Outcomes for Patients on Long-term Imatinib Treatment for Chronic Myelogenous Leukemia
Abstract & Commentary
By William B. Ershler, MD
Synopsis: In a multinational observational study, independent from pharmaceutical support and involving both academic and community treatment centers, long-term follow-up for chronic myelogenous leukemia (CML) patients who, after two years of imatinib therapy, were in complete cytogenetic remission was undertaken for a median of 5.8 years. Although side effects were common, only a very small percentage of patients discontinued the drug and the majority maintained their cytogenetic response. In fact, the incidence of second malignancies and overall survival were no different for the CML patients in this cohort than for the general population in Italy.
Source: Gambacorti-Passerini C, et al. Multicenter independent assessment of outcomes in chronic myelogenous leukemia patients treated with imatinib. J Natl Cancer Inst 2011;103:553-561.
Community-derived data on long-term consequences of imatinib therapy for chronic myelogenous leukemia (CML) have been lacking. To provide this, a multinational, pharmaceutical-independent observational study (the Imatinib Long-Term Side Effects [ILTE] study) was conducted. This study, supported by Italian public funds, included 27 active centers located on five continents.
Consecutive CML patients (n = 832) who were treated with imatinib before 2005 and who were in complete cytogenetic remission (CCyR) after 2 years (± 3 months) of treatment were enrolled. Of the 832 patients, imatinib was the first-line treatment in 354 and was second-line in 478. The majority (89.5%) of those treated as second-line had received initial treatment with interferon, and for them the imatinib was started a median of 1.7 years after the initial diagnosis of CML.
For this study, the observation period began after 2 years of imatinib treatment and only patients in CCyR were enrolled. The incidence of the first serious and/or non-serious adverse event and the loss of CCyR were estimated according to the Kaplan–Meier method and compared by the standard log-rank test. Attainment of negative Philadelphia chromosome hematopoiesis was assessed with cytogenetics and quantitative polymerase chain reaction (PCR). Cumulative incidence of death related or unrelated to CML progression was estimated, accounting for competing risks, according to the Kalbleisch–Prentice method.
At the time of analysis, the median duration of imatinib treatment was 5.8 years. There were 139 recorded serious adverse events, of which 19.4% were considered imatinib-related. A total of 830 non-serious adverse events were observed in 53% of patients, and of these, 560 (68%) were considered imatinib-related. The most frequent were muscle cramps, asthenia, edema, skin fragility, diarrhea, tendon, or ligament lesions. Nineteen patients (2.3%) discontinued imatinib because of drug-related toxic effects. Forty-five patients lost CCyR, at a rate of 1.4 per 100 person-years. Durable (> 1 year) negative Philadelphia chromosome hematopoiesis was attained by 179 patients. Twenty deaths were observed, with a 4.8% mortality incidence rate (standardized incidence ratio = 0.7; 95% confidence interval = 0.40 to 1.10, P = 0.08), and only six of the 20 deaths were associated with CML progression.
When compared to the general Italian public, the age-adjusted death rate for patients who were in CCyR after 24 months of imatinib treatment was not different. Also of importance, the development of non-CML malignancy in this cohort was no different than the expected incidence in the general population.
Imatinib treatment for CML remains the single best example of effective targeted therapy, and its introduction in the late 1990s has dramatically changed the long-term outcome for patients with this disease. The current report, observational by design, provides additional confidence in the success of such treatment. For patients who remain in CCyR after 2 years of imatinib, survival appears no different than the general population, despite the fact that, at least in this cohort, major molecular remission, determined by PCR was apparent in just less than 25%. Yet, the annual loss of CCyR was low (only 45 of the 832 patients over the years of the study). Nonetheless, more than half of the patients had some adverse effects and some of these were clearly sufficient to alter quality of life.
In this group of patients, more than 50% had received prior interferon treatment and it is notable that there was no difference in the durability of CCyR for these patients when compared to those who had received imatinib as first treatment. Earlier reports had indicated that patients with prior exposure to interferon were more likely to reach a durable molecular response;1,2 however, more recent reports have raised questions regarding this conclusion.3
Recently, second-generation tyrosine kinase inhibitors (nilotinib and dasatinib) have produced superior molecular responses when compared to imatinib in Phase 3 trials,4,5 such that the FDA has now approved their use as first-line treatment for chronic phase CML. Yet, long-term outcome data, particularly with regard to side effects, second malignancy, and even durability of response, are not available. Thus, because of the long-term experience with imatinib, such as that provided by the ILTE study, it is quite reasonable to continue with this agent as first line, as was indicated as the personal preference of Douglas Smith in his editorial accompanying the publication of the ILTE study.6
1. Bonifazi F, et al. Chronic myeloid leukemia and interferon-alpha: A study of complete cytogenetic responders. Blood 2001;98:3074-3081.
2. Mahon FX, et al. Follow-up of complete cytogenetic remission in patients with chronic myeloid leukemia after cessation of interferon alfa. J Clin Oncol 2002;20:214-220.
3. Mahon FX, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: The prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 2010;11:1029-1035.
4. Cortes JE, et al. Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase. J Clin Oncol 2010;28:392-397.
5. Kantarjian H, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2010;362:2260-2270.
6. Smith BD. Imatinib for chronic myeloid leukemia: The impact of its effectiveness and long-term side effects. J Natl Cancer Inst 2011;103:527-529.