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

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.

Figure.. Frequency of Medicare Claims for Classes of Chemotherapeutic Agents in Initial Chemotherapy for Patients Diagnosed During 2012-2013, Surveillance, Epidemiology, and End Results (SEER)-Medicare Linked Data

Frequencies were calculated among older adults (aged 66-84 years) who were diagnosed with first primary solid cancer, survived 1 or more years, and received initial chemotherapy, 2012-2013 SEER-Medicare linked data. We ascertained Medicare claims for parenterally administered initial chemotherapy (<12 months following cancer diagnosis), focusing on known leukemogenic agents (alkylating agents, platinum compounds, and topoisomerase II inhibitors; claims codes provided in eTable 4 in the Supplement). SEER-Medicare incompletely captures orally administered agents (eg, cyclophosphamide, temozolomide). “Other specified only” includes any agent listed in eTable 4 in the Supplement other than known leukemogenic agents. eFigure 2 in the Supplement shows trends across the full study period, 2000-2013. eTable 11 in the Supplement provides frequency of claims for specific agents and frequency of unspecified chemotherapy. Additional details regarding SEER-Medicare data also are provided in the eMethods in the Supplement. CNS indicates central nervous system.