Background
Phase III RCT enrolling 846 patients with newly diagnosed chronic-phase Ph+ CML, randomized 1:1:1. The trial established second-generation TKIs as first-line options versus the imatinib standard.
Interventions and follow up
Arm A: Nilotinib 300mg BID
Arm B: Nilotinib 400mg BID
Arm C: Imatinib 400mg daily
Primary endpoint: MMR at 12mo (BCR-ABL on International Scale ≤0.1%)
mFollow up: 12mo (primary); updates at 24mo, 5yr, and 10yr
Arm B: Nilotinib 400mg BID
Arm C: Imatinib 400mg daily
Primary endpoint: MMR at 12mo (BCR-ABL on International Scale ≤0.1%)
mFollow up: 12mo (primary); updates at 24mo, 5yr, and 10yr
Results
12-mo MMR: 44% vs 43% vs 22%, arm A vs B vs C (P<.001 for both nilotinib doses vs imatinib)
12-mo CCyR: 80% vs 78% vs 65%, arm A vs B vs C
24-mo MMR: 72% vs 67% vs 44%, arm A vs B vs C (update: Kantarjian, Lancet Oncol 2011, PMID:21856226)
24-mo CMR: 26% vs 21% vs 10%, arm A vs B vs C
10-yr MMR: 77.7% vs 79.7% vs 62.5%, arm A vs B vs C (update: Kantarjian, Leukemia 2021, PMID:33414482)
10-yr MR4.5: 61.0% vs 61.2% vs 39.2%, arm A vs B vs C
10-yr OS: 87.9% (HR vs imatinib 1.07, 95%CI 0.64–1.76) vs 90.3% (HR 0.79, 95%CI 0.46–1.36) vs 88.3%, arm A vs B vs C
10-yr PFS: 86.2% (HR 1.08, 95%CI 0.67–1.74) vs 89.9% (HR 0.74, 95%CI 0.44–1.25) vs 87.2%, arm A vs B vs C
12-mo CCyR: 80% vs 78% vs 65%, arm A vs B vs C
24-mo MMR: 72% vs 67% vs 44%, arm A vs B vs C (update: Kantarjian, Lancet Oncol 2011, PMID:21856226)
24-mo CMR: 26% vs 21% vs 10%, arm A vs B vs C
10-yr MMR: 77.7% vs 79.7% vs 62.5%, arm A vs B vs C (update: Kantarjian, Leukemia 2021, PMID:33414482)
10-yr MR4.5: 61.0% vs 61.2% vs 39.2%, arm A vs B vs C
10-yr OS: 87.9% (HR vs imatinib 1.07, 95%CI 0.64–1.76) vs 90.3% (HR 0.79, 95%CI 0.46–1.36) vs 88.3%, arm A vs B vs C
10-yr PFS: 86.2% (HR 1.08, 95%CI 0.67–1.74) vs 89.9% (HR 0.74, 95%CI 0.44–1.25) vs 87.2%, arm A vs B vs C
Adverse events
Hepatic/metabolic: Hepatotoxicity any-grade 48.4% vs 53.1% vs 17.5%; hyperglycemia, hypercholesterolemia, elevated amylase/lipase and bilirubin more frequent with nilotinib
Cardiovascular: 10-yr cumulative cardiovascular events 16.5% vs 23.5% vs 3.6%; peripheral arterial occlusive disease; QT prolongation (black-box warning, baseline ECG required) 6.8% vs 7.9% vs 3.9%
Cardiovascular: 10-yr cumulative cardiovascular events 16.5% vs 23.5% vs 3.6%; peripheral arterial occlusive disease; QT prolongation (black-box warning, baseline ECG required) 6.8% vs 7.9% vs 3.9%
Conclusions
Nilotinib significantly improved MMR, deep molecular response (MR4.5), and lowered progression to AP/BP CML versus imatinib, though 10-yr OS and PFS were similar across arms with greater cardiovascular toxicity in the nilotinib arms.
Key Limitations
No OS difference at long-term follow-up despite superior molecular endpoints; cumulative cardiovascular and metabolic toxicity with nilotinib; molecular surrogate endpoints rather than survival as primary; treatment discontinuation over the 10-yr period complicates long-term interpretation.
Clinical Context
Led to FDA/EMA approval of nilotinib for newly diagnosed chronic-phase CML. ELN guidelines list nilotinib as a first-line TKI option; choice among first-line TKIs is individualized by comorbidity and cardiovascular risk profile and by desire for treatment-free remission given deeper molecular responses.
References
Saglio G et al, NEJM, 2010; PMID:20525993
Kantarjian H et al, Lancet Oncol, 2011; PMID:21856226
Kantarjian H et al, Leukemia, 2021; PMID:33414482
Kantarjian H et al, Lancet Oncol, 2011; PMID:21856226
Kantarjian H et al, Leukemia, 2021; PMID:33414482