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 agents (e.g. etoposide and teniposide), via drug-induced MLL gene fusions. However, whether MLL rearrangements (rMLL) and subsequent leukemogenesis are inextricably linked to the cytotoxic effects of the drug remains controversial. To this end, we compared 1) rMLL in blood of children with acute lymphoblastic leukemia (ALL) who did and did not develop t-AML, 2) epipodophyllotoxin-related toxicity in t-AML cases and controls, and 3) the level of rMLL in cells that were sensitive and resistant to etoposide. In children with ALL, rMLL during etoposide treatment appeared independent of the cumulative dose (P = 0.5), although slightly more frequent in children who developed t-AML than those who did not (7 case-control pairs, P = 0.04). Similarly, the frequency of etoposide- or teniposide-related acute toxicities did not differ between t-AML cases and controls (26 case-control pairs, P>0.17). Finally, in 25 human lymphoblastoid cell lines, MLL fusions were common after equitoxic etoposide treatment vs. controls (P < 0.0001) but did not differ in etoposide-sensitive versus resistant cell lines (P = 0.91). Together, these results indicate that epipodophyllotoxin-mediated leukemogenesis is not directly linked to the cytotoxicity of the drug.