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Negative Effect of DNA Hypermethylation on the Outcome of Intensive Chemotherapy in Older Patients with High-Risk Myelodysplastic Syndromes and Acute Myeloid Leukemia following Myelodysplastic Syndrome

Authors' Affiliations: ¹ Division of Haematology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge; ² Division of Haematology, Department of Medicine and ³ Department of Pathology, Radiumhemmet, Karolinska University Hospital, Solna, Stockholm, Sweden; ⁴ Department of Haematology, Aarhus University Hospital, Aarhus, Denmark; ⁵ Department of Haematology, Linköping University Hospital, Linköping, Sweden; ⁶ Department for Haematology and Coagulation Disorders, Malmö University Hospital, Malmö, Sweden; ⁷ Medical Clinic, Department of Haematology, University Hospital of Norrland, Umeå, Sweden; ⁸ Department of Haematology, Rigshospitalet, Copenhagen, Denmark; ⁹ Department of Medicine, Örebro University Hospital, Örebro, Sweden; ¹⁰ Haematopoietic Stem Cell Laboratory and Department of Haematology, Lund University Hospital, Lund, Sweden; ¹¹ Department of Haematology, Sahlgrenska University Hospital, Göteborg, Sweden; ¹² Division of Haematology, Department of Medicine, Sundsvall Hospital, Sundsvall, Sweden; ¹³ Department of Haematology, Ullevål University Hospital, Oslo, Norway; and ¹⁴ Department of Haematology, Uppsala Academic Hospital, Uppsala, Sweden

Requests for reprints: Eva Hellström-Lindberg, Department of Medicine, Division of Haematology, Karolinska University Hospital, Karolinska Institutet, Huddinge, SE-141 86 Stockholm, Sweden. Phone: 46-8-58582506; Fax: 46-8-7748725; E-mail: eva.hellstrom-lindberg{at}ki.se.

Purpose: Promoter hypermethylation of, for example, tumor-suppressor genes, is considered to be an important step in cancerogenesis and a negative risk factor for survival in patients with myelodysplastic syndromes (MDS); however, its role for response to therapy has not been determined. This study was designed to assess the effect of methylation status on the outcome of conventional induction chemotherapy.

Experimental Design: Sixty patients with high-risk MDS or acute myeloid leukemia following MDS were treated with standard doses of daunorubicin and 1-β-D-arabinofuranosylcytosine. Standard prognostic variables and methylation status of the P15^ink4b (P15), E-cadherin (CDH), and hypermethylated in cancer 1 (HIC) genes were analyzed before treatment.

Results: Forty percent of the patients achieved complete remission (CR). CR rate was lower in patients with high WBC counts (P = 0.03) and high CD34 expression on bone marrow cells (P = 0.02). Whereas P15 status alone was not significantly associated with CR rate (P = 0.25), no patient with hypermethylation of all three genes achieved CR (P = 0.03). Moreover, patients with CDH methylation showed a significantly lower CR rate (P = 0.008), and CDH methylation retained its prognostic value also in the multivariate analysis. Hypermethylation was associated with increased CD34 expression, but not with other known predictive factors for response, such as cytogenetic profile.

Conclusions: We show for the first time a significant effect of methylation status on the outcome of conventional chemotherapy in high-risk MDS and acute myelogenous leukemia following MDS. Provided confirmed in an independent study, our results should be used as a basis for therapeutic decision-making in this patient group.