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Laurence Senn, MD; Tibor Kovacsovics, MD; Philip E. Tarr, MD; Pascal Meylan, MD

Arch Intern Med. 2009;169(3):312-313.

Imatinib mesylate, a selective inhibitor of the BCR-ABL tyrosine kinase gene, is now a standard therapy in patients with chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). Recent studies have shown that imatinib alters T-cell–mediated immune responses,^1-4 raising the possibility of opportunistic infections associated with imatinib therapy. So far, few epidemiological data are available to support this hypothesis. We report herein a case of peritoneal tuberculosis (TB) following 4 months of imatinib therapy for CML.

Report of a Case
A 37-year-old Swiss-born man was diagnosed as having BCR-ABL–positive CML, and imatinib mesylate therapy was initiated (400 mg/d). One month later, the imatinib dosage was reduced owing to an elevation in transaminase (3 times the upper limit of normal) and alkaline phosphatase (4 times the upper limit of normal) levels. Serologic test results for human immunodeficiency virus and hepatitis A, B, and C virus were negative, and the abnormal liver test results were attributed to imatinib therapy. Four months later, the imatinib mesylate dosage was again increased to 400 mg/d. One week later, the patient developed abdominal pain, anorexia, and nausea. Abdominal computed tomography revealed ascites, hepatosplenomegaly, and diffuse infiltration of mesenteric fat. An analysis of ascitic fluid revealed a white blood cell count of 1100/µL (50% lymphocytes) (to convert to x10⁹/L, multiply by 0.001). Standard bacterial cultures remained sterile. Findings from a Ziehl-Neelsen stain and mycobacterial culture were negative for organisms. Imatinib therapy was discontinued. Exploratory laparoscopy revealed extensive peritonitis, and peritoneal biopsy specimens demonstrated granulomatous inflammation, with a negative Ziehl-Neelsen stain result but a positive polymerase chain reaction result for Mycobacterium tuberculosis complex and positive cultures for M tuberculosis. The patient had no history of travel to a TB endemic country, prior TB exposure, homelessness, or substance use. A chest radiograph show no abnormalities. The initiation of antituberculous therapy was followed by clinical improvement. Imatinib therapy was not restarted because of a concern for pharmacological interaction with rifampin. After 6 months of antituberculous therapy, the patient underwent a hemopoietic stem cell transplantation without further infectious complications.

At the time of TB diagnosis, 1 month after imatinib therapy discontinuation, there was global lymphopenia (CD3⁺, CD4⁺, and CD8⁺ cells: 190 [76% {percentage of total lymphocytes}], 155 [62%], and 39 [16%] cells/µL, respectively) and no evidence of blast transformation of CML. After 2 months of antituberculous therapy, lymphopenia was still present but less pronounced (CD3⁺, CD4⁺, and CD8⁺ cells: 846 [92%], 619 [67%], and 222 [24%] cells/µL, respectively).

Comment
To our knowledge, this is the second report of TB reactivation in association with imatinib therapy. The incidence of TB in Switzerland is low (<10 per 100 000 population per year), and the patient had no history of TB exposure. Global lymphopenia might have facilitated TB reactivation, but TB itself may induce transient lymphopenia.⁵ In fact, lymphocyte counts rose to subnormal levels after the initiation of antituberculous therapy. The increased incidence of herpes zoster⁶ and previous cases of pulmonary nocardiosis,⁷ pulmonary TB,⁸ and fungal pneumonia⁹ raise the possibility of opportunistic infections associated with imatinib therapy, but more data are needed. It might be prudent to investigate the presence of latent TB (by purified protein derivative skin testing or interferon- release assay) before the initiation of imatinib therapy.

AUTHOR INFORMATION
Correspondence: Dr Senn, Infectious Diseases Service, Department of Medicine, Centre Hospitalier Universitaire Vaudois (CHUV) and University of Lausanne, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland (Laurence.Senn{at}chuv.ch).

Author Contributions: Study concept and design: Senn. Acquisition of data: Senn and Kovacsovics. Analysis and interpretation of data: Senn, Tarr, and Meylan. Drafting of the manuscript: Senn. Critical revision of the manuscript for important intellectual content: Kovacsovics, Tarr, and Meylan. Study supervision: Kovacsovics, Tarr, and Meylan.

Financial Disclosure: None reported.

REFERENCES
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