Immune checkpoint inhibitors (ICIs) are changing the treatments of many patients with cancer. These immunotherapies are generally better tolerated than chemotherapy, and their adverse events are ...immune-related mimicking autoimmune or inflammatory conditions. Although these immune-related adverse events mainly affect the skin, endocrine glands, digestive tract, joints, liver or lungs, all the organs can be theoretically affected, and the haematopoietic system is not spared. This review of the literature will focus on the haematological immune-related adverse events (Haem-irAEs). By reviewing the largest clinical trials of ICIs, we estimate the frequency of Haem-irAEs at 3.6% for all grades and 0.7% for grades III–IV. Frequency of Haem-irAEs of all grades was found to be higher with anti–programmed cell death 1 (4.1%) or anti–programmed cell death ligand 1 (4.7%) than with anti–cytotoxic T-lymphocyte–associated protein 4 (0.5%) (p < 0.0001). From the 63 cases with Haem-irAEs reported in the literature, the mean time to the onset was found to be 10 weeks after ICI initiation, and the large range for occurrence (1–84 weeks) and the regular incidence suggest that Haem-irAEs could occur at any time after ICI therapy. Among the 63 reported cases with Haem-irAEs, the distribution was immune thrombocytopenia (n = 18, 29%), pancytopenia or immune aplastic anaemia (n = 12, 19%), neutropenia (n = 11, 17%), haemolytic anaemia (n = 10, 16%), cytokine release syndrome with haemophagocytic syndrome (n = 7, 11%) and other Haem-irAEs including bicytopenia or pure red cell aplasia (n = 5, 8%). Haem-irAEs are generally highly severe adverse reactions with a mortality rate of Haem-irAEs reported to be 14% (9 deaths among the 63 cases reported). The more severe and life-threatening Haem-irAEs were both cytokine release syndrome with haemophagocytic syndrome and pancytopenia or aplastic anaemia. Haem-irAEs induced by ICIs are potentially life-threatening. By discussing their pathophysiological aspects and clinical picture, we propose in this review clinical guidelines for management.
•Haematological immune-related adverse events are mainly seen with anti-programmed cell death 1 or cell death ligand 1 immunotherapies.•They are varied including immune cytopenia’s, cytokine release syndrome with haemophagocytic syndrome or eosinophil count increase.•The two most severe types were aplastic anaemia and cytokine release syndrome with haemophagocytic syndrome.•Haematological immune-related adverse events are rare events but potentially life-threatening.•If occurred, immediately hold immunotherapy even if severity is of grade I and adequately treat with steroids.
Essentials
Risk factors of bleeding in adult immune thrombocytopenia are not known.
This multicenter study assessed risk factors of bleeding at immune thrombocytopenia onset.
Platelet count ...thresholds associated with bleeding were < 20 × 109 L−1 and < 10 × 109 L−1.
Exposure to anticoagulants was a major risk factor of severe bleeding.
Summary
Background
The aim of this cross‐sectional study was to assess risk factors for bleeding in immune thrombocytopenia (ITP) adults, including the determination of platelet count thresholds.
Methods
We selected all newly diagnosed ITP adults included in the Cytopénies Auto‐immunes Registre Midi‐PyrénéEN (CARMEN) register and at the French referral center for autoimmune cytopenias. The frequencies of any bleeding, mucosal bleeding and severe bleeding (gastrointestinal, intracranial, or macroscopic hematuria) at ITP onset were assessed. Platelet count thresholds were assessed by the use of receiver operating characteristic curves. All potential risk factors were included in logistic regression models.
Results
Among the 302 patients, the frequencies of any, mucosal and severe bleeding were 57.9%, 30.1%, and 6.6%, respectively. The best discriminant threshold of platelet count for any bleeding was 20 × 109 L−1. In multivariate analysis, factors associated with any bleeding were platelet count (< 10 × 109 L−1 versus ≥ 20 × 109 L−1, odds ratio OR 48.2, 95% confidence interval CI 20.0–116.3; between 10 × 109 L−1 and 19 × 109 L−1 versus ≥ 20 × 109 L−1, OR 5.2, 95% CI 2.3–11.6), female sex (OR 2.6, 95% CI 1.3–5.0), and exposure to non‐steroidal anti‐inflammatory drugs (NSAIDs) (OR 4.8, 95% CI 1.1–20.7). A low platelet count was also the main risk factor for mucosal bleeding. Exposure to anticoagulant drugs was associated with severe bleeding (OR 4.3, 95% CI 1.3–14.1).
Conclusions
Platelet counts of < 20 × 109 L−1 and < 10 × 109 L−1 were thresholds for major increased risks of any and mucosal bleeding. Platelet count, female sex and exposure to NSAIDs should be considered for assessment of the risk of any bleeding. Exposure to anticoagulant drugs was a major risk factor for severe bleeding.
The first line treatment of immune thrombocytopenic purpura (ITP) is well established and based on short course of corticosteroids associated with intravenous immunoglobulins (IVIg) for the most ...severe forms. Predniso(lo)ne is the corticosteroid agent usually given but dexamethasone appears as an alternative. Some guidelines recommend to use dexamethasone as first line when a rapid increase of platelet count is required. Dexamethasone could be used rather than IVIg for moderate to severe but non life-threatening bleeding manifestations. Other therapeutic options such as anti FcRn monoclonal antibodies or recombinant FcγR currently in development for ITP could be an option in the future. In newly diagnosed ITP, we unfortunately lack robust predictive risk factors of severity and chronic outcome. Identifying such factors could be helpful for considering the early use of some treatments which are commonly used as second or third line.
Ten years after their licence in France, the use of the two thrombopoietin receptor agonists (TPO-RA), eltrombopag and romiplostim, has deeply modified the landscape of immune thrombocytopenia (ITP) ...treatment. In this review, we summarise data on efficacy and safety of these treatments during ITP, as well as their use in clinical practice. Their place in therapeutic strategy, the recent description of persistant remission after discontinuation of TPO-RA, and future new thrombopoietic agents are also discussed. Their use has progressively increased and early use at a newly diagnosed stage of the disease is under evaluation. However physician have to keep in mind that thromboembolism rates appear to be higher with TPO-RA treatment in ITP patients at high risk of thrombosis, and that data from "real-life" studies with very long term follow up are not available. Finally, the cost of these treatments should also be evaluated in future therapeutic strategies comparisons.
New molecules such as rituximab or thrombopoietin receptor agonists (romiplostim and eltrombopag) have changed the management of immune thrombocytopenia. Therefore, old drugs which are less expensive ...and with a well-known benefit/risk ratio are being underused. We aim to define the place of dapsone, danazol, hydroxychloroquine and vinca-alkaloids at the era of targeted therapy in immune thrombocytopenia. With a response rate around 30% to 50%, dapsone is an interesting second-line therapy to be used just after corticosteroids. Patients with positive antinuclear antibodies can benefit from hydroxychloroquine with a 50% response rate. Because of its side effects, mostly virilization, danazol will be preferentially used in the elderly. Vinca-alkaloids could be temporarily used in patients that do not respond to intravenous immunoglobulins or to limit their use to avoid shortage periods.
To analyse the efficacy and tolerance of infliximab in refractory Takayasu arteritis (TA).
French multicentre retrospective study that included patients with TA. Clinical disease activity was defined ...as new vascular and/or constitutional signs.
Fifteen patients with TA median age 41 (range 17-61) years; 13 women were included. At initiation of infliximab therapy, 14 patients were treated with CSs prednisone; median dose 20 (range 5-35) mg/day, MTX (n = 7) or AZA (n = 4). Infliximab was used at median 5 (range 3-5) mg/kg at a median of every 6 (range 4-8) weeks. A partial or good overall response was noted in 13 (87%) of the 15 cases, 10 (77%) of the 13 cases and 8 (73%) of the 11 cases at 3, 6 and 12 months, respectively. Clinical and biological activities significantly decreased within 3 months (from 11 at baseline to 4 patients at 12 months; P < 0.05), and similarly for CS dose from median 20 (range 5-35) mg/day at baseline to median 6 (range 2.5-30) mg/day at 12 months; P < 0.05. Only one patient was still steroid-dependent at 12 months (vs 8 cases before infliximab). CRP regressed from a median 30 (range 4-70) mg/l to 5 (range 0-57) mg/l and 6 (0-50) mg/l at 3 and 6 months, respectively (P < 0.05). Side effects were two infusion-related reactions, one pulmonary tuberculosis, one severe bacterial infection and EBV reactivation.
This study confirms the interest of infliximab in terms of clinical and biological response, as well as the steroid-sparing effect in TA.
Internal medicine is a medical specialty that is often poorly understood by the general public and sometimes misidentified. In an era of increasing subspecialization and high technicality, it is ...characterized by a comprehensive approach centered on clinical evaluation. Unlike what is observed in most developed countries, where systemic autoimmune diseases are managed by organ specialists based on their mode of presentation, French internists are at the forefront for diagnosing and managing these diseases. Their multidisciplinary training gives them legitimacy to justify this role. Internists also play a crucial role in the management of patients requiring unplanned hospitalizations downstream from emergency departments and in connection with primary care. Internists primarily practice in a hospital setting, with a specific position in the French healthcare system aligned with the training frameworks of all medical specialties. To better define internal medicine, its role in care activities, as well as in education and research, internists organized a General Assembly of internal medicine that took place on September 28, 2023, in Paris. Structured around think tanks focusing on care, education, and research activities, the general assembly aimed to improve visibility on internal medicine and internists. This article recounts the discussions that animated this meeting and highlights the main ideas that emerged. These general assemblies constitute a foundational step and will be followed by a Consultation Conference in order to better identify and promote internal medicine and internists, regardless of their types and places of practice.
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