Etoposide Sensitivity Does Not Predict MLL Rearrangements or Risk of Therapy-Related Acute Myeloid Leukemia.

Therapy-related acute myeloid leukemia (t-AML) can arise from topoisomerase II-directed agents such as etoposide and teniposide, most likely via drug-induced MLL gene fusions. MLL cleavage in its breakpoint cluster region has been linked to apoptosis caused by etoposide and other agents. It has been speculated that the degree of myelotoxicity caused by agents such as etoposide may predispose to t-AML. However, whether drug-induced MLL rearrangements (rMLL) and subsequent leukemogenesis are inextricably linked to the desired drug-induced cytotoxic effects remains a matter of uncertainty. To directly address this question, we compared rMLL in blood samples from and epipodophyllotoxin-related clinical toxicity in children with acute lymphoblastic leukemia (ALL) who did and did not develop t-AML, as well as the level of rMLL in cell lines that were sensitive or resistant to etoposide. In 7 t-AML cases and 7 identically-treated matched controls, rMLL were detectable following etoposide treatment in both cohorts, but at a slightly greater frequency in the former group (P = 0.04, Wilcoxon signed-rank test). However, there was no correlation between the cumulative etoposide dose and the degree of rearrangements (P = 0.5, r2=0.039, Spearman rank correlation). Secondly, etoposide or teniposide-related acute toxicities to the host tissues did not differ between the 14 t-AML cases and the 14 matched controls. The drug-induced reduction in neutrophil and leukocyte counts was not greater among t-AML cases than controls (P>0.17, Wilcoxon signed-rank test), nor was the incidence of infection and gastrointestinal toxicity during epipodophyllotoxin treatment (P>0.22, McNemar’s test). Finally, in 25 human lymphoid cell lines, MLL fusions were more common after etoposide treatment (at equitoxic concentrations) compared to untreated controls (P < 0.0001, paired t test) but did not differ in frequency in etoposide-sensitive versus resistant cell lines (P = 0.91, Mann-Whitney U test). Together, these data indicate that epipodophyllotoxin-mediated leukemogenesis is not directly linked to the cytotoxicity of these agents.