Fostamatinib is available in France since October 2021 for the treatment of adult chronic immune thrombocytopenia (ITP). French health authorities requested a 3-year, prospective, multicenter registry to provide real-world evidence about the effectiveness and safety of fostamatinib. Patients' characteristics, treatment response (ongoing exposure to fostamatinib and a platelet count ≥ 30 × 10 9 /L with no rescue in the previous 4 weeks) after 3, 6, 12, and 24 months (M); bleeding; fostamatinib discontinuation; adverse drug reactions (ADRs) and other events of interest have been analyzed. In total, 164 patients were included (median age: 59 years; 55.5% women; 84.1% had previous bleeding; 30 had secondary ITP; 89.0% had chronic ITP). The median ITP duration was 7.2 years and the median number of previous ITP treatments was 6. The response rate was 44.0% (70/159) at M3, 41.9% (62/148) at M6, 32.4% (44/136) at M12 and 20.0% (21/105) at M24. Concomitant treatment (mostly TPO-RA) was used in > 60.0% of responders at each endpoint. The cumulative discontinuation rate at each endpoint was, respectively, 27.0%, 44.6%, 55.9%, and 76.2%. Seventy-one (43.3%) patients experienced at least one bleeding during fostamatinib exposure; none was fatal. One hundred adverse drug reactions (8 serious) were observed in 61 (36.7%) patients, including diarrhea in 28 (17.1%) patients, arterial hypertension in 17 (10.4%). Seven thrombosis (4.3%) and 40 infections (12 serious) were reported in 25 patients (15.2%), mostly in patients with known risk factors. In conclusion, fostamatinib in combination with TPO-RA should be considered in difficult-to-treat ITP patients. No new safety signal was observed.

Sutimlimab is a monoclonal antibody against complement fraction C1s approved for the treatment of hemolytic anemia due to cold agglutinin disease (CAD). Here, we analyzed and report the largest international CAD cohort of sutimlimab-treated patients ever reported to highlight its safety and effectiveness in the real-world setting. We accrued a cohort of 57 CAD patients (median age 73.5 years, 56% females). At baseline, patients had severe to moderate anemia (median Hb 8.9 g/dL) and active hemolysis, with a substantial transfusion burden despite a median of 2 prior therapies, including corticosteroids and rituximab. After sutimlimab initiation, median Hb increased by 2 g/dL within 2 weeks and reached 12 g/dL in 4 weeks, remaining stable up to 24 months. This improvement was paralleled by an early and durable normalization of hemolytic markers. Objective responses were observed in most patients by week 2, with complete responses in approximately 50% by Week 4 and 55%-60% during long-term follow-up. Peripheral cold-induced symptoms did not improve and were associated with reduced response rates. Inadequate reticulocytosis also predicted poorer response and suggests the combination with recombinant erythropoietin. Sutimlimab was generally well tolerated. Infections were the most frequent adverse events (23%); severe infections predominantly occurred in previously rituximab-treated individuals. Hemolytic exacerbations occurred in 16% of cases, mostly due to infections. Thrombotic complications were rare. Overall, sutimlimab demonstrated rapid, durable effectiveness and a favorable safety profile in heavily pretreated real-world CAD patients.

Background: ADVANCE IV+ (NCT04225156) is an ongoing, phase 3, open-label extension of the ADVANCE IV trial to assess long-term safety and efficacy of efgartigimod in adults (≥18 years) with chronic or persistent immune thrombocytopenia (ITP; platelet count <30 × 109/L). Methods: In ADVANCE IV, participants were randomised 2:1 to receive intravenous (IV) efgartigimod (10 mg/kg) or placebo once weekly (QW) for weeks 1–4, then QW or every other week (Q2W), based on platelet counts, up to week 24. Participants completing ADVANCE IV and meeting inclusion criteria could roll over to ADVANCE IV+. All participants received efgartigimod IV (10 mg/kg) QW or Q2W, dependent upon platelet counts. The primary objective was safety (frequency/severity of treatment-emergent adverse events [TEAEs]; vital signs; laboratory assessments); secondary objectives included assessment of long-term efficacy. Findings: In this interim analysis (data cutoff: 1 September 2023), 101 individuals (mean [standard deviation] age: 49∙7 [17∙2] years) rolled over from ADVANCE IV: 63 from the efgartigimod treatment group (EFG–EFG) and 38 from the placebo group (PBO–EFG). Most (96/101 [95∙0%]) were white and 51∙5% (52/101) were male. The majority of participants (93/101 [92∙1%]) reported one or more TEAE, with most mild or moderate in severity. Serious adverse events (AEs) were reported by 16/101 participants (15∙8%) (EFG–EFG: 10/63 [15∙9%]; PBO–EFG: 6/38 [15∙8%]). Severe (grade ≥3) AEs were reported by 19 participants (18∙8%) (EFG–EFG: 11/63 [17∙5%]; PBO–EFG: 8/38 [21∙1]). There were no treatment-related deaths. A sustained platelet count response (≥50 × 109/L for ≥4/6 weeks between weeks 19 and 24) was observed in 33/101 participants (32∙7%) (EFG–EFG: 23/63 [36∙5%]; PBO–EFG: 10/38 [26∙3%]). The proportion of sustained platelet count responders remained stable throughout the trial. Interpretation: ADVANCE IV+ demonstrated long-term safety and efficacy of efgartigimod in individuals with chronic or persistent ITP, highlighting its value as a treatment option in this patient group.

Adult patients with immune thrombocytopenia (ITP) have an increased risk of venous thrombosis as compared to the general population. The management of ITP in the context of anticoagulation is challenging. We conducted an observational study in the prospective, multicenter, national CARMEN-France registry. Adult patients with newly diagnosed ITP between June 2013 and May 2022 were selected. We assessed the cumulative incidence of venous thrombosis during follow-up with death as a competing event, described these events, and assessed patient outcomes depending on management strategies, with a focus on thromboses that occurred during treatment with thrombopoietin receptor agonists (TPO-RA). Among the 1303 patients selected for this study, 53 experienced venous thrombosis. The cumulative incidence of venous thrombosis was 2.6% (95% CI: 1.8-3.7) at 1 year and 8.6% (95% CI: 5.8-12.0) at 5 years. In patients exposed to TPO-RA, the cumulative incidence was 9.3% (95% CI: 6.2-13.2) and 13.4% (95% CI: 8.6-19.2) at 1 and 5 years of exposure, respectively. Patients who experienced thrombosis were older, had more frequently a history of venous thrombosis and secondary ITP, a more severe ITP, and were more frequently treated with TPO-RAs. Twenty (37.7%) of the 53 events were atypical, including five cerebral venous thromboses. Four patients died, and seven experienced major bleeding. The analysis of different managements of ITP after the thrombotic event suggested that the safest strategy was to promptly control ITP to enable early anticoagulation, including using TPO-RAs. Long-term anticoagulation therapy should be considered in patients treated with TPO-RAs and persistent risk factors for thrombosis.

Autoimmune hemolytic anaemias (AIHAs) represent different subtypes of a rare autoimmune disease in which autoantibodies targeting autoantigens expressed on autologous red blood cells’ (RBCs) membrane are produced, leading to their accelerated destruction. In the presence of hemolytic anaemia, the direct antiglobulin test (DAT) is the cornerstone of AIHA diagnosis. AIHAs are classified according to the isotype and the thermal optimum of the autoantibody, into warm (wAIHAs), cold and mixed AIHAs. wAIHAs, by far the most frequent type of AIHAs, are associated with underlying conditions in ∼50% of cases. Among adults, cold AIHAs include cold agglutinin disease (CAD), and cold agglutinin syndrome (CAS) when there is an underlying condition. Both CAD and CAS are IgM cold-antibody driven AIHAs characterized by classical complement pathway-mediated hemolysis. The management of AIHAs which has has long been empirical is mostly based on corticosteroids±rituximab for wAIHAs and on rituximab±bendamustine for CAD requiring to be treated, complement inhibition with sutimlimab being a new therapeutic option for CAD. This article reporting the French guidelines focused on diagnosis and treatment of adult AIHAs is adapted from the last update of the Protocole National de Diagnostic et de Soins (French protocol for diagnosis and management). These guidelines have been set up and led by the French national center for adult’ immune cytopenias (CeReCAI).

Abstract Pure red cell aplasia (PRCA) is a rare single-lineage bone marrow (BM) failure characterized by anemia with profound reticulocytopenia and severe reduction of erythroid precursors. PRCA is heterogeneous, and diagnosis requires extensive evaluation to distinguish primary from secondary causes, such as thymoma, autoimmune diseases, T-cell large granular lymphocyte expansion, and myelodysplastic syndrome (MDS), the differential diagnosis of which is particularly challenging. Evidence guiding management remains limited because of the rarity of the disease and the lack of prospective studies. We analyzed 121 acquired adult PRCA (excluding Parvovirus B19-associated PRCA) cases across 14 European centers. Secondary forms accounted for 78% of diagnoses, mostly thymoma (23%) or MDS (21%). In a subset of patients, BM immunohistochemistry demonstrated significant depositions of C3, C4d, immunoglobulin M (IgM), and IgG, reducing after immunosuppression. Next-generation sequencing was performed in half of the patients, 36% of whom presented mutations predominantly related to clonal hematopoiesis, except in MDS-associated cases, which often carried multiple non-clonal hematopoiesis mutations. Immunosuppression represented the backbone of therapy: cyclosporine A (CyA) was the most effective agent, with 61% overall response rate (47% complete) and better outcomes when initiated earlier; mammalian target of rapamycin inhibitors (mTORi) showed promising activity as second-line therapy, with responses in 71% of the patients, including CyA-refractory cases. Mortality reached 30%, predominantly because of infectious complications, and was significantly higher in MDS-associated cases. PRCA remains a diagnostically challenging and clinically heterogeneous disorder in which integration of molecular analyses may refine diagnostic accuracy and patient stratification. Immunosuppression remains the mainstay of treatment, with CyA being a reliable first-line treatment and mTORi emerging as encouraging rescue options.

Autoantibodies neutralizing type-I interferons (AAN-I-IFNs) emerge as global, common, and strong determinants of a growing number of severe viral diseases. We report that AAN-I-IFNs+ patients with life-threatening COVID-19 pneumonia harbor circulating type-I IFN-specific B cells indistinguishable from patients bearing T cell tolerance defects of genetic origin. This autoimmune response mobilizes a highly diverse and stable circulating B cell response that is detected prior to severe viral infection and acquires high affinity and neutralization potential to type-I IFNs through extended somatic hypermutation. X-ray crystallography and AlphaFold3 structural analysis of hundreds of patient-derived monoclonal antibodies reveals the extended breadth of this response, targeting three major B cell epitopes covering all facets of type-I IFNs. These findings support a model in which a germinal-center-derived memory B cell response directed against type-I IFNs is established before severe viral infection, providing a core mechanism linking T cell tolerance defect to pathogenic AAN-I-IFNs underlying severe viral diseases.

ABSTRACT:Resistance to B-cell-targeted therapies in immune thrombocytopenia (ITP) has been linked to persistence of autoantibody-producing CD38+ long-lived plasma cells. CD38 antibody daratumumab has been proposed as a potential therapy for ITP. This multicenter, open-label, phase 2 study evaluated safety and efficacy of daratumumab in 21 patients with previously treated ITP. Following a safety run-in, 2 dosing cohorts received 8 and 10 subcutaneous injections of 1800 mg daratumumab weekly, respectively. Primary end points were safety and response (2 consecutive platelet counts ≥50 × 109/L at week 12 for the safety run-in/cohort 1, and at week 16 for cohort 2). At baseline, median platelet count was 17 × 109/L, median number of prior therapies was 4. Most treatment-emergent adverse events were transient grade 1 to 2, most commonly infections (38%). Two patients (4.7%) experienced grade 3 adverse events, 1 infusion-related reaction, and 1 severe acute respiratory syndrome coronavirus 2 infection with acute renal failure. Ten patients (48%) met the primary efficacy end point. Sustained response (2 consecutive platelet counts ≥50 × 109/L at week 24) was achieved in 8 patients (38%), of whom 2 later relapsed. Response and relapse rates did not differ between cohorts. Patient-reported quality of life measured by 36-Item Short-Form Health Survey improved in responding patients. Daratumumab decreased immunoglobulin levels in all patients, and substantially reduced CD38+ cells in peripheral blood and bone marrow. There was no significant difference in antiplatelet antibodies between responders and nonresponders. This study confirms CD38 as an important target in ITP. This trial was registered at clinicaltrials.gov as #NCT04703621, and at the European Clinical Trial Register (EudraCT #2019-004683-22).

The predictive value of cytokines (CK) for malignancy-associated adult hemophagocytic lymphohistiocytosis (M-HLHa) remains uncertain. We evaluated a cytokine-based Risk Score (RS) and the IL-10/IL-6 Ratio to predict M-HLHa. Adult patients (n = 112) from the French HLH cohort (NCT02113917) with complete data for nine key HLH related CK measured by Luminex were first analyzed. Logistic regression was performed, and a RS was subsequently derived and internally validated. In a post hoc analysis, the IL-10/IL-6 ratio obtained using the ELLA cytokine assay was evaluated in 75 patients, 54 of whom also had Luminex testing, plus 25 additional patients from the cohort. The RS and IL-10/IL-6 ratio were then jointly assessed in the 54 patients with results from both platforms. Among the 112 patients, 45 had M-HLHa and 67 non M-HLHa; median age was 48 years and 64 (57%) were male. Eight variables were associated with M-HLHa, of which four were retained in the logistic model: age > 48 years (2.9[1.12-7.33], p = 0.03), TNF-α ≤ 43 pg/mL (3.2[1.16-8.61], p = 0.02), IL-18 > 574 pg/mL (4.9[1.89-12.75], p = 0.001), and IL-10/IL-6 ≥ 1.5 (2.7[1.01-7.31], p = 0.04), with respective weights of 11, 12, 16, and 10. A RS ≥ 20 increased the odds of M-HLHa 17-fold (17.2 [5.4-54.5], p < 0.0001). The IL-10/IL-6 ratio alone (n = 75) showed good performance (AUC 0.83). In the 54 patients with both assays, the RS and IL-10/IL-6 ratio preserved their diagnostic performance (AUC 0.87 and 0.79, respectively). These data support the RS and IL-10/IL-6 Ratio as useful tools to improve the identification of M-HLHa in adults. Trial Registration: clinicaltrials.gov NCT02113917.

Bispecific T-cell engagers (TCEs) represent a new generation of immunotherapies designed to redirect cytotoxic T lymphocytes toward specific cellular targets, particularly B cells and their differentiated progeny. Initially developed in hematology for the treatment of malignant B-cell and plasma-cell disorders, TCEs are now gaining growing interest as potential therapies for severe or refractory autoimmune diseases. By simultaneously binding CD3 on T cells and antigens such as CD19, CD20, or BCMA (B-cell maturation antigen) on B-lineage cells, TCEs induce the targeted elimination of autoreactive B cells and plasma cells responsible for autoantibody production. This approach combines the depth of immune depletion achieved with cellular therapies and the controllability of monoclonal antibodies, offering the potential for rapid, profound, and durable immunomodulation. However, it also raises important questions regarding safety, feasibility, and cost. Compared with CAR-T cell therapies, TCEs offer a more accessible and immediately deployable strategy, while potentially achieving comparable levels of B-cell and plasma-cell depletion, though with shorter exposure and possibly reduced long-term persistence. This review provides an integrated overview of mechanistic, preclinical, and emerging clinical data on the use of TCEs in autoimmune diseases, and discusses their therapeutic potential, and limitations in this evolving field.

Pure red cell aplasia (PRCA) is the most frequent autoimmune cytopenia associated with thymic tumors (TTs). In a nationwide retrospective study, we included 41 patients (22 women, median age 62 years). At PRCA diagnosis, the mean hemoglobin level was 6.6 ± 2.1 g/dL, and the reticulocyte count was 6 ± 5 × 109/L. PRCA was diagnosed before TT (8%, median delay 52 months), simultaneously (46%) or after TT (46%, median delay 34 months). Fourteen patients (34%) had definite Good syndrome. Thymectomy without immunosuppressive treatment provided a single sustainable PRCA response. Twenty-two patients (54%) experienced multiple PRCA relapses (Median 2). When PRCA was present at TT diagnosis, the risk of PRCA relapse was higher (p < 0.01), while TT staging, TT relapse, and Good syndrome were not associated with PRCA relapses. Corticosteroids led to a 77% initial response rate with frequent relapses during taper or at discontinuation. Cyclosporine A provided a 71% response rate. Overall response rates and time to response were similar with corticosteroids and cyclosporine A. Sirolimus led to a 50% response rate in refractory cases. Severe infectious events requiring hospitalizations were frequent (44%). After a mean follow-up of 50 months, five patients (12%) died, three of whom died from TT relapse. Good syndrome was not significantly associated with an increased risk of infection, PRCA relapse, or death. Our findings highlight the severe phenotype of the association of TT and PRCA. While most patients achieve PRCA response under immunosuppressive therapy, high infection incidence and thymoma relapse are responsible for severe morbidity.

Rationale: Patients with sickle cell disease hospitalized for acute chest syndrome (ACS) are at high risk of in situ pulmonary microthrombosis. Objectives: We evaluated whether therapeutic anticoagulation could shorten ACS duration. Methods: TASC (Therapeutic Anticoagulation for Acute Chest Syndrome in Sickle Cell Disease) is a randomized, controlled, double-blind trial conducted in 12 French hospitals (December 2016-April 2021) in adult patients with ACS with no initial thrombosis on chest computed tomography with pulmonary angiogram. We randomized 172 patients (1:1) to receive either prophylactic or therapeutic doses of low-molecular-weight tinzaparin for 7 days. The primary efficacy outcome was time to ACS resolution. The primary safety outcome was major bleeding. Main secondary outcomes included parenteral opioid consumption, transfusion, mortality at hospital discharge, and hospital readmissions at 6 months. Measurements and Main Results: The primary efficacy outcome, time to ACS resolution, analyzed using a Cox model, was shorter with therapeutic anticoagulation than with prophylactic doses (hazard ratio, 0.71; 95% confidence interval, 0.51 to 0.99; P = 0.044). As a supplemental estimate, the restricted mean time to ACS resolution (over a 15-d horizon or discharge) was shorter with therapeutic doses (4.8 ± 0.4 vs. 6.1 ± 0.5 d). The primary safety outcome (major bleeding) did not occur in either group. The cumulative dose of parenteral opioids was lower with therapeutic anticoagulation: median [interquartile range] of 124 [80 to 272] vs. 219 [65 to 378] mg morphine equivalent; difference, -96; 95% confidence interval, -202 to -46; P = 0.02. Other short- and long-term secondary outcomes were similar between groups. Conclusions: In adult patients with ACS, a therapeutic anticoagulation shortened ACS duration and reduced opioid consumption compared with prophylactic doses, without increasing bleeding risk. Clinical trial registered with www.clinicaltrials.gov (NCT02580773).

Mycoplasma pneumoniae (MP), primarily a respiratory pathogen, can cause extra-pulmonary manifestations including cold agglutinin syndrome (CAS). We conducted a national, multicenter, observational, ambispective study to describe the characteristics, risk factors, and outcomes of MP-associated CAS. Adult patients hospitalized for a MP-infection with CAS (hemolytic anemia with hemoglobin < 10 g/dL and C3 positive direct anti-globulin test) were included. Recovery was defined as hemoglobin > 10 g/dL off therapy. We also compared MP-infected patients with or without CAS. Sixty patients (51.7% of females; median age of 48.5 years) were included. CAS was diagnosed a median of 10 days after MP-infection symptoms onset. At diagnosis, the median hemoglobin level was 6.9 g/dL, and 71.7% of patients received red blood cell transfusions. Intensive care unit (ICU) admission was required in 45% of patients, and 16.7% experienced a venous thromboembolic event (VTE). Seventeen patients (28.3%) received glucocorticoids alone, while 40 (66.7%) did not receive any specific treatment for CAS. After a median follow-up of 56 (30-83) days, 90% of patients achieved recovery, while 2 patients (3.3%) died from sepsis and pulmonary embolism. Glucocorticoid use did not significantly impact the rate or timing of recovery. Compared with MP-infected patients from the MYCADO cohort study (n = 1267), CAS patients had significantly more VTE (p < 0.0001) and ICU admissions (p = 0.03). MP-associated CAS typically occurs 10 days after the first symptoms of MP infection and is associated with ICU admissions and VTE. Overall, the prognosis of CAS is good, and glucocorticoids do not appear to influence outcomes.

The diagnosis of hemolysis is still based on straightforward biochemical parameters: haptoglobin (the most sensitive), lactate dehydrogenase (LDH), and unconjugated bilirubin. Anemia is not always present. Reticulocyte counts typically exceed 120×109/L, except in cases of associated vitamin deficiency or during the very early phase of acute hemolysis. When the Direct Antiglobulin Test is negative, a non-autoimmune cause of hemolysis should be considered. A thorough history, careful physical examination, and meticulous review of the peripheral blood smear help to rule out major emergencies such as malaria, thrombotic microangiopathy, severe infections, delayed hemolytic transfusion reaction, or toxic hemolysis. In the absence of a mechanical valve or other intravascular device that could induce hemolysis, second-line laboratory tests should be pursued: hemoglobin phenotyping, eosin-5'-maleimide (EMA) binding test, screening for paroxysmal nocturnal hemoglobinuria (PNH), and enzymatic assays. These tests usually lead to the diagnosis of most corpuscular non-autoimmune hemolytic anemias, including hemoglobinopathies (such as sickle cell disease, thalassemia syndromes, hemoglobin C disease, or unstable hemoglobins), membranopathies (such as hereditary spherocytosis or stomatocytosis), and enzyme deficiencies. The diagnosis of rare causes of hemolysis should be considered at a later stage or in specific contexts, such as alcoholism (Zieve's syndrome), advanced cirrhosis (spur cell anemia), or acute hemolysis in a young patient (Wilson's disease).

BACKGROUND:Current second-line treatments for immune thrombocytopenia (ITP) require long-term administration. Ianalumab, a monoclonal antibody targeting B cells, is being assessed as a short-course second-line therapy in ITP. METHODS:In this phase 3, randomized, double-blind trial, we assigned, in a 1:1:1 ratio, adults with primary ITP and an insufficient response or a relapse after first-line glucocorticoid therapy to receive ianalumab at a dose of 9 mg or 3 mg per kilogram of body weight or placebo once monthly for 4 months. Eltrombopag, an oral thrombopoietin-receptor agonist, was administered once daily in each group according to local prescribing information; the dose was tapered until discontinuation by the end of week 24 in eligible patients. The primary end point was freedom from treatment failure, as determined in a time-to-event analysis, with treatment failure defined by a platelet count of less than 30×109 per liter more than 8 weeks after randomization, initiation of rescue therapy more than 8 weeks after randomization, initiation of new ITP therapy, inability to taper or discontinue eltrombopag because of an inadequate platelet count, or death from any cause, whichever occurred first. The key secondary end point was a stable response at 6 months, defined by a platelet count of at least 50×109 per liter in at least 75% of the measurements between weeks 19 and 25 without use of rescue therapy or new ITP therapy. Safety was assessed. RESULTS:A total of 152 patients underwent randomization: 50 to the 9-mg ianalumab group, 51 to the 3-mg ianalumab group, and 51 to the placebo group. The estimated probability of being free from treatment failure at 12 months was 54% (95% confidence interval [CI], 39 to 67) in the 9-mg group, 51% (95% CI, 36 to 64) in the 3-mg group, and 30% (95% CI, 18 to 43) in the placebo group. The time to treatment failure was significantly longer with ianalumab plus eltrombopag than with placebo plus eltrombopag; the estimated hazard ratio for treatment failure (ianalumab vs. placebo) was 0.55 (P = 0.04) in the 9-mg group and 0.58 (P = 0.045) in the 3-mg group. The percentage of patients with a stable response at 6 months was significantly higher in the 9-mg group than in the placebo group (62% vs. 39%; P = 0.045). The overall frequency of adverse events during the treatment period was generally similar in the three groups. The frequency of serious adverse events was 16% in the 9-mg group, 6% in the 3-mg group, and 4% in the placebo group. CONCLUSIONS:Ianalumab plus eltrombopag led to a longer time to treatment failure than placebo plus eltrombopag. (Funded by Novartis; VAYHIT2 ClinicalTrials.gov number, NCT05653219.).

Introduction Despite the increasing number of therapeutic options for immune thrombocytopenia (ITP), refractory disease remains an unmet need in clinical practice. Anti-CD38 monoclonal antibodies such as daratumumab have recently been shown to be a promising treatment in ITP. The aim of this study was to assess safety and efficacy of daratumumab given for refractory ITP. Patients and methods We conducted an observational, retrospective, multicenter study throughout the network of the French reference center for adult' immune cytopenias including patients receiving compassionate off-label treatment by daratumumab for ITP (either primary or secondary) between 01/01/2020 and 01/06/2025. ITP was diagnosed according to international guidelines. Patients were excluded if daratumumab was given to treat plasma cell malignancy. Complete response (CR) was defined by platelet count >100x109/L and response (R) by platelet count 30 to 100x109/L with at least a 2-fold increase from baseline. Patients who required any other treatment including rescue therapy more than six weeks after first daratumumab infusion were considered non-responders regardless of platelet counts. All patients were informed and gave consent to ‘off-label’ use of daratumumab. The study received institutional review board approval (00011558, UPEC University, AP-HP). Results Twenty-one patients (43% females) with a median age at first daratumumab infusion of 67 years [range 21-88] were included in the study. Eight had secondary ITP (38%; Evans syndrome, n=6, and/or antiphospholipid syndrome (APLS), n=2, or rheumatoid arthritis, n=1). In addition, 2 patients had antibodies against GPIIb-IIIa (acquired Glanzmann syndrome, n=1) and GPVI (n=1) responsible for chronic bleeding symptoms. Median ITP duration was 78 months [range 4-594], and patients had previously received a median number of 8 [range, 3-12] treatment lines for ITP, including corticosteroids (100%), rituximab (100%), intravenous immunoglobulin (95%), thrombopoietin receptor agonists (95%; including eltrombopag [90%] and romiplostim [86%]), mycophenolate mofetil (81%), splenectomy (71%), fostamatinib (48%), and one or more other immunosuppressive drug (43%). Fifteen patients (71%) had bleeding symptoms despite treatment in the previous month. Patients received a median number of 6 [range 3-20] infusions of daratumumab either at 16mg/kg of body weight intravenously (n=10) or at a fixed dose of 1800 mg subcutaneously (n=11) with dexamethasone premedication. Daratumumab was given with other ITP treatments in 15 patients (71%). Median follow up after daratumumab was 16 months [range 1-60]. Ten (48%) patients had adverse events imputable to daratumumab, including 5 patients (24%) with infectious events requiring hospitalization (sepsis, n=2, bacterial pneumonia, n=2, acute tonsillitis, n=1), 2 patients with transient neutropenia (but without infection), and 3 patients with immediate reaction after infusion. During follow-up, 4 patients (19%) died (1 splenectomized patient had campylobacter sepsis 1 month after daratumumab initiation, 1 patient with stroke and APLS had sepsis 23 months after daratumumab, 1 patient died from refractory ITP, and 1 patient with metastatic cancer died from cardiac failure). In the 6 months following daratumumab, among the 10 patients with available gammaglobulin assessment without intravenous immunoglobulin administration, 8 (80%) had concentrations below 6g/L. Overall response (CR+PR) was achieved in 11 patients (52%), including 9 CR (43%), and 2 PR (10%), with a median time to response of 35 days [range 7-84]. Relapses occurred in 3/7 (43%) of responders that had a follow-up >6 months after daratumumab. Four patients had long-lasting CR without any other ITP treatment, with relapses in 2 (50%) after 10 and 32 months, respectively. Two patients with initial CR and experiencing a relapse had a second course of daratumumab, resulting in 2 new initial CR but eventually with relapses in both patients. Discussion Overall, these results suggest that daratumumab has the potential to induce durable remissions even in multirefractory ITP patients, although response appears transient in most responders. However, this came at the cost of a high rate of severe infections in this particular group of heavily treated, frequently splenectomized, immunocompromised and fragile patients. Careful assessment of benefit/risk balance is therefore warranted before daratumumab administration.