Chemotherapy and Secondary Leukemia

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For more than two decades, secondary leukemia has been linked to alkylating agent therapy [13]. The risk of developing secondary leukemia following treatment with alkylating agents appears to be dose and agent-dependent. MOPP chemotherapy (mechlor-ethamine, vincristine, prednisone and procarbazine) has resulted in cumulative frequencies of secondary leukemia ranging from 3-5% at 7 years, and reaching a plateau of 8% at about 10 years [45]. Substituting cyclophosphamide for mechlorethamine has resulted in a reduced risk [51]. Both mechlorethamine and procarbazine are among the most potent leuke-mogens, with cyclophosphamide probably the least leukemogenic of the alkylators used in pediatrics [9]. Alkylating agent-related secondary leukemia is generally associated with abnormalities, usually deletions, of chromosomes 5 and 7.

Secondary leukemias are also associated with epipodophyllotoxins, which are topoisomerase II inhibitors [13,48]. These leukemias are generally associated with a characteristic abnormality involving 11q23at the MLL gene breakpoint. Secondary leukemia following exposure to epipodophyllotoxins has been linked to the schedule of administration, with the risk being far greater in patients receiving this drug once- or twice-weekly, compared with those receiving the more frequently-used schedules of 3-5 doses per week, given at 3-5 week intervals [54]. Perhaps the frequency of administration determines the ability of any given cell to repair DNA damage before it is subjected to further damage from another dose. Although controversy still exists regarding schedule and dose, a recent report from the French Society of Pediatric Oncology found that risk increased regularly with increasing cumulative doses, the highest risk being in those patients who received >6g/m2 [33]. This cohort was 93 times more likely to develop secondary leukemia than patients who received no epipodophyllotoxins. To further complicate risk assessment, the patients who received the higher cumulative doses were also more likely to have received the drug according to one of the following two schedules: 3 days a week for 3 weeks in a row,with one week off, or 21 consecutive days out of 28. In contrast, patients who received this therapy every 3 weeks, and who received <1.2g/m2 or between 1.2-6g/m2 had a relative risk of zero and 3.9, respectively. Although the latter schedule and doses are most commonly used today, surveillance of children who have received potentially 1eukemogenic therapy is nevertheless warranted.

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