[A study to determine the safety and efficacy of imatinib mesylate in patients with chronic phase of chronic myeloid leukemia after interferon therapy failure. Four year follow-up]. / Ocena skutecznosci i bezpieczenistwa stosowania imatinibu mesylate u pacjentów z faza przewlekla przewleklej bialaczki szpikowej po niepowodzeniu leczenia interferonem 4 lata obserwacji.

UNLABELLED: Targeted therapy with the use of imatinib mesylate is a recognized option for patients with chronic myeloid leukemia (CML) not eligible for allogeneic hematopoietic cell transplantation. We present results of a multicenter phase II study on the use of imatinib in chronic phase after failure to interferon-alpha (IFN-alpha). Sixty patients (27 female, 33 male), median age 46 (range, 21-64), were included with hematologic relapse (n= 11), hematologic refractoriness (n=4), cytogenetic relapse/ /+65resistance (n=40) or intolerance to IFN-alpha (n=5). The median time from CML diagnosis was 39 months (range, 4-132), the median time of IFN-alpha therapy equaled 23 months (range, 1-78). Imatinib mesylate was administered at a dose of 400 mg/day for 1 year. In patients who achieved major cytogenetic response (MCR) the therapy was continued until progression. Thirty-three (55%) patients achieved MCR after one year of treatment. At 4 years the cumulative incidence of complete cytogenetic response equaled 40% (95% CI, 29-56). Among 27 patients who did not achieve MCR at 12 moths, in 12 cases the study course was discontinued prematurely because of blast crisis (n=9), prolonged neutropenia (n=l), severe transaminases elevation (n=l) or incidental death not related to the study drug or disease (n=l). The probability of OS at 4 years equaled 82% (95% CI, 72-91) and was lower for patients with the disease duration >36 months and those with Sokal index > or =0.8. Among patients who achieved MCR, the probability of progression-free survival was 78% (95% CI, 69-85). Time to progression (cytogenetic, n=6; blast crisis, n=l) varied from 3-36 months. CONCLUSIONS: Imatinib mesylate is characterized by good tolerance and allows achieving cytogenetic response in more than half of late chronic phase CML patients with failure of interferon therapy. However, the progression rate is substantial, which raises concern regarding the curative potential of monotherapy with imatinib in this group of patients.

Ceramides and glycosphingolipids in maturation process: leukemic cells as an experimental model.

Leukemic cells were used as experimental material to demonstrate changes in the content of GSLs during the development and maturation of neutrophils. The most abundant cellular GSL is LacCer. An elevation in the LacCer level occurs twice during the maturation process: initially, on formation of azurophil granules, and subsequently, (a more significant rise) on formation of specific granules. The formation of the latter is accompanied by an increase in the level of GalGalCer. During the maturation of myeloblasts, there is a simultaneous growth in the content of LacCer and GM3 as well as that of their common precursors, that is, free ceramides. Like other tumor cells, GM3 rich myeloblasts in the peripheral blood from patients with AML are characterized by shedding of gangliosides. The quantitative Cer/GlcCer ratio in these cells seems to be advantageous for the efficacy of chemotherapy in the induction of apoptosis. Myelo- and metamyelocytes achieve the highest level of GSLs. Their entry into the full maturity stage is accompanied by a decrease in the level of GSLs. Patterns of GSLs expression change greatly during development and maturation. However, with respect to the composition and content of GSLs, there are no significant differences between normal and leukemic mature neutrophils. At each stage of the development and maturation of myelogenous leukemic cells, as well as in normal mature neutrophils, there occurs the synthesis of the same molecular species both free ceramides and ceramide portions of LacCer, precursor of more complex GSLs.