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Bone marrow from patient with checkpoint inhibitor-induced ITP before rituximab treatment. H&E stained section of the bone marrow biopsy, 100 × magnification. The bone marrow is moderately hypercellular for age with trilineage hematopoiesis and increased megakaryocytes (black arrows) with a range of morphologies and mild clustering. These findings, coupled with the patient’s peripheral thrombocytopenia and elevated IPF, are compatible with a diagnosis of ITP
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Background
Immune 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...
Similar publications
Children with immune thrombocytopenia (ITP) rarely suffer from life-threatening bleeds (eg, intracranial hemorrhage). In such settings, the combination of IV methylprednisolone (IVMP) with IV immune globulin (IVIG) is used to rapidly increase platelet counts (PCs). However, there are no controlled data to support using combination therapy over IVIG...
Citations
... Данный вид токсичности на фоне терапии ИКТ -одно из наименее описанных нежелательных явлений иммунотерапии. Частота возникновения в большинстве исследований составляет менее 1% [20,21]. ...
... Описаны различные типы цитопении, связанные с ингибиторами контрольных точек иммунного ответа, включая иммунную тромбоцитопению, аутоиммунную гемолитическую анемию, нейтропению и апластическую анемию, панцитопению [21]. ...
... Иммунная тромбоцитопения, безусловно, является наиболее частым гематологическим иоНЯ, за которым следуют гемолитическая и апластическая анемии [22]. Среднее время до развития иммунной тромбоцитопении составляет 70 дней (диапазон от 12 до 173 дней), при этом большинство случаев иоНЯ возникает в первые 12 недель после начала терапии ингибиторами контрольных точек иммунного ответа, а среднее количество тромбоцитов составляет 60×10 9 /л (диапазон <50-104×10 9 /л) и относительное снижение на 70% от исходного уровня (диапазон от 38 до 99%) [21]. ...
Checkpoint inhibitors have radically changed the approach to oncology and have become the new standard of treatment for many solid tumors, significantly increasing the life expectancy of patients. With the advent of a new class of drugs, we are faced with a completely recognized toxicity profile. The spectrum affects other manifestations that affect almost every organ and system of the body. Most often the skin, the secretion of the internal gland, the gastrointestinal tract, lungs, and liver are affected. Complications from the urinary, cardiovascular, muscular-articular, nervous and hematopoietic systems occur less frequently. This article will discuss one of the rare complications that occurs during therapy with checkpoint inhibitors — thrombocytopenia with hemorrhagic syndrome. The main purpose of the article is to increase clinical alertness and highlight the relevance of the problem of rare complications during immunotherapy.
... Qiu et al. reported a case of severe thrombocytopenia and anemia occurring after 4.5 months of atezolizumab, which proved refractory to various treatments, including injection of intravenous immunoglobulin (IVIG), thrombopoietin, and plasma exchange and resulted in the expiration of the patient [35]. This represents the first documented case of refractory immune-related thrombocytopenia and anemia occurring simultaneously, notable for its occurrence in SCLC, while previous cases were observed in patients with NSCLC and melanoma [53,54]. Chen et al. reported an unusual increase in hepatitis B surface antibody (HBs Ab) in a 62-year-old patient with brain metastasis who was previously HBsAg-negative [32]. ...
Simple Summary
This study systematically reviewed case reports to identify rare adverse events in small cell lung cancer (SCLC) patients treated with immune checkpoint inhibitors (ICIs). A literature search, limited to reports published up to 31 December 2023, yielded 24 studies involving various ICIs, including atezolizumab, durvalumab, and nivolumab, either as monotherapy or in combination treatments. The review documented adverse events predominantly affecting the respiratory system, along with neurological, endocrinological, and gastroenterological systems. A total of 87.5% of cases showed symptom improvement, although some reports indicated severe outcomes, including death or persistent sequelae. The findings highlight the unpredictability of ICIs’ adverse effects and emphasize the importance of developing reliable biomarkers and multidisciplinary strategies to enhance patient management and safety in immunotherapy.
Abstract
Background: This study aimed to systematically review case reports documenting rare adverse events in patients with small cell lung cancer (SCLC) following the administration of immune checkpoint inhibitors (ICIs). Methods: A systematic literature review was conducted to identify case reports detailing previously unreported adverse drug reactions to ICIs in patients with SCLC. The scope of the literature reviewed was restricted to case studies on SCLC published up to 31 December 2023. Results: We analyzed twenty-four studies on ICI use for patients with SCLC. There were six reports on atezolizumab, four on durvalumab, and three on adverse events from monotherapy with nivolumab. Reports involving combination treatments were the most frequent, with a total of six, predominantly involving using nivolumab in combination with ipilimumab. Additionally, there was one report each on using pembrolizumab, nofazinilimab, sintilimab, tislelizumab, and toripalimab. We collected detailed information on the clinical course, including patient and disease characteristics, symptoms, treatment for each adverse event, and recovery status. Among the patients included in the case reports, 21 out of 24 (87.5%) had extensive-stage SCLC when initiating ICI therapy, with only 1 patient diagnosed with limited-stage SCLC. Respiratory system adverse events were most common, with seven cases, followed by neurological, endocrinological, and gastroenterological events. Three case reports documented adverse events across multiple systems in a single patient. In most cases, patients showed symptom improvement; however, four studies reported cases where patients either expired without symptom improvement or experienced sequelae. Conclusions: Efforts to develop reliable biomarkers for predicting irAEs continue, with ongoing research to enhance predictive precision. Immunotherapy presents diverse and unpredictable adverse events, underscoring the need for advanced diagnostic tools and a multidisciplinary approach to improve patient management.
... Several humanised monoclonal antibodies have also been identified as potential triggers for the formation of autoantibodies targeting platelets. Monoclonal antibodies causing DITP include efalizumab (anti-CD11a), 17 24 and programmed death-1 or cytotoxic T-lymphocyte antigen 4. 25,26 In the present meta-analysis, drugs causing DITP by bone marrow suppression or toxicity accounted for 9.5% of DITP cases. ...
In the present systematic review and meta-analysis, the authors analysed case reports of drug-induced thrombocytopenia/drug-induced thrombocytopenic purpura (DITP) and its mechanisms. The search included electronic databases for case reports of DITP using specific keywords in MEDLINE via PubMed, PubMed Central, and Embase. All case reports were designated a score/criteria (definite, probable, or possible). The mechanism of DITP was also analysed in each case report. A total of 751 case reports were included in the meta-analysis. The incidences for all-score DITP by random and common effect models were 0.65% (95% confidence interval: 0.61–0.69) and, 0.65% (95% confidence interval: 0.62–0.68), respectively. The number of DITPs with scores of 1, 2, and 3 was found in 151, 300, and 300 patients, respectively. Amongst the drugs, the maximum number of DITPs were caused by antibiotics, antimalarials, monoclonal antibodies, antiplatelet drugs, disease-modifying antirheumatic drugs, anti-epileptics, anti-cancer chemotherapeutics, and non-steroidal anti-inflammatory drugs. Out of 751 cases, 478 patients were hospitalised, and 323 patients had external or internal bleeding, including 62 patients who had major bleeding intracranially or retroperitoneally and required transfusion of two or more units of red blood cells. Mortality occurred in 12 patients. Clinicians should be aware of the potential of drugs causing DITP as an important adverse event, as it may affect patient compliance and adherence to drugs. Unrecognised DITP may lead to severe thrombocytopenia and inappropriate patient management.
... Rituximab is a monoclonal antibody that targets CD20, therefore targeting B cell function, and has been successfully used for treating ICI-induced hematological toxicities, myasthenia gravis, and Sjögren's syndrome [51][52][53][54]. Plasmapheresis depletes pathogenic auto-antibodies by extracorporeal removal and was used in the setting of myasthenia gravis-myositismyocarditis overlap syndrome, with limited success [49,50]. ...
Breast cancer is the most frequently diagnosed malignancy in patients worldwide and the main cause of cancer-related death. Though still incurable, metastatic breast cancer's prognosis has been considerably improved in the past 10 years due to the introduction of new targeted agents, such as immune checkpoint inhibitors (ICI). However, these medications are associated with unique side effects known as immune-mediated adverse events (irAE). In this paper, we review the clinical evidence for the use of ICIs in breast cancer, in both the metastatic as well as neoadjuvant/adjuvant setting, followed by a review of irAE most commonly seen, and the medications used to treat them. Our opinion is that any cancer specialist treating patients with breast cancer should be aware of these side effects for early detection and management, and oncologists should be the leaders of the multidisciplinary team that will take care of them.
... При этом от 50 до 70 % пациентов характеризуются длительной ремиссией [9]. Этот метод наравне с использованием кортикостероидов, ритуксимаба и тромбопоэтинов фигурирует в клинических рекомендациях, в частности рекомендациях Американского общества гематологов (ASH) [10]. Применение этого метода у пациентов с солидными опухолями не изучалось в крупных исследованиях, но оказалось успешным в нашем клиническом случае. ...
Immune-related adverse events (irAE) present a unique challenge in modern oncology. In patient treated with immune checkpoint inhibitors (anti-PD-1, anti-CTLA-4, anti-PD-L1) for solid tumors irAEs rate ranges from 60 to 85 % [1]. irAEs lead to complete treatment discontinuation in approximately 40 % of patients [2]. The most common irAEs are endocrinopathies (up to 10 %), pneumonitis (5 to 10 %), autoimmune hepatitis (up to 20 %), colitis (up to 30 %), and skin toxicity (up to 50 %) [3]. Other forms of adverse events, such as hematologic and cardiovascular toxicities, are very rarely reported. We present a clinical case of two rare adverse events in a patient treated with pembrolizumab for PD-L1‑positive advanced non-small cell lung cancer.
... Hematological irAEs are considered rare in patients receiving ICIs, however, a variety of hematological related toxicities have been reported [58]. These include antibody-mediated hemolytic anemia, thrombotic thrombocytopenic purpura, acquired hemophilia A, autoimmune neutropenia, pancytopenia and autoimmune thrombocytopenia [59][60][61][62][63][64]. Interestingly, cross-reactions that provoke autoimmune thrombocytopenia after sequential treatment with nivolumab and ipilimumab have been described, this might indicate that the same or similar irAEs might re-emerge on subsequent treatment with a different class of agents [64]. ...
... These include antibody-mediated hemolytic anemia, thrombotic thrombocytopenic purpura, acquired hemophilia A, autoimmune neutropenia, pancytopenia and autoimmune thrombocytopenia [59][60][61][62][63][64]. Interestingly, cross-reactions that provoke autoimmune thrombocytopenia after sequential treatment with nivolumab and ipilimumab have been described, this might indicate that the same or similar irAEs might re-emerge on subsequent treatment with a different class of agents [64]. ...
Immune checkpoint inhibitors (ICIs) are a type of cancer immunotherapy that has provided a tremendous breakthrough in the field of oncology. Currently approved checkpoint inhibitors target the cytotoxic T-lymphocyte-associated protein 4 (CTLA4), programmed death receptor-1 (PD-1), and programmed death-ligand 1(PD-L1). One of the most known complications of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs). In this chapter, we will focus on selected rare or very rare irAEs, shedding the light on the other side of the coin of personalized cancer immunotherapy. We will also discuss general management approach of irAEs with an in-depth look on each one of these rare irAEs. The chapter will also cover principles of immunotherapy rechallenge post-occurrence of irAEs, and the impact of irAEs incidence on the efficacy of ICI. We will discuss some of the rare or very rare irAEs including cutaneous irAEs, immune-mediated Hypophysitis, hematological irAEs, ophthalmic irAEs, checkpoint inhibitor pneumo-nitis (CIP), neurologic irAEs, infectious irAEs, and cardiac irAEs. This chapter tried to highlight the significance of identifying emerging rare and very rare irAEs while considering initial assessments and management approaches identified in various clinical practice guideline and primary literature data.
... Isolated case reports and case series have presented the hematologic toxicities induced by ICIs, but the incidence, diagnosis, and biological mechanisms in such patients remain unclear (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) (17), and ICI induced thrombocytopenia in only one case of SCLC (7). Haem-irAEs have not only been poorly understood and described but also lack consensus, whereas other common irAEs have well been characterized and managed. ...
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.
... Hematological toxicities from ICI are among the least described immunotherapy adverse events. Although the incidence in most series is below 1% [59,60], their occurrence is increasing with the widespread use of ICI across multiple types of solid tumors. However, they have not been extensively characterized so far. ...
... Various types of cytopenias have been described related to ICI, including immune thrombocytopenia, autoimmune hemolytic anemia (AIHA), neutropenia, and aplastic anaemia [60]. ...
... Immune thrombocytopenia is, by far, the most common hematological irAE, followed by hemolytic and aplastic anemias [61]. The median time to onset of ICI-induced immune thrombocytopenia is 70 days (range, 12 to 173 days), with most cases occurring in the first 12 weeks after ICI initiation, and an average platelet count of around 60,000/uL (range, <5000 to 104,000/uL) and relative decreases of 70% from baseline (range, 38 to 99%) [60]. ...
Immunotherapy has dramatically changed the therapeutic landscape of oncology, and has become standard of care in multiple cancer types in front or late lines of therapy, with some longstanding responses and outstanding results. Notwithstanding, its use has brought a totally unique spectrum of adverse events, characterized by a myriad of diverse manifestations affecting nearly every organ and system of the body, including the endocrine, nervous, cardiac, respiratory and gastrointestinal systems. Uncommon adverse events, defined as those occurring in less than 1% of patients, comprise an even more heterogeneous group of diseases that are being seen more recurrently as the use of immune check-point inhibitors increases and indications spread in different tumor types and stages. Here, we comprehensively review some uncommon, but exceedingly important, immune-related adverse events, with special emphasis in the clinical approach and diagnostic workup, aiming to reunite the evidence published previously, allowing an increase in awareness and knowledge from all specialists implicated in the diagnosis, treatment, and care of cancer patients treated with immunotherapy.
... Einzelne Fallberichte über Neutropenien, hämolytische oder aplastische Anämien sowie Thrombozytopenien wurden bislang veröffentlicht [36]. Die ITP unter einer Immun-Checkpoint-Inhibition ist bei Melanom-Patienten, aber auch anderen Entitäten möglich; der Verlauf ist in der Regel mild [37], jedoch kommen auch Todesfälle vor [38]. Deswegen erfordern schwere Verläufe wie in dem o.g. ...
... Optionen hierfür stellen Romiplostim und Rituximab dar. Eine Wiederaufnahme der Immuntherapie kann versucht werden; hierfür sind jedoch engmaschige Kontrollen erforderlich [37]. ...
Zusammenfassung
Moderne Immuntherapeutika wie Nivolumab, Pembrolizumab oder Ipilimumab, die sogenannte Immun-Checkpoints blockieren, haben die onkologische Therapie in den letzten Jahren revolutioniert. Mit dem neuen Wirkmechanismus der Blockade wichtiger Kontrollpunkte im Immunsystem zeigen sich jedoch auch eine Vielzahl an unterschiedlichen Nebenwirkungen. Diese treten nicht selten an der Haut auf. Zu den häufigsten dermalen Reaktionen unter Immuntherapie zählen die Vitiligo, Exantheme, blasenbildende Reaktionen oder der Lichen planus. Ausgeprägter Juckreiz kann Patienten stark beeinträchtigen. Der Verlauf bei auf die Haut beschränkten Nebenwirkungen ist häufig mild und gut zu behandeln oder selbstlimitierend. Hauterscheinungen können jedoch auch als Symptom systemischer Reaktionen auftreten. Eine frühe Diagnosestellung, die Einleitung einer adäquaten Therapie sowie eine interdisziplinäre Betreuung bei komplexen Erkrankungen sind entscheidend, um dauerhafte Einschränkungen für die Patienten zu verhindern und eine sichere Behandlung der zugrundeliegenden Tumorerkrankung gewährleisten zu können.
... Other treatment options include intravenous immunoglobulins, TPO-R, and other immunosuppressive therapies, such as azathioprine and rituximab. [5][6][7] In the present case, we started treatment with steroids. In addition, we used TPO-R in a combinational therapy. ...
A 69-year-old man presented with a pulmonary opacity at a regular medical check-up. He had been exposed to asbestos in a chemical fibre manufacturing setting. Positron emission tomography with CT revealed fluorodeoxyglucose accumulations along the right pleura in areas with multiple nodules and irregular pleural thickening. Based on analysis of a CT-guided needle biopsy, we diagnosed epithelioid malignant pleural mesothelioma (MPM). He received neoadjuvant chemotherapy, and subsequently, a pleurectomy and decortication. After 6months, MPM recurred with multiple tumours in the pleural cavity. Nivolumab was administered as salvage immunotherapy. A CT scan demonstrated significant tumour reduction; however, his platelet count was low (8000/μL), and he was diagnosed with nivolumab-induced immune thrombocytopaenia. Oral prednisone and thrombopoietin receptor agonist were delivered, and the platelet count improved; therefore, a sustained cycle of nivolumab was resumed. This case demonstrated that nivolumab could be re-administered for continued antitumor effects, with careful management of immune-related adverse events.
