Juan Luis Steegmann Hospital de la Princesa. Madrid.
Juan Luis Steegmann Hospital de la Princesa. Madrid
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;117:755 63.
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
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;117:755 63.
BMT mortality is at least 25% in the first year if Gratwohl score is 2 or more SCORE OS RFS TRM REL 0 70 60 20 25 1 70 60 25 25 2 60 50 30 30 3 50 35 45 30 4 40 35 50 30 Gratwohl, A., et al. Lancet, 1998. 352(9134): p. 1087 92.
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: 20 40 y: 1 > 40 y: 2 Sex match: Female D, Male R: 1 Time Diagnosis BMT > 1 year : 1 Gratwohl, A., et al. Lancet, 1998. 352(9134): p. 1087 92.
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); 30 40 (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;125:613 20.
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, 2003. 101(2): p. 441 445.
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, 2003. 101(2): p. 441 445.
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 40 49 year group Warlick E, et al Blood 2012;119:4083 90.
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): 1141 1145. Khoury HJ ( 2012), Blood 119 : 3403 3412,
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
Dasatinib as salvage therapy: The mortality during the first year is less than 5% Rea al, EHA 2012
SELECTING THE APPROPRIATE SETTING
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):224 231 2. Jabbour, E., H. Kantarjian, et al. (2010). Blood: blood 2010 2007 293977. 3. Steegmann JL et al. Haematologica. EHA 2010. Manuscript, submitted
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) 1.0 0.9 p<0.0001 Good risk n=20 100% Score <1.5 1.5 <2.5 >2.5 Risk good intermediate poor Cumulative incidence of CCyR 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 p<0.0001 p=0.001 Intermediate risk n=26 Poor risk n=34 21% Prob CCyR 0.0 0 6 12 18 24 30 Months from starting 2G TKI Therapy Milojkovic, D. et al. Haematologica 2010;95:224 231
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. 2011 Feb 10;117(6):1822 7.
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 CA180034 EFS* No CCyR at 12 m Hammersmith EFS, OS CA180034 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):224 231. 2. Jabbour, E., H. Kantarjian, et al. (2010). Blood: blood 2010 2007 293977. 3. Saglio, EHA 2011
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% CA180034 2 EFS: 64% V 26% OS: 85% V 65% 3M: <1% V1 10% VS >10% 6M: 1% VS >1% CAMN1072101 3 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: CA180034 2 No data 1. Milojkovic, Blood 2012 2. Rea et al EHA 2012 3. Giles et al submitted 6M: <1% V1 10% VS >10% 12 M MMR vs CCyR, No MMR CAMN1072101 3 PFS: 86% v 58% v 39% OS: 95% v 82% V 73% CAMN1072101 3 PFS: 97% v 96%
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+ 66 95% Ph+ Strong New Mutation* 12 months No MMR >35% Ph+ Strong New Mutation* No HR to imatinib Strong mutation* Clonal evolution 66% 95% Ph+ 36 65% Ph+ *Mutation poorly sensitive to tyrosine kinase inhibitors. HR=hematologic response. Baccarani M, et al. J Clin Oncol 2009; 27 (35): 6041 6051.
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
A practical example, taking the results from CA180034 ( dasatinib 2nd line): OS by 6 years: 83% if MR1 at 3 m Shah et al 6 year follow up of CA180 034 ASCO 2012
A practical example, taking the results from CA180034 ( dasatinib 2nd line): OS by 6 years: > 83% if PCyR or better at 6 m Shah et al 5 year follow up of CA180 034 ASCO 2011
A practical example, taking the results from CA180034 ( dasatinib 2nd line): OS by 6 years: > 88 % if PCyR or better at 12 m Shah et al 5 year follow up of CA180 034 ASCO 2011
Third line therapy in CP, resistant CCyR could be obtained in 42% of the patients n CHR MCyR CCyR Im D N 1,2 51 70% 22% 43% 24% 33% Im D B 3 37 31% 14% Im N D 1 16 37% 13% Im N B 3 27 35% 27% Im 2G TKI 26 50% 35% Im 2GTKI P* 74 53%** 42%** Garg et al., Blood. 2009 Nov 12;114(20):4361 8. Giles et al., Leukemia. 2010 Jul;24(7):1299 301. Khoury, H.J., et al.,. Blood, 2012. 119(15): p. 3403 12 Gambacorti Passerini et al., Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 3434 Ibrahim, A.R., et al.,. Blood, 2010. 116(25): p. 5497 500. Cortes, J. et al,eha 2012. 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%
With the results of 2G TKI, first line, only a tiny minority did not obtain the 10% threshold at 3 m
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].
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.
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