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Phase II study of targeted therapy with temozolomide in acute myeloid leukaemia and high‐risk myelodysplastic syndrome patients pre‐screened for low O 6 ‐methylguanine DNA methyltransferase expression
Author(s) -
Brandwein Joseph M.,
Kassis Jeannine,
Leber Brian,
Hogge Donna,
HowsonJan Kang,
Minden Mark D.,
Galarneau André,
Pouliot JeanFrançois
Publication year - 2014
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13094
Subject(s) - temozolomide , o 6 methylguanine dna methyltransferase , myelodysplastic syndromes , myeloid leukaemia , medicine , methyltransferase , oncology , decitabine , cancer research , dna methyltransferase , dna , dna methylation , glioblastoma , methylation , gene expression , gene , biology , genetics , bone marrow
Summary Resistance to temozolomide is largely mediated by the DNA repair enzyme O 6 ‐methylguanine DNA methyltransferase ( MGMT ). We conducted a prospective multicentre study of patients with previously untreated acute myeloid leukaemia ( AML ) or high‐risk myelodysplastic syndrome ( MDS ) who were not candidates for intensive therapy. Patient selection was based on MGMT expression by Western blot. Patients with MGMT : ACTB (β‐actin) ratio <0·2 were eligible to receive temozolomide 200 mg/m 2 /d ×7 d. Patients achieving a complete response ( CR ) could receive up to 12 monthly cycles of temozolomide ×5/28 d. Of 166 patients screened, 81 (49%) demonstrated low MGMT expression; 45 of these were treated with temozolomide. The overall response rate was 53%; 36% achieved complete clearance of blasts, with 27% achieving a CR / CR with incomplete platelet recovery ( CR p). Factors associated with a trend toward a higher response rate included MDS , methylated MGMT promoter and standard cytogenetic risk group. Induction and post‐remission cycles were well‐tolerated and most patients were treated on an outpatient basis. Patient who achieved CR / CR p had a superior overall survival compared to partial or non‐responders. In conclusion, targeted therapy based on pre‐selection for low MGMT expression was associated with a higher response rate to temozolomide compared to previous reports of unselected patients.