Maintenance Treatment with Azacytidine for Patients with High Risk Myelodysplastic Syndromes or Acute Myeloid Leukaemia in Complete Remission after Intensive Chemotherapy.

Blood - Tập 110 - Trang 818 - 2007
Michael Grövdal1, Rasheed Khan1, Anni Aggerholm2, Petar Antunovic3, Jan Astermark4, Per Bernell5, Lena-Maria Engström6, Lars Kjeldsen7, Olle Linder8, Lars Nilsson9, Anna Olsson10, Jonas Wallvik11, Jon Magnus Tangen12, Gunnar Öberg13, Sten Eirik Jacobsen9, Peter Hokland2, Anna Porwit14, Eva Hellström-Lindberg1
1Medicine/Haematology, Karolinska Institutet/Karolinska University Hospital Huddinge, Stockholm, Sweden
2Haematology, Aarhus University Hospital, Aarhus, Denmark
3Haematology, Linköping University Hospital, Linköping, Sweden
4Haematology and Coagulation Disorders, Malmö University Hospital, Malmö, Sweden
5Medicine/Haematology, Karolinska University Hospital Solna, Stockholm, Sweden
6Medicine/Haematology, University Hospital of Norrland (NUS), Umeå, Sweden
7Haematology, Rigshospitalet, Copenhagen, Denmark
8Medicine, Örebro University Hospital, Örebro, Sweden
9Haematolopoietic Stem Cell Laboratory and Haematology, Lund University Hospital, Lund, Sweden
10Haematology, Sahlgrenska University Hospital, Göteborg, Sweden
11Medicine/Haematology, Sundsvall Hospital, Sundsvall, Sweden
12Haematolygy, Ullevål University Hospital, Oslo, Norway
13Haematolgy, Uppsala Academic Hospital, Uppsala, Sweden
14Pathology, Radiumhemmet/Karolinska University Hospital Solna, Stockholm, Sweden

Tóm tắt

Abstract Patients with high-risk myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) secondary to MDS may reach complete remission (CR) following intensive chemotherapy but the CR-duration is usually very short. Promoter hypermethylation of e.g. tumour suppressor genes is considered to be important in cancerogenesis and a negative risk factor for survival in patients with MDS. We designed a prospective clinical trial to assess the impact of methylation status on the outcome of induction chemotherapy and to evaluate the effect of maintenance treatment with 5-azacytidine (aza) on CR duration. Sixty patients with a median age of 68 years (54–83) with high risk MDS (n=23) or AML (n=37) following MDS were treated with standard doses of daunorubicin and ara-C. Standard prognostic variables, and methylation status of the P15ink4b (P15), E-cadherin (CDH) and Hypermethylated in Cancer 1 (HIC) genes were analyzed before treatment. Patients in CR were given low dose aza subcutaneously for 5 days/4 weeks until relapse. The CR rate was 40%; significantly lower in patients with high white blood cell counts (P=0.03) and high CD34 expression on bone marrow cells (P=0.02). While P15 status alone was not associated with CR rate (P=0.25) patients with CDH methylation showed a lower CR rate (P=0.008). Moreover, no patient with hypermethylation of all three genes achieved CR (P=0.03). CDH methylation retained its prognostic value in the multivariate analysis. Hypermethylation was associated with increased CD34 expression but not with blast count or cytogenetic risk group. Median duration of CR was 13 months (2 to +37) and 7/ 23 patients (30%) had a CR duration >20 months. Three of four patients with trisomy 8 had CR >20 months. The overall survival of patients reaching CR was 17 months (6 to +40). Methylation status before treatment did not correlate with CR duration. We demonstrate for the first time a significant impact of methylation status on the outcome of conventional chemotherapy in high-risk MDS and MDS-AML and propose that this variable should be further evaluated in prospective studies. CR duration is promising, with a substantial portion of patients showing durable responses.

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Blood

Tập 110

818

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