Abstract 3313

Introduction:

Temozolomide sensitivity is determined by the methylation status of the MGMT promoter. As most AML patients have an unmethylated MGMT promoter, response rates to temozolomide have been very disappointing in the past. We designed this exploratory study to determine whether temozolomide therapy can be tailored according to the MGMT promoter status and to test the hypothesis that protracted, low-dose temozolomide can “prime” leukemia blasts to conventional doses of temozolomide in patients with unmethylated MGMT promoter.

Patients and Methods:

Elderly patients (>60 years of age) with AML and high-risk features (relapsed/refractory, secondary AML or de novo with intermediate or unfavorable cytogenetics) were stratified according to MGMT promoter methylation status. Patients with methylated MGMT promoters received temozolomide 200mg/m2 orally for 7 days, while patients with unmethylated promoters received temozolomide 100mg/m2 orally for 14 days followed by temozolomide 200mg/m2 orally for 7 days.

Results:

36 patients (median age, 75 years) were treated with temozolomide and 31 (86%) were found to have an unmethylated MGMT promoter. Overall response rate for the entire cohort was 36% (CR – 22%, CRp – 8%, LFS- 6%). The median duration of response and median overall survival among responding patients were 29 weeks and 35 weeks, respectively. No differences in outcomes (CR rate, OS rate and duration of remission) were noted among the 2 stratification groups (Table-1) Induction deaths (within 42 days of treatment initiation) occurred in 25% (9/36) of patients and were mostly caused by disease progression. Patients with low HCT-CI scores (≤ 2) had higher ORR 43% vs.0%, fewer induction deaths (17% vs. 67%, respectively) and longer median OS (94 days vs. 25.5 days). Hematological toxicities were the most commonly observed adverse events and difficult to distinguish from disease-related cytopenias.

Table 1

Rates of overall response, resistant disease and induction deaths according to the MGMT methylation status.

Response AssessmentAll Patients (n=36)%Methylated MGMT promoter (n=5)%Unmethylated MGMT promoter (n=31)%p-value
Overall response 13 36 3 60 10 32 0.328 
    CR 8 22 2 40 6 19 0.305 
    CRp 3 8 0 0 3 10 1 
    LFS 2 6 1 20 1 3 0.262 
Resistant disease 17 47 1 20 16 51 0.342 
Induction death 9 25 1 20 8 22 1 
Response AssessmentAll Patients (n=36)%Methylated MGMT promoter (n=5)%Unmethylated MGMT promoter (n=31)%p-value
Overall response 13 36 3 60 10 32 0.328 
    CR 8 22 2 40 6 19 0.305 
    CRp 3 8 0 0 3 10 1 
    LFS 2 6 1 20 1 3 0.262 
Resistant disease 17 47 1 20 16 51 0.342 
Induction death 9 25 1 20 8 22 1 
View Large
Conclusion:

Temozolomide therapy, stratified according to MGMT promoter methylation status, demonstrated clinical activity in elderly patients with AML and high-risk features. Protracted low-dose temozolomide may reverse the temozolomide-resistant phenotype in patients with unmethylated MGMT promoters. Future studies in better-defined populations or in combination are warranted. This trial was registered at ClinicalTrials.gov as NCT00611247.

Disclosures:

Medeiros:Schering-Plough: Research Funding. Off Label Use: Temozolomide for elderly AML.

Topics:
leukemia, myelocytic, acute, methylation, o(6)-methylguanine-dna methyltransferase, temozolomide, c-reactive protein, cyclic amp receptor protein, epley maneuver, adverse event, cytopenia, disease progression

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2010 by The American Society of Hematology
2010
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