Background: Imatinib (IM) is the standard treatment for Ph+ Chronic Myeloid Leukemia (CML) in early Chronic Phase (ECP). Nilotinib (NIL) has demonstrated superior efficacy to IM (ENESTnd trial). The treatment with more than one TKI, may improve the response rates and may decrease the frequency of drug-resistance. The combination of different TKIs is potentially toxic, while the alternating administration of IM and NIL may be better tolerated. Aims: To evaluate the response rates and the long-term outcome of ECP Ph+ CML pts treated with the alternating administration of NIL and IM. Methods: Phase 2 study (ClinicalTrials.gov. NCT00769327). Schedule: NIL 400 mg BID for the first 3 months; IM 400 mg QD for the next 3 months; then, NIL and IM rotating every 3 months, for at least 24 months. The primary end-point was the Complete Cytogenetic Response (CCyR) rate at 12 months. The pts remained on study unless both drugs were discontinued. Failures defined according to 2013 ELN recommendations. Results: 123 pts were enrolled; median age 56 years (range 18-84); 22% high Sokal score; median follow-up 60 months. The CCyR rate at 12 months (primary efficacy variable) was 75%. The cumulative MMR rates by 12, and 60 months were 82% and 84%, respectively. The cumulative MR4.0 rates by 12, and 60 months were 43%, and 62%, respectively. At 60 months, 69% of pts were on study, being the majority on monotherapy with NIL (35%) or IM (23%), and only 11% still on alternating schedule. Twenty-three failures were observed, including 6 (4.8%) progressions to accelerated/blast phase that occurred after a median time of 8 months (4-25 months); 4 pts had an ABL mutation (2 T315I, 1 Y253H, 1 F359V); all pts subsequently died. Athero-thrombotic adverse events (AAE) were observed in 6 (4.8%) pts: 3 acute myocardial infarctions, 1 unstable angina, 1 peripheral arterial occlusive disease and 1 aortic atherosclerosis; 5/6 pts discontinued permanently NIL. Overall, 12 pts died. The 5-year overall survival, progression- free survival, and failure-free survival were 90%, 90%, and 78%, respectively. Summary: The molecular responses observed in this study are in the high range of the previously published studies with TKI firstline, while the long-term outcome measures are comparable. In conclusion, first-line therapy with a rotation policy was at least as good as any other treatment policy, thus providing an alternative to the choice between IM alone and second-generation TKIs alone
LONG-TERM OUTCOME OF ALTERNATING NILOTINIB 400 MG TWICE DAILY AND IMATINIB 400 MG ONCE DAILY AS FRONTLINE TREATMENT OF CHRONIC MYELOID LEUKEMIA: A PHASE 2 STUDY OF THE GIMEMA CML WORKING PARTY
CAVAZZINI, Francesco;
2015
Abstract
Background: Imatinib (IM) is the standard treatment for Ph+ Chronic Myeloid Leukemia (CML) in early Chronic Phase (ECP). Nilotinib (NIL) has demonstrated superior efficacy to IM (ENESTnd trial). The treatment with more than one TKI, may improve the response rates and may decrease the frequency of drug-resistance. The combination of different TKIs is potentially toxic, while the alternating administration of IM and NIL may be better tolerated. Aims: To evaluate the response rates and the long-term outcome of ECP Ph+ CML pts treated with the alternating administration of NIL and IM. Methods: Phase 2 study (ClinicalTrials.gov. NCT00769327). Schedule: NIL 400 mg BID for the first 3 months; IM 400 mg QD for the next 3 months; then, NIL and IM rotating every 3 months, for at least 24 months. The primary end-point was the Complete Cytogenetic Response (CCyR) rate at 12 months. The pts remained on study unless both drugs were discontinued. Failures defined according to 2013 ELN recommendations. Results: 123 pts were enrolled; median age 56 years (range 18-84); 22% high Sokal score; median follow-up 60 months. The CCyR rate at 12 months (primary efficacy variable) was 75%. The cumulative MMR rates by 12, and 60 months were 82% and 84%, respectively. The cumulative MR4.0 rates by 12, and 60 months were 43%, and 62%, respectively. At 60 months, 69% of pts were on study, being the majority on monotherapy with NIL (35%) or IM (23%), and only 11% still on alternating schedule. Twenty-three failures were observed, including 6 (4.8%) progressions to accelerated/blast phase that occurred after a median time of 8 months (4-25 months); 4 pts had an ABL mutation (2 T315I, 1 Y253H, 1 F359V); all pts subsequently died. Athero-thrombotic adverse events (AAE) were observed in 6 (4.8%) pts: 3 acute myocardial infarctions, 1 unstable angina, 1 peripheral arterial occlusive disease and 1 aortic atherosclerosis; 5/6 pts discontinued permanently NIL. Overall, 12 pts died. The 5-year overall survival, progression- free survival, and failure-free survival were 90%, 90%, and 78%, respectively. Summary: The molecular responses observed in this study are in the high range of the previously published studies with TKI firstline, while the long-term outcome measures are comparable. In conclusion, first-line therapy with a rotation policy was at least as good as any other treatment policy, thus providing an alternative to the choice between IM alone and second-generation TKIs aloneI documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
