Progress in the treatment of acute promyelocytic leukemia. Lionel Adès, MD PhD Hopital Saint Louis, Paris Diderot University

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1 Progress in the treatment of acute promyelocytic leukemia Lionel Adès, MD PhD Hopital Saint Louis, Paris Diderot University

2 대한혈액학회 Korean Society of Hematology COI disclosure Name of author : Lionel Adès I have no personal or financial interests to declare: I have no financial support from an industry source at the current presentation.

3 Incidence of APL Less than 10% of AML ~2 new case / millions 150 new case/ year in France Ethnic factors Higher incidence among Latinos in the US Higher BMI among AML High incidence of Therapy related APL

4 Incidence of APL in Korea Nationwide statistical analysis on myeloid malignancies cases older>65 Eun-Hye Park, Blood Research 2015

5 Probability Prognostic Factor in APL PETHEMA-GIMEMA (RFS) 1 Low risk P < High risk Low WBC 10 & Plt >40 Intermediate WBC 10 & Plt 40 High WBC > Months Sanz et al, Blood 2000

6 How to treat low risk APL patient? 6

7 APL are highly sensitive to Anthracyclines ATRA Arsenic Trioxide Gemtuzumab Ozogamycin

8 APL are highly sensitive to Anthracyclines alone Avvisati, Blood 2002 Jean Bernard, Blood 1973

9 APL are highly sensitive to ATRA alone

10 APL are highly sensitive to Arsenic Trioxide alone Ref. n Induction therapy CR (%) ED Shen 20 ATO 0.16mg/kg ATO + ATRA 95 7 Hu 56 ATO 0.16 mg/kg + ATRA 94 6 Matthews 72 ATO 10mg Ghavamzadeh 197 ATO 0.16 mg/kg Estey/Ravandi 82 ATO 0.15 mg/kg (GO in HR) + ATRA 91 (95/81) 9 Shen et al. PNAS 2004, Hu et al. Blood 2005/PNAS2009, Mathews et al. Blood 2005/JCO 2010, Ghavamzadeh et al. Ann Oncol. 2006/JCO2011, Estey/Ravandi et al. Blood 2006/JCO 2009

11 APL are highly sensitive to Gemtuzumab Ozogamycin Lo Coco, Blood 2004

12 Different combinations are very effective Anthracyclines ATRA

13 The PETHEMA Experience Risk Adapted stategy Sanz et al Blood 2010

14 Improvement over Time Sanz et al Blood 2010

15 Different combination are very effective Anthracyclines ATRA Arsenic Trioxide

16 Addition of ATO to Chemo Powell et al. Blood 2010

17 Addition of ATO to Chemo ATO low RISK No ATO low RISK ATO High RISK No ATO High RISK Powell et al. Blood 2010

18 APL2006 Trial (WBC<10) Induction Ida AraC ATRA 12 mg/m 2 x3 200 mg/m 2 x7 until CR R Conso 1 Ida 12 mg/m 2 x3 AraC 200 mg/m 2 x7 Ida 12 mg/m 2 x3 ATO 25 days Ida 12 mg/m 2 x3 ATRA 15 days Conso 2 Ida 9 mg/m 2 x3 AraC 1g/m 2 x8 Ida 9 mg/m 2 x3 ATO 25 days Ida 9 mg/m 2 x3 ATRA 15 days Maint. 2 year Maintenance with intermittent ATRA, and continuous MTX & 6MP

19 Global Survival (%) Overall Survival ARAC arm ATO arm ATRA arm ARAC arm ATO arm ATRA arm Time (months) 19

20 Cumulative incidence of relapse Cumulative incidence of Relapse ARAC arm ATO arm ATRA arm 5y CIR was 3.89%, 0%, and 7.41% in the AraC, ATO and ATRA arms, respectively. P= Time post CR (months) 20

21 Different combination are very effective ATRA Arsenic Trioxide

22 1 st line induction with ATRA & ATO 0/20 relapses in the combined arm vs 7/37 with monotherapy (p<0.05) Shen et al, PNAS 2004

23 ATO & ATRA without Chemo (WBC<10) Lo Coco, NEJM 2015

24 ATO & ATRA without Chemo (WBC<10) Lo Coco, NEJM 2015

25 Extended series of 276 patients Follow-up (41.9 mos) Platzbecker et al. JCO 2017

26 How to treat High risk APL patient?

27 High WBC using Chemo Better outcome over time using a risk Adapted stategy with ATRA during consolidation ARAC during consolidation Sanz et al Blood 2010 Kelaidi et al. J Clin Oncol 2008

28 APL2006 Trial : addition of ATO in high WBC APL Chemo Arm Induction Ida AraC ATRA 12 mg/m 2 x3 200 mg/m 2 x7 until CR R Chemo-ATO Arm Conso 1 Ida 12 mg/m 2 x3 AraC 200 mg/m 2 x7 Ida 12 mg/m 2 x3 AraC 200 mg/m 2 x7 ATO 25 days Conso 2 Ida 9 mg/m 2 x3 AraC 1g/m 2 x8 Ida 9 mg/m 2 x3 AraC 1g/m 2 x8 ATO 25 days Maint. 2 year Maintenance with intermittent ATRA. and continuous MTX & 6MP

29 Cumulative incidence of relapse Time post CR (months) Cumulative incidence of Relapse Chemo arm Chemo ATO arm Chemo Arm Chemo ATO Arm P value Nb of relapses post CR year Cumulative incidence relapse 3.7 [1.0; 9.6] 3.9 [1.0; 10.0] 0.69 No difference in terms of Relapse Chemo Arm Chemo-ATO Arm

30 Global Survival (%) Overall Survival Chemo arm Chemo ATO arm Chemo Arm Chemo ATO Arm Nb of deaths 7 6 P value 2 year OS 95.0 [91.0; 99.9] 96.0 [91.7; 99.9] Chemo arm Chemo ATO arm Time (months) 30

31 MRC AML17 Study: ATRA + ATO Induction Consolidation X 4 Burnett et al. Lancet Oncology 2015

32 AML17: RFS High Risk Burnett et al. Lancet Oncology 2015

33 Early Death rate 33

34 Early Death rate Clinical trials study Nb of patients Period Early death APL % APL % PETHEMA LPA 96, % US intergroup % GIMEMA AIDA % APML % Shanghai % APL ATRA-ATO 0% ATRA-CT 3% 1 Fenaux et al, Blood 2 Ades et al, Blood 3 De la Serna et al, Blood 4 Powell et al, Blood 5 Avvisati et al, Blood 6 Iland et al, Lancet Haem 7 Hu et al, PNAS 8 Platzbecker et al, JCO

35 Early death Real life experience study Nb of patients Period Early death Swedish registry % SEER (USA) % Stanford % Chicago, New York, % Haifa 4 Canadian % Brasil (12 centres) % International Consortium % USA % 1 Lehmann et al, Leuk 2 Park et al, Blood 3 McClellan et al, Haemat 4 Altman et al, Leuk Res 5 Paulson et al, Br J H 6 Jácomo et al, Haemat 7 Rego et al, Blood 8 Rashidi et al, Leuk Res

36 Cause of early death Hemorrhage (major cause) Infection Differentiation syndrome

37 Early death according to WBC Lehmann et al. Leukemia 2017

38 APL in the elderly 38

39 Background In the elderly, the treatment of APL with conventional ATRA-anthracycline based CT regimens is associated with : A relatively high early death rate Limited number of relapses and a high rate of deaths in CR (21% in our experience) Leukemia (2014) 28, ; Blood :1690

40 Different OS but similar Relapse rate Takaaki Ono,, Cancer Science 2012

41 Burnett, Lancet Oncol 2016 Limited experience with ATO APL older than 60 y

42 Conclusion ATO ATRA is now the standard treatment for standard risk APL Nevertheless, ATRA-CxT is still a valid option, but associated with higher myelosuppression In high risk APL, the role of ATO remain to be determine even if ATO appears useful The early death rate is still high 42