2. Evolution of therapy for chronic myeloid leukemia.
Pavlů J et al. Blood 2011;117:755-763
3. Survival in Early Chronic-Phase CML
1.0 Year Total Dead
93% Imatinib 302 15
84% (censored for non-CML death)
0.8 Imatinib 302 31
1990-2000 963 425
1982-1989 364 273
Proportion Alive
0.6 1975-1981 132 129
1965-1974 123 123
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27
Yrs From Referral
The University of Texas M. D. Anderson Cancer Center database.
5. ENESTnd: Nilotinib vs Imatinib in
Newly Diagnosed Chronic Phase CML
• Primary endpoint: MMR at 12 mos; secondary endpoint: CCyR by 12 mos
• Other endpoints: time/duration of MMR and CGCR, EFS, PFS, time to
AP/BP, OS
• Stratification by Sokal risk; MMR defined as ≤ 0.1% BCR-ABL(/ABL ratio) on the
International Scale
R
A Nilotinib 300 mg BID (n = 282)
Newly diagnosed N
CML-CP D
(N = 846) O Nilotinib 400 mg BID (n = 281)
217 centers; M
35 countries
I
Z Imatinib 400 mg QD (n = 283)
E
Saglio G, et al. N Engl J Med. 2010;362:2251-2259.
6. Dasatinib vs Imatinib in Treatment-
Naive CML: DASISION (CA180-056)
Stratified by Hasford risk score
Dasatinib 100 mg QD (n = 259)
N = 519
108 centers Follow-up
26 countries 5 yrs
Imatinib 400 mg QD (n = 260)
• Primary endpoint: confirmed CCyR by 12 mos
• Secondary/other endpoints: rates of CCyR and
MMR; times to confirmed CCyR, CCyR, and MMR;
time in confirmed CCyR and CCyR; PFS; OS
Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270.
7. BELA: Randomized Phase III Trial of
Bosutinib vs Imatinib in Chronic-Phase
CML
Stratified by Sokal risk score
and geographic region
Bosutinib 500 mg/day
(n = 250)
Patients with
previously untreated
chronic-phase CML 5-yr follow-up
(N = 502)
Imatinib 400 mg/day
(n = 252)
• Primary endpoint: CCyR at 12 mos; secondary endpoints:
MMR at 12 mos, duration of CCyR, MMR, and CHR, time
to and rate of AP and BP, safety and tolerability
Gambacorti-Passerini C, et al. ASH 2010. Abstract 208.
8. Frontline Imatinib versus
Second-Generation TKIs
Parameter Imatinib Second-Generation TKIs
Efficacy Excellent Even better
12-mo outcome, %
CGCR 65-70 80-85
MMR 20-25 40-45
AP-BP 3.5 0.4-2.0
Tolerance Excellent Even better
Follow-up, yrs 10 6-7
Cost, $/yr 54,000 90,000-96,000
Saglio G, et al. N Engl J Med. 2010;362:2251-2259.
Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270.
9. Összefoglalás
• Second generation TKI
az első vonalban:
1. Kevesebb progresszió AP/BC –be mint
imatinibbel
2. Gyorsabb, mélyebb és tartósabb molekularis és
cytogenetikai válasz
3. A jobb válasz az idő során fennmarad
4. Second generation TKI terápiát a betegek jól
tolerálják
10. 1. Vonalbeli kezelés
• TKI • Allograft (testvér)
– Kiváló eredmények – Mortalitás 10-20%
– Kevés mellékhatás – Súlyos komplikációk
– Nem hal bele a beteg – Relapsus lehetséges
– De meggyógyul???? – De 60-80% gyógyult!!!!!
11. 1. Vonalbeli kezelés
• TKI • Allograft (testvér)
– Kiváló eredmények – Mortalitás 10-20%
– Kevés mellékhatás – Súlyos komplikációk
– Nem hal bele a beteg – Relapsus lehetséges
– De meggyógyul???? – De 60-80% gyógyult!!!!!
13. Outcome With Second TKIs in CML
• Adverse factors: ECOG ≥ 1 and lack of CG response to imatinib
P = .002
100
P = .001
90
80
P = .007
70
60 Risk Factor, n
50 0
40 1
30 2
20
10
0
24 Month 24 Month 12 Month
EFS OS MCyR
Jabbour E, et al. Blood. 2011;117:1822-1827.
14. Pre- 2G-TKI Therapy Independent Predictive
Factors for CCyR
Parameter Relative risk P value
Low Sokal score at diagnosis 1.6 <0.01
Best cyto response on imatinib
0% 1.0
1-94% 0.3 <0.0001
>94% 0.006
Neutropenia on imatinib 0.16 <0.0001
Milojkovic et al., Haematologica 2010; 95:224-31.
15. Predicting Responses to 2G-TKI
100% Good risk n=20
1.0 p<0.0001
0.9
0.8 p<0.0001
Cumulative incidence of CCyR
Hammersmith scoring system 0.7
Score Risk 0.6
Intermediate risk n=26
<1.5 good 0.5
≥1.5<2.5 intermediate 0.4
p=0.001
0.3
≥2.5 poor Poor risk n=34 21%
0.2
0.1
0.0
0 6 12 18 24 30
Months from starting 2G-TKI therapy
Milojkovic et al., Haematologica 2010; 95:224-31.
18. Outcome of HSCT in CML by disease phase
Imperial College
Pavlu et al., Blood 2010; 117:755-63.
19. EBMT risk assessment in SCT
• Age <20=0, 20-40=1, >40=2
• Disease phase Early=0, int=1, late=2
• Gender of R/D Female into male = 1
• Time to BMT <1 yr = 0, >1 yr = 1
• Donor Sib = 0, VUD = 1
21. Outcome by Gratwohl Score: Imperial College ( 2000-2010)
Pavlů J et al. Blood 2011;117:755-763
22. Optimising Outcome for SCT in CML
Hematopoietic stem cell transplantation Preconditioning C-reactive protein levels
comorbidity index (HCT-CI) (CRP)
Years after HCT Years after HCT
Pavlu et al, Blood 2010; 115:4018-20.
23. BMT szerepe CML-ben
• Közvetlen a diagnózis után
– Jó transzplantációs rizikó
– Beteg preferenciája
• Eredménytelen TKI kezelést követően
– Imatinib failure,
– 2nd generation TKI failure
– T 315 mutáció
• Akcelerált, vagy Blastos fázisban
25. SCT szerepe CML-ben
• Közvetlen a diagnózis után
– Jó transzplantációs rizikó
– Beteg preferenciája
Túl kockázatos!
( Túl hamar!)
• Krónikus fázisban Eredménytelen TKI kezelést követően
– Imatinib failure, (?)
– 2nd generation TKI failure
– T 315 mutáció
• Akcelerált fázisban
• Blastos fázisban
Nem elég eredményes!
( Túl Késő)
Notes de l'éditeur
To predict who will do well on a second generation drug, we developed the Hammersmith score
Just to show SCT activity has fallen over decade but also we are now transplanting too late, for advanced phase disease
We have known for a long time that SCT in advanced phase is not very effective and we do not have a single survivor from SCT in blast crisis at the Hammersmith
Lots of work to try to use the co-morbidity index to predict outcome but difficult in CML because most patients in CP come to transplant very fit. We were unable to show the effect of any isolated organ system but thepresence of i or more co-morbidities did have somedetrimental effect. CRP on admission was te most predictive factor, came as a big surprise, now substantiated by at least two other groups and is not related to the obvious presence of an infection
