Therapy-related leukemia: Clinical characteristics and analysis of new molecular risk factors in 96 adult patients

D. Rund*, S. Krichevsky, S. Bar-Cohen, N. Goldschmidt, M. Kedmi, E. Malik, A. Gural, S. Shafran-Tikva, S. Ben-Neriah, D. Ben-Yehuda

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

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.

Original languageAmerican English
Pages (from-to)1919-1928
Number of pages10
JournalLeukemia
Volume19
Issue number11
DOIs
StatePublished - Nov 2005
Externally publishedYes

Bibliographical note

Funding Information:
Dr Orly Zelig assisted in performing some of the experiments. We thank Lisa Deutsch for statistical analysis. This work was supported by grant #4600 from the Chief Scientist’s Office, Israel Ministry of Health (to DR), grant number 590/03 from the Israel Science Foundation (to DR), and a grant of the Israel Cancer Association (to DB-Y). We gratefully acknowledge the generous support of the Gabriella Rich Foundation and the Caesaria Edmond Benjamin De Rothchild Foundation.

Keywords

  • ABL oncogene
  • CYP34A
  • MDR1
  • Methylation
  • Microsatellite instability
  • NQO1

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