Severe autoimmune hemolytic anemia following immunotherapy with checkpoint inhibitors in two patients with metastatic melanoma: a case report.

Introduction: Over the past decade, immune checkpoint inhibitors such as antibodies against cytotoxicity T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) have become an important armamentarium against a broad spectrum of malignancies. However, these specific inhibitors can cause adverse autoimmune reactions by impairing self-tolerance. Hematologic side effects of immune checkpoint inhibitors, including autoimmune hemolytic anemia (AIHA), are rare but can be life-threatening. Case report: Herein, we report two patients on immune checkpoint inhibitors for metastatic melanoma who developed AIHA with symptoms of dyspnea and fatigue. In the first patient, symptoms alleviated after discontinuation of combined anti CTLA-4 and anti-PD-1 therapy, initiation of corticosteroids and application of a single red blood cell transfusion. Due to subsequent progress of melanoma, combinational anti-PD-1 and tyrosine kinase inhibitor therapy was initiated based on multidisciplinary tumor board decision. After two months, she again developed the described hematological and clinical signs of AIHA leading to cessation of anti-PD-1 therapy and initiation of corticosteroids, which again resulted in an alleviation of her symptoms. Due to further progression, the patient received dacarbazine for several months before she decided to stop any therapy other than palliative supportive care. In the second patient, discontinuation of anti-PD-1 therapy and initiation of corticosteroids entailed a complete alleviation of his symptoms. After refusing chemotherapy due to subsequent melanoma progression, he received radiotherapy of bone metastases and is currently enrolled in a clinical trial. The patient did not develop AIHA ever since. Conclusion: Hematologic immune-related adverse events due to treatment with immune checkpoint inhibitors are rare but can have life-threatening consequences. If dyspnea and other clinical symptoms are present, AIHA should be considered as a potential cause and treated promptly in a multidisciplinary setting. An expanded comprehension of risk factors and pathogenesis of AIHA is needed to identify high-risk patients beforehand, leading to more effective predictive and reactive treatment approaches.

Alectinib-induced Hemolytic Anemia with Positive Direct Antiglobulin Test in a Patient with Lung Adenocarcinoma: A Possible Drug-drug Interaction Effect.

Recent studies have reported that direct antiglobulin test (DAT) results were negative in cases of alectinib-induced hemolytic anemia with abnormal red blood cell (RBC) morphology. We herein report the case of a 72-year-old female patient who was diagnosed with alectinib-induced hemolytic anemia who - in contrast to previous reports - showed a positive DAT result. After discontinuing famotidine and alectinib, the DAT results turned negative; however, when alectinib was resumed, hemolysis recurred. Although alectinib-induced hemolytic anemia has been previously thought to be associated with abnormal morphological changes of the RBCs, we suggest that alectinib-induced anemia may manifest as DAT-positive immune hemolytic anemia because of a complementary effect with other drugs.

Fostamatinib for warm antibody autoimmune hemolytic anemia: Phase 3, randomized, double-blind, placebo-controlled, global study (FORWARD).

Warm antibody autoimmune hemolytic anemia (wAIHA) is characterized by hemolysis and symptomatic anemia with no approved treatment options. Fostamatinib is an oral spleen tyrosine kinase inhibitor approved in the US and Europe for treatment of adults with chronic immune thrombocytopenia. In this phase 3 study, patients with an insufficient response to ≥1 prior wAIHA treatment were randomized to fostamatinib or placebo. The primary endpoint was the proportion of patients to achieve a durable hemoglobin (Hgb) response (Hgb ≥10 g/dL and increase from baseline of ≥2 g/dL on 3 consecutive visits) during the 24-week treatment period. Ninety patients were randomized, 45 to each arm. Of the fostamatinib-treated patients, 35.6% achieved a durable Hgb response versus 26.7% on placebo (p = .398). A post hoc analysis revealed a large placebo response in Eastern European patients. Significantly more patients on fostamatinib from North America, Australia and Western Europe exhibited a durable Hgb response compared to placebo (36% vs. 10.7%, p = .030). After censoring for Hgb values impacted by steroid rescue received during screening and excluding 2 placebo patients found to likely not have wAIHA, a reanalysis demonstrated a difference in durable Hgb response between fostamatinib and placebo (15/45 [33.3%] vs. 6/43 [14.0%], p = .0395). At least 1 AE was reported in 42 (93.3%) and 40 (88.9%) patients receiving fostamatinib and placebo, respectively. The most common AEs in the fostamatinib group were diarrhea (26.7%), hypertension (24.4%), and fatigue (15.6%). In this study, fostamatinib demonstrated a clinically meaningful benefit for patients in Western regions, and no new safety signals were identified.

Sirolimus is effective for primary refractory/relapsed warm autoimmune haemolytic anaemia/Evans syndrome: a retrospective single-center study.

BACKGROUND: Some patients with warm autoimmune haemolytic anaemia (wAIHA) or Evans syndrome (ES) have no response to glucocorticoid or relapse. Recent studies found that sirolimus was effective in autoimmune cytopenia with a low relapse rate. METHODS: Data from patients with refractory/relapsed wAIHA and ES in Peking Union Medical College Hospital from July 2016 to May 2022 who had been treated with sirolimus for at least 6 months and followed up for at least 12 months were collected retrospectively. Baseline and follow-up clinical data were recorded and the rate of complete response (CR), partial response (PR) at different time points, adverse events, relapse, outcomes, and factors that may affect the efficacy and relapse were analyzed. RESULTS: There were 44 patients enrolled, with 9 (20.5%) males and a median age of 44 (range: 18-86) years. 37 (84.1%) patients were diagnosed as wAIHA, and 7 (15.9%) as ES. Patients were treated with sirolimus for a median of 23 (range: 6-80) months and followed up for a median of 25 (range: 12-80) months. 35 (79.5%) patients responded to sirolimus, and 25 (56.8%) patients achieved an optimal response of CR. Mucositis (11.4%), infection (9.1%), and alanine aminotransferase elevation (9.1%) were the most common adverse events. 5/35 patients (14.3%) relapsed at a median of 19 (range: 15-50) months. Patients with a higher sirolimus plasma trough concentration had a higher overall response (OR) and CR rate (p = 0.009, 0.011, respectively). At the time of enrolment, patients were divided into two subgroups that relapsed or refractory to glucocorticoid, and the former had poorer relapse-free survival (p = 0.032) than the other group. CONCLUSION: Sirolimus is effective for patients with primary refractory/relapsed wAIHA and ES, with a low relapse rate and mild side effects. Patients with a higher sirolimus plasma trough concentration had a higher OR and CR rate, and patients who relapsed to glucocorticoid treatment had poorer relapse-free survival than those who were refractory.

A 71-year-old male with a life-threatening recurrence of hemolytic anemia, thrombocytopenia, and acute kidney injury after pembrolizumab therapy: a case report.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. However, their use has been restricted in patients with preexisting autoimmune diseases due to concerns about increased risk of immune-related adverse events (irAEs). CASE PRESENTATION: We present a case of a patient with stage IV lung adenocarcinoma and a history of complement-mediated autoimmune hemolytic anemia in remission. After receiving a single dose of pembrolizumab, the patient experienced life-threatening recurrent hemolytic anemia, de novo thrombocytopenia, diarrhea, myocarditis, and acute kidney injury. Laboratory tests confirmed the diagnosis of Evan's syndrome, with positive PAIgG and direct antiglobulin test. Treatment with intravenous methylprednisolone at a dose of 2 mg/kg resulted in a favorable response, with resolution of symptoms and rapid recovery of kidney function. The probable cause of pre-renal hypoperfusion (evidenced by a BUN-to-creatinine ratio of 48.1) leading to acute tubular injury was attributed to pembrolizumab-induced diarrhea. CONCLUSIONS: This case illustrates a life-threatening recurrence of complement-mediated autoimmune hemolytic anemia induced by ICIs. Clinicians should carefully consider the expected efficacy and potential toxicity before initiating ICIs therapy in patients with preexisting autoimmune diseases. Additionally, the occurrence of acute kidney injury during ICIs therapy adds complexity and requires careful differential diagnosis.

Auto-immune hemolytic anemia and hemophagocytic lymphohistiocytosis as immune-related adverse event in patients with metastatic melanoma and concurrent chronic lymphocytic leukemia: a case series and literature review.

Auto-immune hemolytic anemia (AIHA) and hemophagocytic lymphohistiocytosis (HLH) are both rare immune-related adverse events (irAEs) following treatment with immune checkpoint inhibitors. Consensus treatment guidelines are currently lacking. Patients with a solid malignancy and a concurrent lymphoproliferative disorder, such as chronic lymphocytic leukemia (CLL), might be more prone to develop hematological irAEs. We report the case history of two patients, diagnosed with CLL, who during treatment for metastatic melanoma with nivolumab, a PD-1 immune checkpoint blocking mAb, developed AIHA and HLH in combination with AIHA. Furthermore, we provide a review of the literature on published cases of immune-related AIHA and HLH and their correlation with CLL.

Positive direct antiglobulin tests in cancer patients on immune checkpoint inhibitors: A case series from India.

Tumour cells activate immune checkpoints such as programmed death receptor-1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) signalling pathways to inhibit T lymphocyte activation and thus escape from immune surveillance. Immune checkpoint inhibitors (ICPis) reactivate T lymphocytes to recognize cancer cells by blocking CTLA-4 or PD-1. Autoimmune haemolytic anaemia is a rare, but often severe, complication of ICPis. Therefore, we performed a retrospective clinical case review, including serologic, haematology, and biochemistry laboratory results, of three patients who developed autoantibodies to erythrocytes following treatment with pembrolizumab, an anti-PD-1 inhibitor. Serologic testing of blood samples from these patients showed their red cells were positive for direct antiglobulin test (DAT + for IgG in two cases and IgG with C3d in one case). Antibody detection test was negative. No patient had clinical and laboratory features of haemolysis. There were no additional immune-related adverse events. IgG antibodies coating red cells were neither IgG1 nor IgG3 in class and elution was found negative in all. In conclusion, immunohaematology laboratories should be aware of the possibility of erythroid autoantibodies and their nature in cancer patients receiving ICPis. The result of a positive DAT should be interpreted carefully in these patients to exclude other possible causes of anaemia.

Evans' syndrome induced by atezolizumab plus bevacizumab combination therapy in advanced hepatocellular carcinoma.

An 86-year-old man presented with recurrence of hepatocellular carcinoma (HCC) after surgery. Atezolizumab plus bevacizumab was initiated. After the third course of atezolizumab plus bevacizumab therapy, petechial purpura appeared on the extremities and trunk. Laboratory tests revealed isolated severe thrombocytopenia without evidence of combined coagulopathy. He was diagnosed with immune thrombocytopenic purpura (ITP), and high-dose immunoglobulin and Helicobacter pylori eradication therapies were administered. Improvement in thrombocytopenia was observed; however, 20 days after the onset of ITP, laboratory data revealed hemolytic anemia. Both direct and indirect Coombs tests were positive, and he was diagnosed with Evan's syndrome complicated by ITP and autoimmune hemolytic anemia (AIHA) induced by immune-related adverse events (irAEs). After treatment with prednisolone, the hemoglobin level increased, and hemolytic findings improved on blood tests. We encountered a rare case of Evans' syndrome due to atezolizumab plus bevacizumab therapy for HCC. In atezolizumab plus bevacizumab therapy, hematologic toxicities are not rare adverse events and attention is required.

Silvernanoparticle-induced hemolysis confounded with direct antiglobulin test-negative autoimmune hemolytic anemias diagnosis.

BACKGROUND: We describe here the first patient with recurrent hemolysis related to disinfectant containing silver nanoparticles (AgNps). METHODS: A 58-year-old chemist repeatedly experienced DAT-negative (Coombs-negative) hemolysis during the last 5 years. He was treated with a number of immunosuppressive drugs including 18 times rituximab. The attempt to treat him with cyclosporine A served only to increase the rate of hemolysis. Only by chance, we revealed that the patient regularly used a hand disinfectant containing AgNps. Serological testing was performed using standard techniques. Eryptosis was measured by binding annexin to exposed phosphatidylserine (PS) of the circulating red blood cells (RBCs). RESULTS: Antiglobulin tests remained negative, and PS exposing RBCs were detected two times during the last hemolytic episodes. Hemolysis completely disappeared following discontinuation of AgNp containing products. CONCLUSION: AgNps are increasingly being used in a large variety of products. Recently, it was reported that they induce in vitro prohemolytic and procoagulant effects via oxidative stress and eryptosis. The clinical findings imply the hemolysis was provoked by the patient's regular use of cleansing products containing AgNps. Our finding might help to explain the etiology of hemolytical disorders that may remain obscure in many cases.

Autoimmune hemolytic anemia in patients with relapsed Hodgkin's lymphoma after treatment with penpulimab, a monoclonal antibody against programmed death receptor-1.

In August 2021, penpulimab, an anti-programmed cell death 1 (PD-1) monoclonal antibody, was approved in China for the treatment of adult patients with relapsed or refractory classic Hodgkin's lymphoma who completed at least second-line chemotherapy. Penpulimab is currently in clinical trials in China and Australia for the treatment of nasopharyngeal cancer and non-small cell lung cancer. Several clinical studies have shown that penpulimab is safe and effective, and no immune-related adverse events (irAEs) above grade 3 were observed. A 60-year-old woman with relapsed Hodgkin's lymphoma developed nausea and fatigue after receiving penpulimab monotherapy (200 mg every 2 weeks). Ten days after the second injection, the patient's condition worsened, and biochemical test results confirmed autoimmune hemolytic anemia (AIHA), with a hemoglobin level of 70 g/L (normal range, 115-150 g/L), an unconjugated bilirubin level of 19.08 µmol/L (normal range, 0-17 µmol/L), and positive direct antiglobulin test (DAT) results. On the same day, we treated her with prednisone (2 mg/kg), but her hemoglobin level continued to decline to 51 g/L one day after hormone therapy, so she received an intravenous infusion of washed red blood cells and underwent plasmapheresis, which eventually resolved the AIHA. Considering that the hemoglobin level was < 65 g/L and the irAE was grade 4, penpulimab was discontinued, and the symptoms of AIHA disappeared. From this event, we know that severe AIHA can occur after penpulimab use similar to other PD-1 antibodies. In this case, plasmapheresis showed a good therapeutic effect and should be used as a supplementary means when hormonal and immunosuppressive therapies cannot provide rapid symptom relief. In addition, we recommend regular direct antiglobulin testing, as well as haptoglobin, lactate dehydrogenase and other hemolysis-related laboratory tests, in patients prescribed penpulimab and similar drugs for the early diagnosis and treatment of AIHA.

Possible autoimmune hemolytic anemia induced by secukinumab: a case report.

Secukinumab, an anti-IL-17 monoclonal antibody, has been used to treat psoriasis and psoriatic arthritis since 2015. Several adverse events were reported, such as diarrhea, upper respiratory tract infection, middle ear infection, and neutropenia. Here we report a probable case of autoimmune hemolytic anemia in a 39 years old male with psoriasis and psoriatic arthritis treated with secukinumab. Hemolytic anemia detected after first maintenance dose after completion of induction dose of secukinumab. The patient also had other comorbids, soft tissue infection that also predisposed to autoimmune hemolytic anemia, but secukinumab is still a possible etiology for drug-induced autoimmune hemolytic anemia based on Naranjo´s score. The patient decided to continue secukinumab treatment, interestingly hemoglobin levels improved.

Immunotherapy-associated Autoimmune Hemolytic Anemia.

Over the past decade, the role of immunotherapy treatment in cancer has expanded; specifically, indications for immune checkpoint inhibitors (ICI) have multiplied and are used as first-line therapy. ICIs include cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 inhibitors, as monotherapies or in combination. Autoimmune hemolytic anemia (AIHA) has emerged as a rare yet serious immune-related adverse event in ICI use. This review describes diagnosis and management of immunotherapy related AIHA (ir-AIHA) including an algorithmic approach based on severity of anemia. Suggested mechanisms are discussed, guidance on ICI resumption provided and prognosis reviewed including risk of recurrence.

Autoimmune Hemolytic Anemia After mRNA COVID Vaccine.

Discussion of the hematologic complications of vaccination for severe acute respiratory syndrome coronavirus-2 (COVID-19) has primarily focused on the development of vaccine-associated immune thrombosis with thrombocytopenia (VITT). Other hematologic complications are uncommon. We report the case of a patient who developed immunoglobulin G (IgG)-mediated autoimmune hemolytic anemia (AIHA) after the Moderna COVID-19 messenger ribonucleic acid (mRNA) vaccine.

Delayed autoimmune haemolytic anaemia after artesunate therapy for severe malaria.

We report the case of a 51-year-old man with severe malaria, who developed delayed autoimmune haemolytic anaemia following artesunate therapy. Delayed autoimmune haemolytic anaemia following artesunate therapy has been previously described. Its diagnosis can be challenging in the setting of possible dengue coinfection. Clinicians should be vigilant of this potential side effect of artesunate therapy, especially in patients who later develop signs and symptoms of haemolytic anaemia.

Severe drug-induced immune hemolytic anemia due to cefmetazole: A case report.

OBJECTIVE: To report a case of drug-induced immune hemolytic anemia (DIIHA) that was suspected to have been caused by cefmetazole. CASE SUMMARY: A 93-year-old woman with no previous history of liver complications underwent a contrast-enhanced computed tomography scan, which resulted in a diagnosis of acute cholecystitis. The patient experienced intravascular hemolysis and rapid progression of anemia after being exposed to 2 g/day of cefmetazole. After 48 hours of cefmetazole administration, the patient was transferred to the intensive care unit (ICU) of our facility. In view of the severe autoimmune hemolytic anemia, the patient was started on steroid immunosuppression. The patient's condition further deteriorated for 13 hours after treatment and showed increased lactic acidosis and decreased consciousness, thus, the patient was intubated and managed on a ventilator. Lactic acidosis was not easily controlled, and the patient required continuous renal replacement therapy within 15 hours of ICU admission. Blood pressure was unable to be maintained even with the use of catecholamine, and the patient subsequently died 28 hours after ICU admission. Blood taken immediately after death was used to perform a drug-dependent antibody test where DIIHA due to cefmetazole was diagnosed. CONCLUSION: If there is rapid progression of anemia following drug administration, the possibility of DIIHA needs to be considered. If DIIHA is suspected, identification and immediate discontinuation of the causal drug are essential, and a drug-dependent antibody test should be considered.