Recurrent checkpoint <scp>inhibitor‐induced</scp> warm agglutinin autoimmune hemolytic anemia in a patient with metastatic melanoma
Authors: Steven R. Hwang, Timothy O'Dowd, Svetomir N. Markovic, Alexandra P. Wolanskyj‐Spinner
Journal: American Journal of Hematology (2020)

Checkpoint inhibitors (CPIs) have become more widely used in modern oncology with significant improvement in the prognosis of multiple malignancies including metastatic melanoma, lung cancer, and renal cell carcinoma.1 As the indications for CPIs continue to expand, the number of reported CPI-associated immune-related adverse effects (irAEs) has increased. More recently, warm agglutinin autoimmune hemolytic anemia (WAIHA) has been described in the literature as a CPI-associated irAE.2 The majority of irAEs are managed with high-dose corticosteroids in addition to cessation of CPI therapy. Due to the risk of recurrent WAIHA after reinitiation of CPIs in patients with a prior episode, controversy exists whether these patients should be rechallenged with CPI therapy. Herein, we present a patient who developed three distinct episodes of WAIHA in the setting of CPI therapy. Episode 1: A 67-year-old male was diagnosed with localized melanoma in 2014. He underwent wide local excision with negative margins and negative sentinel lymph node biopsy. In 2016, the melanoma metastasized to involve lung, liver, and bone, prompting initiation of systemic therapy with pembrolizumab and indoximod (an indoleamine 2,3-dioxygenase-1 [IDO-1] inhibitor) as part of a clinical trial. He subsequently achieved a complete radiologic response to therapy. However, after approximately 10 months of therapy (and 12 doses of pembrolizumab), the patient experienced progressive fatigue and decreased exercise tolerance. Initial evaluation revealed hemoglobin of 5.28 mmol/L (previous 7.76 mmol/L), elevated LDH 5.53 μkat/L, undetectable haptoglobin, and positive direct antiglobulin test (DAT) for IgG (2+). The patient was given a presumptive diagnosis of pembrolizumab-induced Coomb's positive, IgG-mediated WAIHA. Pembrolizumab was discontinued and he was treated with a course of oral prednisone 1 mg/kg daily resulting in resolution of hemolysis after 7 days. Prednisone was gradually tapered over 4 weeks. Episode 2: Approximately 2 months after resolution of the patient's initial episode of WAIHA, he presented with neurologic deficits and imaging that noted recurrence of metastatic melanoma with multifocal brain lesions. He underwent whole brain radiation therapy and initiation of ipilimumab and nivolumab. However, after the first dose of combination immunotherapy, the patient developed progressive fatigue. Laboratory evaluation revealed hemoglobin of 5.77 mmol/L (previous 7.39 mmol/L), LDH 11.99 μkat/L, undetectable haptoglobin, and positive DAT for IgG (3+) consistent with recurrence of CPI-induced Coomb's positive, IgG-mediated WAIHA. Ipilimumab and nivolumab were discontinued and he was once again treated with prednisone 1 mg/kg daily. However, after 10 days of prednisone, laboratory evaluation showed ongoing hemolysis. He was subsequently given two doses of intravenous immunoglobulin G (IVIG) 1 g/kg with minimal response. He then received four doses of weekly rituximab 375 mg/m2 resulting in resolution of hemolysis after the second dose. Episode 3: The patient's cancer-directed therapy was switched to temozolomide. However, rapid disease progression prompted another switch in therapy - this time to a regimen consisting of carboplatin, paclitaxel, and pembrolizumab. After 2 months on this regimen (which included three doses of pembrolizumab), the patient presented to our institution with progressive fatigue. On our evaluation, his physical exam was notable for significant skin pallor. Laboratory evaluation revealed hemoglobin of 4.1 mmol/L (previous 5.34 mmol/L), total bilirubin 65.0 μmol/L (direct 8.55 μmol/L), LDH 10.4 μkat/L, and undetectable haptoglobin. Once again DAT was positive for anti-IgG (3+) and negative for anti-C3. He was initiated on oral prednisone 1 mg/kg daily. However serial labs showed persistent transfusion-refractory anemia and evidence of persistent hemolysis. The patient was given a dose of IVIG 1 g/kg with minimal response in laboratory markers. Given his significant history of prior episodes of WAIHA, the decision was made to treat the patient aggressively with initiation of rituximab 375 mg/m2 weekly, and pulse-dose intravenous methylprednisolone 1000 mg daily. He ultimately received four doses of rituximab and 10 doses of methylprednisolone. The patient's anemia stabilized, hemolysis labs improved, and fatigue resolved, allowing the patient to return home on hospital day 7. Unfortunately, a PET scan obtained at post-hospital follow-up showed significant progression of metastatic disease and the patient ultimately opted for hospice care. Our patient's case is notable for multiply recurrent episodes of WAIHA in the setting of utilizing CPIs for refractory metastatic melanoma. Our patient met the criteria proposed by Leaf et al.2 for CPI-induced WAIHA including (a) an abrupt decrease in hemoglobin ≥2 g/dL; (b) laboratory features suggestive of hemolysis including elevated LDH and low haptoglobin; (c) temporal association of WAIHA after initiation of CPI; (d) exclusion of other causes of anemia; and (e) CPI therapy was considered the most likely etiology of WAIHA. The treatment of WAIHA in general is based on decreasing the production of IgG autoantibodies with prednisone (first-line) or other immunosuppressive agents such as rituximab.3, 4 In severe cases of WAIHA, treatments including splenectomy and IVIG are utilized to reduce the effectiveness of autoantibodies in destroying red blood cells.5 The management of CPI-induced WAIHA has not been well established, largely in part due to the paucity of published cases. Among the current reported cases in the literature, all patients were initially treated with glucocorticoids with some requiring additional immunosuppressive therapies.2 Our patient's three episodes of WAIHA over a 3-year period were treated with different immunosuppressive modalities with varying responses (Table 1). This case demonstrates the need for standardization of optimal treatment for hematologic irAEs. After reviewing the published cases and treatment regimens utilized in the literature, we propose a potential algorithm for non-responders to initial treatment with oral prednisone (Figure S1). In addition, the use of CPIs in patients who have previously experienced irAEs has not been well studied. In reviewing recent literature, it appears that the current practice is for consideration of re-trialing CPIs as long as patients are closely monitored.6 In the cohort of patients reviewed by Leaf et al.,2 they concluded that six of seven (86%) of patients who were rechallenged with CPIs did not develop recurrent WAIHA. However, two patients who were reinitiated with CPIs were on concurrent glucocorticoid therapy and another patient developed other irAEs, including ITP, prompting permanent cessation of CPI therapy. This suggests that only three of seven (43%) patients did not develop recurrent WAIHA on true rechallenge. Our patient's case of multiply recurrent CPI-induced WAIHA also supports the notion that the risk of recurrent irAEs in the setting of CPI reinitiation may be higher than previously thought. In summary, we report a patient who developed three distinct episodes of CPI-induced WAIHA while undergoing treatment for metastatic melanoma. We propose a treatment algorithm for CPI-induced WAIHA refractory to initial glucocorticoid therapy. This case also demonstrates the risk of recurrent WAIHA with reinitiation of CPI therapy, highlighting the need to consider potentially serious hematologic irAEs with progression of the underlying malignancy. Figure S1. Treatment algorithm for CPI-induced WAIHA Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.