A Case of Advanced Urothelial Carcinoma Requiring Treatment Following a Positive Interferon‐Gamma Release Assay Prior to Avelumab Administration

ABSTRACT

Introduction

The association between the risk of latent tuberculosis infection (LTBI) reactivation and immune checkpoint inhibitor (ICI) administration has been reported.

Case Presentation

A man in his seventies underwent robot‐assisted laparoscopic radical cystectomy with ileal conduit diversion for muscle‐invasive bladder cancer. Three years postoperatively, CT revealed metastases to the para‐aortic lymph nodes and rectum. Four cycles of gemcitabine and carboplatin were administered, with CT showing a partial response (PR). Avelumab maintenance therapy was initiated following radiotherapy for the rectal metastasis. Prior to avelumab administration, LTBI was diagnosed based on a positive interferon‐gamma release assay (IGRA). Isoniazid was administered concurrently with avelumab for 6 months. No active tuberculosis developed, and PR was maintained.

Conclusion

IGRA screening is advisable prior to ICI initiation. Prompt and appropriate management is warranted in patients with LTBI.

Summary.

• Screening for latent tuberculosis infection is important prior to immune checkpoint inhibitor initiation.

• Prophylactic treatment should be considered for patients with LTBI receiving immune checkpoint inhibitors.

1. Introduction

Avelumab maintenance therapy has shown efficacy in patients without evidence of disease progression after initial platinum‐based chemotherapy [1]. Avelumab is an immune checkpoint inhibitor (ICI) and a human monoclonal antibody targeting programmed cell death‐ligand 1 (PD‐L1) [2]. However, reports have documented latent tuberculosis infection (LTBI) reactivation associated with ICIs [3].

This report presents a case of LTBI diagnosed and treated following a positive T‐SPOT.TB, an interferon‐gamma release assay (IGRA), prior to avelumab initiation.

2. Case Presentation

A 70‐year‐old man with chronic obstructive pulmonary disease, type 2 diabetes, and chronic kidney disease was referred for left‐sided hydronephrosis detected on abdominal ultrasound. He had no prior history of bladder cancer or intravesical Bacillus Calmette‐Guerin therapy. CT, MRI, and cystoscopy identified muscle‐invasive bladder cancer without metastases (Figure 1).

FIGURE 1.

Computed tomography findings at diagnosis of bladder cancer (arrow). (A) Axial plane. (B) Sagittal plane.

Histopathology of the transurethral resection specimen confirmed muscle‐invasive urothelial carcinoma. Thus, his clinical stage was diagnosed as cT3bN0M0. The patient received four triweekly cycles of gemcitabine (1600 mg) and carboplatin (260 mg), followed by robot‐assisted laparoscopic cystectomy with ileal conduit diversion. Final pathology showed high‐grade urothelial carcinoma, ypT2b, ypN0, INFb, ly1, v0, u‐rt0, u‐lt0, ur0, and RM0.

Three years later, he reported difficulty with defecation. CT revealed metastases to the para‐aortic lymph nodes and rectum (Figure 2). After four triweekly cycles of gemcitabine (1500 mg) and carboplatin (237 mg), CT confirmed PR. Because the evaluation of lymph node metastasis was an almost complete response (Figure 3), avelumab maintenance therapy was prescribed following radiotherapy (50 Gy/25 fractions) to the rectal lesion.

FIGURE 2.

Computed tomography (A,B) and colonoscopy (C) findings at diagnosis of metastasis in para‐aortic lymph nodes (A, arrow) and rectum (B, C, arrow).

FIGURE 3.

Computed tomography findings of metastasis after four cycles of tri‐weekly gemcitabine and carboplatin. (A) Para‐aortic lymph nodes (arrow). (B) Metastasis in rectum (arrow).

In our institution, the T‐SPOT.TB test was conducted in all patients prior to treatment initiation. The screening tests revealed a positive result. Pre‐treatment screening showed a positive T‐SPOT.TB result. Chest radiography and CT showed no lesions suggestive of tuberculosis (TB). The patient had no history of TB treatment. LTBI was diagnosed by the Department of Clinical Infectious Diseases. To rule out active disease, gastric fluid culture and PCR testing for Mycobacterium tuberculosis were performed, both yielding negative results. Avelumab and isoniazid (INH; 300 mg daily) were initiated, along with vitamin B6. INH was continued for 6 months without adverse effects or signs of TB activation. PR was maintained after 14 cycles of avelumab.

3. Discussion

LTBI is a condition in which a patient is infected with M. tuberculosis without exhibiting clinical symptoms of active TB infection. Without treatment and follow‐up, it is estimated that 5%–10% of patients with LTBI develop active TB infection [4]. IGRA is considered useful for diagnosing LTBI. T‐SPOT.TB and QuantiFERON‐TB Gold Plus (QFT) are clinically used as IGRAs [5]. In the QFT test, the total amount of interferon‐gamma released in whole blood stimulated with Mycobacterium group‐specific antigen is measured. In contrast, T‐SPOT.TB measures the number of cells producing interferon‐gamma. QFT has been reported to have higher sensitivity and comparable specificity [6, 7] than T‐SPOT.TB. However, the sensitivity of T‐SPOT.TB was high (96.9%).

Following M. tuberculosis infection, dendritic cells phagocytose bacteria and present antigens to T cells. Subsequently, macrophages are activated by inflammatory cytokines such as interferon‐gamma and tumor necrosis factor‐alpha, forming an extracellular matrix that inhibits M. tuberculosis growth. In the matrix, the expression of programmed cell death‐1 (PD‐1) increases, contributing to T cell apoptosis and controlling excessive immune responses. These reactions are inhibited by ICIs via anti‐PD‐1 effects, leading to excessive inflammation due to T cell overactivation. This inflammation disrupts the extracellular matrix, leading to the reactivation and proliferation of M. tuberculosis [8]. Gene expression profiles in patients with active TB are more similar to those in patients with autoimmune diseases than to those with other infections [9, 10], suggesting that TB may share certain characteristics with autoimmune diseases.

In a study comparing ICIs and tyrosine kinase inhibitors (TKIs) among patients with lung cancer, the incidence of active TB was 2298 and 412 per 100,000 person‐years in the ICI and TKI groups, respectively [3]. According to a previous review [11], only nivolumab and pembrolizumab were identified as ICIs associated with the risk of TB reactivation. However, cases of reactivation following avelumab administration have also been reported [12]. Therefore, avelumab is suspected to carry a risk of TB reactivation due to its anti‐PD‐L1 effect.

Prophylactic treatment is recommended for patients with LTBI who are at high risk of developing active TB infection. Risk factors include HIV infection, dialysis, and the use of immunosuppressive drugs, particularly in post‐transplant patients [13]. Treatment options include INH for 6–9 months, INH with rifapentine once weekly for 3 months, INH with rifapentine for 3 months, and rifapentine for 3–4 months [14]. In this case, the patient was treated with INH for 6 months to reduce the number of drugs administered due to concerns regarding drug interactions with avelumab. These protocols could contribute to reducing the risk of TB reactivation in patients receiving ICIs. Positive IGRA results persist after successful LTBI treatment. Therefore, it is essential to pay attention to the presence of active TB based on imaging evaluations such as CT scans and the presence of symptoms such as coughing.

This case describes a patient with LTBI who was diagnosed and treated based on a positive IGRA result prior to avelumab initiation. Although the relative risk of incidence is high in patients with lung cancer, it is unclear in patients with other solid tumors, especially bladder cancer [15]. Thus, the necessity of the screening tests prior to the administration of ICI or chemotherapy in all patients with bladder cancer remains unclear. However, treatment discontinuation due to active TB infection should be avoided. TB screening before ICI administration is reportedly unnecessary in non‐endemic countries [16] or limited to patients with risk factors, such as diabetes and immunodeficiency [15]. However, it is suitable to consider the screening in all cases due to the moderate TB prevalence in Japan [17].

Further studies are required to demonstrate the effectiveness of the screening and treatment for patients who are receiving ICIs. However, it is necessary to continue the administration of ICIs with attention to the risk of developing active TB.

Consent

Written informed consent was obtained from the patient for publication of this report.

Conflicts of Interest

The authors declare no conflicts of interest.