[Adenocarcinoma with Aplastic Anemia as an Immune-related Adverse Event Caused by Pembrolizumab: Report of a Case].

A 74-year-old man was found a left completely atelectasis on chest X-ray. He had undergone left lower lobe resection because of an adenocarcinoma at the age of 58. Bronchoscopy revealed a tumor near the left upper lobe branch entry that obstructed the lumen, and a biopsy confirmed the diagnosis of adenocarcinoma. A left completion pneumonectomy was performed, but #4L and #10 lymph nodes could not be completely resected. Programmed cell death 1-ligand 1( PD-L1) was positive with tumor proportion score (TPS) 15%, so chemotherapy with pembrolizumab+pemetrexed+carboplatin was started about 1.5 months after surgery. Pancytopenia appeared from the seventh course and did not improve after discontinuation of chemotherapy, so we consulted to the hematologist. He was diagnosed as aplastic anemia by bone marrow biopsy. Aplastic anemia was unresponsive to treatment and chemotherapy could not be resumed. He died of exacerbation of lung cancer.

Real-world evidence of incidence and outcomes of aplastic anaemia following administration of immune checkpoint inhibitors.

Aplastic anaemia (AA) is a rare immune-related adverse events (irAEs) after immune checkpoint inhibitors (ICIs) administration with poorly understood incidence and outcomes. We analysed an electronic health record database of 52 303 ICI-treated patients and found 77 (0.15%) cases of AA, with a median onset of 126 days (interquartile range, 58-363 days). The most used treatment for AA was systemic glucocorticoids 60 (77.9%) and 32 (41.6%) patients were able to resume ICI within 1 year. Patients diagnosed with AA had a steep decline in overall survival (OS) within the first 120 days; when compared to propensity score-matched patients without AA, they had a significantly worse OS (hazard ratio 1.72, 95% confidence interval 1.19-2.50; p = 0.003).

Clinical characteristics of antithyroid drug-induced aplastic anemia cases over the past 30 years.

Objective: The authors aimed to investigate the clinical characteristics of antithyroid drug-induced aplastic anemia cases over the past 30 years. Methods: The data of patients with antithyroid drug-induced aplastic anemia were retrieved from PubMed and Wanfang Medical Network databases from 1992 to August 2022. The clinical characteristics, such as age distribution, gender tendency, common symptoms, blood cell count, bone marrow features, treatment strategy, and prognosis, were analyzed. Results: A total of 17 cases (male:female = 1:16) had been retrieved. Patients' age ranged from 16 to 74 years (median 50 years). Among them, 82.3% (14/17) of the patients were administered methimazole (MMI), and 78.6% of them had MMI ≥30 mg/day. In addition, 88.2% (15/17) of the patients had sore throat and fever, and 47.1% (8/17) of the patients had hemorrhagic symptoms. Aplastic anemia occurred within 6 months after initiation of the antithyroid therapy in 94.1% of the patients. Agranulocytosis (94.1%) was the most common and earliest blood cell change, and 47.1% of the patients experienced progressive platelet decline during the treatment process. The treatments include timely withdrawal of antithyroid drugs, broad-spectrum antibiotics, granulocyte colony-stimulating factor (G-CSF)/granulocyte-macrophage colony-stimulating factor (GM-CSF), glucocorticoids and other immunosuppressive agents, and supportive treatments such as erythrocyte transfusion and platelet transfusion. Moreover, 70.6% of the patients had complete or near-complete remission within 8 days to 6 weeks. Conclusion: Aplastic anemia is a rare and serious adverse reaction of antithyroid drugs, which is more common in women. It usually occurs during early treatment with high-dose antithyroid drugs. Most patients have a good prognosis after timely drug ceasing and appropriate treatment.

Acute lymphocytic leukemia in a patient with long-term carbamazepine exposure: Acute lymphoblastic leukemia that develops in a patient who has been using carbamazepine for a long time.

INTRODUCTION: Carbamazepine is an antiepileptic drug used in the treatment of epilepsy, trigeminal neuralgia, and bipolar disorder. Hematological effects that may develop with this anticonvulsant; agranulocytosis, thrombocytopenia, leukopenia, aplastic anemia, eosinophilia, or pancytopenia. CASE REPORT: In this article, we wanted to present a case diagnosed with acute lymphoblastic leukemia after long-term use of carbamazepine because of epilepsy. MANAGEMENT AND OUTCOME: Bone marrow smear was evaluated and blastic cell infiltration was observed. The carbamazepine treatment was discontinued and standard chemotherapy was started for acute lymphoblastic leukemia (CALGB protocol). Levetiracetam was started for epilepsy. DISCUSSION: Carbamazepine is an iminostilbene derivative. Carbamazepine is an antiepileptic drug that exhibits a number of side effects such as headache, abdominal pain, high blood pressure, as well as hematological disorders. In addition to causing thrombocytopenia, hypogammaglobulinemia, leukopenia, and neutropenia, it can have serious effects such as agranulocytosis, aplastic anemia, pure red cell aplasia, leukemia, or DRESS syndrome. The incidence of serious side effects from carbamazepine pharmacotherapy is low, and their exact mechanism of action is still unknown.

Relationship between CYP2C8, UGT1A1, and ABCG2 gene polymorphisms and the exposure, efficacy, and toxicity of eltrombopag in the treatment of refractory aplastic anemia.

PURPOSE: Eltrombopag (ELT) is an effective drug for relapsed/refractory aplastic anemia (AA). Our previous study showed that ELT concentration was correlated with the effects of ELT. However, the factors affecting ELT concentration in patients with relapsed/refractory AA were not clarified. Therefore, we aimed to evaluate correlations between drug disposition-related gene polymorphisms and the concentration, efficacy, and toxicity of ELT. METHODS: Forty-five patients who underwent ELT administration from January 2018 to January 2019 at Peking Union Medical Colleague Hospital (PUMCH) were included. The corresponding clinical information was also collected. ELT plasma concentrations were detected by high-performance liquid chromatography-mass spectrometry (HPLC/MS). CYP2C8, (UGT)1A1, and ABCG21 were genotyped by polymerase chain reaction (PCR). The influence of gene polymorphisms on the plasma concentration, efficacy, and toxicity of ELT was analyzed. RESULTS: The mean dose required to obtain the optimal effects was significantly lower in the UGT1A1*6 variant carriers than in the UGT1A1*6 WT carriers. There was a significant correlation between the (UGT)1A1*6 polymorphism and higher ELT plasma concentrations (> 11.2 µg/mL). By logistic regression analysis, the efficacy of ELT was related to plasma concentration and a combined genotype of (UGT)1A1*6 and ABCG2. There were no significant associations between genotypes and adverse drug reactions (ADRs) or ELT concentrations and ADRs. CONCLUSION: UGT1A1*6 is a predictor of the ELT plasma concentration and may help to determine the initial therapeutic dose in relapsed/refractory AA patients. Both drug exposure and patient genotype should be considered for better responses to ELT.

[Drug-induced bone marrow changes]. / Medikamentös induzierte Knochenmarkveränderungen.

Cytomorphological and histomorphological analysis of bone marrow cells in cases with abnormal production of blood cells must always take the unwanted side effects of drugs into account. Drugs can affect single lineages or the complete bone marrow. Besides quantitative phenomena consisting of hypoplasia or hyperplasia, maturation of blood cells may be disturbed. Disturbances encompass left shifts, which may be extreme, or imitate states of vitamin deficiency and atypia occurring in myelodysplastic syndromes (MDS). In addition, all bone marrow lineages may be affected, simulating aplastic anemia. The spectrum of causative drugs is very broad, and the induced changes are generally not specific enough to identify the underlying drug culprit, which requires knowledge of the patient's drug history. Cytotoxic drugs applied in oncology can induce MDS with an average latency of 2-6 years, or even shorter in the case of drugs interfering with DNA repair.

A case of azathioprine-induced aplastic anemia.

Azathioprine (AZA) is an immunosuppressant that is widely used to treat many disease states including rheumatoid arthritis. We present a patient who was treated with AZA for rheumatoid arthritis and subsequently hospitalized for severe myelosuppression due to acquired aplastic anemia. Upon genetic testing it was found that the patient was thiopurine methyltransferase (TMPT) deficient, a well-documented risk factor for myelosuppression in patients taking azathioprine. We advocate for TPMT and nudix hydrolase 15 (NUDT15) testing prior to initiation of AZA treatment, or close monitoring with a complete blood count post-AZA initiation to avoid these serious side effects.

Integrated Network Pharmacology and Metabolomics Analysis to Reveal the Potential Mechanism of Siwu Paste on Aplastic Anemia Induced by Chemotherapy Drugs.

Purpose: This study aimed to reveal the multicomponent synergy mechanisms of SWP based on network pharmacology and metabolomics for exploring the relationships of active ingredients, biological targets, and crucial metabolic pathways. Materials: Network pharmacology, including TRRUST, GO, and KEGG, enrichment was used to discover the active ingredients and potential regulation mechanisms of SWP. LC-MS and multivariate data analysis method were further applied to analyze serum metabolomics profiling for discovering the potential metabolic mechanisms of SWP on AA induced by Cyclophosphamide (CTX) and 1-Acetyl-2-phenylhydrazine (APH). Results: A total of 27 important bioactive ingredients meeting the ADME (absorption, distribution, metabolism, and excretion) screening criteria from SWP were selected. Interaction networks were constructed and validated based on the 10 associated ingredients with the relevant targets. A total of 125 biomarkers were found by Metabolomics approach, which associated with the development of AA, mainly involved in amino acid metabolism and lipid metabolism. While SWP can reverse the above 12 metabolites changed by AA. Network analysis revealed the synergistic effects of SWP through the 43 crucial pathways, including Sphingolipid signaling pathway, Sphingolipid metabolism, Arginine and proline metabolism, VEGF signaling pathway, Estrogen signaling pathway. Conclusion: The study suggested that SWP is a useful alternative for the treatment of AA induced by CTX + APH. Its potential mechanisms are to improve hematopoietic microenvironment and promote bone marrow hematopoiesis therapies.

Acquired aplastic anemia following SARS-CoV-2 vaccination.

COVID-19 is a potential life-threatening viral disease caused by SARS-CoV-2 and was declared a pandemic by the WHO in March 2020. mRNA-based SARS-CoV-2 vaccines are routinely recommended in immune-compromised patients, including patients with AA, as these patients are at increased risk of contracting COVID-19 and developing a more severe course of disease. Between March 2021 and November 2021 relapse of AA occurred in four (age [median]: 53 years, range 30-84 years) out of 135 patients currently registered at our department and two de novo cases of AA in temporal context to vaccination against SARS-CoV-2, were documented. Median time after first COVID-19 vaccination and relapse of AA was 77 days. All relapsed patients were vaccinated with the mRNA-based vaccine Comirnaty®. Relapse in two out of the four patients was refractory to CsA/eltrombopag, favoring IST with hATG/CsA or BMT, respectively. Our observations should prompt clinicians to take vaccine-induced relapse of AA or de novo AA after SARS-CoV-2 vaccination into account. Furthermore, careful clinical monitoring and vigilance for signs or symptoms that may indicate relapse of AA (e.g., bleeding complications) are indicated.

Eltrombopag as frontline treatment of aplastic anaemia in routine practice: implications on cost and efficacy.

The thrombopoietin mimetic eltrombopag (EPAG) is efficacious in clinical trials of newly diagnosed moderate (M), severe (S) and very severe (vS) aplastic anaemia (AA). Its use in routine practice and resource-constrained settings is not well described. Twenty-five men and 38 women at a median age of 54 (18-86) years with newly diagnosed AA treated consecutively in a 7-year period with EPAG (N = 6), EPAG/cyclosporine (CsA) (N = 33) and EPAG/CsA/anti-thymocyte globulin (ATG) (N = 24) were analyzed. Because EPAG was not reimbursed, peak doses ranged from 25 to 200 mg/day depending on affordability. EPAG/CsA-treated patients were older (median age: 61 years) with less severe AA (MAA, N = 15; SAA, N = 14; vSAA, N = 4), whereas EPAG/CsA/ATG-treated patients were younger (median age: 44 years) with more severe AA (MAA, N = 2; SAA, N = 12, vSAA, N = 10). The overall/trilineage response rates were 83%/50% for EPAG-treated patients; 79%/42% for EPAG/CsA-treated patients and 75%/63% for EPAG/CsA/ATG-treated patients. Adverse events included grade 1 liver derangement (N = 7) and grade 1 dyspepsia (N = 3). The 5-year overall survivals/failure-free survivals were 62%/80% for the entire cohort; 55%/75% for EPAG/CsA-treated patients and 82%/78% for EPAG/CsA/ATG-treated patients. EPAG showed robust efficacy in AA in routine practice. However, EPAG dosage and combinations remain to be optimized for AA of different severities.

Toxic hepatitis-associated aplastic anaemia after dual homeopathic remedies and Gymnema sylvestre use.

Hepatitis-associated aplastic anaemia (HAAA) is a rare condition characterised by onset of acute hepatitis which is followed by development of severe pancytopenia due to bone marrow failure within 6 months. This syndrome can be precipitated by acute viral infections, but the aetiology remains unknown in the majority. Drug-induced HAAA is extremely rare and has been reported with nutritional and dietary supplements in current literature. We report the first cases of ayurvedic herbal and homeopathic remedies-associated HAAA in two patients which proved fatal in both. Evaluation of patients with acute hepatitis and severe pancytopenia must include a detailed evaluation for complementary and alternative medicine use.

Current challenges of hematologic complications due to immune checkpoint blockade: a comprehensive review.

Immune checkpoint blockade has demonstrated durable clinical benefits in a variety of malignancies. These immune checkpoint inhibitors (ICIs) produce unwanted autoimmune reactions due to an impaired self-tolerance. Hematologic immune-related adverse events (heme-irAEs) have been increasingly reported in the literature with a reported fatality rate of 12%. In this review, we illustrate 3 cases treated at Johns Hopkins Hospital for ICI-induced agranulocytosis, aplastic anemia, and thrombocytopenia. We then summarize the available evidence regarding the incidence and prevalence of heme-irAEs. We identified immune thrombocytopenia and hemolytic anemia as the most commonly reported heme-irAEs which are more commonly observed with nivolumab therapy. Median time to onset of heme-irAEs varies between patients but occurs earlier with CTLA-4 inhibitors than with anti-PD-L1/PD-1 agents. We also describe the current challenges regarding the recurrence of heme-irAEs despite immune checkpoint blockade termination. We provide the available evidence supporting a mixed T-cell and B-cell immune-mediated response. Finally, we review the treatment algorithm of these complications and provide treatment alternatives to steroid-refractory cases.

Severe aplastic anemia after COVID-19 mRNA vaccination: Causality or coincidence?

The development of various autoimmune diseases has been reported after COVID-19 infections or vaccinations. However, no method for assessing the relationships between vaccines and the development of autoimmune diseases has been established. Aplastic anemia (AA) is an immune-mediated bone marrow failure syndrome. We report a case of severe AA that arose after the administration of a COVID-19 vaccine (the Pfizer-BioNTech mRNA vaccine), which was treated with allogeneic hematopoietic stem cell transplantation (HSCT). In this patient, antibodies against the SARS-CoV-2 spike protein were detected both before and after the HSCT. After the patient's hematopoietic stem cells were replaced through HSCT, his AA improved despite the presence of anti-SARS-CoV-2 antibodies. In this case, antibodies derived from the COVID-19 vaccine may not have been directly involved in the development of AA. This case suggests that the measurement of vaccine antibody titers before and after allogeneic HSCT may provide clues to the pathogenesis of vaccine-related autoimmune diseases. Although causality was not proven in this case, further evaluations are warranted to assess the associations between vaccines and AA.

Aplastic anemia secondary to tyrosine kinase inhibitor therapy in a patient with chronic myeloid leukemia.

INTRODUCTION: Nilotinib, as the second generation of tyrosine kinase inhibitor, has significant efficacy in patients with chronic myeloid leukemia resistant or intolerant to Imatinib. Aplastic anemia induced by tyrosine kinase inhibitors is an uncommon complication. CASE REPORT: A 34-year-old female case with CML in the chronic phase was treated with Imatinib in first-line therapy. Nilotinib was switched because of failure to achieve complete cytogenetic response at 6 months following Imatinib. Three years with Nilotinib, the patient developed a persistent pancytopenia grade 4 while a major molecular response was achieved. MANAGEMENT & OUTCOME: Nilotinib was discontinued. However, the hematologic finding of the patient had not recovered after three months. A bone marrow biopsy showed marked hypocellularity and fatty tissue without evidence of myelofibrosis. Immunosuppressive therapy was started. Unfortunately, the patient died due to septic and hemorrhagic shock nine months after Nilotinib interruption. According to Naranjo's algorithm, the causality relationship with the drug is probable with a score of 5. DISCUSSION: Aplastic anemia is an uncommon adverse event of tyrosine kinase inhibitors but it can be a fatal complication. The early diagnosis of aplastic anemia related to Nilotinib therapy is needed to avoid further detrimental effects of the drug.

Unexpected pancytopenia: Dasatinib induced aplastic anemia in chronic myeloid leukemia.

INTRODUCTION: The use of TKIs in CML has dramatically altered the natural course of the disease and improved outcomes for patients. TKIs overall have a very favorable safety profile. Dasatinib, a second generation TKI, is commonly used as a first-line treatment option in CML. CASE REPORT: We describe the first two reported cases of first-line dasatinib induced aplastic anemia in CML. In both patients, pancytopenia occurred within one year of diagnosis/starting dasatinib. Both bone marrow biopsies showed hypocellularity with mild fibrosis and persistent BCR-Abl1 positivity. MANAGEMENT & OUTCOME: Dose reduction was attempted without success in both patients. In one patient, multiple TKIs were trialed, while in the other, growth factor support was attempted; neither regimen was effective. Ultimately, the cytopenias associated with dasatinib were only resolved after immunosuppression in one patient and allogeneic stem cell transplant in the other patient. DISCUSSION: Prior reports have shown that aplasia/aplastic anemia can rarely be associated with imatinib and nilotinib. Here we show that dasatinib can lead to this phenomenon as well. This diagnosis should be considered in patients with CML who unexpectedly develop cytopenias.

Characterization and prognosis of temozolomide-induced aplastic anemia in patients with central nervous system malignancies.

BACKGROUND: Temozolomide-induced aplastic anemia (TIAA) is a rare but highly challenging complication of temozolomide (TMZ) therapy. Evidence describing prognosis, clinical characteristics, and treatment of this entity is very limited. METHODS: We performed a multicenter, 22-year observational cohort study of patients with central nervous system (CNS) malignancies treated with temozolomide who developed TIAA, retrospectively analyzing prognosis, complications, and recovery. TIAA was defined using adapted evidence-based severe aplastic anemia criteria incorporating profound cytopenias and a minimum duration (4 weeks) without hematologic recovery. RESULTS: Of 3821 patients with CNS malignancies receiving TMZ, 34 patients (0.89%) met criteria for TIAA. Onset was rapid, with 29 patients (85.3%) developing TIAA before completing a second TMZ cycle. 23 patients (67.6%) ultimately achieved a hematologic recovery. Patients without recovery were more likely to develop febrile neutropenia (72.7% vs. 30.4%, P = .03), infectious complications (45.5% vs. 8.7%, P = .02), require hospitalization (81.8% vs. 43.5%, P = .04), and die (100.0% vs. 60.9%, P = .02). Median overall survival from TIAA diagnosis was 752 days in patients achieving a partial hematologic recovery versus 28 days in those who did not (P < .0001). 29 patients (85.3%) received one or more hematopoietic growth factors; hematologic recovery rates were higher in patients receiving thrombopoietin receptor agonists (81.8% vs. 60.9%) but were not higher in patients receiving granulocyte colony-stimulating factors. CONCLUSIONS: TIAA occurs in <1% of patients receiving TMZ for CNS malignancies, but is highly morbid when it occurs and frequently fatal in the one-third of patients not achieving hematologic recovery. Thrombopoietin receptor agonists may improve the likelihood of a hematologic recovery.

Long-Term Patient-Customized Therapy for a Pathogenic EPO Mutation.

BACKGROUND: Recent advances in genomics have enabled the successful identification of a number of rare pathogenic mutations. Uncovering these mutations is essential as the first step towards devising a cure for the often debilitating and life-limiting diseases arising from them. For many of these mutations targeted agents do not yet exist. Here, we describe the case of a patient who has a novel pathogenic mutation in the erythropoietin (EPO) gene, which is essential for normal erythropoiesis, and who presented with a profound hypoplastic anemia. METHODS: The patient aged 5 months, was started on recombinant erythropoietin, at a standard dose of 500 units (50 U/kg) and subsequently 800 units three time weekly and her blood counts were monitored over 4 years. FINDINGS: A prompt response to the recombinant erythropoietin was found with an increase in hemoglobin levels to 12.8 g/dL and increase in red cell count to 4.89×106/uL. The patient became transfusion independent. The therapy enabled the patient to maintain a hemoglobin level in the normal range without any adverse effects and with no requirement for further blood transfusions. CONCLUSIONS: Patient-customized therapies can be highly effective in the treatment of rare genetic disorders and for many of these disorders effective treatment may already exist in the clinical domain, as described for the patient in this report. FUNDING: This work was supported by the New York Stem Cell Foundation (V.G.S.), a gift from the Lodish Family to Boston Children's Hospital (V.G.S.), and National Institutes of Health Grants R01 DK103794 and R01 HL146500 (V.G.S.).

A case of non-small cell lung cancer with danazol-dependent aplastic anemia induced by pembrolizumab.

Programmed cell death protein 1 immune checkpoint inhibitor is an effective treatment for non-small cell lung cancer. Although hematological immune-related adverse events induced by antiprogrammed-cell-death-protein-1 immunotherapy have been reported, they are rare, and there remain many unknowns. We report the case of a 77-year-old woman with non-small cell lung cancer and pembrolizumab-induced danazol-dependent aplastic anemia. Sixteen days after she received pembrolizumab with carboplatin and pemetrexed as first-line treatments, she developed pancytopenia, including severe thrombocytopenia (1 × 109/L) with oral bleeding, epistaxis, and systemic purpura. We initially diagnosed immune-related thrombocytopenia based on an elevated level of platelet-associated immunoglobulin G (922ng/107 cells), but her thrombocytopenia was refractory to prednisolone (1mg/kg) and thrombopoietin receptor agonists. We eventually diagnosed aplastic anemia based on the findings of bone marrow hypoplasia. Treatment with cyclosporine and danazol 300mg (7.5mg/kg) was initiated. Eighteen days later, her blood cell count increased, and we reduced danazol to 100mg. Twenty-four days after the reduction of danazol, her platelet count dropped again to 14 × 109/L; subsequently, increasing danazol improved her platelet count in a few days. Although aplastic anemia was recovered, she died owing to lung cancer progression. In this case, the thrombocytopenia was noticeable initially; however, pancytopenia appeared a month later, and we diagnosed her with aplastic anemia. Platelet counts improved rapidly with the use of danazol. No effective treatment has yet been established for aplastic anemia induced by antiprogrammed-cell-death-protein-1 immunotherapy, but our case suggests that danazol is an effective therapy.