Juan Luis Steegmann Hospital de la Princesa. Madrid. JL Steegmann

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1 Juan Luis Steegmann Hospital de la Princesa. Madrid.

2 Juan Luis Steegmann Hospital de la Princesa. Madrid

3 No rush,at least in Chronic Phase Blast Phase*: SCT asap, after restablishing CP with TKI Accelerated phase* Near Blast Phase, or AP developing during TKI As Blast Phase Less advanced accelerated phase at diagnosis: Treat as first chronic phase First chronic: Let s see, give me ten minutes * Taken form Pavlu J, Szydlo RM, Goldman JM, Apperley JF. Blood 2011;117:

4 Rational BMT mortality and morbidity Good results with 2GTKI in second line Better knowledge of prognostic factors Tailoring 2nd line therapy Bridging the gap with third line Better results with 2GTKI, 1st line Minimizing the need

5 In BMT done in the last decade in one of the most experienced institutions, roughly 15% of the patients died during the first year after SCT Pavlu J, Szydlo RM, Goldman JM, Apperley JF. Blood 2011;117:

6 BMT mortality is at least 25% in the first year if Gratwohl score is 2 or more SCORE OS RFS TRM REL Gratwohl, A., et al. Lancet, (9134): p

7 And the problem is that most patients treated in 2nd line with 2G TKI have scores greater than 2 Sibling: 0; Unrelated: 1 Phase CP: 0 Patient s age: y: 1 > 40 y: 2 Sex match: Female D, Male R: 1 Time Diagnosis BMT > 1 year : 1 Gratwohl, A., et al. Lancet, (9134): p

8 Besides, revised score developed in the last decade did show that most patients considered here will have a substantial mortality Mortality during the first year: Score 2: 20% ; score 3: 35% Revised EBMT score Age, years: <30 (0); (1); >40 (2) Donor: sibling (0); unrelated (2) Interval diagnosis SCT: <1 year (0); >1 year (1) Sex match: female male (1); all other (0) Passweg JR, et al. BrJ Haematol 2004;125:

9 Even more, non myeloablative SCT are associated with good probability of survival, but substantial risk of GVHD Probability of acute GVHD III IV in the first 3 m: 30% Or, R., et al., Blood, (2): p

10 Non myeloablative SCT s s are associated with substantial risk of chronic GVHD Probability of chronic GVHD first 18 m: 55 % Or, R., et al., Blood, (2): p

11 And RIC was not better in terms of TRM, although DFS was slightly better. Still, mortality in the first year is circa 30% in the year group Warlick E, et al Blood 2012;119:

12 TKI ( Dasatinib, Nilotinib, Bosutinib ) have good results in second line Complete cytogenetic responses: 44% 70% Major molecular responses: 22% 50% Overall survival: 70% Event free survival 50 % Hochhaus A et al EHA 2009 #1091 Shah NP et al ASCO 2010 # 6512 ; Shah NP et al ASCO 2011 # 6512 Rea et al EHA 2012 Kantarjian, H. M., F. J. Giles, et al. (2011). Blood 117(4): Khoury HJ ( 2012), Blood 119 : ,

13 Dasatinib as salvage therapy: 6 year follow follow up: The probability of survival is more than 70% MMR 6years : 40% ( R ) ; 49% ( I ) OS 6years : 68% ( R ) ; 78% ( I ) EFS 6years : 46% ( R ) ; 58% ( I ) Rea al, EHA 2012

14 Dasatinib as salvage therapy: The mortality during the first year is less than 5% Rea al, EHA 2012

15 SELECTING THE APPROPRIATE SETTING

16 2nd line therapy after imatinib can be optimized: Cytogenetic response could be better if: Low Risk Group Previous response to Imatinib No ACA s Ph+ No grade III IV neutropenia* Certain baseline cytogenetic response Shorter time between Failure/intolerance and the start of 2ndG TKI No Resistant mutation 1. Milojkovic D, et al. Haematologica 2010;95 (2): Jabbour, E., H. Kantarjian, et al. (2010). Blood: blood Steegmann JL et al. Haematologica. EHA Manuscript, submitted

17 Predicting Responses to Second Line TKI: Hammersmith Score Cytogenetic response to imatinib (CCyR, 0; 1 94% Ph+, 1; > 95% Ph+, 3) Sokal score (Low risk, 0; int+high, 0.5) Neutropenia 3 4 leading to Im reduction(no, 0; yes, 1) p< Good risk n=20 100% Score < <2.5 >2.5 Risk good intermediate poor Cumulative incidence of CCyR p< p=0.001 Intermediate risk n=26 Poor risk n=34 21% Prob CCyR Months from starting 2G TKI Therapy Milojkovic, D. et al. Haematologica 2010;95:

18 Prognosis with 2 nd line TKIs in CML: MDACC score Adverse factors: Performance Status 1 and lack of CyR to imatinib Jabbour E. et al. Blood Feb 10;117(6):

19 Predicting survival with cytogenetics Model No CyR to Im MDACC EFS ECOG >0 MDACC EFS, OS Displaced all in the multivariate analysis for OS : HR: 2,4: No CyR at 3 m Hammersmith EFS, PFS, OS No PCyR at 6 m Hammersmith EFS, PFS, OS CA EFS* No CCyR at 12 m Hammersmith EFS, OS CA EFS* No MCyR at 12 m MDACC Displaced all in the multivariate analysis for EFS : HR: 2,3 1. Milojkovic D, et al. Haematologica 2010;95 (2): Jabbour, E., H. Kantarjian, et al. (2010). Blood: blood Saglio, EHA 2011

20 Predicting survival with molecular response 3M: 1 10% VS >10% STUDY Hammersmith 1 EFS: 49% v 13% PFS: 91% v 68% OS: 91% v 72% 3M: 1 10% VS >10% CA EFS: 64% V 26% OS: 85% V 65% 3M: <1% V1 10% VS >10% 6M: 1% VS >1% CAMN PFS: 85% v 67% v 42% OS: 95% v 81% V 71% Hammersmith 1 EFS: 58% v 18% PFS: 91% v 74% OS: 91% v 77% 6M: CA No data 1. Milojkovic, Blood Rea et al EHA Giles et al submitted 6M: <1% V1 10% VS >10% 12 M MMR vs CCyR, No MMR CAMN PFS: 86% v 58% v 39% OS: 95% v 82% V 73% CAMN PFS: 97% v 96%

21 Response to 2 nd generation TKI in 2 nd line therapy ELN 09 recommendations Baseline Suboptimal Failure Warning 3 months 36 65% Ph+ No CyR Strong New Mutation* 6 months 1 35% Ph % Ph+ Strong New Mutation* 12 months No MMR >35% Ph+ Strong New Mutation* No HR to imatinib Strong mutation* Clonal evolution 66% 95% Ph % Ph+ *Mutation poorly sensitive to tyrosine kinase inhibitors. HR=hematologic response. Baccarani M, et al. J Clin Oncol 2009; 27 (35):

22 Response to 2 nd generation TKI in 2 nd line therapy ELN 2013 recommendations Baseline Optimal Failure Warning 3 months NO CHR Ph + > 95% or BCR ABL > 10% NEW MUTATIONS 6 months Ph + > 35% or BCR ABL > 10% NEW MUTATIONS 12 months Ph + > 35% or BCR ABL > 1% Any time LOSS OF CHR LOSS OF CCgR or PCgR NEW MUTATIONS CONFIRMED LOSS OF MMR

23 A practical example, taking the results from CA ( dasatinib 2nd line): OS by 6 years: 83% if MR1 at 3 m Shah et al 6 year follow up of CA ASCO 2012

24 A practical example, taking the results from CA ( dasatinib 2nd line): OS by 6 years: > 83% if PCyR or better at 6 m Shah et al 5 year follow up of CA ASCO 2011

25 A practical example, taking the results from CA ( dasatinib 2nd line): OS by 6 years: > 88 % if PCyR or better at 12 m Shah et al 5 year follow up of CA ASCO 2011

26 Third line therapy in CP, resistant CCyR could be obtained in 42% of the patients n CHR MCyR CCyR Im D N 1, % 22% 43% 24% 33% Im D B % 14% Im N D % 13% Im N B % 27% Im 2G TKI 26 50% 35% Im 2GTKI P* 74 53%** 42%** Garg et al., Blood Nov 12;114(20): Giles et al., Leukemia Jul;24(7): Khoury, H.J., et al.,. Blood, (15): p Gambacorti Passerini et al., Blood (ASH Annual Meeting Abstracts) : Abstract 3434 Ibrahim, A.R., et al.,. Blood, (25): p Cortes, J. et al,eha All group: 79% Resistant ** T315I: 77%, 74% MCyR if prior mutation 2,4 : Nilo as third TKI: 25% Bosu as third TKI: 29% MCyR median duration Nilo as third TKI: 18 months Dasa as third TKI: 16 months ( CCyR) Bosu after Dasa: 4,5 months Bosu after Nilo: NR at 48 m Pona: FU too short: Est. 12m: 92%

27 With the results of 2G TKI, first line, only a tiny minority did not obtain the 10% threshold at 3 m

28 A practical example, taking the results from ENESTnd ( Nilotinib 1st line): PFS by 3 years: More than 95 % if MR1 at 3 m Hochhaus A, et al. Haematologica. 2012;97(s1):237 [abstract 0584].

29 Conclusions. In a patient with CML in CP BMT could be a good 3rd line therapy. Do not rush to use it in second line. Detect warning signs before 2nd line TKI treatment. BMT is a good option if failure to 2 nd line, and the EBMT score is 0 3. BMT could be considered in patients not having an optimal response to 2 nd line. Hematologic resistance to Imatinib, Mutations, High Hammersmith or MDACC score Providing EBMT score is 0 2.

30 THANK YOU GRACIAS