Chemotherapy-Induced T-MDS/AML-Associated Genetic Aberrations.

Abstract Therapy-related solid and hematological neoplasias occur according to the treatment regimen and intensity. The cumulative incidence of therapy related myelodysplastic syndromes and acute myeloid leukemias(t-MDS/AML) ranges between 5 and 15% in non-myeloablative and myeloablative treatment protocols respectively. t-MDS/AML share characteristic genetic aberrations which include translocations (e.g. involving 11q23, MLL and t(9;22), inv 16, t(8;21), t(3;21), t(15;17) and cytogenetic aberrations (e.g. 5q-, 7q-). We have investigated if these genetic aberrations are present in patients who underwent chemotherapy. Since we and others have detected aberrations in aleukemic hematopoiesis (Baesecke et al. Blood. 2002;100:2267–2268) we also wanted to determine if t-MDS/AML early recognition can be performed by this screening. We enrolled patients with Non Hodgkin Lymphoma, either treated by conventional or high dose chemotherapy, included in the MegaChoep protocoll of the German high grade lymphoma study group. Samples were taken as fresh peripheral blood stem cells (PBSCT), bone marrow aspirates (BM) or peripheral blood (PB) after informed consent according to the convention of Helsinki. PBSC of healthy adult donors and cord blood of healthy newborn were used as control. Blood samples were submitted to RT- or Real-Time PCR (sensitivity 10–4 to 10–5) of t(9;22), inv 16, t(8;21), t(15;17) and MLL-partial tandem duplications (MLL-PTD). RNA preparation, reverse transcription, and PCR were performed in separate laboratories. Cytogenetic analysis was performed by FISH (probes EGR1-del5, p53, cep7-del 7, MLL and cep8-tris 8). The results of the ongoing study are as follows. In the cord blood control group, positive samples were t(15;17) 1.7% (1/60 samples), inv 16 5.6% (3/54), t(8;21) 2.8% (1/36), t(9;22) 3.4% (2/59), MLL-PTD primary PCR 0% (0/34). No positive results were observed in PBSC samples of healthy donors (22 samples). 53 samples of patients of which 21 were PBSC and 32 were BM or PB have been investigated so far. 34/53 patients (64.2%) underwent a high dose chemotherapy. In 9.4% (5/53) the translocation t(15;17) was detected. All five samples were PBSC. No amplification of inv 16, t(8;21) and t(9;22) was observed. In FISH analysis two of 18 patient PBSC samples (11%) exhibited aberrations in the p53 locus, which were classified as abnormal but still non-clonal. Our results confirm the existence of AML-associated translocations in cord blood at frequencies, which by far exceed the incidence of AML in healthy individuals. Compared to these findings the incidence of t-AML- associated aberrations in patients who underwent chemotherapy-induced genotoxic stress is lower than expected. Positive PCR-results of this group may thus be more informative concerning the detection of a leukemic clone and the risk of attracting a t-MDS/AML. Positive patients are currently under observation and the number of samples and aberrations in the ongoing study is increased.