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1.
Cwynarski  KLaylor  RMacchiarulo  E  et al.  Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro. Leukemia 2004;18 (8) 1332- 1339
PubMedArticle
2.
Dietz  ABSouan  LKnutson  GJBulur  PALitzow  MRVuk-Pavlovic  S Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo. Blood 2004;104 (4) 1094- 1099
PubMedArticle
3.
Gao  HLee  BNTalpaz  M  et al.  Imatinib mesylate suppresses cytokine synthesis by activated CD4 T cells of patients with chronic myelogenous leukemia. Leukemia 2005;19 (11) 1905- 1911
PubMedArticle
4.
Sinai  PBerg  REHaynie  JMEgorin  MJIlaria  RL  JrForman  J Imatinib mesylate inhibits antigen-specific memory CD8 T cell responses in vivo. J Immunol 2007;178 (4) 2028- 2037
PubMedArticle
5.
Jones  BEOo  MMTaikwel  EK  et al.  CD4 cell counts in human immunodeficiency virus-negative patients with tuberculosis. Clin Infect Dis 1997;24 (5) 988- 991
PubMedArticle
6.
Mattiuzzi  GNCortes  JETalpaz  M  et al.  Development of Varicella-Zoster virus infection in patients with chronic myelogenous leukemia treated with imatinib mesylate. Clin Cancer Res 2003;9 (3) 976- 980
PubMed
7.
Lin  JTLee  MYHsiao  LT  et al.  Pulmonary nocardiosis in a patient with CML relapse undergoing imatinib therapy after bone marrow transplantation. Ann Hematol 2004;83 (7) 444- 446
PubMedArticle
8.
Takashima  MIgaki  NMatsuda  T  et al.  Malignant gastrointestinal stromal tumor of the small intestine complicated with pulmonary tuberculosis during treatment with imatinib mesylate. Intern Med 2005;44 (2) 114- 119
PubMedArticle
9.
Speletas  MVyzantiadis  TAKalala  F  et al.  Pneumonia caused by Candida krusei and Candida glabrata in a patient with chronic myeloid leukemia receiving imatinib mesylate treatment. Med Mycol 2008;46 (3) 259- 263
PubMedArticle
Research Letters
February 9, 2009

Peritoneal Tuberculosis After Imatinib Therapy

Arch Intern Med. 2009;169(3):312-316. doi:10.1001/archinternmed.2008.581

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,14 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 ×109/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-γ release assay) before the initiation of imatinib therapy.

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Article 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@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
1.
Cwynarski  KLaylor  RMacchiarulo  E  et al.  Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro. Leukemia 2004;18 (8) 1332- 1339
PubMedArticle
2.
Dietz  ABSouan  LKnutson  GJBulur  PALitzow  MRVuk-Pavlovic  S Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo. Blood 2004;104 (4) 1094- 1099
PubMedArticle
3.
Gao  HLee  BNTalpaz  M  et al.  Imatinib mesylate suppresses cytokine synthesis by activated CD4 T cells of patients with chronic myelogenous leukemia. Leukemia 2005;19 (11) 1905- 1911
PubMedArticle
4.
Sinai  PBerg  REHaynie  JMEgorin  MJIlaria  RL  JrForman  J Imatinib mesylate inhibits antigen-specific memory CD8 T cell responses in vivo. J Immunol 2007;178 (4) 2028- 2037
PubMedArticle
5.
Jones  BEOo  MMTaikwel  EK  et al.  CD4 cell counts in human immunodeficiency virus-negative patients with tuberculosis. Clin Infect Dis 1997;24 (5) 988- 991
PubMedArticle
6.
Mattiuzzi  GNCortes  JETalpaz  M  et al.  Development of Varicella-Zoster virus infection in patients with chronic myelogenous leukemia treated with imatinib mesylate. Clin Cancer Res 2003;9 (3) 976- 980
PubMed
7.
Lin  JTLee  MYHsiao  LT  et al.  Pulmonary nocardiosis in a patient with CML relapse undergoing imatinib therapy after bone marrow transplantation. Ann Hematol 2004;83 (7) 444- 446
PubMedArticle
8.
Takashima  MIgaki  NMatsuda  T  et al.  Malignant gastrointestinal stromal tumor of the small intestine complicated with pulmonary tuberculosis during treatment with imatinib mesylate. Intern Med 2005;44 (2) 114- 119
PubMedArticle
9.
Speletas  MVyzantiadis  TAKalala  F  et al.  Pneumonia caused by Candida krusei and Candida glabrata in a patient with chronic myeloid leukemia receiving imatinib mesylate treatment. Med Mycol 2008;46 (3) 259- 263
PubMedArticle
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