Nilotinib is a potent and selective BCR-ABL inhibitor. The phase 3 ENESTnd trial demonstrated superior efficacy of nilotinib vs imatinib, with higher and faster molecular responses. After a median of 24 months, the rates of progression to accelerated-blastic phase (ABP) were 0.7% and 1.1% with nilotinib 300mg and 400mg BID, respectively, significantly lower compared to imatinib (4.2%). Nilotinib has been approved for the frontline treatment of Ph+ CML. With imatinib 400mg (IRIS trial), the rate of any event and of progression to ABP were higher during the first 3 years. Consequently, a confirmation of the durability of responses to nilotinib beyond 3 years is extremely important. Aims. To evaluate the response and the outcome of patients treated for 3 years with nilotinib 400mg BID as frontline therapy. Methods. A multicentre phase 2 trial was conducted by the GIMEMA CML WP (ClinicalTrials.gov.NCT00481052). Minimum 36-month follow-up data for all patients will be presented. Definitions: Major Molecular Response (MMR): BCR-ABL/ABL ratio <0,1%IS; Complete Molecular Response (CMR): undetectable transcript levels with ≥10,000 ABL transcripts; failures: according to the revised ELN recommendations; events: failures and treatment discontinuation for any reason. All the analysis has been made according to the intention-totreat principle. Results. 73 patients enrolled: median age 51 years; 45% low, 41% intermediate and 14% high Sokal risk. The cumulative incidence of CCgR by 12 months was 100%. CCgR at each milestone: 78%, 96%, 96%, 95%, 92% at 3, 6, 12, 18 and 24 months, respectively. The overall estimated probability of MMR was 97%, while the rates of MMR at 3, 6, 12, 18 and 24 months were 52%, 66%, 85%, 81% and 82%, respectively. The overall estimated probability of CMR was 79% at 30 months, while the rates of CMR at 12 and 24 months were 12% and 27%, respectively. No patient achieving a MMR progressed to ABP. Over 3 years of observation, only one patient progressed to ABP, at 6 months, and subsequently died (high Sokal risk, T315I mutation). AEs were mostly grade 1 or 2 and manageable with appropriate dose adaptations. During the first 12 months, the mean daily dose was 600-800mg in 74% of patients. Nilotinib last daily dose was as follows: 800mg in 46 (63%) patients, 600mg in 3 (4%) patients and 400mg in 18 (25%). Six permanent discontinuations: 2/6 deaths (1:ABP, 1: mental deterioration and starvation, unrelated to study drug). 3/6, recurrent episodes of amylase and/or lipase increase (no pancreatitis) and 1/6, atrial fibrillation (other epysodes before nilotinib): 2 patients are currently on imatinib second-line and 2 on dasatinib third-line. With a median follow-up of 39 months, the estimated probability of overall survival, progression-free survival and failure-free survival was 97%, the estimated probability of event-free survival was 91%. Conclusions. The rate of failures was very low during the first 3 years. Responses remain stable. The high rates of responses achieved during the first 12 months are being translated into optimal outcome for most of patients.
NILOTINIB 400 MG BID FRONTLINE: WITH A FOLLOW-UP OF 3 YEARS, RESULTS REMAIN EXCELLENT AND STABLE. (A GIMEMA CML WP PHASE 2 TRIAL)
CAVAZZINI, Francesco;
2011
Abstract
Nilotinib is a potent and selective BCR-ABL inhibitor. The phase 3 ENESTnd trial demonstrated superior efficacy of nilotinib vs imatinib, with higher and faster molecular responses. After a median of 24 months, the rates of progression to accelerated-blastic phase (ABP) were 0.7% and 1.1% with nilotinib 300mg and 400mg BID, respectively, significantly lower compared to imatinib (4.2%). Nilotinib has been approved for the frontline treatment of Ph+ CML. With imatinib 400mg (IRIS trial), the rate of any event and of progression to ABP were higher during the first 3 years. Consequently, a confirmation of the durability of responses to nilotinib beyond 3 years is extremely important. Aims. To evaluate the response and the outcome of patients treated for 3 years with nilotinib 400mg BID as frontline therapy. Methods. A multicentre phase 2 trial was conducted by the GIMEMA CML WP (ClinicalTrials.gov.NCT00481052). Minimum 36-month follow-up data for all patients will be presented. Definitions: Major Molecular Response (MMR): BCR-ABL/ABL ratio <0,1%IS; Complete Molecular Response (CMR): undetectable transcript levels with ≥10,000 ABL transcripts; failures: according to the revised ELN recommendations; events: failures and treatment discontinuation for any reason. All the analysis has been made according to the intention-totreat principle. Results. 73 patients enrolled: median age 51 years; 45% low, 41% intermediate and 14% high Sokal risk. The cumulative incidence of CCgR by 12 months was 100%. CCgR at each milestone: 78%, 96%, 96%, 95%, 92% at 3, 6, 12, 18 and 24 months, respectively. The overall estimated probability of MMR was 97%, while the rates of MMR at 3, 6, 12, 18 and 24 months were 52%, 66%, 85%, 81% and 82%, respectively. The overall estimated probability of CMR was 79% at 30 months, while the rates of CMR at 12 and 24 months were 12% and 27%, respectively. No patient achieving a MMR progressed to ABP. Over 3 years of observation, only one patient progressed to ABP, at 6 months, and subsequently died (high Sokal risk, T315I mutation). AEs were mostly grade 1 or 2 and manageable with appropriate dose adaptations. During the first 12 months, the mean daily dose was 600-800mg in 74% of patients. Nilotinib last daily dose was as follows: 800mg in 46 (63%) patients, 600mg in 3 (4%) patients and 400mg in 18 (25%). Six permanent discontinuations: 2/6 deaths (1:ABP, 1: mental deterioration and starvation, unrelated to study drug). 3/6, recurrent episodes of amylase and/or lipase increase (no pancreatitis) and 1/6, atrial fibrillation (other epysodes before nilotinib): 2 patients are currently on imatinib second-line and 2 on dasatinib third-line. With a median follow-up of 39 months, the estimated probability of overall survival, progression-free survival and failure-free survival was 97%, the estimated probability of event-free survival was 91%. Conclusions. The rate of failures was very low during the first 3 years. Responses remain stable. The high rates of responses achieved during the first 12 months are being translated into optimal outcome for most of patients.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.