Intermittent dosage of imatinib mesylate in CML patients with a history of significant hematologic toxicity after standard dosing.

Hematologic toxicity is reported as one of the most important problems connected with imatinib mesylate (IM) treatment in patients with chronic myelogenous leukemia (CML). Withholding the drug or application of growth factors is recommended in this situation. This study introduced a novel approach using intermittent dosage of IM in order to avoid prolonged interruptions in therapy, to allow spontaneous recovery in blood count and, simultaneously, to achieve intermittently therapeutic plasma drug levels. A retrospective analysis of intermittent therapy (iT) in 12 patients with CML is presented. All patients had intermediate-to-high prognostic scores. Two patients had history of autologous stem cell transplantation. Initial standard therapy with IM was indicated for resistance to interferon (eight subjects) and for accelerated phase in four cases (one of them cytogenetic) and lasted for 1 - 6 months. iT with 300 - 600 mg of IM 1 - 5 times a week was started after significant hematologic toxicity occurred. In three patients treated 3 - 5 times a week, hematologic recovery allowed reintroduction of full dose after 3 - 7 (mean 4.6) months. In three patients, one-to-three doses per week were sufficient to maintain the cytogenetic response for a mean of 30.6 months (range 29 - 33). Six patients tolerated more frequent dosage of 4 - 5 times a week for a mean of 17.8 months (range 3 - 28). Five patients improved their cytogenetic response during iT, while hematologic progression occurred in one patient. Development of a cytogenetic abnormality in a Ph-negative clone was observed in one patient. Overall, two complete and five major cytogenetic responses were achieved. The sensitivity of Bcr/Abl kinase to inhibition by IM was proved in seven patients tested by Crkl phosphorylation assay. Measurement of plasma IM concentrations in three subjects showed concentrations fully compatible with the dosage applied suggesting normal intestinal absorption. iT with IM is a feasible and safe strategy for short-time 'bridging' management of patients with significant hematologic toxicity after standard daily dosing. Long-term iT with IM does not seem to compromise the cytogenetic response in patients with sensitivity of Bcr/Abl kinase to IM and should be considered as a plausible treatment option in patients with persistent signs of myelotoxicity.

A lower dosage of imatinib is sufficient to maintain undetectable disease in patients with chronic myeloid leukemia with long-term low-grade toxicity of the treatment.

The information about chronic myeloid leukemia (CML) patients with a deep molecular response of ≥ 4.5 log reduction (MR4.5) in whom the dose of imatinib (IM) had to be reduced to relieve toxicity is insufficient. In 205 CML patients the dose of IM was reduced in 19 (31.2%) out of 61 patients with MR4.5. The patients (12 pretreated with interferon-alpha) achieved MR4.5 after an average of 27.7 months. The duration of MR4.5 before the reduction of the dose was 16-123 (mean = 56.7) months. After the IM reduction (200 mg daily to 400 mg twice weekly for 15-90 (mean = 48) months) MR4.5 or major molecular response (MMR) was maintained in 14 (73.7%) and 2 (10.5%) patients, respectively. Three patients who lost MMR (15.8%) after the discontinuation of IM regained MR4.5 after the reintroduction of a lower dose. A lower dosage of IM should be tested for the management of side effects in patients with MR4.5 in prospective studies.

Individually determined dosing of filgrastim after autologous peripheral stem cell transplantation in patients with malignant lymphoma--results of a prospective multicentre controlled trial.

OBJECTIVES: To explore the safety and effectiveness of the individually determined application granulocyte-colony stimulating factor (G-CSF) after autologous peripheral blood stem cell transplantation (ASCT). METHODS: The administration of G-CSF from day +5 (arm A) was compared in a randomised, controlled trial with delayed, individually determined administration (G-CSF started when WBC >or= 0.5 x 10(9)/L and ANC >or= 0.1 x 10(9)/L or at day +10; arm B), and with placebo (arm C). RESULTS: One hundred and six patients, median age 45 (range 21-64), all with malignant lymphoma treated with BEAM chemotherapy were analysed. A significant difference in the time to neutrophil engraftment and in the duration of neutropenia <0.5 x 10(9)/L and <1.0 x 10(9)/L was observed between the arms (P = 0.04-<0.0001) with a 1-d prolongation of the median durations in arm B in comparison with arm A but a 2-4-d prolongation in the placebo arm C in comparison with arm B. The median number and range of days to neutrophil engraftment >0.5 x 10(9)/L after graft re-infusion was 10 (9-14) in arm A; 11 (9-19) in arm B; and 14 (10-30) in arm C (P < 0.0001). Engraftment of platelets to >20 x 10(9)/L and >50 x 10(9)/L was significantly delayed in the arms using G-CSF in comparison with placebo (P = 0.04-0.002) without any increase in bleeding or in transfusion requirement. There was no difference in the incidence and duration of transplant-related complications and their treatment between the arms. CONCLUSIONS: Our study has confirmed the safety of individually determined administration of G-CSF. The optimal timing of G-CSF application after ASCT in patients with good-quality grafts is shortly before expected spontaneous engraftment.