[Show abstract][Hide abstract] ABSTRACT: Imatinib 400 mg/day is the standard treatment for patients with chronic phase chronic myeloid leukemia. Recent reports suggested higher and more rapid cytogenetic and molecular responses with higher doses of imatinib.
In this prospective international, multicenter phase III study, 227 patients with pre-treated Philadelphia chromosome-positive, BCR-ABL-positive chronic myeloid leukemia were randomized to a standard-dose imatinib arm (400 mg/day) or a high-dose imatinib arm (800 mg/day for 6 months followed by 400 mg/day as maintenance therapy). In this planned interim analysis hematologic, cytogenetic and molecular responses as well as toxicity were evaluated.
Compared to the standard-dose, high-dose imatinib led to higher rates of major and complete cytogenetic responses at both 3 months (major: 21% versus 37%, P=0.01; complete: 6% versus 25%, P<0.001) and 6 months (major: 34% versus 54%, P=0.009; complete: 20% versus 44%, P<0.001). This was paralleled by a significantly higher major molecular response rate at 6 months in the high-dose imatinib arm (11.8% versus 30.4%; P=0.003). At 12 months, the rates of major cytogenetic response (the primary end-point) were comparable between the two arms (57% versus 59%). In contrast to non-hematologic toxicities, grade 3/4 hematologic toxicities were more common in the high-dose arm. Cumulative complete cytogenetic response rates were higher in patients without dose reduction in the high-dose arm (61%) than in the patients with no dose reduction in the standard-dose arm (36%) (P=0.014).
This is the first randomized phase III trial in patients with pre-treated chronic phase chronic myeloid leukemia demonstrating improvements in major cytogenetic response, complete cytogenetic response and major molecular response rates with high-dose imatinib therapy (ClinicalTrials.gov Identifier: NCT00327262).
[Show abstract][Hide abstract] ABSTRACT: We evaluated safety and efficacy of imatinib (600 mg) in 36 c-KIT+ acute myeloid leukemia patients not amenable to receive conventional chemotherapy. No patient achieved complete remission. One patient obtained a hematologic improvement (platelet increase with transfusion independence). Median overall survival was 3 months (0.5-44+). Non-hematologic toxicity was overall mild.
[Show abstract][Hide abstract] ABSTRACT: The hypereosinophilic syndrome (HES) may be associated with the fusion of the platelet derived growth factor receptor a (PDGFRalpha) gene with the FIP1L1 gene in chromosome 4 coding for a constitutively activated PDGFRalpha tyrosine kinase. These cases with FIP1L1-PDGFRalpha rearrangement have been reported to be very sensitive to the tyrosine kinase inhibitor imatinib mesylate.
A prospective multicenter study of idiopathic or primary HES was established in 2001 (Study Protocol Registration no. NCT 0027 6929). One hundred and ninety-six patients were screened, of whom 72 where identified as having idiopathic or primary HES and 63 were treated with imatinib 100 to 400 mg daily.
Twenty-seven male patients carried the FIP1L1-PDGFRalpha rearrangement. All 27 achieved a complete hematologic remission (CHR) and became negative for the fusion transcripts according to reverse transcriptase polymerase chain reaction (RT-PCR) analysis. With a median follow-up of 25 months (15-60 months) all 27 patients remain in CHR and RT-PCR negative, and continue treatment at a dose of 100 to 400 mg daily. In three patients imatinib treatment was discontinued for few months, the fusion transcript became rapidly detectable, and then again undetectable upon treatment reassumption. Thirty-six patients did not carry the rearrangement; of these, five (14%) achieved a CHR, which was lost in all cases after 1 to 15 months.
All patients meeting the criteria for idiopathic or primary HES should be screened for the FIP1L1-PDGFRalpha rearrangement. For all patients with this rearrangement, chronic imatinib treatment at doses as low as 100 mg daily ensures complete and durable responses.
[Show abstract][Hide abstract] ABSTRACT: Chronic Myeloid Leukemia (CML) has always been an ideal model to understand the molecular pathogenesis of human leukaemias and the way to cure them. This can be ascribed to the fact that CML was the first human cancer demonstrated to be strongly associated to the presence of a recurrent chromosomal translocation (the t(9;22)(q34;q11) that creates the Philadelphia (Ph)-chromosome) and to a specific molecular defect, the formation of a hybrid BCR-ABL gene that generates new fusion proteins endowed with a constitutive tyrosine-kinase (TK) activity, strongly implicated in the pathogenesis of the disease. The introduction into clinical practice of imatinib, (Glivec, Gleevec, Novartis), a potent tyrosine kinase inhibitor of the Bcr-Abl protein as well as of a restricted number of other TKs, has not only produced a substantial improvement in the treatment of CML, but represents a major break-through in the perspective of opening a new era, that of molecularly targeted therapy, in the management of other types of leukemia, lymphoma and cancer in general.
Journal of biological regulators and homeostatic agents 18(2):246-51. · 5.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: High dose imatinib improves cytogenetic and molecular remissions in pretreated Ph+/BCR-ABL+ CML chronic phase patients: first results from the randomized CELSG Phase III CML 11 "ISTAHIT" Study. Haematologica. 2010; 96:xxx doi:10.3324/haematol.2009.013979 Publisher's Disclaimer. E-publishing ahead of print is increasingly important for the rapid dissemination of science. Haematologica is, therefore, E-publishing PDF files of an early version of manuscripts that have completed a regular peer review and have been accepted for publication. E-publishing of this PDF file has been approved by the authors. After having E-published Ahead of Print, manuscripts will then undergo technical and English editing, typesetting, proof correction and be presented for the authors' final approval; the final version of the manuscript will then appe-ar in print on a regular issue of the journal. All legal disclaimers that apply to the journal also pertain to this production process.