Background
Phase III RCT enrolling 1,106 patients with newly diagnosed chronic-phase CML. Crossover was permitted for treatment failure or intolerance. The landmark trial that established imatinib as the standard of care.
Interventions and follow up
Arm A: Imatinib 400mg daily
Arm B: IFN-alfa 5 million units/m2 daily + cytarabine 20mg/m2 daily x10d/mo
Primary endpoint: Progression-free survival (death from any cause, progression to accelerated/blast phase, loss of complete hematologic or major cytogenetic response, or rising white-cell count)
mFollow up: 19mo (initial); 10.9yr (final). 65.6% of the IFN/cytarabine arm crossed over to imatinib, so the 10-yr analysis focused on patients initially randomized to imatinib.
Arm B: IFN-alfa 5 million units/m2 daily + cytarabine 20mg/m2 daily x10d/mo
Primary endpoint: Progression-free survival (death from any cause, progression to accelerated/blast phase, loss of complete hematologic or major cytogenetic response, or rising white-cell count)
mFollow up: 19mo (initial); 10.9yr (final). 65.6% of the IFN/cytarabine arm crossed over to imatinib, so the 10-yr analysis focused on patients initially randomized to imatinib.
Results
MCyR: 87.1% vs 34.7%, P<.001
CCyR: 76.2% vs 14.5%, P<.001
Freedom from progression to AP/blast crisis: 96.7% vs 91.5%, P<.001
10-yr OS (imatinib arm): 83.3% overall; high Sokal 68.6%, intermediate 80.3%, low 89.9% (update: Hochhaus, NEJM 2017, PMID:28273028)
10-yr completed imatinib treatment: 48.3%
10-yr best CCyR: 82.8%; best MCyR 89.0%
CCyR: 76.2% vs 14.5%, P<.001
Freedom from progression to AP/blast crisis: 96.7% vs 91.5%, P<.001
10-yr OS (imatinib arm): 83.3% overall; high Sokal 68.6%, intermediate 80.3%, low 89.9% (update: Hochhaus, NEJM 2017, PMID:28273028)
10-yr completed imatinib treatment: 48.3%
10-yr best CCyR: 82.8%; best MCyR 89.0%
Adverse events
Hematologic/cytopenias: Imatinib-associated cytopenias, generally grade 3-4 in <5%
Other: Edema, hypophosphatemia, nausea, diarrhea, rash, muscle cramps, reduced bone density; well tolerated overall; monitor creatinine and LFTs for possible dose adjustment
Other: Edema, hypophosphatemia, nausea, diarrhea, rash, muscle cramps, reduced bone density; well tolerated overall; monitor creatinine and LFTs for possible dose adjustment
Conclusions
Landmark trial that transformed CML management: imatinib was superior to IFN-alfa/cytarabine in cytogenetic response, progression-free survival, and tolerability, establishing TKI therapy as standard of care.
Key Limitations
Extensive crossover (65.6%) from the comparator arm precluded a valid randomized OS comparison; long-term outcomes reported descriptively in the imatinib arm; comparator (IFN/cytarabine) is no longer a relevant standard.
Clinical Context
Cemented FDA/EMA approval of imatinib as first-line therapy for chronic-phase CML and ushered in the TKI era. ELN guidelines retain imatinib as a standard first-line TKI; second-generation TKIs are alternatives offering deeper molecular responses.
References
O'Brien SG et al, NEJM, 2003; PMID:12637609
Hochhaus A et al, NEJM, 2017; PMID:28273028
Hochhaus A et al, NEJM, 2017; PMID:28273028