Imatinib Long Term Effects (ILTE) Study: An Independent, International Study in CML Patients.

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 industry-sponsored trials and long-term field studies are lacking, the ILTE study was conceived as an industryindependent, academic, multicenter trial supported by the Italian Drug Safety Agency (AIFA). ILTE is an international study on a retrospective cohort and includes 31 centers in Europe, North/South America, Africa 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 Complete Cytogenetic Response (CCyR) after two years of imatinib treatment. Study endpoints were

• survival,

• serious adverse events (SAE, including second cancers),

• toxicities not qualifying as SAE (NSAE) but judged by the referring physician as substantially impacting quality of life,

• loss of CCyR, and

• development of PCR negativity.

A total of 957 patients were enrolled, 92% of which met eligibility criteria. The median age of eligible patients was 50 (range 15–92) years; 59% of patients were males and the median follow-up was 3.1 years (excluding the first 2 years of treatment). As of Dec. 31 2007, 2564 person years were available for analysis. Eleven deaths were observed (only 3 of them caused by relapsed CML), with a standardized rate of 0.4/100 person years and an observed/expected ratio of 0.48 (95% CI = 0.24–0.85). One-hundred SAE were recorded (rate 3.9/100 person years, most frequent type “heart failure”), with 21% being considered related to imatinib. Second cancers were documented in 28 patients (rate 1.1/100 person years), with an observed/expected ratio of 1.27 (95% CI = 0.84–1.84). Among the 576 NSAE recorded (0.65/patient) the most frequent types were “edema, cramps, skin fragility, diarrhea”; 71% of them were related to imatinib. A total of 12 patients (1.4 %) discontinued imatinib because of toxicities during the period of observation. Thirty-four patients lost CCyR, corresponding to a rate of 1.4/100 person years (1.0 in patients with imatinib as first-line treatment, 1.5 in patients who were treated with imatinib >6 months after diagnosis), with stable or increasing rates over time. Finally, 214 patients (24.5%) developed durable (> 1 year) PCR negativity.

In conclusion, the first 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 lower than expected in 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 ¼ of cases. Follow-up and further analysis are ongoing. (Presented on behalf of the ILTE Investigators group)