 (95% CI, 2.40–11.71) P<0.0001 RR=41.84 (95% CI, 5.66–309) P<0.0001) EFS PFS Survival Jiang Q et al. ASH 2011 Abstract No. 162

22. Imatinib versus transplant for previously imatinib-untreated AP CML patients EFS rate at 6 years 71.8% 39.2% Jiang Q, et al. Blood. 2011. 17;117:3032-40. OS rate at 6 years 83.3% 51.4% PFS rate at 6 years 95.2% 48.3% A cohort study was designed to compare the outcomes of imatinib vs. allo-HSCT for AP CML from April 2001 to Sep 2008, 132 pts were enrolled.

23. CML duration ≥ 12 months hemoglobin < 100 g/L peripheral blood blasts ≥ 5% Independent adverse prognostic factors prior to treatment for both OS and PFS In an attempt to determine whether choice of therapy contributed to the survival differences, we categorized the entire cohort into 3 groups: - low-risk (no factor): n = 40 - intermediate-risk (any factor): n = 59 - high-risk (at least two factors): n = 33 Jiang Q, et al. Blood. 2011. 17;117:3032-40.

24. EFS, OS and PFS in low-risk AP CML patients by therapy Absence of significant differences between the two groups. Jiang Q, et al. Blood. 2011. 17;117:3032-40.

25. EFS, OS and PFS in intermediate-risk AP CML patients by therapy EFS & OS did not differ in terms of therapy mode. More relapse developed in the imatinib group. Jiang Q, et al. Blood. 2011. 17;117:3032-40.

26. EFS, OS and PFS in high-risk AP CML patients by therapy Allo-HSCT was significantly superior to imatinib. Jiang Q, et al. Blood. 2011. 17;117:3032-40.

27. Conclusions Allo-HSCT is superior to imatinib, conferring significant survival advantages to high- and intermediate-risk patients. We recommend those patients receive an early transplant after achieving a second CP with imatinib. Jiang Q, et al. Blood. 2011. 17;117:3032-40.

28. Conclusions (Cont’d) Outcomes of imatinib and allo-HSCT were equally good in low-risk patients with CML in AP. For low-risk patients, imatinib may remain the primary option so long as MRD is carefully monitored, and allo-HSCT should be considered if there is evidence of imatinib resistance. Jiang Q, et al. Blood. 2011. 17;117:3032-40.

29. TKIs versus transplant for previously TKI- untreated BP CML patients by therapy OS EFS OS PFS Allo-HSCT was significantly superior to TKIs. Data from Peking University People's Hospital

30. Outline Current status of CML in China TKI treatment for CML patients: experience from single center Transplant in the TKI era: experience from single center Therapeutic choices for CML patients based on financial constraints

31. What will be the first option for CP CML patients in China? TKIs, a life-long therapy, are used mainly through partially paid patient access program. 2 nd generation TKIs are more expensive than imatinib, not covered by insurance and approved by SFAD only for a second-line therapy for imatinib-failure patients. So, imatinib will be the mainstay choice as a first-line option for CML.

32. What is the role of transplant in the TKI era for CML in China? Transplant offers the possibility of a cure with less cost than TKIs therapy. One-off transplant versus the expense of lifetime TKI therapy. So, transplant perhaps will remain a first choice for a few young CP CML patients with an HLA-identical donor and a second-line option following imatinib for those who can’t afford a long-term 2 nd generation TKI therapy.

33. What is our next move? To find ways to make TKIs more widely available to more CML patients and increase accessibility of affordable therapeutic approaches. To improve CML management according to international guidelines by routine cytogenetic and molecular monitoring. To identify early signs of resistance to TKIs and enable a timely switch to alternative therapies.