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

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 n 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.

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

“…Associations have been observed for glutathione S-transferase genes ( GSTM1 , GSTT1 and GSTP1 ), particularly among those with prior exposure to chemotherapeutic agents that are known GSTP1 substrates, 144 and for P-glycoprotein (encoded by MDR1 ), a cell membrane protein that impacts response to numerous chemotherapeutic agents. 145 A number of studies also have evaluated key DNA repair genes, including mismatch repair family members MLH1 146,147 and MSH2 , 148,149 RAD51 , 150 and XRCC3 . 151–153 Other polymorphisms in candidate genes from DNA repair pathways include ERCC2 of the nucleotide excision repair pathway 154 and two common functional p53-pathway variants.…”

Risk stratification using a new prognostic score for patients with secondary acute myeloid leukemia: results of the prospective AML96 trial

“…8 Cytogenetically low-risk sAML patients were excluded, as they accounted for only n ¼ 4. Patients aged p60 years received intravenous double-induction chemotherapy containing cytosine arabinoside (100 mg/m 2 , days 1-8), mitoxantrone (10 mg/m 2 , days [4][5][6][7][8] and etoposide (100 mg/m 2 , days 4-8) ( ¼ MAV) in the first induction and cytosine arabinoside (2 Â 1000 mg/m 2 , days 1-5) and m-AMSA (100 mg/m 2 , days 1-5) ( ¼ MAMAC) during the second induction therapy. Patients with intermediate cytogenetic risk and an HLA-identical sibling donor were referred for allogeneic hematopoietic stem cell transplantation (HSCT).…”

“…5 Mutations induced by cytotoxic therapy, genetic predispositions that affect drug metabolism and DNA repair are implicated in the etiology of tAML. 6 The poor prognosis is based on cytogenetic abnormalities and the comorbidities of the underlying malignancy or acquired during previous cytotoxic therapy. Only 10-15% of the patients with de novo MDS or AML harbor the unbalanced aberrations 5q-/-5 or 7q-/-7, whereas in patients with tMDS or tAML, the incidence rises to 50-60%.…”

Advances in the understanding of susceptibility to treatment‐related acute myeloid leukaemia

“…Worrillow et al (2003) demonstrated that the variant C allele was significantly over-represented in t-AML samples from patients who had previously undergone alkylating treatment with an odds ratio of 4AE02 when compared with controls. MSI The same patients have since been studied using different methodology and a lower degree of MSI was found (Rund et al, 2005). was also shown to occur in 13/34 of t-AML samples and two of these were homozygous for the MSH2 IVS12-6 variant (C) allele.…”