The risks of chemotherapy-related acute myeloid leukemia have changed significantly over the last 30 years, increasing in people treated for non-Hodgkin’s lymphoma and decreasing in people treated for ovarian cancer and myeloma.

Further, treatment-associated acute myeloid leukemia (t-AML) has increased since 2000 in people treated for esophageal, prostate, and cervical cancers, and in those treated since the 1990s for bone and joint cancers and endometrial cancers, reported Lindsay Morton, Ph.D., and her associates online Feb. 14 in Blood (2013 Feb. 14 [doi: 10.1182/blood-2012-08-448068]).

The incidence of t-AML is likely to increase because more patients have been treated with cytotoxic agents over the last 10 years, wrote Dr. Morton, of the division of Cancer Epidemiology and Genetics at the National Cancer Institute, and her colleagues. More research is needed "to evaluate the leukemogenicity of new targeted and immunomodulatory agents introduced into the clinic, and increasing use of (neo) adjuvant and maintenance therapies," they said.

"It will be interesting to evaluate the role of a patient’s genetic susceptibility to treatment-related leukemia," Dr. Morton said in a press release. "If certain inherited traits predispose patients to a second malignancy as a result of treatment, clinicians could more accurately weigh the risk of leukemia against the established benefits of chemotherapy."

The researchers based their conclusions on cancer registry data from nine Surveillance, Epidemiology, and End Results (SEER) registries for more than 400,000 adults treated from 1975 to 2008 with chemotherapy for their first primary malignancy. Despite major changes in cancer treatments, no large published study has attempted to quantify the risks of AML after chemotherapy for different types of primary malignancies in adults since 1984, they pointed out.

No data on specific drugs and doses were available in the SEER registries, but "our results are consistent with changing treatment practices and differential leukemogenicity of specific treatments, with increasing t-AML risks after chemotherapy likely associated with increasing use of (neo) adjuvant therapy, multiple courses of therapy, duration/intensity of treatment, and newly introduced agents," the authors said.

Among the 426,068 patients treated between 1975 and 2008, 801 subsequently developed AML. That rate is 4.7 times higher than the 170.5 cases expected for the general population. The risks of t-AML during this time were "especially pronounced" among those treated for cancers of the bone/joints (19.25 times greater risk than the general population), soft tissue (14.41), ovary (8.68), lung (6.82), non-Hodgkin’s lymphoma (16.65), and myeloma (10.43).

The "striking changes" in the risk in t-AML after initial treatment for non-Hodgkin’s lymphoma "may be explained by more widespread use of subsequent therapy for persistent or relapsed/refractory non-Hodgkin’s lymphoma," they wrote.

The risk of t-AML after chemotherapy for ovarian cancer and myeloma dropped significantly over time. The risk associated with lung cancer treatment also declined, but the drop was not statistically significant. The drop in t-AML associated with treatment for ovarian cancer is "consistent" with the shift from the alkylating agent melphalan to platinum-based chemotherapy in the early 1980s, the authors said. The drop in t-AML in myeloma patients may be due to decreases in the dose and/or length of treatment with melphalan. A possible drop in t-AML associated with lung cancer may reflect "modest advances in treatment," they added.

The risk of t-AML was significantly increased among patients treated during 1999-2008 for cancers of the esophagus, anus, cervix, and prostate, although this conclusion was based on small numbers.

For breast cancer, the risks was greatest during 1975-1978 and significantly lower in the 1980s, with a nonsignificant increase in the 1990s, reflecting the higher t-AML risk that is "concentrated in the initial years" after a diagnosis of breast cancer.

The risks were not significantly higher for cancers of the stomach, colon, and rectum.

The study was supported by the Intramural Program of the National Cancer Institute. Dr. Morton’s coauthors were from the NCI, the Veterans Affairs Medical Center in Oklahoma City, and the department of pediatrics at the University of Chicago. The authors had no disclosures.

Commentary: Could transplants account for the increase?

Dr. Steven Coutré comments: While interesting, this report provides little insight into possible reasons for an observed increase in treatment-associated acute myeloid leukemia. As the authors point out, t-AML has declined in patients treated for ovarian cancer, likely due to a change in the standard chemotherapy used. For non-Hodgkin’s lymphoma, one would like to know if there has been a similar change in treatment, in the opposite direction, that accounts for an increase in t-AML. Is there a greater use of transplant, which is known to be associated with t-AML? Have these patients been treated more intensively with alkylator-based regimens?

Dr. Coutré is associate professor, division of hematology, and director of the hematology clinic at Stanford (Calif.) University. He had no disclosures.

e.mechcatie@elsevier.com

Treatment-related AML rises in non-Hodgkin's lymphoma