Highlights EHA Matera Report del gruppo LMC

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1 Highlights EHA 12- Matera Report del gruppo LMC Moderatore: Prof Vincenzo Liso e Prof Giovanni MarCnelli Relatore: Dr Massimo Breccia PartecipanC: Antonio Lazzaro,Tommaso Caravita, AntonieIa Pia Falcone, Gaetano Palumbo, Paolo Casula

2 1^ domanda Alla luce dei risultac riportac dopo 3 anni di follow- up degli studi DASISION ed ENESTnd, come pensate di uclizzare dasacnib e nilocnib in prima linea? - Per tut i pazienc indiscntamente? - Solo per alcune categorie di rischio? - Fate differenza tra giovani e anziani?

3 Quali vantaggi in prima linea? Maggiore rapidità con elevata incidenza di risposte citogenetiche complete Minore identificazione di pazienti in risposta sub-ottimale/ failure nei primi mesi di terapia Maggiore incidenza di RMM e RMC (anche 4.5 log) Attività elevata anche nei pazienti intermedio/alto rischio Minore rate di progressioni in CB nei primi anni

4 Cumulative Incidence of MMR (BCR-ABL 0.1%) 100 P< Dasatinib 100 mg QD Imatinib 400 mg QD % with MMR fold higher likelihood of achieving MMR with dasatinib; HR=1.62 ( ) By 1 year 46% By 2 years 64% 46% By 3 years 68% 55% 23% Months MMR 3-y cumulative rates Hasford Risk Score Low Intermediate High Dasatinib 83% 65% 61% Imatinib 65% 57% 43% ASCO 12 4

5 Cumulative Incidence of MR 4 and MR 4.5 Dasatinib 100 mg QD Imatinib 400 mg QD 40 35% P= % 40 P= % with MR % 5% 18% 22% % with MR % 2% 17% 9% 22% 12% Months Months MR 4 = BCR-ABL 0.01% MR 4.5 = BCR-ABL % ASCO 12 5

6 Incidenza cumulativa di MR 4.5* ENESTnd 3-Year Results n Patients With MR 4.5, % Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD By 1 Year 11%, P < %, P <.0001 Δ 6%-10% By 3 Years 32%, P < %, P =.0003 Δ 13%-17% 15% 0 1% ASCO * Equivalent 12 to BCR-ABL transcript levels of % (IS). 6 Time Since Randomization, Months Differences in the rates of MR 4.5 between the nilotinib and imatinib arms continued to increase from 2 to 3 years 36 Data cutoff: 27Jul11. Larson, et al. Leukemia 12 Clark RE, et al. Haematologica. 12;97(s1):237 [abstract 0583].

7 ENESTnd 3-Year Results MMR a 3 aa in base all età Patients With Response, % Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD P <.0001 P <.0001 n = The highest rate of MMR was achieved by patients treated with nilotinib 300 mg BID, regardless of age Data cutoff: 27Jul11. Larson, et al. Leukemia 12 Clark RE, et al. Haematologica. 12;97(s1):237 [abstract 0583].

8 ENESTnd 3-Year Results MR 4.5 a 3 aa in base al rischio Sokal Patients With MR 4.5, % n = P =.0468 P =.0101 P =.0003 P =.0099 P =.3542 P = Low Sokal Intermediate Sokal High Sokal Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD Rates of MR 4.5 were consistently higher in patients treated with nilotinib vs imatinib across low, intermediate, and high Sokal risk scores ASCO 12 8 Data cutoff: 27Jul11. Larson, et al. Leukemia 12 Clark RE, et al. Haematologica. 12;97(s1):237 [abstract 0583].

9 Transformation to AP/BP CML by 3 Years Dasatinib 100 mg QD Imatinib 400 mg QD Number of patients, n N On study Including follow-up beyond discontinuation (ITT) a a Yearly evaluations after discontinuation are currently stipulated per protocol; additional information on patient status may be provided by investigators at other times ASCO 12 9

10 Progressione a AP/BC* nel Core Treatment P =.0003 ENESTnd 3-Year Update Number of Patients, n 2 P = P = % 1.1% 4.2% 0.7% 1.8% 6.0% Including Clonal Evolution 2 5 P =.0085 Nilotinib 300 mg BID Nilotinib 400 mg BID Imatinib 400 mg QD 17 Nessuna nuova progressione è avvenuta dall ultimo follow-up dei 2 anni * Progression to AP/BC or death following progression. Data ASCO cut-off: 12 27Jul Saglio G, et al. Blood. 11;118(21):8-9 [abstract 452].

11 Risposte 1^ domanda E necessario inserire tut i pazienc in trials controllac. Per tut i pazienc indiscntamente? Sulla base della safety, compliance, cosc (!). Non indicazioni sicure. Solo per alcune categorie di rischio? Sicuramente alc rischi (100% concordanza) Non pieno accordo su basso/intermedio rischio Fate differenza tra giovani e anziani? No

12 2^ domanda Pensate che i risultac presentac della valutazione molecolare precoce al terzo mese possano influenzare la vostra pracca clinica? In che modo?

13 Molecular and Cytogenetic Response at 3 Months a P< % P< % Dasatinib 100 mg QD Imatinib 400 mg QD % of patients >1-10% 1% 64% >1-10% PCyR CCyR 67% PCyR CCyR 1% n//n 198/ / / /221 10% BCR-ABL at 3 Months PCyR/CCyR at 3 Months n BCR-ABL of <10% and 1% are not fully concordant with PCyR and CCyR, respectively n 96% and 83% of dasatinib and imatinib pts with PCyR had <10% BCR-ABL, respectively n 68% and 26% of dasatinib and imatinib pts with CCyR had 1% BCR-ABL, respectively a Calculated from total number of evaluable patients with PCR assessments at 3 months ASCO 12 13

14 PFS 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 % not progressed 40 0 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 ASCO 12 14

15 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% 3-year OS 10% = 95.9% >10% = 85.9% P= BCR-ABL at 3 months 1% >1 10% 3-year OS 10% = 96.0% >10% = 88.0% P= >10% 0 >10% Months Months 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 ASCO 12 15

16 Transformation (ITT) to AP/BP According to BCR-ABL Transcript Level at 3 Months Dasatinib 100 mg QD Imatinib 400 mg QD Number of transformations, n % % 3 a N Total 1% >1-10% >10 BCR-ABL transcript level at 3 months % b a Of the 3 pa*ents transforming a2er achieving a rapid and deep response at 3 months, 1 pa*ent transformed a2er ~12 months of poor treatment adherence, 1 pa*ent transformed 6 months a2er switching to ima*nib, and 1 transformed while receiving dasa*nib b One pa*ent in the ima*nib arm transformed but did not have a BCR- ABL transcript measurement at 3 months ASCO 12 16

17 BCR-ABL a 3 Mesi % of Patients n n % >1-10% 67% Nilotinib 300 mg BID (N = 258) Imatinib (N = 264) 1% >1-10% 33% 9% 1% n % BCR-ABL Level at 3 Months > 10% Reasons for unevaluable samples: Atypical transcripts: 5 patients on nilotinib, 2 patients on imatinib Missing samples: 4 patients on nilotinib, 5 patients on imatinib Discontinued: 15 patients (incl.1 progression) on nilotinib, 12 patients (incl.1 progression) on imatinib PFS/OS events prior to 3 months: 1 PFS event in each arm, no deaths ASCO ENESTnd Landmark Analysis *Calculated from total number of evaluable patients with PCR assessments at 3 months. Hochhaus A, et al. Haematologica. 12;97(s1):237 [abstract 0584].

18 ENESTnd Landmark Analysis Incidenza cumulativa di MMR in base a BCR-ABL Levels a 3 mesi (Nilotinib 300 mg BID) % With MMR Pat 1% 1 > 1% 10% 89 > 10% 24 By 1 Year 76% 40% By 2 Years 89% 67% 29% % Time Since Randomization (Months) ASCO Data cut-off: 27Jul11. Hochhaus A, et al. Haematologica. 12;97(s1):237 [abstract 0584].

19 PFS* in base a BCR-ABL Levels a 3 mesi (Nilotinib 300 mg BID) ENESTnd Landmark Analysis % Without Progression or Death % > 1% 10% > 10% Pat Evt Cen Censored observations Time Since Randomization (Months) 96.5% 95.6% 82.9% P =.968 P =.014 P =.0021 between 10% vs > 10% * PFS includes both progression events occurring on study drug and also after discontinuation of study drug during follow-up, as well as death due to any cause on study or after discontinuation of study drug during follow-up. After discontinuation of study drug, progression information was prospectively collected every 3 months for up to 5 years. Data cut-off: 27Jul11. ASCO Hochhaus A, et al. Haematologica. 12;97(s1):237 [abstract 0584].

20 Overall Survival in base a BCR-ABL Levels a 3 mesi (Nilotinib 300 mg BID) ENESTnd Landmark Analysis % 96.9% 86.7% P =.003 between 10% vs > 10% P =.42 P =.006 % Alive % > 1% 10% > 10% Censored observations Pat Evt Cen Time Since Randomization (Months) ASCO 12 Data cut-off: 27Jul11. Hochhaus A, et al. Haematologica. 12;97(s1):237 [abstract 0584].

21 Si: 100% RisultaC 2^ domanda Più aiento monitoraggio se inizio imacnib in prima linea con possibile early switch a seconda generazione Se in seconda generazione? Dipende dalla Cpologia del paziente - passo all altro inibitore - penso al TMO? Rivalutare il dato a 6 mesi!

22 3^ domanda Pensate che lo score EUTOS sia uno score valido da uclizzare al baseline? Lo uclizzate nella pracca clinica quocdiana?

23 Applicazioni score EUTOS: dac EHA 12 German study IV (Saussele et al) pazienc: 88% low and 12% high risk - Differenza significacva nel tempo di raggiungimento della MMR e nella % di MMR GIMEMA (CastagneT et al) pazienc traiac con nilocnib: 95% low and 5% high - Differenza significacva in termini di MMR, FFS, PFS, OS

24 RisultaC 3^ domanda Pensate che lo score EUTOS sia uno score valido da uclizzare al baseline? - Incertezza Lo uclizzate nella pracca clinica quocdiana? - Non ancora v Necessità di cercare faiori biologici per caraierizzare i pazienc all esordio

25 4^ domanda Nuove informazioni sono disponibili per la possibile sospensione di imacnib. Pensate che sia opportuno? Partecipereste a trials per la sospensione dei TKIs?

26 Rousselot et al - 58 pts sospendono imacnib RisultaC dall EHA - 18 con ripetuta MR+ senza perdere MMR in 23 mesi - 66% dei pts è rimasto libero dal traiamento uclizzando il criterio di perdita di MMR CML08 (Australia) - 40 pts che sospendono imacnib - 22 recidive - RFS 42% - FaIori preditvi per la recidiva: alto rischio Sokal, breve durata traiamento con IFN

27 RisultaC 4^ domanda Nuove informazioni sono disponibili per la possibile sospensione di imacnib. Pensate che sia opportuno? Si (alcuni pensano solo per pazienc anziani) Partecipereste a trials per la sospensione dei TKIs? Si solo se trials controllac