Unusual outcome of treatment of thymoma with immunotherapy: case report

Introduction

Thymoma is a rare neoplasm arising from the thymic epithelial cell and present with paraneoplastic syndrome in up to 50% of cases (1). Use of immune check point inhibitors (ICIs) is particularly challenging given high incidence of immune-related adverse effects (irAEs) (2). In clinical trials, the utilization of ICI alongside concurrent immunosuppressant therapies is a frequent practice for addressing the paraneoplastic manifestations associated with thymoma. Here we report a case of thymoma associated with paraneoplastic aplastic anemia that exhibited remarkable response to immunotherapy atezolizumab when cyclosporine held. This case highlights the potential efficacy of ICI in treatment of thymoma and suggesting a careful balance between immunosuppression and immunotherapy for optimal patient outcomes. We present this case in accordance with the CARE reporting checklist (available at https://med.amegroups.com/article/view/10.21037/med-24-20/rc).

Case presentation

A 63-year-old female presented with progressive shortness of breath who underwent computed tomography (CT) scan and found to have an anterior mediastinal mass. The patient has a medical history of hypertension and mitral valve regurgitation. Physical exam was negative with exception of decrease air entry at the left upper lung. Positron emission tomography (PET) scan showed mass with invasion of left upper lung, left pericardial and left pleural metastasis i.e., stage IVB thymoma. Blood testing was significant for normocytic anemia with mild thrombocytopenia. Biopsy results revealed a predominant epithelial type, with few immature T lymphocytes. The tumor cells exhibited palisading around the perivascular space, displaying mild to moderate cellular atypia. Immunohistochemical (IHC) stains were positive for Oscar keratin, Pax8, and P40, with background thymocytes marked with TdT, CD5, CD3, and programmed death ligand-1 (PD-L1) at 95%. These findings were consistent with thymoma World Health Organization (WHO) class B3.

Following the initiation of treatment with CAP, the patient experienced a short-term partial response. However, she subsequently developed aplastic anemia characterized by worsening anemia, reticulocytopenia and thrombocytopenia. A bone marrow biopsy revealed erythroid hypoplasia without dysplasia, attributed to her thymoma. Consequently, she started treatment with cyclosporine.

In response to disease progression, capecitabine and gemcitabine initiated. Restaging scans indicated ongoing disease advancement in the mediastinum, accompanied by extensive pleural metastasis (Figure 1A).

Figure 1 Imaging and hematological response to treatment with atezolizumab in relation to cyclosporine use. The upper panel illustrates the treatment timeline and imaging results, while the lower panel presents the patient’s platelet count and hemoglobin levels during treatment. (A) Imaging shows the treatment timeline with CAP, highlighting a disease progression as indicated by red arrows. (B) Imaging continues to indicate the lack of response and disease progression on atezolizumab while on cyclosporine treatment. (C) Imaging depicts a significant and positive response to atezolizumab treatment after the discontinuation of cyclosporine. (D) Disease recurrence is evident in the imaging upon the reintroduction of cyclosporine, marked by red arrows. The lower panel presents the patient’s platelet count and hemoglobin levels throughout the treatment period. This figure was created with BioRender.com. CAP, cisplatin, doxorubicin, and cyclophosphamide.

The decision was then to start atezolizumab in early 2022, while cyclosporine continued for aplastic anemia. However, restaging scans after three cycles showed ongoing disease progression (Figure 1B). It was then suggested that cyclosporine might be blunting her ICI response. Consequently, the decision made to hold cyclosporine in May 2022, given stable blood counts. After the fourth cycle, a repeat CT chest revealed a remarkable response to immune therapy (Figure 1C). However, the patient developed immune-related dermatitis, worsening anemia, and thrombocytopenia. Atezolizumab held, yet she maintained good overall disease control for around 15 months with a small area of progression in the mediastinum (Figure 1D). Her blood counts responded to eltrombopag, and she remained stable and transfusion independent. A graph of her hemoglobin and platelets counts is shown in Figure 1 (lower panel).

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Discussion

Treatment of recurrent thymoma remains challenging due to rarity of disease and low response rate with using chemotherapeutic agents (3). Multiple immune check points inhibitors assessed for safety and efficacy such as pembrolizumab which was evaluated for safety and efficacy in open label phase II trial that included seven patients with thymoma. Two of them had B3 thymoma and the rest were B2 thymoma. The overall response rate was 28.6% with duration of response not reached at 15 months. Five of seven patients with thymoma reported grade ≥3 immune-related adverse events, including hepatitis, myocarditis, thyroiditis, glomerulonephritis, and colitis (4).

Avelumab was evaluated for efficacy and safety in phase 1 trial that included 7 patients with thymoma, the objective response rate (ORR) was 57% (5). The trial did analysis of tumor infiltrate post treatment with avelumab which revealed predominance of lymphocytes with a mature CD8 positive T-cell phenotype and low level of T regulatory cell, raising the question of the rule of CD8 T-cell in development of immune related side effect as well as explaining the robust response to ICI.

Despite the low baseline tumor mutational burden (TMB) and the rarity of microsatellite instability-high (MSI-H) thymomas compared to other cancers, a study suggests a higher-than-expected response rate to ICIs for TMB-high or MSI-H thymomas. This enhanced response is likely attributed to the unique role of the thymus in T-cell development and the associated immune microenvironment (6).

This case shed the light on the rule and potential reduction of efficacy of ICI with concomitant use of immunosuppressant agents that is frequently used in treatment of paraneoplastic syndrome associated with thymoma such as myasthenia gravis and aplastic anemia. Immunosuppressant agents such as steroid or cyclosporine blunts the effect of CD8 T-cell and is associated with reduced efficacy of ICI therapy.

Conclusions

In our case, patient with WHO type B3 thymoma had no response to 3 cycles atezolizumab when used with concomitant cyclosporine, however, a profound response to atezolizumab within one cycle occurred when cyclosporine was held. This case highlights the efficacy if ICI in treatment of thymoma and it also shed light into the negative impact of concomitant use immunosuppressant that are frequently used concomitantly in treatment of paraneoplastic manifestations of thymoma.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://med.amegroups.com/article/view/10.21037/med-24-20/rc

Peer Review File: Available at https://med.amegroups.com/article/view/10.21037/med-24-20/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-24-20/coif). J.M. received funding support from Gilead, Atara, CRISPR, Precision Biosciences, Scripps, FATE Therapeutics and ADC Therapeutics; and participated the advisory board in Gilead. K.P. received payment or honoraria for lectures or speaking from Medscape, DAVA Oncology, Intellisphere LLC, and Curio Science LLC; and participated the advisory board in Jazz and AstraZeneca. He also reports other financial interests from Verastem and Dragonfly Therapeutics. J.N.M. received honoraria grant for speaking at an education meeting for Advanced Practice Provider Oncology Summit (APPOS) in 2023. A.J.S. participated in development of a patient facing app with intellectual property that is licensed to a commercial entity, InveniQA. She also received honoraria grant for speaking at an education meeting for APPOS in 2023–2024 and for Upper Midwest Oncology Education Network (UMOEN); and served as a member of Mayo Clinic Cancer Center Data Safety Monitoring Board. K.L. reports consulting activities (all honoraria to institution) with Amgen, Boehringer Ingelheim Pharmaceuticals, Janssen Biotech and Novartis; payment for presentations with AstraZeneca Interdisciplinary Corporation; CME activities with OncLive and MJH Life Sciences, MD Outlook and Targeted Oncology; advisory boards with AstraZeneca, Janssen, Jazz Pharmaceuticals, Mirati Therapeutics, Novartis, Regeneron, Takeda, and Targeted Oncology; and research support (to institution) from AstraZeneca and Mirati Therapeutics. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and national research committees and with the Helsinki Declaration (as revised in 2013). Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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