Toxicity

IM administered to patents with CML is not without side effects, which may be classified as hematologic or nonhematologic. Both categories are for the most part manageable and only infrequently necessitate abandoning the use of the drug.

Patients who previously received treatment with IFN-« and sustain grade 3 or 4 neutropenia or thrombocytopenia on IM generally have a lower incidence of major or complete cytogenetic remission and shorter progression free survival than those without hematologic toxicity (74- 76). The outlook for newly diagnosed patients who sustain major degrees of hematologic toxicity is not necessarily inferior to that of those who tolerate the drug well. Neutropenia can be managed by administration G-CSF as often as is required to maintain a neutrophil count above 1.0 x 109/L. Paradoxically thrombocytopenia may on occasion also respond to G-CSF. Persisting severe cytopenias will necessitate altering IM administration. Because of the possibility that administering the IM at daily doses less than 300 mg may induce resistance, it is currently conventional either to reduce the dose from 400 to 300 mg/day (but no lower) or temporarily to interrupt administration entirely and to resume treatment when the neutrophil count has risen again. Anemia attributable to IM usually responds to administration of erythro-poietin and should not therefore be an indication for modifying drug dosage. It is notable that patients who received IM as treatment for gastrointestinal stromal tumors do not experience any significant hematologic toxicity, an observation that implies that the cytopenias seen in CML must be due to some inadequacy of residual normal hematopoiesis.

The list of side effects experienced by patients taking IM at 400 mg/day is extensive and includes edema, nausea, muscle cramps, bone pains, rashes, fatigue, headache, hemorrhage, and vomiting (77). Only a few of the symptoms have occurred with any frequency at grades 3 or 4; fatigue and depression have been the most common. The fluid retention often takes the form of infraorbital edema, but it may on rare occasion be more generalized. It usually responds to treatment with diuretics. In some cases where side effects have been attributed to IM and the drug was interrupted, it can safely be resumed under short-term cover of corticosteroids. In other cases the patients should be judged as "intolerant" and must therefore be treated by others means. Abnormal liver chemistry with raised hepatic enzymes occurs with some frequency and should be monitored closely, since the hepatic disturbance may progress and rare deaths attributable to hepatic failure in association with IM have been reported (78). Very rarely death due to cerebral edema has been attributed to IM (79).

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