Abstract

Imatinib has become the treatment of choice for most with CML. The standard dose (SD) for CP CML is 400 mg daily, but pre-clinical and clinical observations suggest that higher doses (HD) may be more effective. We have treated 222 with previously untreated CML in early CP with imatinib in 3 consecutive trials: one using SD imatinib (400 mg/day) (n=50; all entered in April 2001) and 2 subsequent trials using 400 mg twice daily (total dose 800 mg/day) (n= 172; from June 2001 until present). The 2 HD trials had identical inclusion criteria and will be considered together for this analysis. Pts followed for at least 3 months (mo) are evaluable (n=210) for this report (n=49 at 400mg, 161 at 800 mg). The median age was 48 years (range, 15 to 84); platelets were >450 x109/L in 71 pts (34%), 78 (37%) had peripheral blood (PB) blasts, and 11 (5%) had clonal evolution. Sokal risk group classification was good in 128 (61%) pts, intermediate in 61 (29%) pts, and poor in 21 (10%) pts. There was no difference in pre-treatment characteristics between the standard SD and HD groups. The results at 18 months are as follows:

Response% Responsep value*
400 mg/day800 mg/day
CR=Complete remission, Molecular Major=BCR-ABL/ABL <0.05%, Molecular CR=BCR-ABL undetectable (confirmed by nested PCR), *p value by log-rank 
Median follow-up (months) 36 19  
Cytogenetic CR 81 96 0.0002 
Cytogenetic Major 99 93 0.15 
Molecular Major 47 67 0.0007 
Molecular CR 24 0.02 
Response% Responsep value*
400 mg/day800 mg/day
CR=Complete remission, Molecular Major=BCR-ABL/ABL <0.05%, Molecular CR=BCR-ABL undetectable (confirmed by nested PCR), *p value by log-rank 
Median follow-up (months) 36 19  
Cytogenetic CR 81 96 0.0002 
Cytogenetic Major 99 93 0.15 
Molecular Major 47 67 0.0007 
Molecular CR 24 0.02 

Four pts treated with SD have transformed (3 to BP, 1 to AP) and 3 (2 to BP, 1 to AP) in the HD groups (p=0.05) (median time to transformation 11 mo, range 3 to 27). Estimated progression-free survival at 12 mo is 92% in the SD group and 99% in the HD group (p=0.42) (p=0.12 for the estimated transformation-free-survival, 94% and 99% for SD and HD at 12 mo). 4 have died (1 in SD and 3 in HD). Extramedullary toxicity was similar in the 2 groups, but myelosuppression was more common with HD, with grade ≥3 anemia, neutropenia and thrombocytopenia occurring in 7%, 39%, and 27% of pts receiving HD, respectively, and 4%, 20% and 12% of pts receiving SD. At 12 mo, the median actual dose for the HD group is still 800mg, with 40/112 (36%) evaluable having required dose reduction. This compares with 7/43 (14%) of those treated with SD. We conclude that high-dose imatinib results in higher rates of complete cytogenetic and molecular remissions, with some increase in myelosuppression.

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