肿瘤合并免疫性血小板减少症及免疫相关血细胞减少

The pathogenesis of immune thrombocytopenia (ITP) is complex and involves the dysregulation of immune cells, such as T and B lymphocytes, and several cytokines that promote the production of autoantibodies. In the context of cancer patients, ITP can occur in both primary and secondary forms related to anticancer therapies or the disease itself. Objective: In light of these data, we decided to prepare a literature review that will explain the classification and immunological determinants of the pathogenesis of ITP and present the clinical implications of this condition, especially in patients with cancer. Materials and methods: We reviewed the literature on immunological mechanisms, therapies, and challenges in treating ITP, particularly on cancer patients. Results: The results of the literature review show that ITP in cancer patients can be both primary and secondary, with secondary ITP being more often associated with anticancer therapies such as chemotherapy and immunotherapy. Innovative therapies such as TPO-RA, rituximab, Bruton’s kinase inhibitors, and FcRn receptor inhibitors have shown promising results in treating refractory ITP, especially in patients with chronic disease. Conclusions: ITP is a significant clinical challenge, especially in the context of oncology patients, where both the disease and treatment can worsen thrombocytopenia and increase the risk of bleeding complications. Treatment of oncology patients with ITP requires an individualized approach, and new therapies offer effective tools for managing this condition. Future research into immunological mechanisms may bring further advances in treating ITP and improve outcomes in cancer patients.

… may respond to therapy for immune thrombocytopenia. … IMMUNE THROMBOCYTOPENIA with accelerated platelet … Until recently, an association between immune thrombocytopenia …

… malignancies can also be associated with secondary immune thrombocytopenia. Due to the broad differential diagnosis associated with cancer related thrombocytopenia, a careful …

BACKGROUND Immune thrombocytopenia (ITP) is an autoimmune disease treated with immunosuppressive agents, thrombopoietin receptor agonists, immunomodulation drugs and/or splenectomy. Patients with ITP have been found to have increased risk ofhematological malignancies. Studies investigating stomach/liver cancer are contradictory and the risk of developing other solid tumors is largely unknown. We aimed at estimating risk of overall and organ-specific cancers in patients with primary ITP. METHODS The study population was Swedish patients with at least one ITP diagnosis recorded in the National Patient Register and a 1:10 matched comparison cohort from the population. The study period covers 1997-2016. The Cancer Register and the Cause of Death Register provided data on malignancies and deaths, respectively. Primary ITP was identified using an established algorithm. We used time-split Cox models to estimate hazard ratios (HRs) with 95 % confidence intervals (CIs), adjusted for age, sex, index-year, county, income, education, Charlson score and number of in- and outpatient contacts. RESULTS In total 66,134 individuals were included in the study. Patients with ITP had higher risk of gastro-intestinal, skin (all morphologies), lymphoid and hematological cancers. Adjusted HR (95 % CI) for cancer was 1.37 (1.27-1.48), with highest risk during the first year, but with increased risk remaining for up to 20 years for men. For women, the overall risk was increased during the first year, HR (95 % CI) 2.00 (1.55-2.60). A significantly increased liver cancer risk was seen up to 9 years after diagnosis. CONCLUSION Patients with primary ITP have higher risk of cancer than the population. The observed increased risk does not seem to be solely due to surveillance bias, but might be associated with ITP or its treatments. Treating hematologists need to have high index of suspicion for cancer.

Prostate cancer frequently metastasizes to bone, but bone marrow involvement is relatively less common. In advanced prostate cancer, significant bone marrow infiltration can result in hematologic abnormalities such as anemia and thrombocytopenia. We report the case of a patient who presented with a new diagnosis of thrombocytopenia at the same time that he presented with prostate cancer metastatic to bone. He was found to have immune thrombocytopenia (itp) which responded to treatment with steroids. We discuss this case and review the literature on itp in the setting of advanced malignancy.

… as immune thrombocytopenic purpura (ITP) or disseminated intravascular coagulation (DIC). In this context, particularly challenging is the condition of thrombocytopenic cancer patients …

Immune checkpoint inhibitors (ICI) are associated with unique immune-related adverse events (irAEs). Immune-related thrombocytopenia (irTCP) is an understudied and poorly understood toxicity; little data are available regarding either risk of irTCP or the effect of irTCP on clinical outcomes of patients treated with ICI. We conducted a retrospective review of sequential cancer patients treated with ICI between 2011 and 2017 at our institution. All patients who received ICI alone or in combination with other systemic therapy in any line of treatment were included; those with thrombocytopenia ≥ grade 3 at baseline were excluded. We calculated the incidence of ≥ grade 3 irTCP and overall survival (OS). Patient factors associated with irTCP were assessed. We identified 1,038 patients that met eligibility criteria. Overall, 89 (8.6%) patients developed grade ≥ 3 thrombocytopenia; eighteen were attributed to ICI (1.73% overall). Patients who developed grade ≥ 3 irTCP had worse overall survival compared to those whose thrombocytopenia was unrelated to ICI (4.17 vs. 10.8 month; HR. 1.94, 95% CI 1.13, 3.33; log-rank p = 0.0164). Patients with grade ≥ 3 irTCP also had worse survival compared to those without thrombocytopenia (4.17 vs. 13.31 months; HR 2.22, 95% CI 1.36, 3.62; log-rank p = 0.001). The incidence of irTCP appeared lowest among those treated with PD-1/L1 monotherapy (p = 0.059) and was not associated with cancer type, smoking status, age, gender, race, or line of therapy. Unlike other irAEs, we found that irTCP was associated with worse overall survival. The incidence of irTCP appeared lowest among those treated with PD-1/L1 monotherapy.

Immune checkpoint inhibitors (ICIs), including antibodies targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1), are being extensively used on advanced human malignancies therapy. The treatment with ICIs have acquired durable tumor inhibition and changed the treatment landscape in lung cancer. Immune-related adverse events including pneumonitis and thyroiditis have been well described, but less frequent events, such as ICIs-induced thrombocytopenia, are now emerging and may sometimes be severe or fatal. Since early detection and prompt intervention are crucial to prevent fatal consequences, it is of outmost importance that medical staff is aware of these potential toxicities and learn to recognize and treat them adequately. This review focuses on the epidemiology, clinical presentation, mechanisms, and clinical management of ICIs-induced thrombocytopenia in patients with lung cancer. We also present a patient with advanced lung adenocarcinoma who received the PD-L1 inhibitor atezolizumab and eventually developed severe thrombocytopenia. The case indirectly suggests that cytokine changes might contribute to immune dysregulation in ICIs-induced thrombocytopenia.

… of immune thrombocytopenia associated with immune … PD-1/PD-L1 inhibitor-induced immune thrombocytopenia: A … and outcome criteria in immune thrombocytopenic purpura of adults …

Abstract Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but are associated with immune-related adverse events (irAEs). Pembrolizumab, an anti-PD-1 antibody, is widely used in non-small cell lung cancer (NSCLC), yet immune thrombocytopenia remains a rare but potentially fatal complication. We report a case of a 55-year-old male with metastatic NSCLC who developed pembrolizumab-associated immune thrombocytopenia. The patient initially responded well to combination therapy with pembrolizumab, carboplatin, and pemetrexed, achieving a metabolic complete response. However, after several cycles, he experienced recurrent grade 3 thrombocytopenia. Immune thrombocytopenia was suspected and managed with corticosteroids, leading to platelet recovery. Upon pembrolizumab rechallenge, thrombocytopenia recurred, necessitating permanent discontinuation of pembrolizumab while continuing pemetrexed maintenance. This case underscores the need for early recognition and prompt management of ICI-induced thrombocytopenia to ensure patient safety while optimizing oncologic outcomes.

Immune checkpoint inhibitors, including antibodies targeting programmed cell death protein-1 (PD-1) and its receptor programmed cell death ligand-1 (PD-L1), represent promising therapeutic strategies for advanced human malignancies. However, a subgroup of patients experiences various autoimmune toxicities, termed immune-related adverse events (irAEs), that occur as a result of on-target and off-tumor autoimmune responses. Although irAEs are generally confirmed to be less severe than toxicities caused by conventional chemotherapy and targeted therapy, uncommon irAEs, such as immune thrombocytopenia, may occur with a very low incidence and sometimes be severe or fatal. This review focuses on the epidemiology, clinical presentation, and prognosis of immune thrombocytopenia occurring in advanced cancer patients induced by immune checkpoint inhibitors, especially in those with PD-1 or PD-L1 inhibitor treatment. We also first present one patient with non-small cell lung cancer who received the PD-L1 inhibitor durvalumab and developed severe thrombocytopenia.

Background Immune checkpoint inhibitors (ICIs), an enormous oncological breakthrough in the last 10 years, have become the standard treatments for several types of solid cancers. Although ICIs are generally well tolerated and result in favorable outcomes, they also cause unique immune-related adverse events (irAEs) across bodily systems and organs. Compared to most common irAEs, which occur in the endocrine, skin, pulmonary system, and gastrointestinal tract, haematological irAEs (haem-irAEs) are relatively rare but potentially life-threatening events that are occasionally irreversible and refractory. Currently, haem-irAEs are not sufficiently understood, management, and lack consensus, while other common irAEs have well been characterized and managed. The reports of ICI-related thrombocytopenia in small cell lung cancer (SCLC) are rarely seen. Hence, we reported a rare case of severe steriod-resistant ICI-related thrombocytopenia after received chemotherapy plus anti-PD-L1 inhibitor in SCLC patient. Our case exemplifies the diagnosis, diagnosis of exclusion, treatment, and prognosis of thrombocytopenia in the pattern of combination therapy, meanwhile, the subject of diagnosis, therapies, therapeutic strategies for refractory type and incidence, potential biomarkers, mechanisms and prognosis in ICI-related thrombocytopenia have been fully discussed. Case Description Herein, we present a 64-year-old man diagnosed advanced SCLC developed refractory immune-related severe thrombocytopenia, who achieved favorable outcomes of cancer following chemotherapy combined with atezolizumab administrated. Routine blood re-examination on the third day of 6th therapy showed a thrombocyte count of 11×109/L. Combined the medical history and the results of laboratory tests, the diagnosis of ICI-induced thrombocytopenia was confirmed. Despite large doses of methylprednisolone, immunoglobulin, and rituximab, intermittent platelet transfusion, thrombopoietin being administrated to the patient, there were no signs of platelet count and hemoglobin improvement. Currently, this is the first case about atezolizumab induced thrombocytopenia in SCLC patient, while there is extremely rare haem-irAEs reported in SCLC. Conclusions Although ICI-related severe thrombocytopenia is rare, it may persist or even be fatal. Clinicians should pay more attention to its diagnosis and prompt treatment. Once developed thrombocytopenia, large doses of methylprednisolone, ntermittent platelet transfusion, thrombopoietin should be timely administrated, also plasma exchange or rilzabrutinib, other immunosuppressive drugs, or IL-6 inhibitor warrant apply if steriod-resistant.

Oxaliplatin-induced immune thrombocytopenia is a rare manifestation of oxaliplatin hypersensitivity, presenting as an acute onset of severe thrombocytopenia after oxaliplatin administration. No standard therapeutic approach outside of permanent discontinuation of oxaliplatin exists. Here, we present a case of oxaliplatin-induced immune thrombocytopenia occurring after oxaliplatin retreatment for metastatic colon cancer. Possible mechanisms of disease and approach to treatment are discussed.

Antibodies targeting the receptor programmed death 1 on T cells have been approved for the treatment of lung cancer. Immune checkpoint inhibitors (ICIs) induce various immune-related adverse events. Life-threatening hematotoxicity can be provoked by ICI therapy. Although ICI-related endocrinopathy and interstitial lung disease have been well documented, hematotoxicity requiring intensive treatment is relatively rare. We describe a case of nivolumab induced thrombocytopenia after transient mild fever. A 77-year-old man with non-small cell lung cancer was administered nivolumab (240 mg/body, every 2 weeks) as second line therapy. On the day 2 after the first nivolumab infusion, he had a fever and his C-reactive protein level was elevated. Thoracic computed tomography revealed no interstitial lung disease or pneumonia. The fever resolved on day 9 and was not seen thereafter. On day 15 after the first nivolumab infusion, severe thrombocytopenia suddenly emerged. A bone marrow examination revealed no dysplasia or invasion. Based on the presence of high platelet-associated IgG titer, normal bone marrow plasticity and a lack of effectiveness of platelet infusion, we diagnosed nivolumab-induced immune thrombocytopenia. Daily administration of 60 mg of prednisolone restored the patient's platelet count and platelet-associated IgG. We also found that there was significant shrinkage of the primary lesion and that stable disease was achieved. One must be aware of this relatively rare side effect and the unusual clinical findings that could be associated with immunoreaction.

Improved medical care could have altered the clinical presentation and survival of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) complicated by autoimmune disease cytopenia (AID cytopenia). We reviewed the clinical characteristics, treatment, and outcome of AID cytopenia that was diagnosed in 75 (4.3%) of 1750 patients with CLL seen at a single institution over 10 years. When compared with the historical reported data, our study shows a lower rate of autoimmune hemolytic anemia (2.3%), and similar rates of immune thrombocytopenia (2.0%), and pure red blood cell aplasia (0.5%). AID cytopenia occurred at all stages of CLL, responded well to treatment, did not alter overall survival, and contributed to death in only 6 (12%) patients. We propose that more sensitive and accurate diagnostic methods for CLL have decreased the perceived prevalence of AID cytopenia and that improvements in management could have increased the survival of these patients.

… caused by aetiologies distinct from their CLL (eg another malignancy, iron deficiency, chronic … (A) Patients with autoimmune cytopenia (AID) had better survival from diagnosis of CLL (…

We analyzed prevalence, characteristics, clinical correlates, and prognostic significance of autoimmune cytopenia in patients with chronic lymphocytic leukemia. Seventy of 960 unselected patients (7%) had autoimmune cytopenia, of whom 19 were detected at diagnosis, 3 before diagnosis, and 48 during the course of the disease. Forty-nine patients had autoimmune hemolytic anemia, 20 had immune thrombocytopenic purpura, and 1 had both conditions. A clear association was observed between autoimmune cytopenia and poor prognostic variables (ie, high blood lymphocyte count, rapid blood lymphocyte doubling time, increased serum β-2 microglobulin level, and high expression of ζ-associated protein 70 and CD38). Nevertheless, the outcome of patients with autoimmune cytopenia as a whole was not significantly different from that of patients without this complication. Furthermore, no differences were observed according to time at which cytopenia was detected (ie, at diagnosis, during course of disease). Importantly, patients with advanced (Binet stage C) disease because of an autoimmune mechanism had a significantly better survival than patients in advanced stage related to a massive bone marrow infiltration (median survivals: 7.4 years vs 3.7 years; P = .02). These results emphasize the importance of determining the origin of cytopenia in patients with chronic lymphocytic leukemia for both treatment and prognostic purposes.

… GS and autoimmune cytopenia was frequently … associated autoimmune cytopenia was observed in 23.6% of cases. Thirty percent of the affected patients had several forms of cytopenia. …

… paper we show that autoimmune thrombocytopenia is not an uncommon complication in solid tumors. According to the recent proposal for the standardization of terminology of immune …

… In this study, we describe the prevalence of malignant lymphoma-associated autoimmune … Immune thrombocytopenia is a rare but well-described association of Hodgkin’s disease, …

… 4 yr prior to admittance due to pancytopenia. A diagnosis of RAEB was made, and … malignancy-associated vasculitides only rarely are accompanied by high levels of circulating …

Autoimmune cytopenia is frequently a presenting manifestation of common variable immune deficiency (CVID). Studies characterizing the CVID phenotype associated with autoimmune cytopenias have mostly been limited to large referral centers. Here, we report prevalence of autoimmune cytopenias in CVID from the USIDNET Registry and compare the demographics and clinical features of patients with and without this complication. Investigators obtained demographic, laboratory, and clinical data on CVID patients within the USIDNET Registry. Patients were considered to have autoimmune cytopenia if they had a diagnosis of hemolytic anemia, immune thrombocytopenia (ITP), or autoimmune neutropenia. Baseline characteristics and associated complications of those with autoimmune cytopenia (+AC) and those without (−AC) were compared. Of 990 CVID patients included in the analysis, 10.2% (N = 101) had a diagnosis consistent with autoimmune cytopenia: ITP was diagnosed in 7.4% (N = 73), hemolytic anemia in 4.5% (N = 45), and autoimmune neutropenia in 1% (N = 10). Age at diagnosis, gender, and baseline Ig values did not differ between the +AC and –AC groups. The +AC group was significantly more likely to have one or more other CVID-associated non-infectious complications (OR = 2.9; 95%-CI: 1.9–4.6, P < 0.001), including lymphoproliferation, granulomatous disease, lymphomas, hepatic disease, interstitial lung diseases, enteropathy, and organ-specific autoimmunity. Autoimmune cytopenias are a common manifestation in CVID and are likely to be associated with other non-infectious CVID-related conditions. In light of prior studies showing increased morbidity and mortality in CVID patients with such complications, a diagnosis of autoimmune cytopenia may have prognostic significance in CVID.

Immune-mediated cytopenia after allogeneic haematopoietic stem-cell transplantation is rare. The pathophysiology of immune-mediated anaemia, thrombocytopenia, and neutropenia, which occur alone or in combination with other cytopenias, is unclear and most probably a consequence of immune dysregulation. Risk factors for this complication have been identified in retrospective studies but these should be interpreted with caution and should not be generalised to this heterogeneous patient population. Diagnosis is challenging, requires awareness of such complications, and has to be differentiated from a multitude of other, and sometimes overlapping, possible complications. The clinical course of immune-mediated cytopenia is highly variable. Treatment requires an interdisciplinary approach and ranges from observation to symptomatic measures and directed therapies. Intensive immunosuppression is associated with an increased risk of infections and relapse, and current treatments are based on approaches in patients who have not undergone transplantation. Plasma cell-directed therapies, immunomodulation, and receptor-stimulating agents can be used to treat immune-mediated cytopenia.

Abstract Immune thrombocytopenia (ITP) can be associated with lymphoproliferative diseases (LPD) or solid tumors. A systematic review of published literature was conducted to evaluate response to treatment of ITP secondary to malignancy. Primary outcome was overall response (complete response+response) to first-line treatments [steroids alone or in combination with intravenous immunoglobulins (IVIg)]. Among secondary outcomes, overall response to second-line treatments [splenectomy, rituximab or thrombopoietin receptor agonists (TPO-RA)] and death were evaluated. Of the retrieved 238 text articles, 108 were analyzable, for a total of 154 patients: 142 in 105 case reports and 12 in 3 observational studies. Thirty-nine patients had solid tumors, 114 LPD, and 1 both. The median follow up was 19 months (IQR, 9–40). The overall response was 50% (62% in solid tumors, 46% in LPD) after steroids and 47% (67% in solid tumors, 36% in LPD) after steroids+IVIg, which are lower than historical responses observed in primary ITP (≈80%). The overall responses to rituximab (used in LPD only), splenectomy and TPO-RA (70%, 73% and 92%, respectively) were similar to those observed in primary ITP. Seven patients (6%) died due to bleeding events. ITP secondary to malignancy appears to be associated with unsatisfactory response to first-line treatments.

Immune thrombocytopenia (ITP) is a rare paraneoplastic syndrome of solid tumor malignancies. In previously described cases of renal cell carcinoma (RCC) associated with secondary ITP, treatment has consisted of nephrectomy, splenectomy, and corticosteroids. Here, we describe a case of metastatic RCC presenting with a right ventricular mass and subsequent development of secondary ITP. The clinical course was complicated by recurrent severe thrombocytopenia despite treatment with corticosteroids, rituximab, and thrombopoietin receptor agonists, precluding cancer-directed therapy and anticoagulation. Further study is needed to determine the optimal management strategy for malignancy-associated ITP.

The pathogenesis of immune thrombocytopenia (ITP) is increasingly being elucidated, and its etiology is becoming more frequently identified, leading to a diagnostic shift from primary to secondary ITP. The overlap between autoimmunity, immunodeficiency, and cancer is evident, implying more interdisciplinarity in daily care. This mini-review is based on an expert meeting on ITP organized by the Intercontinental Cooperative ITP Study Group and presents the challenges of hematologists in understanding and investigating “out of the box” concepts associated with ITP.

Immune thrombocytopenia (ITP) is an acquired autoimmune disease that occurs in adults and children. In Malaysia, the clinical practice guideline (CPG) for the management of ITP was issued in 2006, which focused almost exclusively on primary ITP (pITP), and only a few secondary ITP (sITP) forms were addressed. All published (twenty-three) sITP articles among children and adults in Malaysia, identified on the academic databases were retrieved. The articles were published between 1981 and 2019, at a rate of 0.62 publications per year. The publications were considered low and mainly focused on rare presentation and followed-up of secondary diseases. This review revealed that sITP in Malaysia is commonly associated with autoimmune diseases (Evan’s syndrome, SLE and WAS), malignancy (Kaposi’s sarcoma and breast cancer) and infection (dengue haemorrhagic fever, Helicobacter pylori and hepatitis C virus). The relationship between ITP and autoimmune diseases, malignancy and infections raise the question concerning the mechanism involved in these associations. Further studies should be conducted to bridge the current knowledge gap, and the further information is required to update the existing CPG of management of ITP in Malaysia.

Immune checkpoint inhibitors (ICIs) are a recent breakthrough in antitumor drugs, although their overall safety has not been fully defined. Compared to conventional chemotherapy, ICIs exhibit different patterns of immunotoxicity, and immune-related adverse events (irAEs) have an immunological basis that is more toxic than usual and have a broad spectrum of manifestations involving different organ systems. Early recognition of symptoms and timely intervention are very important in managing immunerelated adverse events (irAEs). In this study, we report a case of delayed immune thrombocytopenia in a patient treated with nivolumab for Small Cell Lung Cancer (SCLC). We found that thrombocytopenia was associated with the presence of platelet antibodies, autoantibodies, and thyroglobulin antibodies, accompanied by a decrease in the number of helper T cells and regulatory T cells. Platelets returned to normal after the removal of antibodies by plasma exchanges and methylprednisolone. We hypothesized that thrombocytopenia in patients was an antibody-driven and T-cell-mediated process. Although these observations indirectly suggest that cytokine changes contribute to immune dysregulation during irAE, prospective validation is needed to explain the confounding etiologies that may contribute to cytokine dysregulation. Therefore, studying the relationship between T cell subpopulations, cytokines and irAE in a larger population may be crucial for identifying biomarkers for ICI.

Few studies have investigated long‐term survival in patients with primary immune thrombocytopenia (pITP). Further, changes in prognosis over the past decades and prognosis of secondary immune thrombocytopenia (sITP) are largely unstudied. Our objectives were to study comorbidity‐adjusted prognostic changes and causes of death in chronic pITP and sITP patients.

Primary immune thrombocytopenic purpura (ITP) remains a diagnosis of exclusion both from nonimmune causes of thrombocytopenia and immune thrombocytopenia that develops in the context of other disorders (secondary immune thrombocytopenia). The pathobiology, natural history, and response to therapy of the diverse causes of secondary ITP differ from each other and from primary ITP, so accurate diagnosis is essential. Immune thrombocytopenia can be secondary to medications or to a concurrent disease, such as an autoimmune condition (eg, systemic lupus erythematosus [SLE], antiphospholipid antibody syndrome [APS], immune thyroid disease, or Evans syndrome), a lymphoproliferative disease (eg, chronic lymphocytic leukemia or large granular T-lymphocyte lymphocytic leukemia), or chronic infection, eg, with Helicobacter pylori, human immunodeficiency virus (HIV), or hepatitis C virus (HCV). Response to infection may generate antibodies that cross-react with platelet antigens (HIV, H pylori) or immune complexes that bind to platelet Fcγ receptors (HCV) and platelet production may be impaired by infection of megakaryocyte bone marrow-dependent progenitor cells (HCV and HIV), decreased production of thrombopoietin (TPO), and splenic sequestration of platelets secondary to portal hypertension (HCV). Sudden and severe onset of thrombocytopenia has been observed in children after vaccination for measles, mumps, and rubella or natural viral infections, including Epstein-Barr virus, cytomegalovirus, and varicella zoster virus. This thrombocytopenia may be caused by cross-reacting antibodies and closely mimics acute ITP of childhood. Proper diagnosis and treatment of the underlying disorder, where necessary, play an important role in patient management.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment and prognosis of a variety of solid tumors. However, exaggerated immune activation can lead to immune-related adverse events (irAEs), among which hematologic irAEs remain poorly characterized. This study evaluated the frequency, spectrum, and risk factors of treatment-emergent cytopenia in patients with melanoma, renal cell carcinoma (RCC), and urothelial carcinoma (UCC) treated with ICIs. We retrospectively reviewed patients at the American University of Beirut Medical Center who received at least one dose of ICIs between January 2019 and January 2024. Clinical, treatment, and laboratory data were collected from electronic medical records. Binary logistic regressions assessed the relationships between potential predictors and development of treatment-emergent cytopenia. The primary outcome of interest was the incidence of at least one treatment-emergent cytopenia. We included 153 patients (median age 68.21 years, 64.7% male, mean BMI 27.6 ± 4.32 kg/m²) receiving ICIs for melanoma (27.45%), RCC (27.45%), or UCC (45.09%). Pembrolizumab (52.94%) and nivolumab (23.52%) were the most used ICIs, with 28.1% receiving combination therapy. Initially, 47.05% of patients had pre-treatment anemia (mostly grade 1), while thrombocytopenia was rare (5.9%, all grade 1), and no patients had neutropenia. Following initiation with ICIs, 61.43% (94/153) experienced at least one new-onset or worsening treatment-emergent cytopenia. Most common were anemia (46.4%), followed by thrombocytopenia (27.45%) and neutropenia (26.14%). Pancytopenia occurred in 15.6% and bicytopenia in 18.3%. Median time to first hematologic disturbance was 1.39 months (mean 4.71 months, IQR (Long et al., Ann Oncol, 35:1191-1199, 2024); (Motzer et al., N Engl J Med, 378:1277-1290, 2018); (Gupta et al., ESMO Open, 10:104506, 2025), ~ 5.8 cycles). Most treatment-emergent cytopenia were grade 1 (71.24%), fewer grade 2 (20.26%) and 3 (8.49%). There was no grade 4 or 5 events or hematology-related fatalities. Supportive treatment included transfusions in 22.22% and (granulocyte colony-stimulating factor (G-CSF) administration in 12.41%; no patient required steroids, IVIG, or treatment discontinuation due to hematologic irAEs. Univariate regression analysis evaluating the predictors of developing at least one treatment-emergent cytopenia showed that lower baseline hemoglobin and a history of anemia were significant factors (p < 0.001; OR = 0.56 and p < 0.002; OR = 6.50, respectively). Additionally, regression analysis showed that baseline hemoglobin (OR 0.42, p < 0.001) and eosinophil count (OR 1.42, p = 0.004) were significant predictors of anemia and thrombocytopenia, respectively. On multivariable analysis, hemoglobin emerged as a significant predictor, with HGB showing an OR of 0.91 (95% CI: 0.869–0.963, p = 0.001). Although usually rare in literature, we found treatment-emergent cytopenia to be common but mild and manageable with ICIs. Early monitoring and supportive care are key.

Chimeric antigen receptor T-cell (CAR T-cell) therapy has revolutionized the treatment of lymphoid malignancies. Prolonged cytopenias, though poorly understood, have emerged as important considerations in the treatment process. In this review, we classified cytopenias into early (< 30 days post CAR T infusion), and late-occurring (after day 30 post infusion). We identified previous chemotherapy and lymphodepletion chemotherapy as the major risk factors contributing to early cytopenia. Product characteristics, such as costimulatory domains, and side effects of therapy such as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) were identified as contributing factors to prolonged cytopenias occurring more than 30 days post CAR-T infusion. We recommend close monitoring with frequent checks, enhanced care with granulocyte colony stimulating factor (GCSF) support for grade 3-4 neutropenia, blood transfusion for severe anemia (Hb < 7g/dL), platelets for severe thrombocytopenia (< 10,000/µL) and thrombopoietin (TPO) mimetics such as eltrombopag or romiplostim for prolonged severe thrombocytopenia in patients at high-risk of hemorrhagic complications.

Inborn errors of immunity (IEI) are often associated with higher cancer risks, especially lymphoma, and genetic predispositions underlie many hematologic malignancies. Cytopenias following cancer treatment may occur sporadically or persist due to incomplete immune reconstitution. Recent findings suggest these abnormalities may indicate a previously undiagnosed IEI. Data on the prevalence and long-term follow-up of cytopenias in childhood cancer survivors (CCSs) remain limited. To evaluate the prevalence of persistent cytopenias (PCs) in a cohort of CCSs followed at our late effects clinic (IRCCS Giannina Gaslini) and describe their clinical, immunologic, and genetic characteristics. PCs were defined as those lasting over 12 months post-treatment or starting 6-12 months post-treatment and lasting over a year. CNS tumor survivors and those treated with allogenic marrow transplantation were excluded. Immunological and genetic analysis (NGS of 162 IEI genes or WES) were performed in patients with PC. Twenty (2.7%) out of 751 eligible CCSs (including 304 hematologic malignancies) showed PC, which was more common in patients with hematologic malignancies history (p < 0.00001). Patient characteristics and PC type are shown in Figure 1A. During follow-up, 6/20 patients developed autoimmune signs (10% incidence at 5 years, Figure 1B) at a median of 6.0 years post-treatment, 3/20 showed concomitant benign lymphoproliferation (EBV related in 1 case). Peripheral lymphocyte subsets revealed decreased B-memory and T-regulatory cells, increased activated δγ/HLADR+ T cells and B-naïve cells, and a shift to memory T cells (Figure 1C). Figure 1. Features of 20 CCSs with persistent cytopenia (A), cumulative incidence of autoimmune phenomena (B), and lymphocyte subpopulations (C). 12/20 patients were screened by genetic analysis, which in 6/12 (50%) of them showed pathogenic variants in TNFRSF13B, MAGT1, ITK, CEBPA, AIRE, and SAMD9 genes, related to auto/dysimmunity. 3/6 further developed subsequent neoplasms (SNs) (lymphomas, sarcoma, and giant-cell carcinoma). In our cohort, the prevalence of PC following cancer treatment is overall low but higher in CCSs treated for hematologic malignancies, a finding consistent with the literature. PC may suggest underlying IEI, especially when associated with features like autoimmunity, peculiar immunophenotype, and lymphoproliferation. Careful and prolonged follow-up is necessary for the potential development of autoimmunity and SNs. Further studies are needed to confirm these findings and broaden their application to all CCSs with post-treatment immunologic abnormalities.

… Here, we describe a case of oxaliplatin-induced immune-mediated cytopenia after a prolonged exposure to the agent. Immune-mediated thrombocytopenia was strongly suspected as …

Background:Anti-programmed cell death 1 antibody nivolumab is a promising agent for various cancers. Immune-related adverse events are recognized; however, bi-cytopenia with nivolumab has not been reported. Case presentation:A 73-year-old man was diagnosed with advanced primary malignant melanoma of the esophagus with liver, lung, and lymph node metastases. Previous therapies including dacarbazine and radiation of 39 Gy to the esophageal region were performed, but the liver metastases deteriorated. The patient was then administered nivolumab (2 mg/kg, every 3 weeks). After 3 cycles, the esophageal tumor and lymph nodes showed marked reductions in size, the lung metastases disappeared, and the liver metastases shrank partially. The treatment continued with 7 cycles for 4 months. However, severe anemia and thrombocytopenia appeared in the 6th cycle, and intermittent blood transfusions were required. The patient received high-dose intravenous methylprednisolone therapy for bi-cytopenia, but it was ineffective. Seven months after the initiation of nivolumab, the patient died of tumor. Although the mechanisms of bi-cytopenia were unclear, it could have been induced by nivolumab. Conclusion:The present case shows a rare but serious life-threatening bi-cytopenia possibly associated with nivolumab and suggests the importance of awareness of hematological adverse events during nivolumab therapy.

Summary. The aim of the study was to determine peculiarities of the distribution, diagnosis and development of immune cytopenias in patients with chronic lymphocytic leukemia (CLL) and to evaluate the efficacy of the different therapeutic approaches. Materials and Methods: Treatment response and survival of 83 patients with CLL complicated by immune cytopenia (IC) were analyzed. Treatment schedules in 58 medicated patients included corticosteroids; chemotherapy (COP, CHOP regimens), immunotherapy (rituximab alone), immunochemotherapy (rituximab-containing regimens — R-COP, R-CHOP). Twenty-five patients underwent splenectomy. Results: The use of corticosteroids, as the first line of treatment, resulted in short-term remission in most patients. Chemotherapy was effective in a half of CLL patients, but duration of the remission did not exceed 32 months in CLL associated with autoimmune hemolytic anemia and immune thrombocytopenia. After rituximab monotherapy (10 patients) the stable remission was reached in 60% of the patients with median relapse-free survival of 40 months. Rituximab containing chemotherapy (22 patients) caused the long-term remission in 72% of the patients with median relapse-free survival of 76 months. Splenectomy performed in 25 patients with CLL complicated by IC was effective in 70% of the patients. The outcome of splenectomy depends on IC entity. The best response was registered in associated immune thrombocytopenia (median overall survival 118 months), the worst — in Fisher — Evans syndrome (15 months). Conclusions: The treatment of patients with CLL complicated by ICs should be individualized. For CLL patients without significant enlargement of lymph nodes and spleen, low lymphocytosis, associated with autoimmune hemolytic anemia or immune thrombocytopenia, the monotherapy with rituximab is optimal. In case of occurrence of autoimmune hemolytic anemia, immune thrombocytopenia or Fisher — Evans syndrome in CLL patients with enlargement of lymph nodes, spleen, significant lymphocytosis, the use of R-COP or R-CHOP schemes, 4–6 courses, is the most effective. Splenectomy is indicated in patients with massive splenomegaly, the resistance to medication, recurrent relapses after adequate therapy.

Immune checkpoint inhibitors (ICIs) targeting CTLA-4, PD-1, and PD-L1 have transformed cancer therapy but may trigger rare, sometimes fatal hematologic immune-related adverse events (irAEs). The most frequent hematologic irAEs are anemia, thrombocytopenia, and pancytopenia, which occur more often with CTLA-4 inhibitors and in patients receiving combination therapy. Risk is heightened when ICIs are combined with chemotherapy or radiation. Common symptoms include fatigue, abnormal bleeding, easy bruising, and recurrent infections. Diagnosis relies on laboratory studies, histologic evaluation, and review of medication history. Management typically involves ICI discontinuation and immunosuppression with corticosteroids or rituximab; adjunctive options include IVIG, transfusions, or plasmapheresis depending on severity. Research is also exploring cytokines such as IL-2, IL-7, and IL-15 for ICI-related lymphopenia. Current evidence is drawn mainly from case reports and small series, highlighting the need for larger studies to clarify incidence, mechanisms, and optimal management. Recent pharmacovigilance and outcomes data confirm these events remain rare and can present late, underscoring the need for long-term surveillance and robust monitoring systems [Fletcher K and Johnson DB 2024; Durbin SM et al. 2025; Yang Y. et al. 2024; Han X. et al. 2025].

Cancer immunotherapy via immune-checkpoint inhibition (ICI) by antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and cell death protein 1 (PD-1) have significantly improved the outcome of metastasized melanoma and of a rapidly increasing number of other cancer types. The anti-tumor effect is often accompanied by immune-related adverse events (irAE). Hematological irAE, specifically neutropenia, are rarely observed. However, neutropenia is associated with high morbidity and mortality due to infection complications. Thus, early detection and treatment is crucial. We present the clinical course of two patients with severe neutropenia after ICI therapy and demonstrate the difficulty of the diagnosis when a comedication of metamizole, a well-known analgesic drug used to treat cancer pain, is present. Further, we provide a comprehensive descriptive and statistical analysis of published data on diagnostics, treatment and infection complication in patients with at least grade 4 neutropenia by a systematic database search. Finally, 34 patients were analyzed, including the two case reports from our cohort. The median onset of neutropenia was 10.5 weeks after first ICI administration (interquartile range: 6 weeks). In 76% (N = 26), a normalization of the neutrophil count was achieved after a median duration of neutropenia of 13 days. In a subsample of 22 patients with detailed data, the infection rate was 13%, proven by positive blood culture in 3 cases, but 68% (N = 15) presented with fever > 38 °C. Treatment regime differed relevantly, but mainly included G-CSF and intravenous corticosteroids. Death was reported in 14 patients (41%), 3 of whom (9%) were associated with hematological irAE but only two directly associated with neutropenia. With an increasing number of cancer patients eligible to ICI therapy, the incidence of severe hematological toxicities may rise substantially over the next years. Clinicians working in the field of cancer immune therapies should be aware of neutropenia as irAE to provide immediate treatment.

The existing data with regard to immune-related neutropenia (irN), a rare (incidence—1%) immune-related adverse event of immune checkpoint inhibitors, are scarce. Eight patients with irN were identified through internal databases of 3 participating Israeli cancer centers. In addition, 11 original articles focusing on the clinical course of 24 patients with irN were selected during the PubMed search. Descriptive analysis of clinical and pathologic factors related to irN was performed (n=32); the effect of these on the irN outcomes was assessed. An algorithm for irN evaluation and treatment was proposed. The median time-to-onset of irN (n=32) was 60 days (range, 10–465 d). Grade 3–5 irN, febrile neutropenia, and irN-related death occurred in 81%, 50%, and 9% of patients, respectively. In all, 56%, 22%, 62%, and 25% of patients received PO corticosteroids, IV corticosteroids, granulocyte colony–stimulating factor (GCSF), and intravenous immunoglobulins (IVIG), respectively, with an improvement/resolution rate of 84%. Odds ratios for irN improvement/resolution were as follows: 1.40 [95% confidence interval (CI), 0.03–68.72], 0.43 (95% CI, 0.04–4.22), 2.60 (95% CI, 0.07–97.24), 0.36 (95% CI, 0.03–4.38), 4.02 (95% CI, 0.16–99.48), 2.01 (95% CI, 0.32–12.70), 1.08 (95% CI, 0.02–49.89), 0.42 (95% CI, 0.06–2.91), and 2.73 (95% CI, 0.42–17.51) for granulocyte hyperplasia, granulocyte/all lineage hypoplasia, granulocyte maturation blockade, lymphocyte infiltration on bone marrow biopsy, IV corticosteroids, PO corticosteroids, cyclosporine, IVIG, and GCSF, respectively (P>0.05 for all factors). IrN recurrence rate following immune checkpoint inhibitors rechallenge was 80%. IrN is a rare, life-threatening, early-onset immune-related adverse event. Differentiating between the central, peripheral, and modified peripheral types allows a better prognosis definition. Corticosteroids and GCSF represent the main treatment approaches; IVIG and cyclosporine should be used as salvage treatment.

There has been less volume of literature focusing on the Immune-related Hematological Adverse Drug Events (Hem-irAEs) of Immune Checkpoint Inhibitors (ICPis) in cancer patients. Furthermore, there has been no consensus about the management of hematological toxicity from immunotherapy in the recently published practice guidelines by the European Society for Medical Oncology (ESMO). We conducted a systematic review of case reports/series to describe the diagnosis and management of potentially rare and unrecognized Hem-irAEs. We searched Medline, OVID, Web of Science for eligible articles. Data were extracted on patient characteristics, Hem-irAEs, and management strategies. We performed quality assessment using the Pierson-5 evaluation scheme and causality assessment using the Naranjo scale. Our search retrieved 49 articles that described 118 cases. The majority of patients had melanoma (57.6%) and lung cancer (26.3%). The most common Hem-irAEs reported with ICPis (such as nivolumab, ipilimumab, and pembrolizumab) were thrombocytopenia, hemolytic and aplastic anemias. Less reported adverse events included agranulocytosis and neutropenia. Steroids were commonly used to treat these adverse events with frequent success. Other used strategies included intravenous immunoglobulins (IVIG), rituximab, and transfusion of blood components. The findings of this review provide more insights into the diagnosis and management of the rarely reported Hem-irAEs of ICPis.

INTRODUCTION With the increasing use of checkpoint inhibitors, rare immune-related adverse events (irAE) are being identified. Haematological irAE (hem-irAE) are difficult to treat and have shown high mortality rates. In order to improve side-effect management for these potentially life-threatening events, we analysed frequency, severity and outcomes. PATIENTS AND METHODS Patients who developed hem-irAE while being treated with immune checkpoint inhibitors (ICI) therapy were retrospectively identified from 18 international cancer centres. RESULTS In total, more than 7626 patients treated with ICI were screened, and 50 patients with hem-irAE identified. The calculated incidence amounts to 0.6% and median onset was 6 weeks after the ICI initiation (range 1-128 weeks). Thrombocytopenia and leucopaenia were the most frequent hem-irAE with 34% (17/50) and 34% (17/50), respectively, followed by anaemia 28% (14/50), hemophagocytic lymphohistiocytosis (4% (2/50)), aplastic anaemia (2% (1/50)), acquired haemophilia A (2% (1/50)) and coagulation deficiency (2% (1/50)). Simultaneous thrombocytopenia and neutropenia occurred in two patients, concurrent anaemia and thrombocytopenia in one patient. Other than cessation of ICI (in 60%) and corticosteroids (in 78%), treatment included second-line immunosuppression in 24% of cases. Events resolved in 78% (39/50), while 18% (9/50) had persistent changes, and 2% (1/50) had fatal outcomes (agranulocytosis). CONCLUSION Hem-irAE can affect all haematopoietic blood cell lineages and may persist or even be fatal. Management may require immunosuppression beyond corticosteroids. Although these irAE are rare, treating physicians should be aware, monitor blood counts regularly and promptly act upon detection.

… as autoimmune cytopenias, the pathophysiology in the post-allogeneic HCT setting is not clearly allo- or auto-immune, hence our preference for the term immune-mediated cytopenias. …

Simple Summary Data on immune checkpoint inhibitor (ICI)-related cytopenias are scarce. The aim of the study was to further characterize grade ≥ 2 ICI-related cytopenias using the French pharmacovigilance database. Immune thrombocytopenia and autoimmune hemolytic anemia were the most frequently reported ICI-related cytopenias (50.7% and 25.3%, respectively). Nearly half were grade ≥ 4, and 4.4% of patients died from cytopenia-related complications. Using the French pharmacovigilance database, this study provides a comprehensive analysis of ICI-related cytopenias that are rare but potentially life-threatening adverse drug reactions. Early recognition and timely initiation of appropriate treatment are key in their management in clinical practice. Abstract Immune checkpoint inhibitor (ICI)-related cytopenias have been poorly described. This study aimed to further characterize ICI-related cytopenias, using the French pharmacovigilance database. All grade ≥ 2 hematological adverse drug reactions involving at least one ICI coded as suspected or interacting drug according to the World Health Organization criteria and reported up to 31 March 2022, were extracted from the French pharmacovigilance database. Patients were included if they experienced ICI-related grade ≥ 2 cytopenia. We included 68 patients (75 ICI-related cytopenias). Sixty-three percent were male, and the median age was 63.0 years. Seven patients (10.3%) had a previous history of autoimmune disease. Immune thrombocytopenia (ITP) and autoimmune hemolytic anemia (AIHA) were the most frequently reported (50.7% and 25.3%, respectively). The median time to onset of ICI-related cytopenias was 2 months. Nearly half were grade ≥ 4, and three patients died from bleeding complications of refractory ITP and from thromboembolic disease with active AIHA. Out of 61 evaluable responses, complete or partial remission was observed after conventional treatment in 72.1% of ICI-related cytopenias. Among the 10 patients with ICI resumption after grade ≥ 2 ICI-related cytopenia, three relapsed. ICI-related cytopenias are rare but potentially life-threatening. Further studies are needed to identify risk factors of ICI-related cytopenias.

Immune checkpoint inhibitors (ICIs) have become an important treatment modality for various malignancies. Due to excessive inflammatory and immune responses, immune-related adverse events (irAEs), such as rash, pruritis, pneumonitis, hepatitis, hypothyroidism, hyperthyroidism and fatigue, can occur. Acquired immune thrombocytopenia is a rare irAE that can lead to severe low platelet counts and hemorrhage. A retrospective observational analysis was conducted on data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS). We searched for all reports recorded in the FAERS covering the period from 2011 Q1 to 2023 Q4 for target agents. Signal analysis was performed using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN) and multi-item gamma Poisson shrinker (MGPS) algorithm. Nonparametric tests were used to compare the time to onset of thrombocytopenia-associated fractures between different regimens. There were 404 reports of immune thrombocytopenia in the FAERS database. Immune thrombocytopenia was associated with all ICIs except tremelimumab, and signals were detected by all 4 methods. The median time to the onset of immune thrombocytopenia caused by PD-1, PD-L1 and CTLA-4 inhibitors was 47 days (range: 21-139.2), 21 days (range: 13–131) and 9 days (range: 7–27), respectively. The Weibull shape parameter test revealed that pembrolizumab-, durvalumab-, and ipilimumab-induced thrombocytopenia had a random failure-type profile, and nivolumab- and atezolizumab-induced thrombocytopenia were characterized by an early failure-type profile. There was a significant reporting signal of ICI-induced thrombocytopenia associated with most ICIs. Immune thrombocytopenia has a greater incidence in males, elderly individuals and Asian populations, and PD-1 inhibitors were the most common cause. Clinicians should be aware of the signs of potential serious adverse events.

Immune checkpoint inhibitors (ICIs) have been widely adopted in the treatment of malignant tumors, and their durable antitumor effects have revolutionized cancer therapy. Immune checkpoint inhibitor‐induced thrombocytopenia (ICIIT) represents a rare but potentially severe or even fatal hematologic toxicity associated with immunotherapy. Therefore, it is imperative for healthcare professionals to recognize this potential adverse event and to understand its identification and management. However, the pathophysiological mechanisms underlying ICIIT remain incompletely understood, and both its diagnosis and treatment pose significant challenges. This review summarizes current knowledge on the epidemiology, prognosis, diagnosis, pathogenesis, and clinical management strategies of ICIIT. The findings of this review may serve as critical evidence to aid clinicians in the recognition and treatment of ICIIT and to inform future research efforts. Subsequent studies should aim to identify predictive biomarkers and develop novel therapeutic approaches to improve patient outcomes.

INTRODUCTION Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) are used for a variety of cancers and are associated with a risk of developing immune-related adverse events, most commonly dermatitis, colitis, hepatitis, and pneumonitis. Immune-mediated hematologic toxicities have been reported, but are less well-described in the literature. Immune thrombocytopenia (ITP) is a rare autoimmune, hematologic adverse event that has been reported with PD-1/PD-L1 inhibitors. METHODS We performed a retrospective observational analysis of the United States Food and Drug Administration Adverse Event Reporting System (FAERS) data. We searched for cases of ITP reported with exposure to PD-1/PD-L1 inhibitors from initial FDA approval for each agent to September 30, 2022. Disproportionality signal analysis was done by calculating the reporting odds ratio (ROR). Oxaliplatin was used as a positive control for sensitivity analysis as it is an anticancer therapy that has been associated with drug-induced ITP. A systematic review of the PubMed database was also conducted to identify published cases of PD-1/PD-L1 inhibitor-induced ITP. RESULTS There were 329 reports of ITP with ICIs in the FAERS database that were reviewed for a disproportionality signal, including atezolizumab (n = 27), durvalumab (n = 17), nivolumab (n = 160), and pembrolizumab (n = 125). The ROR was significant for atezolizumab (ROR 5.39, 95 % CI 3.69-7.87), avelumab (ROR 10.32, 95 % CI 4.91-21.69), durvalumab (ROR 7.91, 95 % CI 4.91-12.75), nivolumab (ROR 9.76, 95 % CI 8.34-11.43), and pembrolizumab (ROR 12.6, 95 % CI 10.55-15.06). In our systematic review, we summated 57 cases of ICI-induced ITP. Nivolumab and pembrolizumab had the most reported cases of ITP in the literature. Most cases reported (53 %) included ITP-directed therapies beyond corticosteroids for the management of ICI-induced ITP. CONCLUSION There is a significant reporting signal of ITP with several ICI agents. Clinicians should be aware of and monitor for signs of this potentially serious adverse event.

Immune checkpoint inhibitors (ICIs) have achieved significant success in cancer treatment, yet their associated adverse effects, particularly ICI-related thrombocytopenia (irTCP), are gaining increasing attention. IrTCP leads to serious complications, which affect treatment outcomes and quality of life. Clinical manifestations of irTCP may vary from mild to severe, necessitating careful monitoring during ICIs therapy. To date, several immune-mediated mechanisms, including the destruction of platelets and bone marrow suppression, have been revealed to play crucial roles in the pathogenesis of irTCP. Despite advancements in understanding these mechanisms, challenges remain in the timely diagnosis and effective management of irTCP. In this review, we synthesize the latest findings in the field and elucidate the mechanisms, clinical manifestations, diagnostic approaches, and management strategies of irTCP, aiming to provide insights for clinical practice and future research directions.

Immune-related hematological adverse events are amongst the rare but potentially life-threatening complications of immune checkpoint inhibitors. The spectrum of these toxicities is broadening as the number of patients exposed to these agents is increasing. Yet, they are still relatively unknown to many clinicians, possibly due to a lack of specific diagnostic criteria, which poses a challenge for their recognition and proper reporting, and partly due to their low incidence, often too low to be noted in most clinical trial publications. Since early detection and prompt intervention are crucial to prevent fatal consequences, it is of outmost importance that medical staff and patients be aware of these potential toxicities and learn to recognize and treat them adequately. This publication outlines strategies and offers guidance on the detection, diagnosis, risk assessment, monitoring and management of immune-related thrombocytopenia, a relatively common example of immune-related hematological toxicity of immune checkpoint inhibitors.

… ) induced by immune checkpoint inhibitors (ICIs) are uncommon. Immune thrombocytopenia (… and keywords included nivolumab, PD-1 inhibitors, immune checkpoint inhibitors, immune …

Additional supporting information may be found online in the Supporting Information section at the end of the article. Table SI. Haematological, cardiac, and renal response in evaluable patients treated with venetoclax. ORR, overall response rate; CR, complete response; VGPR, very good partial response PR, partial response; SD stable disease; PD, progressive disease. Table SII. Adverse events reported during treatment with venetoclax, as recorded according to the Common Terminology Criteria for Adverse Events version v5.0. Fig S1. Overall survival, estimated by Kaplan Meier curve, from the time of venetoclax initiation to death.

Introduction: An increasing number of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) have been reported during clinical treatment. We aimed to explore the clinical characteristics of patients with ICIs-induced ITP under different therapeutic strategies based on the FAERS database and explore the potential biological mechanisms in combination with TCGA pan-cancer data. Methods: Data from FAERS were collected for ICIs adverse reactions between January 2012 and December 2022. Disproportionality analysis identified ICIs-induced ITP in the FAERS database using the reporting odds ratio (ROR), proportional reporting ratio (PRP), Bayesian confidence propagation neural network (BCPNN), and multi-item gamma Poisson shrinker algorithms (MGPS). The potential biological mechanisms underlying ITP induced by ICIs were examined using TCGA transcriptome data on cancers. Results: In the FAERS, 345 ICIs-induced ITP reports were retrieved, wherein 290 (84.06%) and 55 (15.94%) were reported as monotherapy and combination therapy, respectively. The median age of the reported patients with ICIs-induced ITP was 69 years (IQR 60-76), of which 62 (18%) died and 47 (13.6%) had a life-threatening outcome. The majority of reported indications were lung, skin, and bladder cancers, and the median time to ITP after dosing was 42 days (IQR 17-135), with 64 patients (43.5%) experiencing ITP within 30 days of dosing and 88 patients experiencing ITP in less than 2 months (59.9%). The occurrence of ICIs-induced ITP may be associated with ICIs-induced dysregulation of the mTORC1 signaling pathway and megakaryocyte dysfunction. Conclusion: There were significant reporting signals for ITP with nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab/ipilimumab, and pembrolizumab/ipilimumab. Patients treated with anti-PD-1 in combination with anti-CTLA-4 are more likely to have an increased risk of ICIs-induced ITP. Patients with melanoma are at a higher risk of developing ITP when treated with ICI and should be closely monitored for this risk within 60 days of treatment. The potential biological mechanism of ICIs-induced ITP may be related to the dysfunction of megakaryocyte autophagy through the overactivation of the mTOR-related signaling pathway. This study provides a comprehensive understanding of ICIs-induced ITP. Clinicians should pay attention to this potentially fatal adverse reaction.

This Review Series, edited by past Associate Editor Catherine Bollard, looks at the role of immunotherapy in nonmalignant hematologic diseases. These 3 state-of-the-art reviews focus on the role of complement and complement inhibitors across a spectrum of diseases, the special immunologic challenges of hematopoietic stem cell transplant for nonmalignant diseases where patients have an intact immune system, and the hematologic complications of immune checkpoint inhibitors.

BackgroundImmune checkpoint inhibitors, including antibodies against programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), are being used with increasing frequency for the treatment of cancer. Immune-related adverse events (irAEs) including colitis, dermatitis, and pneumonitis are well described, but less frequent events are now emerging with larger numbers of patients treated. Herein we describe the incidence and spectrum of thrombocytopenia following immune checkpoint inhibitor therapy and two severe cases of idiopathic thrombocytopenic purpura (ITP).Case presentationsA 47-year-old female with recurrent BRAF mutant positive melanoma received combination anti-PD-1 and anti-CTLA-4. Two weeks later, she presented with mucosal bleeding, petechiae, and thrombocytopenia and was treated with standard therapy for ITP with steroids and intravenous immunoglobulin (IVIG). Her diagnosis was confirmed with bone marrow biopsy, and given the lack of treatment response, she was treated with rituximab. She began to have recovery and stabilization of her platelet count that ultimately allowed her to be retreated with PD-1 inhibition with no further thrombocytopenia. A second patient, a 45-year-old female with a BRAF wild-type melanoma, received anti-PD-1 monotherapy and became thrombocytopenic 43 days later. Three weeks of steroid treatment improved her platelet count, but thrombocytopenia recurred and required additional steroids. She later received anti-CTLA-4 monotherapy and developed severe ITP with intracranial hemorrhage. Her ITP resolved after treatment of prednisone, IVIG, and rituximab and discontinuation of checkpoint inhibition. In a retrospective chart review of 2360 patients with melanoma treated with checkpoint inhibitor therapy, <1% experienced thrombocytopenia following immune checkpoint inhibition, and of these, most had spontaneous resolution and did not require treatment.ConclusionsThrombocytopenia, especially ITP, induced by immune checkpoint inhibitors appears to be an uncommon irAE that is manageable with observation in mild cases and/or standard ITP treatment algorithms. In our series, the majority of patients had mild thrombocytopenia that resolved spontaneously or responded to standard corticosteroid regimens. However, in two severe cases, IVIG and rituximab, in addition to steroids, were required. Checkpoint inhibition was resumed successfully in the first patient but rechallenge was not tolerated by the second patient.

Safe and effective prophylactic vaccines are urgently needed to contain the coronavirus disease 2019 (COVID-19) pandemic. However, several vaccination-related adverse effects have been reported. Here, we report a rare case of severe immune thrombocytopenia occurring 3 days after receiving the mRNA-1273 (Moderna) COVID-19 vaccine in an Asian woman with a history of refractory lung adenocarcinoma treated with durvalumab, an immune checkpoint inhibitor. Treatment with platelet transfusion (12 units) and oral prednisolone (1 mg/kg per day) significantly improved her hemoptysis with thrombocytopenia. To the best of our knowledge, this is the first case of ITP following Moderna inoculation among Asians. This study highlights a potential adverse effect of mRNA-based COVID-19 vaccines in cancer patients receiving immune checkpoint inhibitors.

Abstract Ipilimumab, nivolumab, and pembrolizumab represent a new class of immunotherapeutic drugs for treating patients with advanced cancer. Known as checkpoint inhibitors, these drugs act to upregulate the cellular and humoral immune response to tumor antigens by inhibiting T-cell autoregulation. As a consequence, they can be associated with immune-related adverse events (irAEs) due to loss of self-tolerance, including rare cases of immune-related cytopenias. We performed a retrospective clinical chart review, including serologic, hematology, and chemistry laboratory results, of two patients who developed red blood cell (RBC) autoantibodies during treatment with a checkpoint inhibitor. Serologic testing of blood samples from these patients during induction therapy with ipilimumab and nivolumab, respectively, showed their RBCs to be positive by the direct antiglobulin test (IgG+, C3+) and their plasma to contain panreactive RBC autoantibodies. Neither patient had evidence of hemolysis. Both patients developed an additional irAE during treatment. A literature review for patients who had developed immune-mediated cytopenia following treatment with a checkpoint inhibitor was performed. Nine other patients were reported with a hematologic irAE, including six with anemia attributable to autoimmune anemia, aplastic anemia, or pure RBC aplasia. Hematologic irAEs tend to occur early during induction therapy, often coincident with irAEs of other organs. In conclusion, checkpoint inhibitors can be associated with the development of autoantibodies, immune-mediated cytopenias, pure RBC aplasia, and aplastic anemia. Immunohematology reference laboratories should be aware of these agents when evaluating patients with advanced cancer and new-onset autoantibodies, anemia, and other cytopenias. Immunohematology2017;33:15–21.

Background: Immune checkpoint inhibitors (ICIs) targeting PD-1, PD-L1, and CTLA-4 have transformed cancer therapy. However, their expanding use is associated with immune-related adverse events (irAEs), including a less characterized subset of hematologic toxicities. Autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), aplastic anemia, and pancytopenia are potentially life-threatening manifestations, but current knowledge is limited to case reports and small series. These events are often underreported in clinical trials due to rarity and limited follow-up. Large-scale pharmacovigilance is needed to better defined their incidence and risk profile. Methods: We conducted a retrospective pharmacovigilance analysis using the FDA Adverse Event Reporting System (FAERS) from Q1 2014 through Q1 2025. Hematologic cytopenias were identified using MedDRA preferred terms of pancytopenia, neutropenia, thrombocytopenia, aplastic anemia, AIHA, ITP, agranulocytosis, and hemolysis. ICIs were identified by both generic and brand names. Disproportionality was assessed using reporting odds ratios (RORs) and 95% confidence intervals, comparing ICI-associated cytopenia reports to all other FAERS reports. Regimen complexity was determined using FAERS therapy-sequence metadata to classify reports as monotherapy or combination. Time trends in cytopenia reporting were visualized across the study period. Results: Among 294,685 cytopenia reports, 13,847 (4.7%) involved at least one ICI. Nivolumab, pembrolizumab, and atezolizumab accounted for over 85% of these cases. Disproportionality analysis revealed the highest signal was seen with atezolizumab and AIHA (ROR 24.8, 95% CI: 22.8–27.0). Other notable signals included durvalumab with pancytopenia (ROR 1.67), ipilimumab with thrombocytopenia (ROR 1.43), and pembrolizumab with AIHA (ROR 1.74). Combination regimens accounted for 73.3% of ICI-related cytopenia reports, 6.9% occurred with monotherapy, and 19.8% had incomplete regimen data. Temporal trends showed a steep rise in ICI-associated cytopenias beginning in 2016, peaking between 2021–2023, mirroring ICI adoption across cancer types. Conclusions: In this decade-long pharmacovigilance analysis, hematologic irAEs, particularly AIHA and ITP, were disproportionately associated with ICIs, most notably anti–PD-L1 agents. Most occurred with combination regimens, but monotherapy regimenss were not exempt. Our findings emphasize the importance of early recognition, diagnostic evaluation, and multidisciplinary management of new-onset cytopenias during immunotherapy. These real-world data complement clinical trial findings and support enhanced risk stratification and safety monitoring in oncologic practice. Further prospective and mechanistic studies are warranted to guide prevention strategies as ICI use continues to expand.

Background Immune checkpoint inhibitors (ICIs) have been a breakthrough in cancer therapy. ICI therapy is generally better tolerated than cytotoxic chemotherapy; however, hematological adverse events (AEs) have not been fully analyzed. Hence, we performed a meta-analysis to evaluate the incidence and risk of ICI-related hematological AEs. Methods A systematic literature search was performed using PubMed, EMBASE, Cochrane Library, and the Web of Science Core Collection. Phase III randomized controlled trials (RCTs) involving ICI combination regimens were selected. The experimental group received ICIs with systemic treatment, and the control group received only the same systemic treatment. Odds ratios (ORs) for anemia, neutropenia, and thrombocytopenia were calculated using a random-model meta-analysis. Results We identified 29 RCTs with 20,033 patients. The estimated incidence rates for anemia of all grades and grades III-V were 36.5% (95% confidence interval (CI) 30.23 - 42.75) and 4.1% (95% CI 3.85 - 4.42), respectively. The incidence of neutropenia (all grades 29.7%, grades III-V 5.3%) and thrombocytopenia (all grades 18.0%, grades III-V 1.6%) was also calculated. Conclusion Treatment with ICIs seemed unlikely to increase the incidence of anemia, neutropenia, and thrombocytopenia in all grades. However, programmed cell death-1 receptor ligand inhibitors significantly increased the risk of grades III-V thrombocytopenia (OR 1.53; 95% CI 1.11 - 2.11). Further research is needed to examine the potential risk factors.

Immune checkpoint inhibitors (ICIs) are able to reactivate the immune system, thereby enhancing the anti‐tumor effects. However, over‐activated T cells may induce immune‐related adverse events (irAEs). Hematological irAEs are rarely reported which mainly represent monolineage cytopenia or pancytopenia, including autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), neutropenia and aplastic anemia, sometimes even life‐threatening diseases such as hemophagocytic lymphohistiocytosis. Here, the clinical manifestations of hematological irAEs are summarized and recommendations for diagnosis and treatment proposed.

Immune checkpoint inhibitors (ICI) have demonstrated clinical utility in various cancers, but they also induce immune-related adverse events (irAEs) such as thyroiditis, pneumonitis, or colitis. Immune-related(IR) hematologic toxicities, including anemia, neutropenia, thrombocytopenia, or pancytopenia are rarely reported but can be fatal. However, the underlying immunobiology of IR hematologic toxicities by ICIs has been very poorly investigated. We report a case of IR pancytopenia by ICIs including an in-depth analysis of single-cell RNA sequencing for the bone marrow (BM). A 57-year-old man with metastatic clear cell renal cell carcinoma was treated with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) and showed rapid tumor reduction. After 7 months of ICI treatment, he showed fever and pancytopenia with hemoglobin - 8.3 g/dl, platelet count - 64,000 /㎕, WBC count - 2500 cells/㎕, absolute neutrophil count - 745 cells/㎕, MCH - 25.9pg, MCV - 82.0fl, MCHC - 31.5g/dl, RDW - 18.2% and reticulocyte count - 1.65%. Direct and indirect antiglobulin test was negative. On BM aspiration, the number of erythroid and megakaryocytic series was slightly increased and that of myeloid series was in the normal range. In BM biopsy, cellularity was 70-80% and three hematopoietic series showed mild hyperplasia. There were no abnormal findings in morphology and chromosomal analysis. BM diagnosis was idiopathic cytopenia of undetermined significance. Although he was treated with methylprednisolone (1mg/kg), hematologic improvement was minimal. Cyclosporine demonstrated the hematologic response in the case. After 5 months of immune suppressive therapy (6-month-discontinuation of nivolumab), he maintained anti-tumor responses by ICIs. We cautiously re-challenge nivolumab as maintenance therapy, but the pancytopenia reappeared. ICI was permanently terminated, and therapy was changed to axitinib (VEGF tyrosine kinase inhibitor). To gain comprehensive insights, we performed single-cell analysis on BM aspirate. Our approach aimed to retain the integrity of both mononuclear cells and granulocytes without cryopreservation by analyzing the sample promptly after collection. Following this, we segregated the sample into distinct fractions, namely bone marrow mononuclear cells (BMMC) and whole blood (BM), and subjected both fractions to in-depth single-cell analysis. This method allowed us to explore the cellular composition and heterogeneity within the BM aspirate, contributing valuable insights to our research. The analysis detected 19,227 cells and identified unique cellular subsets, including terminally differentiated CD8+ T cells (CD8 T EF) and T Helper 17 cells (T H17), which are not commonly found in BM. CD8 T EF cells expressed activation and exhaustion markers, HLA-DRA and KLRG1. Additionally, T H17 cells demonstrated elevated expression of typical T H17 markers RORC and CCR6, as well as polyfunctional markers, including KLRB1, TNFRSF4, and TNFRSF18. Interestingly, previous studies on IR-myocarditis have shown an increased presence of CD8 T EF in the peripheral blood. Moreover, the studies have associated aplastic anemia with the T H17 cell population. These findings offer significant insights into the molecular and cellular mechanisms, as well as the BM microenvironment, contributing to the IR hematologic toxicities by ICIs.

Immune checkpoint inhibitors target suppressor receptors, including cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death ligand 1 (PD-L1). The activated T cells are not antigen specific; therefore, the blockade of the immune checkpoint may result in the development of autoimmune adverse events. The most common immune-related adverse events (irAEs) are rash, colitis, and endocrinopathies. However, irAEs that affect the hematologic system are rare and can affect red blood cells (e.g., autoimmune hemolytic anemia), white blood cells, and platelets (e.g., immune thrombocytopenia). Usually one cell line is affected; however, in some cases, multiple cell lines can be affected. Other changes in the hematologic system can also be affected (e.g., cryoglobulinemia, cytokine release syndrome). Due to the rarity and lack of recognition of these AEs, the timing, spectrum of events, and clinical presentation are poorly understood. Management of hematologic irAEs usually involves the use of steroids; however, other agents (e.g., IVIG, cyclosporine, rituximab) or procedures (e.g., plasma exchange, transfusions) can also be used.

Immune checkpoint inhibitors are molecules that increase the endogenous immune response against tumors. They have revolutionized the field of oncology. Since their initial approval for the treatment of advanced melanoma, their use has expanded to the treatment of several other advanced cancers. Unfortunately, immune checkpoint inhibitors have also been associated with the emergence of a new subset of autoimmune-like toxicities, known as immune-related adverse events. These toxicities differ depending on the agent, malignancy, and individual susceptibilities. Although the skin and colon are most commonly involved, any organ may be affected, including the liver, lungs, kidneys, and heart. Most of these toxicities are diagnosed by excluding other secondary infectious or inflammatory causes. Corticosteroids are commonly used for treatment of moderate and severe immune-related adverse events, although additional immunosuppressive therapy may occasionally be required. The occurrence of immune-related toxicities may require discontinuation of immunotherapy, depending on the specific toxicity and its severity. In this article, we provide a focused review to familiarize practicing clinicians with this important topic given that the use of immune checkpoint inhibitors continues to increase.

In cancer patients, thrombocytopenia can result from bone marrow infiltration or from anticancer medications and represents an important limitation for the use of antithrombotic treatments, including anticoagulant, antiplatelet, and fibrinolytic agents. These drugs are often required for prevention or treatment of cancer-associated thrombosis or for cardioembolic prevention in atrial fibrillation in an increasingly older cancer population. Data indicate that cancer remains an independent risk factor for thrombosis even in case of thrombocytopenia, since mild-to-moderate thrombocytopenia does not protect against arterial or venous thrombosis. In addition, cancer patients are at increased risk of antithrombotic drug-associated bleeding, further complicated by thrombocytopenia and acquired hemostatic defects. Furthermore, some anticancer treatments are associated with increased thrombotic risk and may generate interactions affecting the effectiveness or safety of antithrombotic drugs. In this complex scenario, the European Hematology Association in collaboration with the European Society of Cardiology has produced this scientific document to provide a clinical practice guideline to help clinicians in the management of patients with cancer and thrombocytopenia. The Guidelines focus on adult patients with active cancer and a clear indication for anticoagulation, single or dual antiplatelet therapy, their combination, or reperfusion therapy, who have concurrent thrombocytopenia because of either malignancy or anticancer medications. The level of evidence and the strength of the recommendations were discussed according to a Delphi procedure and graded according to the Oxford Centre for Evidence-Based Medicine.

… with a small-cell lung cancer of extended stage, associated with ITP-like syndrome, which … cancer. This case is, to our knowledge, the second reported ITP-like syndrome in a cancer …

… In conclusion, patients with lymphomas had a higher rate of ITP than did patients with other types of cancer, treatment of ITPassociated cancer may improve platelet count. …

Chemotherapy-induced thrombocytopenia (CIT) is a common yet underrecognized complication of systemic chemotherapy, particularly in gastrointestinal (GI) cancers. Despite progress in targeted and immune-based therapies, platinum-based and fluoropyrimidine regimens, especially oxaliplatin-containing protocols, remain standard in GI cancer treatment and are linked to high rates of CIT. This complication often leads to treatment delays, dose reductions, and elevated bleeding risk. This review provides a comprehensive overview of the pathophysiology, clinical implications, and management strategies of CIT in GI malignancies.CIT arises from several mechanisms: direct cytotoxicity to megakaryocyte progenitors, disruption of the marrow microenvironment, thrombopoietin dysregulation, and immune-mediated platelet destruction. Platinum agents, antimetabolites, and immune checkpoint inhibitors can contribute to these effects. Oxaliplatin-induced CIT may occur acutely via immune mechanisms or chronically through marrow suppression. CIT affects 20–25% of solid tumor patients, with highest rates in those receiving gemcitabine (64%), carboplatin (58%), and oxaliplatin (50%). Within GI cancer regimens, FOLFOXIRI and S-1 plus oxaliplatin show higher CIT incidence compared to FOLFIRI and CAPIRI.Thrombocytopenia is graded by severity, from mild (Grade 1-2) to severe (Grade 3-4), and often necessitates treatment adjustments, transfusions, or supportive therapies. Current strategies include chemotherapy dose modification, platelet transfusion, and thrombopoietin receptor agonists (TPO-RAs) like romiplostim and eltrombopag. While platelet transfusions help in acute settings, TPO-RAs may preserve dose intensity and reduce bleeding. Emerging agents targeting megakaryopoiesis and marrow protection offer promising avenues for long-term management.

… among patients with thrombocytopenia due to cancer or cancer treatment are similar [44]. … of >40,000/mcL in cancer patients with an acute cancer-associated thrombus and a high …

Chemotherapy-induced thrombocytopenia (CIT) is a common complication of the treatment of non-hematologic malignancies. Many patient-related variables (e.g., age, tumor type, number of prior chemotherapy cycles, amount of bone marrow tumor involvement) determine the extent of CIT. CIT is related to the type and dose of chemotherapy, with regimens containing gemcitabine, platinum, or temozolomide producing it most commonly. Bleeding and the need for platelet transfusions in CIT are rather uncommon except in patients with platelet counts below 25x109/L in whom bleeding rates increase significantly and platelet transfusions are the only treatment. Nonetheless, platelet counts below 70x109/L present a challenge. In patients with such counts, it is important to exclude other causes of thrombocytopenia (medications, infection, thrombotic microangiopathy, post-transfusion purpura, coagulopathy and immune thrombocytopenia). If these are not present, the common approach is to reduce chemotherapy dose intensity or switch to other agents. Unfortunately decreasing relative dose intensity is associated with reduced tumor response and remission rates. Thrombopoietic growth factors (recombinant human thrombopoietin, pegylated human megakaryocyte growth and development factor, romiplostim, eltrombopag, avatrombopag and hetrombopag) improve pretreatment and nadir platelet counts, reduce the need for platelet transfusions, and enable chemotherapy dose intensity to be maintained. National Comprehensive Cancer Network guidelines permit their use but their widespread adoption awaits adequate phase III randomized, placebo-controlled studies demonstrating maintenance of relative dose intensity, reduction of platelet transfusions and bleeding, and possibly improved survival. Their potential appropriate use also depends on consensus by the oncology community as to what constitutes an appropriate pretreatment platelet count as well as identification of patient-related and treatment variables that might predict bleeding.

… treatment of ITP, no sufficient evidence is available to recommend a preferred subsequence of treatments … the practice in ITP treatment in UK (Mc Donald W, personal communication). …

BACKGROUND The use of immune checkpoint inhibitors (ICIs) has expanded substantially across tumor types, establishing them as a cornerstone of modern oncology. However, the frequency and severity of immune-related adverse events (irAEs) remain underestimated, particularly hematologic toxicities, which can be life-threatening and require distinct management approaches compared to cytotoxic or targeted therapies. METHODS We performed literature reviews using PubMed to identify and analyze reported cases of the most frequent hematologic irAEs; autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and pure red cell aplasia (PRCA), in patients with solid tumors. In parallel, we report three illustrative cases from our institution to highlight diagnostic pitfalls and management strategies. RESULTS The median onset of hematologic irAEs occurs after approximately 3 cycles of ICI therapy for AIHA and ITP, and after 4 cycles for PRCA. Most patients achieved remission with corticosteroid therapy; however, 10-15% were steroid-refractory or relapsed, requiring second-line immunosuppressive agents. Rechallenge with ICIs remains controversial due to a recurrence rate of irAE, although it may be feasible and clinically beneficial in carefully selected patients. CONCLUSION As the use of ICIs continues to rise, prompt recognition and management of hematologic irAEs are critical to minimize morbidity and to avoid premature discontinuation of immunotherapy. Increased clinician awareness and standardized diagnostic algorithms are essential to preserve both safety and efficacy.

Hematotoxicity represents a frequent chimeric antigen receptor (CAR) T-cell related adverse event and remains poorly understood. In this multicenter analysis, we studied patterns of hematopoietic reconstitution and evaluated potential predictive markers in 258 patients receiving Axicabtagene ciloleucel (Axi-cel) or Tisagenlecleucel (Tisa-cel) for relapsed/refractory large B-cell lymphoma. We observed profound (ANC<100/µl) and prolonged (≥day 21) neutropenia in 72 and 64% of patients respectively. The median duration of severe neutropenia (ANC<500/µl) was 9 days. We aimed to identify predictive biomarkers of hematotoxicity using the duration of severe neutropenia until day +60 as the primary endpoint. In the training cohort (n=58), we observed a significant correlation with baseline thrombocytopenia (r= -0.43, P=0.001) and hyperferritinemia (r=0.54, P<0.0001) on uni- and multivariate analysis. Incidence and severity of CRS, ICANS and peak cytokine levels were not associated with the primary endpoint. We calculated the CAR-HEMATOTOX model, which included markers associated with hematopoietic reserve (e.g. platelet count, hemoglobin and ANC) and baseline inflammation (e.g. C-reactive-protein, ferritin). This model was validated in two independent cohorts from Europe (n=91) and the USA (n=109), and discriminated patients with severe neutropenia ≥/<14 days (pooled validation: AUC=0.89, Sensitivity 89%, Specificity 68%). A high CAR-HEMATOTOX score resulted in a longer duration of neutropenia (12 vs. 5.5 days, P<0.001), and a higher incidence of severe thrombocytopenia (87% vs. 34%, P<0.001) and anemia (96% vs. 40%, P<0.001). The score implicates pre-CART bone marrow reserve and inflammatory state as key features associated with delayed cytopenia and will be useful for risk-adapted management of hematotoxicity.

Immune-related adverse events (irAEs) have limited the widespread clinical application of immune checkpoint inhibitors (ICIs). Hematological toxicities are rare but serious irAEs. This study comprehensively analyzes ICI-related hematological adverse events using the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS).database. We extracted ICI adverse events from the FAERS database between January 2004 and January 2025. Disproportionality analyses using four algorithms identified hematological signals. To eliminate the influence of combined medication, we separately conducted disproportionality analysis on all ICI reports and on reports of ICI monotherapy. Multivariable logistic regression was employed to assess the risk factors for hematological adverse events. Of all ICI reports in FAERS, 3.73% were for hematological adverse events. Among the 14 detected hematological signals, pure red cell aplasia, immune-mediated pancytopenia, acquired hemophilia, and Evans syndrome are rare and severe irAE. Among 6,259 cases of ICI-related hematological AEs, approximately 88.68% were reported by healthcare professionals, and fatal outcomes were reported in 16.49% of cases. The median onset time is 20 days.The median age of patients was 67 years (IQR: 58–73). Male was associated with a significantly lower risk of hematological toxicity compared to females (OR = 0.92, 95% CI: 0.90–0.96; P < 0.05). Patients aged ≥ 65 years also had a reduced risk compared to those < 65 years (65–74 years: OR = 0.64, 95% CI: 0.62–0.67; ≥75 years: OR = 0.75, 95% CI: 0.72–0.79; both P < 0.05 ). ICI combination with chemotherapy significantly increased the risk of hematological toxicity (OR = 3.56, 95% CI: 3.44–3.69; P < 0.05), while combination with targeted agents reduced the risk (OR = 0.73, 95% CI: 0.69–0.76; P < 0.05). To our knowledge, this is among the first studies to utilize real-world big data for disproportionality analysis focused on ICI monotherapy, uncovering rare and severe hematological irAE. Multivariable logistic regression revealed that following ICI treatment, females are at a higher risk than males for hematological toxicities; likewise, ICI–chemotherapy increases the risk compared to ICI monotherapy. Clinicians should pay more attention to these rare irAEs and identify and treat them as early as possible, especially in patients with high-risk factors.

Immune checkpoint inhibitors (ICIs), especially those targeting the programmed-death 1 (PD-1) receptor and its ligands, have become indispensable agents in solid tumor anti-cancer therapy. Concerning hematological malignancies, only nivolumab and pembrolizumab have been approved for the treatment of relapsed and refractory classical Hodgkin lymphoma and primary mediastinal large B cell lymphoma to date. Nevertheless, clinical research in this field is very active. The mechanism of action of ICIs is based on unblocking the hindered immune system to recognize and eliminate cancer cells, but that also has its costs in the form of ICI-specific immune related adverse events (irAEs), which can affect any organ system and can even be lethal. In this article, we have reviewed all prospective blood cancer clinical trials investigating ICIs (both monotherapy and combination therapy) with available toxicity data with the purpose of determining the incidence of irAEs in this specific setting and to offer a brief insight into their management, as the use of immune checkpoint blockade is not so frequent in hemato-oncology.

Immune checkpoint inhibitors (ICIs) have shown remarkable clinical effects in many cancer types. However, ICIs could also induce severe organ system toxicities, including those of the hematological system. The present study aimed to extensively characterize the hematological toxicities of ICIs immunotherapy. Data were extracted from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database from January 1, 2014, to March 31, 2019. Disproportionality analysis, including information component (IC) and reporting odds ratio (ROR), was used to detect potential disproportionality signal. The lower boundary of the 95% confidence interval of IC (IC025) exceeding zero or that of ROR (ROR025) exceeding one was considered statistically significant for detecting disproportionality signal. A total of 29 294 335 records were extracted from the database, with 132 573 related to ICIs. Overall, hematological adverse events (AEs) were more frequently reported in ICIs (IC025: 0.81; ROR025: 1.80). On further analysis, hematological AEs were overreported in female patients (female vs male, ROR025: 1.04) and anti‐CTLA‐4 monotherapy groups (anti‐CTLA‐4 vs anti‐PD‐1, ROR025: 1.33) and polytherapy groups (polytherapy vs monotherapy, ROR: 1.20, ROR025: 1.11). Moreover, class‐specific hematological AEs were also detected and differed in unique ICI regimens. Notably, disseminated intravascular coagulation had the highest proportion of death outcomes among the top 10 most frequently reported ICI‐associated hematological AEs. Our study shows a high reporting frequency of hematological AEs induced by ICI monotherapy (especially by anti‐CTLA‐4 therapy) and reinforced by polytherapy. A spectrum of class‐specific disproportionality signal was also detected; some were fatal and reported for the first time. The heterogeneous clinical spectrum of hematological toxicities, including the non‐negligible proportion of death as reported outcome, are warranted to be reminded by clinicians. Early recognition and management of ICI‐related hematological AEs are highly important and further studies are needed to confirm the results of our study.

Classically, patients with solid and hematologic malignancies have been treated with a combination of chemotherapy with or without a holistic targeted strategy using approved conventional therapy. While the evidence-based use of Immunomodulatory drugs and Immune checkpoint inhibitors (ICIs), including those targeting the PD-1, PD-L1 and CTLA-4, have reshaped the treatment paradigm for many malignant tumors and significantly stretched the life expectancy of patients, as for any interventional therapy, the rise in ICI applications, was associated with the observation of more immune-related hematological adverse events. Many of these patients require transfusion support during their treatment in line with precision transfusion. It has been presumed that transfusion-related immunomodulation (TRIM) and the microbiome can pose immunosuppressive effects on the recipients. Looking to the past and beyond and translating available data into practice in the evolving role of pharmaceutical therapy to ICI-receiving patients, we performed a narrative review of the literature on the immune-related hematological adverse events of ICIs, immunosuppressive mechanisms linked to blood product transfusions, as well as the detrimental impact of transfusions and its related microbiome on the sustained efficacy of ICIs and the patients' survival outcomes. Recent reports are pointing to the negative impact of transfusion on ICI response. Studies have concluded that packed RBC [PRBC] transfusions lead to an inferior progression-free and overall survival in patients with advanced cancer receiving ICIs, even after adjustments for other prognostic variables. The attenuation of the effectiveness of immunotherapy likely results from the immunosuppressive effects of PRBC transfusions. It is, therefore, wise to look retrospectively and prospectively at the impact of transfusion on ICI effects and adopt, in the interim, a restrictive transfusion strategy, if applicable, for those patients.

Immunotherapy has generated tremendous hope for patients with cancer that is refractory to standard approaches. Hematologic malignancies have taken the lead in harnessing the most recent advances in cell-based immunotherapies, such as CAR T cells, and some patients have achieved durable remissions. However, these T-cell-engaging therapies are associated with a new set of toxicities which need to be managed by caretakers, oncologists, nurses, and healthcare staff. In this review we provide an overview of the toxicity of some of these revolutionary agents including bispecific T cell engagers, checkpoint inhibitors, chimeric antigen receptor T-cells.

IntroductionImmunotherapy with the anti-cytotoxic T-lymphocyte antigen-4 monoclonal antibody ipilimumab has been shown to improve overall survival in previously treated and treatment-naïve patients with unresectable stage III or IV melanoma. Consistent with its proposed immunomodulating mechanism of action, the most common toxicities associated with ipilimumab therapy are immune-related in nature and include those related to the skin and gastrointestinal tract, with endocrine and hepatic events also frequent. Other rare adverse events, including haematological aberrations, may also occur and can have serious consequences if unrecognised. Here we describe three patients who developed serious haematological adverse events during or after treatment with ipilimumab.Case presentationThree Caucasian patients (two women aged 68 and 49 years and one man aged 70 years) with metastatic melanoma experienced anaemia and/or leukopenia (neutropenia) with toxicity of various grades during or after treatment with ipilimumab, without significant changes to other haematological values. Two of the patients stopped treatment after the third ipilimumab dose, one because of severe anaemia that required blood transfusion and the other due to febrile neutropenia that was treated with antibiotics and granulocyte-macrophage colony-stimulating factor stimulation. The third patient developed anaemia and leukopenia after treatment during the follow-up period. The results of autoimmunity tests performed were positive and corticosteroids were used to treat these events as per side-effects treatment algorithms specifically developed for the management of immune-related adverse events associated with ipilimumab, an approach that was safe and effective.ConclusionsHaematological toxicity is a rare but potentially serious immune-related side effect of ipilimumab therapy. However, if promptly recognised and treated, haematological toxicity is manageable and can be reversed with standard corticosteroid treatment as recommended for other ipilimumab immune-related side effects.

Background/Objectives: The advent of immune checkpoint inhibitors (ICIs) and targeted therapies has revolutionized advanced melanoma treatment but introduced unique immune-related adverse events (irAEs). Hematological irAEs (Hem-irAEs) are rare but carry disproportionately high morbidity and mortality. This review systematically synthesizes current literature to comprehensively understand the incidence, pathophysiology, clinical presentation, and management of Hem-irAEs in modern melanoma therapy. Methods: A comprehensive Web of Science literature search (January 2015 to January 2026) identified studies reporting hematological adverse events associated with melanoma immunotherapy and targeted therapies. After screening 2274 records, 130 relevant studies were included for quantitative data extraction, focusing on incidence rates and toxicity grading. Results: Hem-irAEs occur infrequently (under 4% overall incidence for ICIs) but possess staggering mortality rates between 12% and 15.5%. The most common manifestations are immune thrombocytopenia (ITP), autoimmune hemolytic anemia, and neutropenia. Combination regimens significantly amplify toxicity frequency and severity. Diagnosis requires meticulous baseline monitoring and bone marrow biopsies to differentiate peripheral destruction from central marrow failure. First-line management mandates ICI discontinuation and high-dose corticosteroids, utilizing targeted second-line immunosuppressants for refractory syndromes. Conclusions: Hem-irAEs embody a profound clinical paradox: while mild toxicities often herald a robust anti-tumor response, severe hematological events drastically increase non-cancer mortality, negating these oncological benefits. Navigating this “double-edged sword” demands a paradigm shift toward proactive risk stratification. Integrating predictive biomarkers including baseline autoantibodies, Human Leukocyte Antigens (HLA) profiling, and systemic inflammatory indices is crucial to identify vulnerable populations before treatment. Optimizing outcomes requires highly personalized vigilance to balance the life-saving efficacy of immunotherapy against the catastrophic threat of hematopoietic failure.

Background Programmed cell death-1 (PD-1) inhibitor-related hematologic toxicities are a category of rare but clinically serious and potentially life-threatening adverse events; however, little is known about their risks across different treatment regimens and tumor types. The objective of this study was to compare the incidences of PD-1 inhibitor-related hematologic toxicities among different therapeutic regimens and tumor types. Methods Twenty-six original articles on PD-1 inhibitor trials were identified based on a PubMed search completed on September 26, 2017. The incidences of hematologic toxicities were collected. Results A total of 26 studies containing 5,088 patients were included in the meta-analysis. PD-1 inhibitor monotherapy was associated with an increased risk of all-grade anemia in cancer patients (5%, 95% CI 4%–6%), particularly in patients with renal cell carcinoma (RCC) (8%, 95% CI 6%–12%), compared with all-grade thrombocytopenia (2%, 95% CI 1%–5%), leukopenia (2%, 95% CI 1%–3%), and neutropenia (1%, 95% CI 0–1%). However, low incidences of high-grade hematologic toxicities were observed in cancer patients treated with PD-1 inhibitor monotherapy. The use of PD-1 inhibitors in combination with ipilimumab, peptide vaccines, or chemotherapy had significantly higher risks than PD-1 inhibitor monotherapy for all-grade anemia (13%, 95% CI 5%–31%), thrombocytopenia (6%, 95% CI 2%–18%), leukopenia (5%, 95% CI 1%–35%), neutropenia (4%, 95% CI 1%–26%), and only high-grade thrombocytopenia (4%, 95% CI 1%–15%). In addition, all-grade and high-grade hematologic toxicities in chemotherapy and everolimus treatment arms were more frequent than in PD-1 inhibitor monotherapy arms. Conclusion The risks of PD-1 inhibitor-related hematologic toxicities were higher in RCC than in other cancers, and during combination therapy. These results may contribute toward enhancing awareness among clinicians about frequent clinical monitoring when managing PD-1 inhibitors.

BACKGROUNDS Immune-related adverse events were reported in patients treated with immune checkpoint inhibitors (ICIs). However, with the increasing number of immune-related adverse events (irAEs), the differences of each immune checkpoint inhibitor regimen had not been fully assessed. METHODS Disproportionality analysis was used in data mining of the suspected adverse events after ICIs administration based on the Food and Drug Administration Adverse Event Reporting System (FAERS) from January 2004 to December 2019. The onset time and fatality proportion of ICI-associated irAEs were further evaluated. RESULTS A total of 32,441 reports of ICI-associated irAEs were gathered. This study showed that all ICI regimens generated lung toxicity and endocrine toxicity signals. Colitis, pneumonitis and interstitial lung disease were the most common ICI-associated irAEs. Five regimens including durvalumab monotherapy, ipilimumab monotherapy, ipilimumab plus nivolumab, ipilimumab plus pembrolizumab, durvalumab plus tremelimumab were associated with irAEs. Anti-PD-1 agents generated more signals of ocular toxicities than anti-PD-L1 agents, while anti-PD-L1 agents reported more signals of hematologic toxicities. Anti-CTLA-4 agents showed more signals of gastrointestinal toxicities compared with anti-PD-1 or anti-PD-L1 agents. The highest fatality proportion of lung toxicities with durvalumab monotherapy, hematological toxicities with avelumab monotherapy, renal and skin toxicities with cemiplimab monotherapy were found. CONCLUSION Our results demonstrated that each ICI regimen had different characteristics of irAEs. Pembrolizumab had the highest fatality proportion. Ipilimumab plus pembrolizumab had the shortest median time to onset irAEs. Further studies were expected to assess whether there were clinically relevant differences exist among ICIs.

Background Life-threatening immune-related adverse events (irAEs) that require hospital admission are not uncommon in patients treated with immune checkpoint inhibitors (ICIs). The clinical and hematological parameters are attractive biomarkers as potential predictors of irAE. Methods This is a retrospective study of patients with melanoma and lung cancer treated with ICIs between 2015 and 2019 at the University of South Alabama Mitchell Cancer Institute. Fisher’s exact test, Pearson Chi-squared test, log-rank test, and Cox proportional hazard model were used to evaluate clinical and hematological parameters as possible predictors of irAE. Results The cohort consisted of 160 patients treated with at least two doses of ICI, of which 54 (33.8%) patients had melanoma and 106 (66.3%) had lung cancer. Incidence of irAE did not have any bearing on the overall survival (OS) or progression-free survival (PFS) of the cohort. The clinical factors associated with irAE were dual-agent therapy (ipilimumab/nivolumab combination) and high disease burden (≥ 2 metastatic sites). The irAE-group had a lower mean platelet-to-lymphocyte ration (PLR, 200 vs. 257, P = 0.04). Although not statistically significant at the level of 0.05, other factors such as type of cancer (lung cancer > melanoma (P = 0.06)), stage at treatment (stage IV > stage II and III disease (P = 0.06)), and higher absolute lymphocyte counts (P = 0.07) showed a considerable association with irAE and warrants further review with different patient data. Conclusions Irrespective of ICI used to treat lung cancer and melanoma, patients with high disease burden and dual-agent ICI therapy were more prone to irAE. The only hematological parameter that may predict the incidence of irAE is low baseline PLR.