Saglio G, Kim DW, Issaragrisil S, et al. . N Engl J Med. 2010; 362:2251-2259.
Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia
 

Kantarjian H, Shah NP, Hochhaus A, et al. . N Engl J Med. 2010; 362:2260-2270.
Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia
 

The IRIS study1  and its companion long-term analyses2,3 established the natural history of imatinibtreated newly diagnosed chronic-phase (CP) CML. The trial cemented the importance of achieving an early complete cytogenetic response (CCR) and major molecular remission (MMR) — therapeutic milestones that translate into excellent long-term responses. No patients who achieved an MMR by 18 months progressed to the accelerated or blast phase. With eight years of follow-up, 85 percent of patients remain alive, the estimated event-free survival is 81 percent, and freedom from progression to advanced CML is 92 percent.3  Annual rates of progression to advanced CML remain less than 0.5 percent after five years.

Despite ushering in a revolution in the treatment of CML, these data indicate that imatinib leaves some people behind on the battlefield. Naturally, the rally cry has been “stronger, quicker, better.” Although higher starting doses of imatinib in newly diagnosed patients generated more rapid and higher-quality cytogenetic and molecular remissions, standard dosing exhibited a “catch-up” phase and comparable long-term results.4  With their ability to overcome most BCR-ABL kinase domain mutations, the more potent second-generation ABL kinase inhibitors dasatinib and nilotinib could salvage responses in a substantial proportion of patients with imatinib-resistant or intolerant CML and outperform dose-escalated imatinib in CP patients. Thus, the stage was set for a frontline showdown.

Results from the upfront trials of standard-dose imatinib versus nilotinib (ENESTnd) and dasatinib (DASISION) are reported in the New England Journal of Medicine. In the ENESTnd trial, two doses of nilotinib (300 mg and 400 mg bid) were evaluated; in the DASISION study, a dasatinib dose of 100 mg daily was employed. Dasatinib and both nilotinib doses exhibited more rapid and significantly higher rates of CCR and MMR by 12 months (Table). Dasatinib’s benefits over imatinib were maintained across all Hasford risk categories; similarly, both nilotinib doses were superior to imatinib among patients with a high Sokal risk score. Progression to accelerated or blast-crisis CML occurred in a fewer number of patients treated with nilotinib or dasatinib. The safety profiles of the drugs were generally similar, with low rates of discontinuation and several non-overlapping, manageable toxicities.

Table. Comparable Efficacy of Nilotinib and Dasatinib Versus Imatinib in Newly Diagnosed CP CML

Table. Comparable Efficacy of Nilotinib and Dasatinib Versus Imatinib in Newly Diagnosed CP CML
ENESTndDASISION
ImatinibNilotinibNilotinibImatinibDasatinib
 400 mg daily 300 mg bid 400 mg bid  400 mg daily 100 mg daily 
% CCR: 12 months 65% 80% 78% 66% 77% 
% MMR: 12 months 22% 44% 43% 28% 46% 
% MMR: 3, 6, 9 months 1%, 12%, 18% 9%, 33%, 43% 5%, 30%, 38% 0.4%, 8%, 18% 8%, 27%, 39% 
Progression to AP/BC 11 (4%)* 2 (< 1%)* 1 (< 1%)* 9/260 (3.5%)** 5/259 (1.9%)** 
ENESTndDASISION
ImatinibNilotinibNilotinibImatinibDasatinib
 400 mg daily 300 mg bid 400 mg bid  400 mg daily 100 mg daily 
% CCR: 12 months 65% 80% 78% 66% 77% 
% MMR: 12 months 22% 44% 43% 28% 46% 
% MMR: 3, 6, 9 months 1%, 12%, 18% 9%, 33%, 43% 5%, 30%, 38% 0.4%, 8%, 18% 8%, 27%, 39% 
Progression to AP/BC 11 (4%)* 2 (< 1%)* 1 (< 1%)* 9/260 (3.5%)** 5/259 (1.9%)** 
View Large

*Both doses of nilotinib were significantly better than imatinib with respect to the time to progression to the accelerated phase or blast crisis (P = 0.01 for the 300-mg group; P = 0.004 for the 400-mg group)

**At 12 months, the estimated rates of progression-free survival were similar for patients receiving dasatinib and imatinib.

These data support the efficacy and safety of nilotinib and dasatinib in patients with newly diagnosed CP CML. The 12-month outcomes for both drugs indicate superiority of imatinib; however, longer follow-up will determine whether these efficacy margins are maintained and substantial differences in progression-free and overall survival materialize. At the time this article went to press, nilotinib (300 mg twice daily) had been approved by the FDA for frontline treatment. Dasatinib was under FDA review and bosutinib remained under trial investigation. Both physician and patient choice regarding which tyrosine kinase inhibitor to use will depend on several factors, such as dosing schedule (daily for dasatinib and twice daily for nilotinib) and distinct side effect profiles. For patients with in-depth responses to imatinib, there is no reason to change. In newly diagnosed patients, it may be time to pass the baton. Even so, reports of imatinib’s demise are greatly exaggerated.

1.
O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004.
2.
Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417.

Competing Interests

Dr. Gotlib serves on the Steering Committee of a Novartis-sponsored trial of midostaurin (PKC412) for systemic mastocytosis and is a member of the National Comprehensive Cancer Network’s Guidelines Committee for CML.