Tailored temozolomide therapy according to MGMT methylation status for elderly patients with acute myeloid leukemia

Abstract

Temozolomide sensitivity is determined by methylation of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter. This study assessed whether the temozolomide dose can be tailored by MGMT promoter status and whether protracted, low-dose temozolomide can ''prime'' blasts in patients with unmethylated MGMT (unMGMT). Elderly patients with high-risk AML were stratified by MGMT methylation. Patients with methylated MGMT (mMGMT) received temozolomide 200 mg/m 2 orally for 7 days every 4 weeks, while patients with unMGMT received temozolomide 100 mg/m 2 orally for 14 days followed by 200 mg/m 2 orally for 7 days every 6 weeks. Of 36 patients (median age, 75 years), 31 (86%) had an unMGMT promoter. Overall response rate for the entire cohort was 36%. Patients with mMGMT and unMGMT had similar response rates (40% vs. 29%). Median duration of response and overall survival (OS) among responders were 29 and 35 weeks, respectively. Induction deaths (ID) occurred in 25% of patients, mostly caused by disease progression. Hematological toxicities were the most common adverse event. Toxicities were similar between patients on conventional versus protracted schedules. High HCT-CI scores were predictive of lower CR rate, higher ID, and shorter OS, while bone marrow blast count <50% at screening predicted for improved responses. Temozolomide, dosed according to MGMT methylation status, demonstrated modest clinical activity in elderly patients with AML, especially in those presenting with fewer comorbidities and low disease burden. The trial was registered on www.ClinicalTrials.gov as #NCT00611247. Am. J. Hematol. 87:45-50, 2012. V

Phase II study of targeted therapy with temozolomide in acute myeloid leukaemia and high‐risk myelodysplastic syndrome patients pre‐screened for low O6‐methylguanine DNA methyltransferase expression

“…The high complete response rate (4/5, 80%) in patients with methylated MGMT promoter cannot be explained on the basis of differences in MGMT protein expression alone, as levels in this group did not differ from those with low MGMT protein but unmethylated promoter. Although these numbers are small, another recent study also found a high CR rate (3/5, 60%) in patients with methylated MGMT promoter (Medeiros et al , ). As hypermethylation of genes tends to occur in clusters in AML and MDS, it is possible that other suppressed genes may be contributing to the high chemosensitivity in these cases.…”

Sequential azacitidine plus lenalidomide combination for elderly patients with untreated acute myeloid leukemia

“…Four patients remain on study and in first CR without evidence of disease progression, with follow-up times of 104, 71, 70 and 59 weeks. Three patients are in second CR following various salvage therapies [clofarabine followed by non-myeloablative stem cell transplantation (n=2) and temozolomide 12 (n=1)], and two patients are receiving supportive care. The overall response rate (CR+CRi+PR) was 41% (CR = 19%, CRi = 9% and PR = 12%).…”

Tumor characterization and stratification by integrated molecular profiles reveals essential pan-cancer features

“…About one-fifth of LAML samples in subgroup-6 were described with MGMT methylation. Increased MGMT activity is associated with resistance to cancer therapy using an alkylating agent, temozolomide, which has been shown to inhibit cell growth in leukemia cell lines [28]. Thus, hypermethylation of MGMT , inhibiting the expression of this gene, is of clinical interest for LAML.…”