{"doi":"10.1002/ajh.25812","title":"Recurrent checkpoint <scp>inhibitor‐induced</scp> warm agglutinin autoimmune hemolytic anemia in a patient with metastatic melanoma","abstract":"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 ","journal":"American Journal of Hematology","year":2020,"id":114989,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9563,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":540539,"name":"T. O'Dowd","orcid":null,"position":1,"is_corresponding":false},{"id":514671,"name":"Svetomir N. Markovic","orcid":"0000-0002-9238-4325","position":2,"is_corresponding":false},{"id":525256,"name":"Alexandra P. Wolanskyj","orcid":"0000-0003-1618-5049","position":3,"is_corresponding":false},{"id":539585,"name":"Steven R. Hwang","orcid":"0000-0002-6536-1291","position":0,"is_corresponding":true}],"reference_count":7,"raw_metadata":null,"created_at":"2026-07-18T23:13:33.226937Z","pmid":"32243616","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}