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.

The simultaneous occurrence of polycythemia vera (PV) and chronic lymphocytic leukemia (CLL) is a rare event that offers a possibility to study their common origin. PV originates from self-renewing hematopoietic stem cells (HSC) with both lymphoid and myeloid potential(1–3). It has been reported that CLL also originates from self-renewing HSC with a potential for both lymphoid and myeloid differentiation(4, 5). We report 3 females with concomitant CLL and PV whose X-chromosome inactivation patterns of the neoplastic cells revealed that granulocytes/platelets and B-lymphocytes used different X-chromosome alleles. These data indicate that both PV and CLL have arisen independently and from different HSC.

The occurrence of significant hematologic toxicity in patients with CML during the treatment with standard continuous dosing of imatinib (IM) is associated with inferior prognosis. In order to avoid prolonged interruptions of therapy in such patients and, possibly, to prevent induction of resistance we adopted a strategy of intermittent treatment (I-T): the daily dose of 300–600 mg of IM was given once to five times weekly. Here we report the experience with I-T in 10 patients (7 women and 3 men) aged 25 to 74 (me=49,3) years treated with I-T for median of 19,5 months (range: 4–26). Patients have 4–152 (me=23,5) months long history of CML at the initiation of IM therapy that was indicated for accelerated phase (in 4 patients), cytogenetic (3) or hematologic (2) resistance or toxicity after interferon (1). 7 of them were previously treated with interferon, 2 with hydroxyurea and one with busulfan only. Two patients have the history of autologous peripheral stem cell transplantation. Additional cytogenetic aberration (+8) was present before IM therapy in one patient and in other two cases interstitial deletions of 9q were identified. 5 patients had high and 5 intermediate Sokal score, while the value of Euro score was high in each case. All patients received initially the standard treatment (300–600mg daily) with IM for 1–6,5 (m=2,5) months resulting in hematologic remission with various degree of myelosupression in each of them. Hematologic toxicity was the reason for the discontinuing of therapy in 7 patients for 0,5–4 months. One patient was treated before introduction of I-T with daily dose of 100–150mg of IM for 11 months. In 7 cases complete hematologic remission was maintained by I-T and in one of them steady regeneration in blood counts allowed reintroduction of full dose standard therapy. Hematologic progression occurred in two patients. Both of them were successfully switched to full daily dosing of IM. Two patients improved their cytogenetic response during I-T. In four cases major cytogenetic remission achieved with standard dosing was maintained. Using interphase FISH the level of cytogenetic response was below 10% in 5 patients at the latest examination. In one patient the development of +8 in BCR/ABL negative cells was observed. In some cases in vitro tests for evaluating the sensitivity to IM and screening for BCR/ABL tyrosine-kinase mutation were performed. We conclude that the I-T with IM might serve as a reasonable and cost-effective alternative in heavily pre-treated or in high-risk patients with CML who could not be offered allogeneic stem cell transplantation or experimental therapy. Using this strategy, major cytogenetic remissions was achieved in two and maintained in other four patients. I-T allows safe tailoring the actual dose of IM in order to avoid excessive hematologic toxicity. Our observations need to be validated in larger cohort of patients during longer follow-up.