Association of Therapy for Autoimmune Disease With Myelodysplastic Syndromes and Acute Myeloid Leukemia.
OBJECTIVE
Therapy-related myeloid neoplasms are a potentially life-threatening consequence of treatment for autoimmune disease (AID) and an emerging clinical phenomenon.


OBJECTIVE
To query the association of cytotoxic, anti-inflammatory, and immunomodulating agents to treat patients with AID with the risk for developing myeloid neoplasm.


METHODS
This retrospective case-control study and medical record review included 40 011 patients with an International Classification of Diseases, Ninth Revision, coded diagnosis of primary AID who were seen at 2 centers from January 1, 2004, to December 31, 2014; of these, 311 patients had a concomitant coded diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Eighty-six cases met strict inclusion criteria. A case-control match was performed at a 2:1 ratio.


METHODS
Odds ratio (OR) assessment for AID-directed therapies.


RESULTS
Among the 86 patients who met inclusion criteria (49 men [57%]; 37 women [43%]; mean [SD] age, 72.3 [15.6] years), 55 (64.0%) had MDS, 21 (24.4%) had de novo AML, and 10 (11.6%) had AML and a history of MDS. Rheumatoid arthritis (23 [26.7%]), psoriasis (18 [20.9%]), and systemic lupus erythematosus (12 [14.0%]) were the most common autoimmune profiles. Median time from onset of AID to diagnosis of myeloid neoplasm was 8 (interquartile range, 4-15) years. A total of 57 of 86 cases (66.3%) received a cytotoxic or an immunomodulating agent. In the comparison group of 172 controls (98 men [57.0%]; 74 women [43.0%]; mean [SD] age, 72.7 [13.8] years), 105 (61.0%) received either agent (P = .50). Azathioprine sodium use was observed more frequently in cases (odds ratio [OR], 7.05; 95% CI, 2.35- 21.13; P < .001). Notable but insignificant case cohort use among cytotoxic agents was found for exposure to cyclophosphamide (OR, 3.58; 95% CI, 0.91-14.11) followed by mitoxantrone hydrochloride (OR, 2.73; 95% CI, 0.23-33.0). Methotrexate sodium (OR, 0.60; 95% CI, 0.29-1.22), mercaptopurine (OR, 0.62; 95% CI, 0.15-2.53), and mycophenolate mofetil hydrochloride (OR, 0.66; 95% CI, 0.21-2.03) had favorable ORs that were not statistically significant. No significant association between a specific length of time of exposure to an agent and the drug's category was observed.


CONCLUSIONS
In a large population with primary AID, azathioprine exposure was associated with a 7-fold risk for myeloid neoplasm. The control and case cohorts had similar systemic exposures by agent category. No association was found for anti-tumor necrosis factor agents. Finally, no timeline was found for the association of drug exposure with the incidence in development of myeloid neoplasm.
Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona.
Natalie
N
Ertz-Archambault
Division of Health Sciences Research, Section of Biostatistics, Mayo Clinic, Phoenix, Arizona.
Heidi
H
Kosiorek
Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona.
Gretchen E
GE
Taylor
Department of Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, Arizona.
Katalin
K
Kelemen
Division of Health Sciences Research, Section of Biostatistics, Mayo Clinic, Phoenix, Arizona.
Amylou
A
Dueck
Department of Information Technology, Mayo Clinic, Phoenix, Arizona.
Janna
J
Castro
Division of Planning and Practice Analysis, Mayo Clinic, Phoenix, Arizona.
Robert
R
Marino
Division of Planning and Practice Analysis, Mayo Clinic, Phoenix, Arizona.
Susanne
S
Gauthier
Department of Hematology and Oncology, Mayo Clinic, Rochester, Minnesota.
Laura
L
Finn
Department of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona.
Lisa Z
LZ
Sproat
Department of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona.
Jeanne
J
Palmer
Department of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona.
Ruben A
RA
Mesa
Department of Hematology and Oncology, Mayo Clinic, Rochester, Minnesota.
Aref
A
Al-Kali
Department of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida.
James
J
Foran
Department of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona.
Raoul
R
Tibes
D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D001327:Autoimmune Diseases / Q000188:drug therapy*; D001379:Azathioprine / Q000627:therapeutic use; D016022:Case-Control Studies; D003520:Cyclophosphamide / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015994:Incidence; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology*; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D008942:Mitoxantrone / Q000627:therapeutic use; D009173:Mycophenolic Acid / Q000627:therapeutic use; D009190:Myelodysplastic Syndromes / Q000453:epidemiology*; D016017:Odds Ratio; D011565:Psoriasis / Q000188:drug therapy; D012189:Retrospective Studies; D012307:Risk Factors; D014481:United States / Q000453:epidemiology
D007166:Immunosuppressive Agents; D003520:Cyclophosphamide; D008942:Mitoxantrone; D015122:Mercaptopurine; D009173:Mycophenolic Acid; D001379:Azathioprine; D008727:Methotrexate