Abstract

Sokal risk formulation was elaborated 25 years ago, based on very simple factors (age, spleen size, platelet count, and percentage of myeloblasts in the peripheral blood), based on patients treated with conventional chemotherapy. In spite of that, Sokal risk score is still the major prognostic factor for response to treatment with the tyrosine kinase inhibitor, Imatinib mesylate (IM). Since several preclinical, pharmacokinetic and clinical studies suggested that the therapeutic efficacy of IM may be concentration/dose–dependent, we assigned prospectively 217 adult patients with Ph pos CML, Sokal high risk (SHR), to be treated front line with IM 400 mg or 800 mg (Clin.Trials Gov. NCT00514488), comparing the cytogenetic and the molecular response rates at 3, 6, and 12 months. Cytogenetic response was evaluated by chromosome banding analysis (CBA) of marrow metaphases, and by FISH analysis of marrow cells in case of insufficient metaphase number. Molecular response was evaluated by RT-Q-PCR (PB), according to the international scale. The results are shown in Table 1. No difference between the two arms was significant at any time point. In the 400 mg arm, the median daily dose of IM was 400 mg, with 87% of patients receiving 350 to 400 mg. In the 800 mg arm, the median daily dose of IM was 720 mg, with 63% of patients receiving 600 to 800 mg. The CCgR rate was 86%, vs 66% in the patients who received a median daily dose of 600 to 800 or less than 600 mg daily, respectively (p=0.013). With a median follow up of 31 months (range 1–49 months), progression-free and overall survival are higher than 90% in both arms. Based on an intention-to-treat analysis, this study did not show a significant benefit of 800 mg over 400 mg in SHR patients, but the patients who could comply with the high dose had a better cytogenetic outcome.

 3 months 6 months 12 months 
 400 800 400 800 400 800 
(1)Refusal, or lost to follow-up, or protocol violations 
(2)Failure was defined according to the ELN recommendations (
Baccarani et al,
Blood
2006
;
108
:
1809
–1920
(3)No Ph pos metaphases out of at least 20 marrow cell metaphases, by CBA, or < 1% BCR-ABL positivity out of at least 200 marrow cells, by FISH 
(4)BCR-ABL:ABL < 0.10 and < 0.005 by RT-Q-PCR, converted to the International Scale. 
No. of pts 109 108 109 108 109 108 
Dropouts(1) 4% 4% 5% 7% 5% 8% 
D/C adverse events 1% 2% 4% 4% 4% 7% 
Failure(2) 1% 1% 9% 10% 16% 15% 
CCgR(3) 19% 25% 49% 52% 58% 64% 
MolR>3.0 log(4) 7% 12% 25% 31% 33% 40% 
MolR>4.5 log(4) 1% 2% 3% 9% 10% 19% 
Transcript level (median) 2.085 1.122 0.378 0.108 0.084 0.036 
 3 months 6 months 12 months 
 400 800 400 800 400 800 
(1)Refusal, or lost to follow-up, or protocol violations 
(2)Failure was defined according to the ELN recommendations (
Baccarani et al,
Blood
2006
;
108
:
1809
–1920
(3)No Ph pos metaphases out of at least 20 marrow cell metaphases, by CBA, or < 1% BCR-ABL positivity out of at least 200 marrow cells, by FISH 
(4)BCR-ABL:ABL < 0.10 and < 0.005 by RT-Q-PCR, converted to the International Scale. 
No. of pts 109 108 109 108 109 108 
Dropouts(1) 4% 4% 5% 7% 5% 8% 
D/C adverse events 1% 2% 4% 4% 4% 7% 
Failure(2) 1% 1% 9% 10% 16% 15% 
CCgR(3) 19% 25% 49% 52% 58% 64% 
MolR>3.0 log(4) 7% 12% 25% 31% 33% 40% 
MolR>4.5 log(4) 1% 2% 3% 9% 10% 19% 
Transcript level (median) 2.085 1.122 0.378 0.108 0.084 0.036 

Table 1: Summary of cytogenetic and molecular results. All percentages are calculated based on all randomized patients, according to the intention-to-treat principle. p-values are > 0.10 for all comparisons.

Disclosures: Baccarani:novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Research Funding; Wyeth: Consultancy, Honoraria. Simonsson:novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy. Porkka:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; roche: Consultancy. Martinelli:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Wyeth: Speakers Bureau. Pane:Novartis: Research Funding. Saglio:Novartis: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Rosti:Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

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