Evans syndrome during pembrolizumab therapy for upper urinary tract cancer

Introduction Immune checkpoint inhibitors are available for the treatment of advanced urothelial carcinoma; however, serious adverse events occasionally occur. Here, we report a rare case of Evans syndrome attributed to the use of an immune checkpoint inhibitor. Case presentation A 56‐year‐old man was diagnosed with left renal pelvic cancer and underwent left laparoscopic radical nephroureterectomy. Eight months postoperatively, computed tomography revealed para‐aortic lymph node metastasis. Despite receiving chemotherapy, the disease progressed, and pembrolizumab was initiated. After 26 months of pembrolizumab treatment, the patient developed fever and anemia. Hematologic examination confirmed the diagnosis of Evans syndrome. He was treated with blood transfusions and corticosteroids, and gradual symptom improvement was observed. Conclusion This report highlights the potential risk of Evans syndrome associated with immune checkpoint inhibitor treatment. Clinicians should be aware of this possibility and consider early intervention with corticosteroids.


Introduction
The ICI, Pem, has been indicated for treatment of unresectable UC that has progressed after chemotherapy. Although this treatment has shown improved outcomes for UC, some patients may experience irAEs.
Here, we report a rare case of ES complicated by AIHA and ITP as irAEs in a patient receiving Pem for upper urinary tract UC.

Case presentation
A 56-year-old man with gross hematuria underwent left laparoscopic radical nephroureterectomy. The pathological diagnosis was UTUC (pT2N0M0). Eight months postoperatively, CT revealed metastasis to the para-aortic lymph nodes; thus, gemcitabine and carboplatin chemotherapy was initiated. However, after two cycles of chemotherapy, further metastatic lymph node enlargement was observed, indicating progressive disease.
After 26 months (33 cycles) of Pem treatment, the patient developed fever and general fatigue. Physical examination revealed pale eyelid conjunctiva and yellowish ocular conjunctiva. Additionally, the patient experienced mild subcutaneous bleeding in the lower extremities.
Blood tests revealed severe anemia, low platelet count, and elevated LDH level. Elevated liver enzymes and bilirubin levels indicated hemolysis or worsening liver function (Table 1). Contrast-enhanced CT revealed hepatosplenomegaly and enlarged lymph nodes in the mesentery and hepatic hilum but no evidence of bleeding or infection (Fig. 1). A blood transfusion was determined to be necessary. Further examination revealed positive results for irregular antibodies and direct and indirect Coombs tests (Table 1). Bone marrow puncture revealed no malignant findings. No evidence of hemorrhage, disseminated intravascular coagulation, or primary hepatobiliary disease was found, and other hematologic diseases, such as malignant lymphoma, were ruled out. Finally, based on the diagnostic criteria set forth by the Ministry of Health, Labor, and Welfare, we diagnosed the patient with ES as he met the criteria for both AIHA and ITP. 1,2 Upon admission, oral prednisolone (35 mg/day) administration was initiated. RBC and platelet transfusions were deemed necessary; however, both improved over time (Fig. 2). Following 34 days of oral prednisone treatment, the patient was discharged and has since maintained stable health with oral prednisone (5 mg/day).

Discussion
The patient developed ES as an irAE during second-line Pem therapy for metastatic UTUC following chemotherapy. The patient achieved remission after prompt diagnosis and oral steroid therapy.
ES was first described in 1951 as an autoimmune disease concomitant or secondary to AIHA or ITP. 3 Approximately 50% of ES cases are classified as secondary ES, which is associated with a higher mortality rate than primary ES. The etiology of ES should be accurately determined at the time of diagnosis, as it may influence subsequent treatment strategies. 4 Autoimmune diseases and lymphomas are the most common causes of secondary ES. 4 Overall, 61% of the cases were reported to develop AIHA and ITP simultaneously, while 39% exhibit asynchronous onset. However, a clear trend regarding which disease manifested first was not established. 4 As this patient experienced anemia; jaundice, with elevated reticulocyte, indirect bilirubin, and LDH; AIHA; and ITP with thrombocytopenia, drug-induced secondary ES was strongly suggested. Additionally, considering the occurrence of anemia and thrombocytopenia in the patient, we concluded that it was a case of ES with almost simultaneous development of AIHA and ITP.
ICIs have been increasingly used as systemic therapy for advanced malignancies. While ICIs have demonstrated anticancer effects, their use is associated with the loss of selftolerance and the occurrence of irAEs. 5 The incidence of hematologic toxicity due to immunotherapy has been reported to be as high as 1%. 6 AIHA, specifically attributed to Pem, is considered rare, accounting for only 0.146% of all AEs caused by Pem. 7 Nonetheless, approximately 30% of patients with AIHAs presenting as irAEs have new-onset or complications of other hematologic diseases such as ITP. 8 Leaf et al. reported 14 cases of AIHA caused by ICIs, four of which (28.6%) had additional hematological toxicity. The breakdown of the primary disease was melanoma in two out of these four cases (50%), non-small cell lung cancer in one case (25%), and acute myeloid leukemia in one case (25%). 8 Therefore, clinicians should excise caution and consider the possibility of ES when managing patients with hematologic abnormalities.
Corticosteroids, particularly prednisolone, are the primary therapy for ES, typically administered at a dose range of 1-2 mg/kg/day. 9 To minimize the risk of steroid-associated AEs, gradually tapering the steroid dose based on the patient's clinical presentation is crucial. 10 When steroid treatment proves ineffective, second-line options, such as rituximab, may be considered. However, limited data are available regarding its efficacy in patients with secondary ES. 10,11 In cases of pronounced thrombocytopenia, IVIg should be considered as a potential treatment option. 12 IVIg may serve as a primary treatment in cases where steroid therapy is not indicated or not suitable. However, when combined with steroids, it may lead to a rapid increase in platelet count. 13 Our patient was managed with a daily dose of prednisolone at 0.5 mg/kg (equivalent to 35 mg/day). The steroid dosage used in this study was relatively lower than that  20 with a short mean follow-up of 7.7 months. Conversely, Williams et al. described a case of jaundice due to AIHA and cholangitis occurring two years after the completion of Pem treatment for melanoma. Therefore, greater attention should be paid to the development of hematologic toxicity following prolonged treatment with Pem. 15

Conclusion
We present the first case of UTUC with ES that was successfully treated using corticosteroids. ES should be considered in the differential diagnosis of patients with Pem-induced hematologic toxicity.