1. ¹Department of Hematology, Hadassah Hospital, Jerusalem, Israel
2. ²Department of Medicine, Hadassah Hospital, Jerusalem, Israel
3. ³Hebrew University-Hadassah Medical School, Ein Kerem, Jerusalem, Israel
4. ⁴Department of Human Genetics, Hadassah Hospital, Jerusalem, Israel

Correspondence: Professor D Rund, Deparment of Hematology, Hadassah University Hospital, Ein Kerem, Jerusalem IL91120, Israel. Fax: +972 2 6423067; E-mail: rund@cc.huji.ac.il

Received 12 April 2005; Accepted 3 August 2005; Published online 15 September 2005.

Abstract

Therapy-related leukemia or myelodysplasia (t-leuk/MDS) is a serious problem that is increasing in frequency. We studied the clinical characteristics of 96 patients (pts) with a mean age of 48 years, and analyzed the molecular parameters that could predispose to t-leuk/MDS. Hematological malignancies were the most common primary (53%), followed by breast and ovarian cancer (30% combined). The mean latency until the development of t-AML was 45.5 months. Median survival was 10 months. Cytogenetics was abnormal in 89% of pts. FLT3 internal tandem duplications were found in six of 41 (14.6%) pts, of whom four had an abnormal karyotype. Analysis of drug metabolism and disposition genes showed a protective effect of the CYP3A4 1^*B genotype against the development of t-leuk/MDS, whereas the CC genotype of MDR1 C3435T and the NAD(P)H:quinone oxidoreductase1 codon 187 polymorphism were both noncontributory. Microsatellite instability (MSI) analysis using fluoresceinated PCR with ABI sequence analyzer demonstrated that 41% of pts had high levels of MSI in four or more of 10 microsatellite loci. Immunohistochemistry demonstrated reduced expression of MSH2 and MLH1 in 6/10 pts with MSI as compared to 0/5 of pts without MSI. In conclusion, genetic predisposition as well as epigenetic events contribute to the etiology of t-AML/MDS.