Imatinib Long Term Effects (ILTE) Study: An International Study to Evaluate Long-Term Effects in CML Patients.

Abstract 2199

Poster Board II-176

Imatinib is an effective first line therapy for chronic myeloid leukemia (CML) and has substantially changed its biological and clinical behavior. Durable complete cytogenetic responses (CCyR) were reported in the majority of patients, with a rather benign side effect profile, despite the ‘off target’ inhibition of several other kinases, including Kit, PDGFR and Lck. Since available information is largely based on sponsored trials and long-term field studies are lacking, the ILTE study was conceived as an independent, academic, multicenter trial supported by the Italian Drug Safety Agency (AIFA) and Regione Lombardia. ILTE is an international study on a retrospective cohort and includes 31 centers in Europe, North/South America, Africa, Middle East and Asia; therefore it is uniquely positioned to present a global picture of imatinib long-term effects. Consecutive patients with Ph+ CML who started imatinib between 01 September 1999 and 31 December 2004 were eligible if they were in CCyR after two years of imatinib treatment. Study endpoints were (a) survival, (b), serious adverse events (SAE, including second cancers), (c) toxicities not qualifying as SAE (NSAE) but judged by the referring physician as substantially impacting quality of life, (d) loss of CCyR, and (e) development of PCR negativity. A total of 948 patients were enrolled, 88% of which met eligibility criteria after centers were visited and monitored. The median age of eligible patients was 51 (range 18-92) years; 59% of patients were males and the median follow-up was 4.0 years (excluding the first 2 years of treatment). As of Dec. 31 2008, 3255 person years were available for analysis. Twenty one deaths were observed (only 6 of them [28%] caused by relapsed CML), with a standardized rate of 0.6/100 person years and an observed/expected ratio of 0.7 (95% CI = 0.43-1.07, p=ns). A total of 138 SAE were recorded (rate 4.2/100 person years, most frequent type “heart failure”), with 19.5% being considered related to imatinib. Second cancers were documented in 29 patients (rate 0.9/100 person years), with an observed/expected ratio of 1.02. Among the 761 NSAE recorded (rate 23.4/100 person years) the most frequent types were cramps, asthenia,edema, skin fragility, diarrhea; 69% of them were considered related to imatinib. A total of 18 patients (2.2 %) discontinued imatinib because of toxicities during the period of observation. Forty patients lost CCyR, corresponding to a rate of 1.3/100 person years (1.0 in patients with imatinib as first-line treatment, 1.4 in patients who were treated with imatinib >6 months after diagnosis), with stable or increasing rates over time. Finally, 256 patients (36.0 %) developed durable (> 1 year) PCR negativity.

In conclusion, this report from ILTE shows that CML patients on imatinib die unfrequently of CML related causes, do not appear to have substantially higher second cancer rates than the general population, have mortality rates similar to an age/sex matched population and do not show new types of imatinib-related adverse events. They also experience a low but steady rate of loss of CCyR and develop PCR negativity in approximately 1/3 of cases. Follow-up and further analysis are ongoing. (Presented on behalf ofthe ILTE Investigators group)