1Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.
2Department of Infectious Disease, Chonnam National University Hwasun Hospital, Hwasun, Korea.
3The Brain Korea 21 Project, Center for Biomedical Human Resources at Chonnam National University, Gwangju, Korea.
Bortezomib administration leads to a transient decrease in CD4+ T cells, increasing the susceptibility to opportunistic infections. The activation and proliferation of CD4+ T cells are particularly important in the host's defense against tuberculosis infection. The aim of this study was to determine the incidence and clinical significance of tuberculosis infection in patients with multiple myeloma (MM) treated with a bortezomib-containing regimen.
We retrospectively investigated the incidence of
All patients received chemotherapy prior to bortezomib administration, and the median duration from diagnosis to bortezomib administration was 12.4 months (range, 0.2-230). We diagnosed tuberculosis in 8 patients (8/115, 7%): 7 patients had a pulmonary granulomatous lesion prior to chemotherapy and 1 developed reactivation of tuberculosis, but none of them died of uncontrolled tuberculosis infection. In 50% of patients with tuberculosis, bortezomib-containing therapy was interrupted. This resulted in significantly lower response rates to the bortezomib-containing therapy (
Tuberculosis infection was not uncommon among the patients with MM who were treated with bortezomib-containing therapy, and tuberculosis infection in these patients resulted in an interruption of bortezomib administration, which significantly affected patient outcomes. Therefore, early diagnosis and treatment of tuberculosis infection are critical to avoid worsening outcomes in such patients.
Tuberculosis (TB), caused by an infection of
Bortezomib is a proteasome inhibitor and one of the novel agents used in the treatment of MM. Bortezomib is known to induce apoptosis in rapidly proliferating and neoplastic cells, and a recent study showed that bortezomib prevents the activation of nuclear factor (NF)-kappa B. This leads to the inhibition of T-cell activation, including that of CD4+ T cells, which fulfill essential immune functions [5, 6]. Activation and proliferation of CD4+ T cells are crucial to the host's defense against TB infection ; thus, the suppression of T-cell immunity resulting from bortezomib-containing treatments potentially increases the risk of TB in MM patients . The aim of our study was to investigate the incidence of TB in MM patients treated with a bortezomib-containing regimen.
We retrospectively investigated the incidence of TB infection in 115 patients diagnosed with MM, who were treated with bortezomib-containing salvage chemotherapy between November 2004 and July 2010. Eighty-two patients received treatment with bortezomib (1.3 mg/m2 i.v. on days 1, 4, 8, and 11), cyclophosphamide (150 mg/m2 orally on days 1-4), thalidomide (50-100 mg/day orally every day), and dexamethasone (20 mg/m2 i.v. on days 1, 4, 8, and 11 every 3 weeks) (Vel-CTD), while 33 patients were given Vel-CD; Vel-CD is similar to Vel-CTD but does not contain thalidomide . We retrospectively reviewed the medical records, including the clinical history, chest radiographs, and computed tomography (CT) scans prior to bortezomib-containing chemotherapy to assess evidence of previous TB infection and possible reactivation of the disease in the patients. TB was diagnosed on the basis of respiratory symptoms, chest CT scans, sputum
Categorical data and continuous variables were assessed using Fisher's exact and the Mann-Whitney
The median age of patients was 63 years (range, 39-82 years). All patients received chemotherapy prior to the initiation of a bortezomib-containing regimen, and the median number of prior regimens was 1 (range, 1-4). Patients received a median of 8 (range, 1-22) cycles of bortezomib-containing salvage chemotherapy. The median duration from diagnosis of MM to the bortezomib-containing chemotherapy was 12.4 months (range, 0.2-230 months), and 24% of patients previously received autologous stem cell transplantation (Table 1). Neither interferon-γ release assay (IGRAs) nor TB skin test was performed prior to the initiation of bortezomib-containing therapy. All patients were routinely evaluated for TB infection using simple chest radiography at the start of bortezomib-containing salvage chemotherapy, and 13 (11.3%) of the 115 patients underwent chest CT for the evaluation of associated lung abnormalities. One patient was diagnosed with active pulmonary TB prior to receiving bortezomib-containing chemotherapy, while 8 (7%) of 115 patients were diagnosed with TB infection during bortezomib-containing treatment (Table 1). The median duration from the start of bortezomib-containing treatment to the confirmed diagnosis was 58 days (range, 7-247 days). In all the patients who were diagnosed with TB during bortezomib-containing treatment, pulmonary infiltration was detected using chest CT. In 5 of these patients, TB infection was documented through sputum culture and in 1 patient, through sputum acid-fast bacillus microscopy. Two patients were diagnosed without bacteriologic confirmation because it was not possible to perform bronchoscopic evaluation due to grade 4 asthenia; nevertheless, the typical characteristics of TB on CT, such as bronchiectasis and centrilobular nodules with branching linear structures (tree-in-bud opacities) were observed. In addition, clinical symptoms were consistent with TB, and these patients did not have evidence of other non-TB diseases. Seven of the 115 patients showed signs of previous pulmonary granulomatous lesions at diagnosis of MM, but only 1 patient experienced reactivation of TB during bortezomib treatment. The baseline characteristics of patients enrolled in the study are reported in Table 1.
There was no statistical difference in age, performance status, paraprotein subtype, stage at the start of bortezomib-containing chemotherapy, and prior treatment between patients with (TB+) or without TB infection (TB-). The male gender was more frequently associated with TB+ (
The treatment outcomes of novel agents for MM are promising, but these therapies are thought to have specific toxicities that differ from traditionally used agents. Bortezomib is known to have important adverse effects, including peripheral neuropathy, myelosuppression, and gastrointestinal disturbances. Heider et al.  reported a decline of CD4+ T cells in 77% of MM patients who were treated with bortezomib. In addition, the median CD4+ lymphocyte count significantly declined in all patients. Considering these results, the occurrence of herpes zoster in patients with MM treated with bortezomib could be explained by the decline in CD4+ counts. The effect of bortezomib treatment could potentially also influence the susceptibility of these patients to infections associated with low CD4+ T cells, such as
A limitation of our study was that bortezomib was administered in combination with other agents, and these agents may well have influenced patients' susceptibility to TB infection. Bortezomib was given in combination with thalidomide. Thalidomide is considered an adjuvant treatment for TB in some studies [11, 12], because it co-stimulates T lymphocytes and is thought to have a greater effect on CD8+ than on CD4+ T cells . Bortezomib was also used with other immunosuppressant agents, specifically cyclophosphamide and dexamethasone. In this study, patients received low-dose cyclophosphamide (150 mg/m2 on days 1-4, every cycle). A previous study showed that low-dose cyclophosphamide selectively depletes CD4+CD25+ T cells . Steroids are known to be an independent risk factor, and patients receiving a daily dose of ≥15 mg of corticosteroid for ≥1 month had an increased risk of developing TB . To identify the influence of bortezomib on patients' susceptibility to TB infection, a direct comparison between patients who receive bortezomib and patients who receive steroid-containing salvage chemotherapy minus bortezomib is required .
In our study, 4 (50%) of the patients diagnosed with active pulmonary TB had interrupted consecutive treatment with bortezomib-containing regimens because of severe asthenia. This caused poor prognosis in all patients, even though 3 of the 4 patients showed a partial response to bortezomib-containing treatment at diagnosis with active pulmonary TB. In 2 patients, consecutive treatment of the bortezomib-containing regimen was interrupted for more than 5 weeks because of anti-TB treatment, and these patients showed disease progression within 5 months after initiation of an anti-TB regimen. The remaining 2 patients received continuous treatment for MM, and they were alive at the last follow-up. Patients with TB tended to receive fewer cycles of chemotherapy and lower bortezomib cumulative dosages compared with patients without TB, although statistical significance was not reached. We speculate that fewer cycles of chemotherapy and lower bortezomib cumulative dosages would affect best response rates and survival in MM patients with TB. Our findings emphasize that effective screening and early diagnosis for pulmonary TB infection are important in the treatment of MM patients. We propose that chest radiography screening should be performed prior to bortezomib treatment for the detection of healed or active pulmonary TB lesions. Even though skin testing with purified protein derivative of tuberculin (TST) is widely used to screen latent
Overall survival analyses in multiple myeloma patients with or without tuberculosis infection during bortezomib-containing chemotherapy (