19. Myelodysplasia and Acute Leukemia
Myelodysplastic syndromes (MDSs) and acute myeloid leukemia (AML) are clonal hematopoietic disorders associated with cytopenias, defective marrow maturation, and, ultimately, unregulated blast proliferation. Many cases of MDS evolve into AML, and although the two diseases are distinct, they share a continuous spectrum.
The majority of MDS and AML cases are idiopathic, but exposure to toxins and radiation can increase risk. Drugs can also induce MDS [85, 86]. Alkylating agents (such as nitrogen mustard, cyclophosphamide, melphalan, busuflan, chlorambucil) are the most frequently cited perpetrators. Risk has been related to total dose, duration, and specific type of alkylating agent. Procarbazine and nitrosoureas are also associated with myelodysplasia and leukemia. There can be a latent period of 2–8 years prior to development of t-MDS or AML. Leukemia induced by these agents is commonly preceded by a myelodysplastic syndrome. These leukemias are typically FAB M1 or M2 morphologically. Complex chromosomal abnormalities are typical, commonly with deletions of chromosome 5 and 7 and trisomy 8.
A distinct syndrome of secondary leukemia is related to topoisomerase II inhibitors, which includes the epipodophyllotoxins (etoposide and teniposide), anthracyclines (daunomycin, epirubicin, and doxorubicin.), and mitoxantrone. Leukemia with these agents has a shorter latency period than that associated with alkylating agents, often less than 2 years and usually presents without a prior MDS. Morphologically, acute myelomonocytic leukemias with a karyotypic abnormality involving 11q23 are commonly seen.
Treatment-related acute promyelocytic leukemia has also been described, most commonly in association with topo II inhibitors [87]. These also have a relatively short latency from treatment without a preceding preleukemic phase. Like de novo APL, t(15;17) with PML-RAR alpha rearrangements are common. Treatment outcomes are relatively favorable when treated like de novo APL, unlike the poor prognosis seen in other t-AML types.
In patients receiving adjuvant chemotherapy for breast cancer, the risk of acute leukemia increases with age, with the intensity of therapy, and with the use of breast radiotherapy [88]. Many of these patients have received both alkylating agents and anthracyclines, both of which are leukemogenic. In addition, an increased risk of AML has been noted in breast cancer patients who received G-CSF along with adjuvant chemotherapy in some [89] but not all studies [90].
Stem cell transplantation, used in high risk, relapsed, and refractory hematologic malignancies, is associated with a risk of secondary MDS and leukemia. Whether the disease is induced by pretransplant therapy or the transplant itself remains uncertain.
Radioimmunotherapy, developed for non-Hodgkins lymphoma, may be associated with some risk of leukemogenesis. However, as with transplant patients, some of the risk may be related to stem cell damage from prior treatments or perhaps an increased risk related to the underlying disease itself. Small numbers of patients treated with radioimmunotherapy alone have shown a seemingly low risk for leukemia [93].