Background
Phase III RCT enrolling 519 patients with newly diagnosed Ph+ chronic-phase CML, randomized 1:1 to compare first-line dasatinib versus imatinib.
Interventions and follow up
Arm A: Dasatinib 100mg daily
Arm B: Imatinib 400mg daily
Primary endpoint: Confirmed complete cytogenetic response (CCyR) by 12mo (confirmed on 2 assessments ≥28 days apart)
mFollow up: 12mo (primary); 5-yr update reported
Arm B: Imatinib 400mg daily
Primary endpoint: Confirmed complete cytogenetic response (CCyR) by 12mo (confirmed on 2 assessments ≥28 days apart)
mFollow up: 12mo (primary); 5-yr update reported
Results
12-mo confirmed CCyR: 77% vs 66%, P=.007
12-mo MCyR: 46% vs 28%, P<.001
CCyR by 3/6/9mo: 54% vs 31%, 73% vs 59%, 78% vs 67%, arm A vs B (faster with dasatinib)
Cumulative 5-yr MMR: 75% vs 64%, P=.0022 (update: Cortes, JCO 2016, PMID:27217448)
5-yr MR4: 39% vs 28%, arm A vs B
Cumulative 5-yr MR4.5: 42% vs 33%, P=.0251
5-yr OS: 91% vs 90%, arm A vs B; HR 1.01, 95%CI 0.58–1.73
5-yr PFS: 85% vs 86%, arm A vs B; HR 1.06, 95%CI 0.68–1.66
12-mo MCyR: 46% vs 28%, P<.001
CCyR by 3/6/9mo: 54% vs 31%, 73% vs 59%, 78% vs 67%, arm A vs B (faster with dasatinib)
Cumulative 5-yr MMR: 75% vs 64%, P=.0022 (update: Cortes, JCO 2016, PMID:27217448)
5-yr MR4: 39% vs 28%, arm A vs B
Cumulative 5-yr MR4.5: 42% vs 33%, P=.0251
5-yr OS: 91% vs 90%, arm A vs B; HR 1.01, 95%CI 0.58–1.73
5-yr PFS: 85% vs 86%, arm A vs B; HR 1.06, 95%CI 0.68–1.66
Adverse events
Hematologic/cytopenias: Grade 3-4 neutropenia 29% vs 24%, thrombocytopenia 22% vs 14%, anemia 13% vs 19% (arm A vs B)
Pleural effusion/fluid: Any-grade pleural effusion 28% vs 0.8% (grade 3-4 ~3%; thoracentesis required in 12%); rate higher at age >65 (~60%) vs ≤65 (~25%); effusion did not affect response
Discontinuation due to AE: 16% vs 7%; QTc prolongation and interstitial pneumonitis also reported
Pleural effusion/fluid: Any-grade pleural effusion 28% vs 0.8% (grade 3-4 ~3%; thoracentesis required in 12%); rate higher at age >65 (~60%) vs ≤65 (~25%); effusion did not affect response
Discontinuation due to AE: 16% vs 7%; QTc prolongation and interstitial pneumonitis also reported
Conclusions
Dasatinib produced faster and deeper cytogenetic and molecular responses than imatinib, but at 5 years there was no difference in PFS or OS between the two first-line strategies.
Key Limitations
No survival or progression advantage despite superior molecular endpoints; characteristic pleural effusion toxicity, particularly in older patients; 5-yr surrogate endpoints; open dosing and discontinuation patterns affect long-term comparison.
Clinical Context
Supported FDA/EMA approval of dasatinib for newly diagnosed chronic-phase CML. ELN guidelines include dasatinib as a first-line TKI option; pleural effusion risk and cardiopulmonary comorbidity guide selection versus other TKIs.
References
Kantarjian H et al, NEJM, 2010; PMID:20525995
Cortes JE et al, JCO, 2016; PMID:27217448
Cortes JE et al, JCO, 2016; PMID:27217448