Nuove possibilità di cura nelle neoplasie mieloidi e linfoidi croniche. Prima linea della leucemia mieloide cronica. Centro congressi Villa Cagnola

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1 Nuove possibilità di cura nelle neoplasie mieloidi e linfoidi croniche Prima linea della leucemia mieloide cronica Centro congressi Villa Cagnola Gazzada-Shianno (VA) 31/10/2014 Ester Pungolino A.O. Ospedale Niguarda Ca Granda, Milano

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3 Nuove Raccomandazioni ELN Definizione di risposta 2009 RISPOSTA OTTIMALE RISPOSTA SUBOTTIMALE FALLIMENTO WARNINGS (ALLERTA) BASALE NA NA NA - Alto rischio - CCA/Ph+ 3 mesi - CHR e almeno - CyR Minore (Ph+ 65%) 6 mesi - Almeno PCyR (Ph+ = 35%) - Non CyR (Ph+ > 95%) - Meno di PCyR (Ph+ > 35%) 12 mesi - CCyR - PCyR (Ph+ 1-35%) - Meno di CHR NA - Non CgR (Ph+ > 95%) - Meno di PCyR (Ph+ > 35%) 18 mesi - MMolR - Meno di MMolR - Meno di CCyR NA Sempre - MMolR stabile o in miglioramento - Perdita di MMolR - Perdita di CHR - Mutazioni * - Perdita di CCgR - Mutazioni ** - CCA/Ph+ In rosso le variazioni rispetto alle raccomandazioni del 2006 *Poco sensibili ad imatinib; ** Insensibili ad imatinib Baccarani et al. JCO 2009 NA - Meno di MMolR - Ogni incremento dei livelli di trascritto - CCA/Ph-

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7 Five-year overall survival of patients grouped according to molecular response at 3 months (imatinib) B Hanfstein et al, Leukemia (2012)

8 Five-year overall survival of patients grouped according to molecular response at 6 months (imatinib) B Hanfstein et al, Leukemia (2012)

9 Five-year OS and PFS of patients grouped according to molecular response at 6 months (imatinib) B Hanfstein et al, Leukemia (2012)

10 First-line dasatinib and baseline comorbidity Figure 1. DASISION (CA ) study design: An ongoing, global phase 3 study Treatment naïve pts with CML-CP (N=519) 108 centers 26 countries Dasatinib 100 mg QD (n=259) Randomized* Imatinib 400 mg QD (n=260) *Stratified by Hasford risk score Follow-up 5 years BMS Confidential - Not for Further Copying or Distribution Minimum follow-up: 12 months (Primary and current analysis) ASH

11 DASISION: First-Line Dasatinib vs Imatinib in CML-CP CCyR Was Achieved Faster For Dasatinib Compared With Imatinib 100 Dasatinib 100mg QD Imatinib 400mg QD P= CCyR (%) ONHQ10NP Month 3 Month 6 Month 9 Month 12 In a separate analysis of time to CCyR, the likelihood of achieving a CCyR at any time was ~50% greater with dasatinib than with imatinib (stratified log-rank P<0.0001; HR=1.5) 10 EHA 2010, Abstract # 725

12 DASISION: First-Line Dasatinib vs Imatinib in CML-CP MMR Rates Were Higher For Dasatinib Compared With Imatinib 100 Dasatinib 100 mg QD 80 Imatinib 400 mg QD P< P< ONHQ10NP023 MMR (%) Month 3 Month 6 Month 9 Month 12 Any time 11 EHA 2010, Abstract # 725

13 DASISION: First-Line Dasatinib vs Imatinib in CML-CP MMR Rates By 12 Months Across Hasford/EURO Risk Groups 100 Dasatinib 100mg QD Imatinib 400mg QD 80 MMR (%) ONHQ10NP n=86 n=87 n=124 n=123 n=49 n=50 Low Intermediate High EHA 2010, Abstract # 725

14 Dasision: Cumulative CCyR and MMR Rates (ITT) Più rapida Più profonda Kantarjian et al Blood 2012

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18 Dasision 36 months 3 months a 100 Dasatinib 100 mg QD 84% had 10% BCR-ABL PFS According to BCR-ABL Level at 100 Imatinib 400 mg QD 64% had 10% BCR-ABL % not progressed BCR-ABL at 3 months 1% >1 10% >10% Months 3-Year PFS 10% = 93.1% >10% = 68.2% P= BCR-ABL at 3 months 1% >1 10% >10% Months 3-Year PFS 10% = 95.9% >10% = 75.3% P< Subjects at risk 1% >1-10% >10% Subjects at risk 1% >1-10% >10% a Calculated from total number of evaluable patients with PCR assessments at 3 months A. Hochhaus EHA 2012

19 Dasision 36 months OS According to BCR-ABL Level at 3 Months a Dasatinib 100 mg QD 84% had 10% BCR-ABL Imatinib 400 mg QD 64% had 10% BCR-ABL % alive BCR-ABL at 3 months 1% >1 10% >10% 3-year OS 10% = 95.9% >10% = 85.9% P= BCR-ABL at 3 months 1% >1 10% >10% 3-year OS 10% = 96.0% >10% = 88.0% P= Months Months Subjects at risk Subjects at risk 1% >1-10% >10% % >1-10% >10% a Calculated from total number of evaluable patients with PCR assessments at 3 months A. Hochhaus EHA 2012

20 ENESTnd 36 months (Nilotinib 300 mg BID and Imatinib) PFS* by BCR-ABL Levels at 3 Months Nilotinib: 258 Pz (>10% 24 Pz) Imatinib: 264 Pz (>10% 88 Pz)

21 ENESTnd 36 months (Nilotinib 300 mg BID and Imatinib) Overall Survival by BCR-ABL Levels at 3 Months Nilotinib Imatinib

22 ENESTnd 36 months (Nilotinib 300 mg BID and Imatinib) PFS* by BCR-ABL Levels at 6 Months Nilotinib: 255 Pz (>1% 43) Imatinib: 250 Pz (>1% 123)

23 ENESTnd 36 months (Nilotinib 300 mg BID and Imatinib) Overall Survival by BCR-ABL Levels at 6 Months Nilotinib Imatinib

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25 Quali TKIs oggi per la LMC? TKI FDA Approval II Line I Line Imatinib Dasatinib Nilotinib Bosutinib Ponatinib Tra il 2010 ed il 2012 molte nazioni hanno a disposizione 3 TKIs in prima linea

26 Quali cambiamenti nella LMC ? Cambia il peso della risposta molecolare Ci sono 3 farmaci a disposizione per il trattamento in prima linea (Imatinib, Dasatinib, Nilotinib) Risposte più rapide e profonde con TKIs di II generazione Si modificano le raccomandazioni dell ELN

27 ELN 2013 recommendation: response definition, optimal and failure Cytogenetic Responses Molecular Responses Optimal 3 mo MinorCyR (Ph+ 65%) Ph+ 35% NA BCR-ABL 10% 6 mo PCyR (Ph+ 35%) Ph+ 0% NA BCR-ABL < 1% 12 mo CCyR (Ph+ 0%) NA NA BCR-ABL 0.1% 18 mo NA NA MMR (BCR-ABL 0.1%) NA At any time NA NA MMR BCR-ABL 0.1% Failure Cytogenetic Responses Molecular Responses mo < CHR Ph+ > 95% NA NA 6 mo No CyR (Ph+ > 95%) Ph+ > 35% NA BCR-ABL > 10% 12 mo < PCyR (Ph+ > 35%) Ph+ > 0 NA BCR-ABL > 1% 18 mo < CCyR NA NA NA At any time Loss of CCyR; CCA/Ph+ Baccarani M, et al. Blood. 2013;122(6): Loss of CCyR; CCA/Ph+ Mutations Confirmed loss of MMR; mutations

28 ELN 2013 recommendation: warning, an intermediate zone between optimal and failure Warning Cytogenetic Responses Molecular Responses mo No CyR (Ph+ > 95%) Ph % NA BCR-ABL > 10% 6 mo < PCyR (Ph+ > 35%) Ph+ 1-35% NA BCR-ABL 1-10% 12 mo PCyR (Ph+ 1-35%) NA NA BCR-ABL 0.1-1% 18 mo NA NA < MMR NA At any time NA Baccarani M, et al. Blood. 2013;122(6): CCA/Ph ( 7, or 7q ) Loss of MMR or mutations; Increase in transcript levels NA

29 Kinase Selectivity Profiles of Imatinib, Nilotinib, and Dasatinib IC 50 <10 nm Imatinib nm nm nm Nilotinib Dasatinib Differences in kinase selectivity TKIs may cause differing safety profiles

30 Selectivity of Tyrosine Kinase Inhibitors Imatinib (Phos. IC 50 ) PDGFR 72 nm > Kit 99 nm > BcrAbl 221 nm > Src >1000 nm Nilotinib (Phos. IC 50 ) BcrAbl 20 nm > PDGFR 75 nm > Kit 209 nm > Src >1000 nm Dasatinib (Phos. IC 50 ) Src 0.1 nm > BcrAbl 1.8 nm > PDGFR 2.9 nm > Kit 18 nm Bosutinib (Phos. IC 50 ) Src 3 nm > BcrAbl 85 nm > PDGFR >3000 > Kit >10000 nm 1. Manley PW, et al. Proc Am Assoc Cancer Res 2007;48: Weisberg E, et al. Cancer Cell 2005;7: Remsing Rix LL, et al. Leukemia 2009;23:477.

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32 Nilotinib ha più -Cefalea -Prurito -Rash - bilirubina, glicemia, lipasi - PAOD Dasatinib ha più -Versamento pleurico -Sanguinamento gastroenterico -Infezioni

33 Quale terapia in prima linea per la CML? Tre TKI a disposizione con tre diversi profili di tollerabilità diversi tempi e profondità di risposta Scelta del trattamento in base a caratteristiche cliniche del Pz progetto di cura/obiettivi

34 GRAZIE PER L ATTENZIONE