Differences in Haematological and Non Haematological Toxicity during Treatment with Imatinib in Early and Late Chronic Phase Chronic Myeloid Leukemia Patients

Imatinib is a relatively specific inhibitor of the BCR/ABL tyrosine kinase, effective in chronic myeloid leukaemia (CML). Aim of present study was to analyse the frequency and type of hematological and non hematological adverse events in our series of late and early chronic phase CML patients treated with imatinib and correlate the grade of hematological toxicity with the response obtained. Hematological adverse events were seen in 59 out of 150 (39%) late CP patients: 20 patients (34%) experienced toxicity grade 1, 25 (42%) had toxicity grade 2 and 14 (24%) had toxicity grade 3–4. Of 100 early CP patients, 26 (26%) experienced hematological adverse event: 42% had toxicity grade 1, 50% had toxicity grade 2 and 7% had toxicity grade 3–4. Statistical differences were detected between early and late CP patients for grade 1–2 and 3–4 toxicity. Median duration of toxicity in late CP patients was 20 days (range 4–41) for grade 1, 16 days (range 4–27) for grade 2 and 18 days (range 8–40) for grade 3–4. In early CP patients the median duration of toxicity was 10 days (range 4–21) for grade 1, 14 days (range 6–28) for grade 2 and of 10 days (range 7–15) for grade 3–4. We analysed the clinical features associated to a greater risk of myelosuppression and found that a lower haemoglobin level was significant in early CP patients while a history of cytopenia during IFN therapy and a longer time elapsing from diagnosis was significant in late CP patients. The occurrence of hematological toxicity in late CP patients was associated to the persistent lack of complete cytogenetic response, whereas this correlation was not apparent in early CP patients. We compared the incidence of non hematological adverse events occurring in late and in early CP patients and found that in these latter some side effects were more frequent, such as weight gain, periorbital oedema (p=0.02), muscle cramps (p=0.03), skin rashes (p=0.002), diarrhoea (p=0.01), weeping (p=0.001) and infections (p=0.001). In late CP patients compared to early CP patients, we found as significant the occurrence during therapy of bone pain (p=0.001) and of hemorrhagic symptoms (p=0.002) in the absence of severe thrombocytopenia. Grade 3–4 adverse events were recorded at rates below 4% and decreased over time: in late CP patients hemorrhages and muscle cramps were the most common side effects of grade 3–4, whereas in early CP patients the most frequent events were nausea, weight gain and cutaneous rash. Cardiac toxicity was observed in 3 out of 250 patients and cardiac events most frequently occurred in elderly patients with pre-existing conditions that predispose to fluid retention, with overall frequency of these events being 1%. In conclusion, we have observed that hematological and non-hematological side effects during imatinib therapy are different among late and early CP patients and that severe hematological toxicity may influence cytogenetic response.