Despite the significant improvement in the outcome of patients with CML that resulted from the introduction of imatinib therapy, there is need for improvement. The estimated EFS rate at 7 years in the IRIS study was 81%, with a considerable number of patients not accounted for after they were removed from study for various reasons.1
In an intent-to-treat analysis from a single institution accounting for all patients, EFS was reported to be 81% at 5 years, but it is 63% if patients who do not achieve MCyR or patients who discontinue therapy because of toxicity are also considered as experiencing treatment failure.15
To improve these results, we investigated nilotinib as initial therapy for patients with early chronic-phase CML. Nilotinib is more potent in vitro than imatinib,8
has induced CCyR in more than 40% of patients after treatment failure with imatinib,10
and induces fewer ABL KD mutations than imatinib.16
The results of this study were encouraging, with a high rate of CCyR (98%) with these responses occurring early after therapy initiation such that 96% of patients had already achieved CCyR by 6 months. To put these results in perspective, we analyzed them in the context of historical data in similar patients treated at our institution with imatinib, either at a standard or high dose. The CCyR occurred at a higher overall rate and considerably faster with nilotinib than with standard-dose imatinib (6-month CCyR: 96% with nilotinib v
45% with imatinib17
) and high-dose imatinib (12-months CCyR: 97% with nilotinib v
70% with high-dose imatinib17
). The higher rate of CCyR is by itself a positive finding, but even if confirmed in randomized trials, it would represent a modest improvement considering that the overall rate of CCyR with standard-dose imatinib is already approximately 80%. The main advantage achieved with nilotinib seems to be the earlier occurrence of responses. The significance of early responses is controversial. It has been suggested that the outcome of patients who achieve CCyR is equivalent regardless of the time required to achieve this response.18
However, this analysis only considers patients who achieve a CCyR, thus selecting patients with already a favorable outcome. Even in this analysis, there was a trend for more durable remissions in patients who achieved their response within 6 months. However, a patient who has not achieved a CCyR at any given time faces the dual and somewhat competing possibilities of continuing to improve until achieving a CCyR at a later time, or of not improving or even experiencing progression. As more time evolves without achieving a CCyR, the probability of eventually achieving CCyR decreases, and the risk of progression increases.19
In a similar analysis for molecular response with imatinib,17
the rates of molecular response were higher than those reported with imatinib, with MMR rates at 12 months of 46% with standard-dose imatinib, 54% with high-dose imatinib, and 81% with nilotinib.
Regardless of the possible significance of the earlier responses, this analysis should be considered with caution because, although the inclusion criteria for all studies are similar without obvious imbalances in patient characteristics, comparisons are made with imatinib-treated historical cohorts. Prospective randomized trials are needed to clarify whether nilotinib therapy improves response rates, time to response, and, more importantly, the long-term outcome (EFS and TFS) compared with imatinib therapy. Also, the results reported here are comparable to those achieved with dasatinib in a parallel study reported separately conducted in parallel to this study, with patients allocated to each study in alternating sequence.
Of note, three patients experienced transformation to blast phase. One of these patients had high-risk disease with 12% blasts at the time treatment was started. Despite achieving a CCyR after 3 months of therapy (never MMR) and no treatment interruptions, the patient experienced a sudden blastic transformation. Two other patients experienced transformation after treatment discontinuation; one patient experienced transformation to lymphoid blast phase shortly after discontinuing therapy because of liver toxicity, and the other patient experienced transformation 8 months after receiving a stem-cell transplantation in CCyR (achieved on nilotinib). Despite the possible attenuating circumstances that could have contributed to these transformations (ie, high blast count at start, prolonged treatment interruptions), further follow-up and larger series will be required to determine whether there might be an increased risk of such events with nilotinib.
Treatment with nilotinib is well tolerated. The most common adverse events were elevation of liver and pancreatic function tests, particularly bilirubin (indirect), with no clinical consequences. Myelosuppression was also frequent but was mild in most patients, was always transient, usually occurred early during the course of therapy, and responded to transient treatment interruptions and dose reductions. The overall rate of adverse events seems lower in the front-line setting than what is reported with nilotinib after imatinib failure.5
This is not an unexpected finding and similar to what was reported with imatinib front-line therapy or after interferon failure.20,21
The toxicity profile compares favorably with what has been reported with imatinib. In this report, the rates of grade 3 or 4 anemia (5%), neutropenia (12%), and thrombocytopenia (11%) seen with nilotinib are similar to the rates reported with imatinib 400 mg daily (4%, 25%, and 17%, respectively)22
or 800 mg daily (5% to 10%, 14% to 36%, and 18% to 25%, respectively).23,24
Among nonhematologic adverse events, elevations of lipase and bilirubin (grade 3 or 4 in 6% and 8% of patients, respectively, in this report) have not been reported in detail in studies using imatinib. However, these are usually biochemical abnormalities with no clinical impact, and no cases of pancreatitis were observed.
We conclude that nilotinib is an effective initial therapy for patients with CML in early chronic phase, with a high rate of response and rapid achievement of CCyR in nearly all patients within 6 months from the start of therapy. These results were achieved with a favorable toxicity profile, and accrual to the study continues. The possible superiority of this approach compared with the current standard of imatinib 400 mg daily needs to be evaluated in randomized studies to assess whether such intervention will result in improved EFS and OS. Such studies are ongoing.