title: 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.
abstract: 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 (CRp). 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/CRp 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.
authors.affiliation: Princess Margaret Hospital, Toronto, ON, Canada.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Brandwein
authors.forename: Jeannine
authors.initials: J
authors.lastname: Kassis
authors.forename: Brian
authors.initials: B
authors.lastname: Leber
authors.forename: Donna
authors.initials: D
authors.lastname: Hogge
authors.forename: Kang
authors.initials: K
authors.lastname: Howson-Jan
authors.forename: Mark D
authors.initials: MD
authors.lastname: Minden
authors.forename: André
authors.initials: A
authors.lastname: Galarneau
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Pouliot
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D015254:DNA Modification Methylases / Q000096:biosynthesis*; D045643:DNA Repair Enzymes / Q000096:biosynthesis*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000201:enzymology / Q000401:mortality; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide
keywords: acute myeloid leukaemia; chemotherapy; drug resistance; myelodysplastic syndrome; temozolomide