Cytogenetics, Not Just Previous Therapy, Determines the Course of Therapy-Related Myeloid Neoplasms

Therapy-related myeloid neoplasm (t-MN) is the term recently proposed by the World Health Organization to cover the spectrum of malignant disorders that were previously described as therapy-related myelodysplastic syndromes (t-MDSs) or acute myeloid leukemia (tAML). t-MN is a well-recognized clinical syndrome that occurs as a late complication after cytotoxic therapy. Currently comprising 15% to 20% of all cases of AML, the incidence of t-MN is rising as a result of increasing numbers of survivors of cancer who are at risk, and changes in treatment regimens. The term therapy-related leukemia is descriptive and is based on a patient’s history of exposure. Although a causal relationship is implied, the mechanism remains to be proven. These neoplasms are thought to be the direct consequence of mutational events that are induced by cytotoxic therapy, or to arise via the selection of a myeloid clone with a mutator phenotype that has a markedly elevated risk for mutational events. Several distinct clinical and cytogenetic subtypes of t-MN are recognized that are closely associated with the nature of the preceding treatment. The latency between primary diagnosis and therapyrelated disease ranges from a few months to more than 10 years, depending in part on the cumulative dose or dose-intensity of the preceding therapy as well as the exposure to specific agents. The majority of patients have clonal chromosome abnormalities in bone marrow cells at diagnosis. Although the spectrum of cytogenetic abnormalities in t-MN is similar to that of primary MDSs and de novo AML, the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosome 5 and/or 7, is considerably higher in t-MN. t-MN provides a unique opportunity to examine the effects of mutagens on carcinogenesis in humans as well as the role of genetic susceptibility to cancer. The mechanisms of leukemogenesis that are uncovered in t-MN will likely apply to those subtypes of de novo AML that share the same cytogenetic abnormalities. The etiology and specific predisposing features of t-MN remain elusive because, fortunately, only a small fraction of patients who are exposed to cytotoxic therapy develop the syndrome. It has not yet been possible to determine if the development of t-MN is a stochastic event, occurring by chance, or if certain individuals are at higher risk—perhaps because of a DNA-repair deficiency or a heritable predisposition such as altered drug metabolism. The identification of such an underlying preexisting condition would facilitate the screening and counseling of patients before treatment for their primary disease. Two distinct groups of patients with t-MN have been described. The more common subtype of t-MN, seen in approximately 75% of patients, typically occurs 5 to 7 years after first exposure to alkylating agents or radiation, is often preceded by MDS, and is frequently accompanied by clonal cytogenetic abnormalities such as loss of all or part of chromosomes 5 or 7. Mutations of the P53 tumor suppressor gene are also common. The risk is related to total cumulative exposure over time to alkylating agents and seems to be higher in those who have also received radiation therapy (RT), that is, combined-modality therapy (CMT). In contrast, some individuals develop t-AML after treatment with topoisomerase II inhibitors. Their latency period is often only 1 to 3 years, antecedent MDS is rare, and gene rearrangements involving MLL at 11q23 or RUNX1/ AML1 at 21q22 are common. Ionizing radiation, both medical and environmental, has long been associated with the development of secondary malignant neoplasms. High-energy photons cause DNA double-strand breaks. Cells within the high-energy field are killed; those in the penumbra may only be damaged and then incorrectly repaired. In addition, multiple fields from different angles are used to limit the dose that is delivered to normal tissues, but this allows low-energy scatter to a wide area. Bystander and abscopal effects may participate in mutagenesis. Finally, stray radiation that leaks through the accelerator housing and multiple computed tomography scans used for treatment planning contribute to the total body dose. How leukemogenic is modern radiation therapy? In the article that accompanies this editorial, Nardi et al at the Massachusetts General Hospital and the MD Anderson Cancer Center compare clinical characteristics and outcomes among 47 patients who developed t-MN after RT alone, 181 patients who developed t-MN after chemotherapy or CMT, and 222 patients who presented with primary MDSs or de novo AML. On the basis of their observations, the authors propose that myeloid neoplasms that occur after RT alone should not be classified together with t-MN because the features of the small cohort that they studied were more similar to those of their de novo leukemia group than to the characteristics of the patients with t-MN who had received chemotherapy or CMT. However, if one examines the cytogenetic features of these three groups, the explanation for their findings becomes clear. The proportion of patients with normal karyotypes was 43% in the RT-only group and 45% in the de novo leukemia group, but only 14% in the chemotherapy/CMT group. In contrast, deletions or loss of chromosomes 5 and/or 7 were observed JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 19 JULY 1 2012