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Original Investigation
December 20, 2018

Association of Chemotherapy for Solid Tumors With Development of Therapy-Related Myelodysplastic Syndrome or Acute Myeloid Leukemia in the Modern Era

Author Affiliations
  • 1Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • 2Surveillance Research Program, Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
  • 3Human Genetics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
JAMA Oncol. Published online December 20, 2018. doi:10.1001/jamaoncol.2018.5625
Key Points

Question  What is the association of therapy-related myelodysplastic syndrome or acute myeloid leukemia (tMDS/AML) with chemotherapy for solid cancer in the modern treatment era?

Findings  In this population-based study of 700 612 adults in a US cancer data registry, based on 1619 tMDS/AML cases, the risk of tMDS/AML was significantly increased 1.5-fold to more than 10-fold after chemotherapy for 22 of 23 solid cancer types investigated (all except colon cancer).

Meaning  Although tMDS/AML is rare, gains in solid cancer survival from modern treatment approaches should be balanced against tMDS/AML risks and other chemotherapy-related adverse effects; continued efforts to develop effective agents and cancer treatment approaches with fewer late sequelae are needed.

Abstract

Importance  Therapy-related myelodysplastic syndrome or acute myeloid leukemia (tMDS/AML) is a rare, usually fatal complication of chemotherapy, including certain alkylating agents, topoisomerase II inhibitors, and platinum compounds. With the introduction of new chemotherapeutic agents, expanded indications for established agents, and increased neoadjuvant and adjuvant chemotherapy, tMDS/AML risks in the modern age are poorly understood.

Objectives  To quantify tMDS/AML risk after chemotherapy for solid cancer among United States adults since 2000 and correlate tMDS/AML risk patterns with chemotherapy treatment practices.

Design, Setting, and Participants  A population-based cohort study was conducted using cancer registries from the Surveillance, Epidemiology, and End Results (SEER) Program and Medicare claims. Risk analyses included 1619 tMDS/AML cases among 700 612 adults (age, 20-84 years) who were diagnosed with first primary solid cancer during 2000 to 2013 (followed up through 2014), received initial chemotherapy, and survived 1 year or longer, as reported to SEER. Descriptive analyses were conducted of SEER records linked with Medicare claims for chemotherapy in 165 820 older adults (age, 66-84 years) receiving initial chemotherapy for a first primary solid cancer in 2000-2013. Data analysis was conducted from October 2017 to April 2018.

Exposures  Receipt of initial chemotherapy for solid cancer.

Main Outcomes and Measures  Second primary tMDS/AML.

Results  Based on 1619 tMDS/AML cases in the SEER database (mean [SD] age, 64.3 [12.2] years; 1148 [70.9%] female), tMDS/AML risks were statistically significantly elevated after chemotherapy for 22 of 23 solid cancers (all except colon). Relative risks ranged from 1.5 to greater than 10 and excess absolute risks from 1.4 to greater than 15 cases per 10 000 person-years compared with the general population. Overall survival following tMDS/AML diagnosis was poor (1270 of 1619 patients [78.4%] died; median overall survival, 7 months). For patients treated with chemotherapy at the present time, approximately three-quarters of tMDS/AML cases expected to occur within the next 5 years will be attributable to chemotherapy. In the SEER-Medicare database, use of known leukemogenic agents, particularly platinum compounds, in initial chemotherapy increased substantially since 2000, most notably for gastrointestinal tract cancers (esophagus, stomach, colon, and rectum; 10% in 2000-2001 to 81% during 2012-2013).

Conclusions and Relevance  Large-scale, United States population-based data demonstrate excess tMDS/AML risks following chemotherapy for nearly all solid tumor types, consistent with expanded use of known leukemogenic agents in the 21st century. Continued efforts to reduce treatment-related adverse events, particularly for solid cancer patients with favorable prognosis, are needed.

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