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Masszi Tamás: Őssejt transzplantáció (Cml_sct_2012)
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Masszi Tamás: Őssejt transzplantáció (Cml_sct_2012)

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  • 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

Masszi Tamás: Őssejt transzplantáció (Cml_sct_2012) Masszi Tamás: Őssejt transzplantáció (Cml_sct_2012) Presentation Transcript

  • Őssejt-transzplantáció CML - 2012 Masszi Tamás SE. III. Belklinika , Szent László Kórház
  • Evolution of therapy for chronic myeloid leukemia. Pavlů J et al. Blood 2011;117:755-763
  • 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 ReferralThe University of Texas M. D. Anderson Cancer Center database.
  • CML 1. CP Imatinib eredmények Schiffer, C. A. Blood 2010;116:3686-3687Copyright ©2010 American Society of Hematology. Copyright restrictions may apply.
  • 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) ESaglio G, et al. N Engl J Med. 2010;362:2251-2259.
  • 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; OSKantarjian H, et al. N Engl J Med. 2010;362:2260-2270.
  • 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 tolerabilityGambacorti-Passerini C, et al. ASH 2010. Abstract 208.
  • 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 90,000-96,000Saglio G, et al. N Engl J Med. 2010;362:2251-2259.Kantarjian H, et al. N Engl J Med. 2010;362:2260-2270.
  • 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
  • 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!!!!!
  • 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!!!!!
  • De mi legyen második vonalban??
  • 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 MCyRJabbour E, et al. Blood. 2011;117:1822-1827.
  • Pre- 2G-TKI Therapy Independent Predictive Factors for CCyRParameter Relative risk P valueLow Sokal score at diagnosis 1.6 <0.01Best cyto response on imatinib 0% 1.0 1-94% 0.3 <0.0001 >94% 0.006Neutropenia on imatinib 0.16 <0.0001 Milojkovic et al., Haematologica 2010; 95:224-31.
  • 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 CCyRHammersmith 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.
  • Transplant Activity since 1980 Imperial College50454035302520151050 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 0819191919191919191919191919191919191919202020202020202020 1st chronic phase Advanced phase Hammersmith Hospital 1980 - 2007
  • Outcome of HSCT in CML by disease phase Imperial College Pavlu et al., Blood 2010; 117:755-63.
  • 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
  • EBMT risk assessment in SCT Gratwohl et al, Lancet 1998,
  • Outcome by Gratwohl Score: Imperial College ( 2000-2010) Pavlů J et al. Blood 2011;117:755-763
  • Optimising Outcome for SCT in CMLHematopoietic 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.
  • 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
  • SCT for CML: effect of disease phase
  • 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)