La sospensione della terapia: il nostro nuovo obiettivo Gi Giuseppe S li Saglio Imatinib discontinuation French STIM experience The overall probability of maintenance of CMR at 24 and 36 months h was 39% (95% CI 29 29-48). 48) 39% Molecular M l l relapse l occurred d iin 61 pts t with ith 58 relapses l occurring i d during i th the first 7 months 3 late relapses at month 19, 20 and 22, respectively Mahon FX, et al. Blood 2011;118:abstract 603 Imatinib discontinuation Summary y of imatinib-discontinuation studies • STIM1,2, n=100 – CP-CML, imatinib ≥ 400mg/d frontline or post IFN-α for a least 36 months – Undetectable BCR-ABL for at least 24 months confirmed at study entry* • CML83,4, n=40 – CP-CML, imatinib frontline or post IFN-α for at least 36 months – Undetectable BCR-ABL on continuing imatinib for at least 2 years** • A-STIM, A STIM, n n=34 345 – CP-CML, imatinib frontline or post IFN-α – MR4.5 or CMR4.5 for at least 24 months • Japanese survey6, n=43 – Imatinib stopped for at least 6 months due to any cause except progression, transplantation or death – Undetectable BCR-ABL on continuing imatinib for at least 12 months*** months • Korean retrospective study7, n=14 – Undetectable BCR-ABL on continuing imatinib for at least 12 months*** 1Mahon et al. Lancet Oncol. 2010; 11: 1029‐1035 2Mahon et al. Blood (ASH) 2011; 118: Abstract 603 5Rousselot et al. Blood (ASH) 2011; 118: abstract 3781 3Ross et al. Leukemia 2010; 24: 1719‐1724 6Takahashi et al. Haematologica 2012; 97: 903‐906 4Ross et al. Haematologica 2012; abstract 0189 7Yhim et al. Leukemia Research 2012; 36: 689‐693 *50 000 copies at least of ABL at study entry **RT‐PCR sensitivity of at least 4.5log ***RT‐PCR sensitivity of at least 4 logs Imatinib discontinuation Australian CML8 experience (Twister) 43% Ross M et al, Haematologica 2012; 97:[abstract 0189]. Prerequisites q for TKI discontinuation Prerequisites for discontinuation Mahon FX, et al. Blood 2011;118:abstract 603. Sustained CMR after stopping imatinib according to duration of CMR before cessation 78% vs. 15%, P = .0002 by Log‐rank test Takahashi N et al., Haematologica, 2012; 97:903-06. Factors associated with outcome after imatinib cessation Study Significant factors STIM study1 Sokal risk group Imatinib treatment duration CML8 study2 Sokal risk group Prior exposure to IFN Japanese survey3 Imatinib treatment duration Duration of undetectable BCR BCR-ABL ABL transcripts Imatinib dose intensity Prior exposure to IFN Korean retrospective study4 Sokal risk group Time to undetectable BCR-ABL transcripts Imatinib a b treatment ea e du duration a o 1Mahon et al. Blood (ASH) 2011; 118: Abstract 603 3Takahashi et al. Haematologica 2Ross et al. Haematologica 4Yhim et al. Leukemia Research 2012; 36: 689‐693 2012; abstract 0189. 2012; 97: 903‐906 Deep molecular response according to BCRABL transcripts level at 3 months Branford et al. Blood 2013 121:3818-3824; Prepublished online March 20, 2013 TKI discontinuation: Are there risks? 10 % BCR-ABL/ABL 1 0,1 Start again Stop 0 01 0,01 0 001 0,001 STIM: A STIM Among the th 59 with ith recurrence, 49 achieved hi d again i CMR after ft imatinib i ti ib rechallenge. A median time of 4 months (range 0–21) was necessary for CMR to recur. Mahon et al., Lancet Oncol. 2010; 11:1029-1035. TKI discontinuation: Are there risks? 9 No events of relapse to AP or BC have been reported 10 9 No acquired drug‐resistance: Sensitivity to imatinib is preserved % BCR-ABL/ABL 1 0,1 Start again Stop 0 01 0,01 0 001 0,001 STIM: A STIM Among the th 59 with ith recurrence, 49 achieved hi d again i CMR after ft imatinib i ti ib rechallenge. A median time of 4 months (range 0–21) was necessary for CMR to recur. Mahon et al., Lancet Oncol. 2010; 11:1029-1035. After discontinuation, some patients may show fluctuation in MRD CML patient in CP CML patient in CP 31 years old Low risk Sokal score Rousselot P, personal data. Kaplan-Meier estimate of TFR defined as loss of MMR and defined as loss of CMR Percent s survivall 100 80 65% 60 40 37% 20 0 P = 0.003 0 12 24 36 48 60 72 84 96 108 Months Rousselot P et al., JCO in press TFR= treatment free remission (i) (ii) (iii) (iv) (v) (vi) Goh et al. Leukemia &Lymphoma 2011 Goh et al. Leukemia &Lymphoma 2011 Can we improve p the discontinuation rate? ENESTnd: Cumulative incidence of MR4.5 Nilotinib 300 mg g BID 100 Nilotinib 400 mg BID Patients W With MR4.5, % Imatinib 400 mg QD 80 By 4 Years By 1 Year 60 40% P < .0001 40%, 0001 40 37%, P = .0002 ∆ 14%-17% ∆ 6%-10% 20 11% P < .0001 11%, 0001 23% 7%, P < .0001 1% 0 0 6 12 18 24 30 36 42 48 54 60 Time Since Randomization, Months Data cutoff: July 27, 2012. MR4.5, molecular response of BCR-ABLIS ≤ 0.0032%. Hochhaus A, et al. Haematologica. 2013; (s1): [abstract P712]. ENESTnd: MR4.5 by 4 years according to Sokal risk Pattients W With MR R4.5, % 80 70 P = .1688 P = .0004 P = .0183 60 P = .0040 P = .1092 1092 50 P = .0066 30 20 48 45 40 38 34 29 32 31 24 10 13 0 n = 103 103 104 Low Sokal Nilotinib 300 mg BID 101 100 101 Intermediate Sokal Nilotinib 400 mg BID 78 78 78 High Sokal Imatinib 400 mg QD Rates of MR4.5 by 4 years were consistently higher with nilotinib vs i ti ib iin patients imatinib ti t with ith llow, iintermediate, t di t or hi high hS Sokal k l risk i k scores Data cutoff: July 27, 2012. Hochhaus A, et al. Haematologica. 2013; (s1): [abstract P712]. 2nd generation TKI discontinuation STOP 2G-GKI experience CP‐CML TKI therapy ≥ 3 years TKI therapy ≥ 3 years 2G‐TKI frontline or after imatinib intolerance or resistance Undetectable BCR‐ABL* ≥ 24 months • • • STOP 2G‐TKI D1 M12 M24 Year 1 Year 2 RQ‐PCR monthly RQ‐PCR Every 2‐3 months Primary endpoint: survival without loss of MMR Molecular relapse: loss of MMR L Loss off MMR ttriggered i d ttreatment t t resumption ti M36 M48 M60 Year 3‐5 RQ‐PCR Every 3‐6 months *Molecular monitoring performed in local laboratories filling international standardization requirements international standardization requirements. *20 000 copies of ABL at least. Rea et al. Blood (ASH) 2012; 120: Abstract 916 2nd generation TKI discontinuation Survival w without M MMR losss % STOP 2G-GKI experience 61.1% 80 95% CI: 45.6‐76.6) 60 40 20 0 • Survival without MMR loss at 12 months 100 0 6 12 18 24 30 36 42 Months since 2G‐TKI discontinuation As of November 30, 2012, 39 patients with a minimum follow-up of 6 months (median 17 months months, range: 7 7-38) 38) were analyzed – 16/39 patients lost MMR – Median time to MMR loss was 3 months (1-25) Rea et al. Blood (ASH) 2012; 120: Abstract 916 Expectations for best achievable response to therapy in CML continue to increase ¾ As treatments for chronic myeloid leukaemia (Ph+ CML) have improved, expectations for responses have increased: HR → CCyR → MMR1 UMRD Ph+ CML Diagnosis CHR CCyR MMR CMR MR4.5 UMRD Time on Treatment CCyR, complete cytogenetic response; CHR, complete haematologic response; UMRD, undetectable molecular residual disease; HR, haematologic response; MMR, major molecular response. Baccarani et al., J Clin Oncol. 2009;27(35):6041-6051. Expectations for best achievable response to therapy in CML continue to increase ¾ As treatments for chronic myeloid leukaemia (Ph+ CML) have improved, expectations for responses have increased: HR → CCyR → MMR1 UMRD Ph+ CML Diagnosis CHR CCyR MMR TFR: CMR Treatment‐free remission MR4.5 Maintenance UMRD of MMR without therapy Time on Treatment CCyR, complete cytogenetic response; CHR, complete haematologic response; UMRD, undetectable molecular residual disease; HR, haematologic response; MMR, major molecular response. Baccarani et al., J Clin Oncol. 2009;27(35):6041-6051. Medical Rationale and Clinical Benefits of Treatment-Free Remission Medical Rationale • Discontinuation studies demonstrating proof of concept regarding successfully stopping imatinib therapy • Molecular M l l responses ffrom ENESTnd and ENESTcmr better with nilotinib • Patient & Investigator interest Patient Benefits • “Operational” cure • Alleviate chronic low grade AEs • Reduce risk of developing long term AEs • Pregnancy g y • Minimize Drug Drug Interactions ( (elderly) y) • Health economic advantages vs chronic lifelong TKI therapy Kamel MALEK / for Business Use Only /Confidential, Do not Circulate / April 13, 2013 ENESTfreedom: Study Design Overview • MR 4.5 at study entry YES ENRO OLLMENT T • De novo CP Ph+ CML adult patients treated with Tasigna® for ≥ 2 years Nilotinib Consolidation Phase Durable MRD* 52 weeks • Other I/E criteria met TFR Phase (up to 192 weeks) NO Nilotinib Continuation Phase (52 weeks) *Per protocol durable MRD The 4 llastt quarterly Th t l performed f d PCR assessments must fulfill the 3 following criteria: 1- the last assessment is MR4.5 2 no assessmentt worse than 2th MR4 3- no more than two assessments between MR4 and MR4.5 E Enrolling lli Kamel MALEK / for Business Use Only /Confidential, Do not Circulate / April 13, 2013 Durable MRD* YES NO Nilotinib Prolonged Continuation Phase TFR-2 Phase (up to 192 weeks) ENESTop: Study Design Overview • MR 4.5 at study entry No Confirmed Loss of MR 4.5 Nilotinib Consolidation Phase 52 wks ENRO OLLMENT T • CP Ph+ CML adult patients treated for ≥ 3 years with TKIs (IM th then Nilotinib for ≥ 2 years) TFR Phase (years 2 ) Yes Not eligible g to TFR • Other I/E criteria met Recruitment is ongoing 6 countries t i in i EGM including i l di Australia, A t li Russia R i and d Tunisia T i i KaAustamel MALEK / for Business Use Only /Confidential, Do not Circulate / April 13, 2013 Grazie dell’attenzione Giuseppe Nicola Saglio