S/MPD. These patients were treated with Gleevec 400 mg daily. The ages of the enrolled patients ranged from 20 to 86 years. A further 24 patients with MDS/MPD aged 2 to 79 years were reported in 12 published case reports and a clinical study. These patients also received Gleevec at a dose of 400 mg daily with the exception of three patients who received lower doses. Of the total population of 31 patients treated for MDS/MPD, 14 (45%) achieved a complete hematological response and 12 (39%) a major cytogenetic response (including 10 with a complete cytogenetic response). Sixteen patients had a translocation, involving chromosome 5q33 or 4q12, resulting in a PDGFR gene re-arrangement. All of these patients responded hematologically (13 completely). Cytogenetic response was eva luated in 12 out of 14 patients, all of whom responded (10 patients completely). Only 1(7%) out of the 14 patients without a translocation associated with PDGFR gene re-arrangement achieved a complete hematological response and none achieved a major cytogenetic response. A further patient with a PDGFR gene re-arrangement in molecular relapse after bone marrow transplant responded molecularly. Median duration of therapy was 12.9 months (0.8-26.7) in the 7 patients treated within the phase 2 study and ranged between 1 week and more than 18 months in responding patients in the published literature. Results are provided in Table 17. Response durations of phase 2 study patients ranged from 141+ days to 457+ days.
Table 17 Response in MDS/MPD Complete Hematologic Response Major Cytogenetic Response
N N (%) N (%)
Overall Population 31 14 (45) 12 (39)
Chromosome 5 Translocation 14 11 (79) 11 (79)
Chromosome 4 Translocation 2 2 (100) 1 (50)
Others / no Translocation 14 1 (7) 0 (0)
Molecular Relapse 1 NE1 NE1
1 NE: Not eva luable
14.5 Aggressive Systemic Mastocytosis
One open-label, multicenter, phase 2 study was conducted testing Gleevec in diverse populations of patients with life-threatening diseases associated with Abl, Kit or PDGFR protein tyrosine kinases. This study included 5patients with aggressive systemic mastocytosis (ASM) treated with 100 mg to 400 mg of Gleevec daily. These 5 patients ranged from 49 to 74years of age. In addition to these 5 patients, 10 published case reports and case series describe the use of Gleevec in 23additional patients with ASM aged 26 to 85years who also received 100 mg to 400 mg of Gleevec daily.
Cytogenetic abnormalities were eva luated in 20 of the 28ASM patients treated with Gleevec from the published reports and in the phase 2 study. Seven of these 20patients had the FIP1L1-PDGFRα fusion kinase (or CHIC2 deletion). Patients with this cytogenetic abnormality were predominantly males and had eosinophilia associated with their systemic mast cell disease. Two patients had a Kit mutation in the juxtamembrane region (one Phe522Cys and one K509I) and four patients had a D816V c-Kit mutation (not considered sensitive to Gleevec), one with concomitant CML.
Of the 28patients treated for ASM, 8 (29%) achieved a complete hematologic response and 9 (32%) a partial hematologic response (61% overall response rate). Median duration of Gleevec therapy for the 5 ASM patients in the phase 2 study was 13months (range 1.4-22.3months) and between 1month and more than 30months in the responding patients described in the published medical literature. A summary of the response rates to Gleevec in ASM is provided in Table18. Response durations of
