Leukemias and myelodysplastic syndromes secondary to drug, radiation, and environmental exposure

Abstract

The median latency of 2 degrees MDS/AL is 4 to 5 years. A high percentage of patients with 2 degrees MDS/AL convert to 2 degrees AL. Survival of either is less than 1 year. A constellation of morphologic abnormalities from all 3 cell lines produces a unique appearance. Both 2 degrees MDS and 2 degrees AL are difficult to classify by the FAB system. With the exception of the identification of karyotypic abnormalities, the biology of 2 degrees MDS/AL remains largely unexplored. Alterations of chromosomes 5 and 7 predominate, but other associated cytogenetic abnormalities are being increasingly recognized. A synthesis of data regarding 2 degrees MDS/AL resulting from the treatment of several primary malignancies generates the tentative conclusions that (a) many of the alkylating agents, and the nonclassic alkylating agent procarbazine, are leukemogens; (b) melphalan is a more potent leukemogen than cyclophosphamide. None of the other alkylating agents has been clearly established to be more or less potent than another; (c) increasing duration or amount of alkylator-based chemotherapy increases the risk of leukemogenesis; (d) low doses of radiation delivered to large volumes of bone marrow are weakly leukemogenic. High doses of radiation delivered to small volumes are not. Due to the latter, there is minimal additive risk for 2 degrees MDS/AL among studies using alkylator-based chemotherapy and radiotherapy, either concurrently or sequentially; (e) the older patient (greater than 40) is at increased risk for 2 degrees MDS/AL, at least in Hodgkin's disease. Children may be at lesser risk than adults, and younger children at lesser risk than older children; (f) the risk of 2 degrees MDS/AL peaks within the first decade after treatment for the primary malignancy. The incidence rates during the second decade are low. Identified occupational/environmental risks for 2 degrees MDS/AL include benzene, ambient and diagnostic radiation exposure, and perhaps ethylene oxide. The similarities in karyotype abnormalities among leukemic cells of those whose occupations expose them to chemical hazard, and those who are exposed to cytotoxic agents, suggest that many more environmental leukemogens have yet to be discovered. Karyotype is an important prognostic factor for both achievement of CR and for survival. Nonaggressive treatment approaches have not proven useful, although the use of hematopoietic growth factors offers promise in this area. Combination chemotherapy is justified in patients with adequate performance statuses and "favorable" karyotypes. Allogeneic bone marrow transplantation is currently the only curative approach, and can be applied without attempts to first reduce the leukemic burden.