Cytogenetic Response in Relation to the Adherence to Treatment with Imatinib Mesylate: A Case Control Study.

Introduction: The treatment of chronic myeloid leukemia (CML) suffered a dramatic change with the introduction of Imatinib mesylate. This drug has become the choice for first line treatment of CML. However, it has been shown that the effectiveness of the treatment requires a high compliance with the prescribed dose for a long period of time, and sub-dosing has been associated with a delay in achieving cytogenetic response and development of resistance. We conducted a prospective case-control study, in order to analyze how a better compliance affects the cytogenetic response to Imatinib.

Materials and Methods: Between January and June 2006, 24 patients with newly diagnosed Phi (+) chronic phase CML were recruited and followed for the next 12 months. Patients were put on 400mg of Imatinib and were asked to note down all taken doses, and reasons for non-compliance. During each of the monthly visits, the dosing schedules were revised, non-adherence reasons were discussed and the medication was counted. All adverse events were noted and graded according to the NCI CTCAE (VERSION 3.0) code. Reductions or interruptions in the schedule were only allowed for related adverse events with a CTC score ≥3. All other events were treated accordingly, without modifications in the Imatinib dosing. As a control group, we matched each case with a chronic phase Phi (+) CML patient from our data base (controls were matched for sex, age, and hematological response). Only patients who received treatment with Imatinib and with complete information about dosing and adverse events were acceptable as controls. Compliance was measured as: mg taken /mg prescribed x 100 during the study period. Cytogenetic response was reported as the percentage of t(9;22) negative metaphases.

Results: Twenty-four patients, 14 males with median age 55 yo (range: 23–82) were included in the study; three were lost to follow up, leaving only twenty-one for analysis of compliance. At the end of the year of follow up, all patients have achieved a complete hematological response. Compliance during the 12 months was 96.1 ± 9% 1SD for the cases group, which is clearly superior to the 80% reported in the setting of clinical trials. As for one year cytogenetic response, 60 ± 25% of the control group achieved a mayor response (Phi < 35%), while 89.9 ± 20% of the cases achieved that same response. This difference is statistically significant with a p=0.027. The incidence of adverse events was similar for both groups, being nausea, vomiting, peripheral edema and skin rash the most common ones. As for hematological toxicity, CTC grade 1–2 leucopenia (11%) and thrombocytopenia (17%) were the more frequent. However, although moderate, these were the main reasons for interruption or reduction of Imatinib dosage in the control group.

Conclusions: This study shows that improving compliance is associated with a better cytogenetic response. As this response is the ultimate goal in the treatment of CML patients, physicians should make an effort to assure the best adherence to the treatment and avoid sub-dosing. Doing this will help patients obtain a better cytogenetic response which has already proved to be essential for long term survival in CML.