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.

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.

To assess efficacy and safety of dapsone in adult immune thrombocytopenia (ITP), a multicenter randomized controlled trial (RCT) and a real-word study cohort were performed. Participants were adults with primary ITP, transient response to corticosteroids ± intravenous immunoglobulin, and a platelet count ≤ 30x109/L (or ≤ 50x109/L with bleeding). Patients in the RCT were randomized in arm A (prednisone x3weeks+dapsone for 12 months) or arm B (prednisone alone). The observational study involved dapsone initiation at 100 mg/d with standard follow-up. The primary endpoint was the response rate (platelet count >30x109/L and ≥2×baseline) at 52 weeks, with the response rate at 24 weeks and adverse events as secondary endpoints. The RCT enrolled 93 patients (54.8% female), median age 48.5 years (46 in arm A, 47 in arm B). In the intention-to-treat analysis, 78.3% of patients in group A discontinued dapsone after a median of 4.6 weeks due to adverse events (66.7%) or lack of efficacy (33.3%). The response rate at week 52 was 21.7% (95% CI:10.9%-36.4%) in group A versus 8.5% (95% CI:2.7%-18.6%) in group B (p=0.17). The observational study, which was conducted after the end of the RCT, included 46 patients (52.2% female), median age 50.7 years. Adverse events occurred in 30.4%, leading to discontinuation of dapsone in 23.9%, and 13.6% (95% CI: 5.2%-27.4%) met the primary efficacy endpoint. Results from both studies showed an unfavorable risk-benefit ratio for the use of dapsone in adult primary ITP and suggest that, whenever available, second-line options should be used. NCT02627417, NCT02877706

The incidence of febrile neutropenia in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients is high. In AML patients receiving intensive chemotherapy, levofloxacine prophylaxis was associated with a reduction of the incidence of febrile neutropenia wich did not affect mortality in a meta-analysis (Owattanapanich et al, Hematology, 2019). In patients treated with azacitidine (AZA), who are typically treated in an outpatient setting, reducing the incidence of febrile neutropenia may be crucial. We conducted a multicenter phase III open-label randomised (1:1) study to evaluate levofloxacine as antibacterial prophylaxis in AML and MDS patients treated with AZA. Patients aged over 18y treated with AZA in first line either for AML or for intermediate 2 or high-risk MDS according to IPSS were eligible. Associations of AZA with other treatments were allowed. Patients randomised in the experimental arm (A) received levofloxacine 500 mg daily during the first 3 cycles of AZA. Those in the reference arm (B) received no prophylaxis. The primary endpoint was the incidence of febrile neutropenia causing an hospitalisation and start of an other systemic antibiotic treatment during the first three cycles. One-year overall survival (OS) was assessed as secondary endpoint. From July 2018 to July 2024, 59 patients (MDS: n=44, AML: n=15) were enrolled in the study. Twenty-nine patients were assigned to arm A and 30 patients to arm B. Median age was 75 [IQR: 70-80] and 61% (n=36) were males. Among the 29 patients in the arm A, the median effective duration of the levofloxacine prophylaxis was 71 [IQR: 29-90] days, 65 [IQR:35-90] days for MDS patients and 77 [IQR: 18-87] days for AML patients. Toxicity was the reason for prophylaxis interruption in 7 patients (24%). Eight patients (13.3%) experienced at least one adverse event that was considered treatment-related, all of which were grade 1 or 2. Tendinitis was the most common (4 patients). Adverse events involved 50 patients (83.3%) (arm A 24/29, arm B 26/30). Febrile events incidence did not significantly differ between the 2 arms (p=0.58), with 5 patients (17.2%) in arm A having experienced febrile events and 8 patients (26.7%) in arm B. The median time to febrile event was 31 days (range 12-49) among the 5 patients from the arm A, and 20.5 days (range 1-36) among the 8 patients from the arm B. No febrile events in arm A were grade 4-5 while 4 events (50%) in arm B were grade 4-5 (p=0.11). Among the 4 patients in arm B with grade 4-5 febrile events, 3 died due to this event, and 2 had probable pneumopathy. In a multivariate logistic regression analysis, risk factors for febrile events included low baseline neutrophils count (<0.5 G/L) (p=0.03), low baseline albumin level (<34g/dL) (p=0.01), and age over 75 (p=0.03). Two over 5 febrile events in arm A (40%) and 3/8 febrile events in arm B (37.5%) had microbiological documentation. Carbapenem and glycopeptide precription did not significantly differ between the 2 arms (carbapenem: 2/29 vs 1/30 patients, p=0.61 ; glycopeptide: 1/29 vs 2/30 patients, p=1). Twelve patients in the experimental arm and 17 patients in the reference arm died during the study. Median OS was 12.2 months from day 1 of the first cycle of AZA. Cause of death was a febrile event in 3 patients (17.6%) in arm B and none of the patients in arm A, and the disease progression in 4 patients (33.3%) in arm A and 7 patients (41.2%) in arm B. OS did not significantly differ between the 2 arms (p=0.16). One-year survival rate was 57% (95%CI: 42%-79%) in arm A and 50% (95%CI: 35%-71%) in arm B. Levofloxacine prophylaxis did not significantly reduced febrile events incidence or improve survival in MDS / AML patients treated with AZA. However, several deaths attributed to febrile events in the reference arm suggest a probable benefit of levofloxacine in this setting but the limited size of this trial does not enable us to confirm it. Larger studies would be useful to investigate this question.

Autoimmune hemolytic anemias (AIHA) encompass with three main different subtypes based on the properties of the autoantibody: warm AIHA (wAIHA), cold agglutinin disease/syndrome (CAD/CAS; i.e., primary/secondary AIHA with exclusively cold antibodies, respectively), and mixed AIHA (mAIHA). The epidemiology of AIHA has been assessed using retrospective cohort studies including up to 308 patients, or cohorts based on claims databases that often lack detailed clinical and biological data. This study aimed to describe the clinical and biological characteristics at diagnosis of AIHA by subtypes, in a multicenter, prospective cohort in France. The data source was the Carmen-France Registry, that includes prospectively all adults with AIHA in the 50 participating centers. We selected the patients included between January 2015 and February 2025. AIHA diagnosis was based on international consensus criteria. The clinical and biological characteristics of patients at AIHA onset were described, as well as the causes of secondary AIHA, and the treatments used within the first week following the diagnosis. During the study period, 413 AIHA patients were included in the registry: 283 (68.5%) had wAIHA, 64 had CAD/CAS (15.5%), and 66 (16.0%) had mAIHA. The median age at diagnosis was 69 years (Q1-Q3: 56-79) and was similar between AIHA subtypes. There was a slight male predominance among wAIHA patients (148 males, 52.3%), and a female predominance among CAD/CAS (42 females, 65.6%) and mAIHA patients (38 females, 57.6%). A Charlson Comorbidity Index median score ≥1 was more frequent among the patients with wAIHA and mAIHA than CAD/CAS (respectively, 49.8%, 60.6% and 39.1%). Before AIHA diagnosis, 225 (54.5%) patients had cardiovascular risk factors: 150 (36.3%) had hypertension, 66 (16.0%) had dyslipidemia, 58 (14.0%) had diabetes, and 45 (10.9%) patients had active or recent cessation of smoking. In total, 51 (12.3%) patients had a history of arterial thrombosis, and 42 (10.2%) of venous thrombosis. At AIHA onset, 40 (62.5%) patients had symptoms of anemia in CAD/CAS versus 212 (74.9%) and 48 (72.7%) in wAIHA and mAIHA, respectively. In wAIHA, 123 (43.5%) had jaundice versus 18 (28.1%) and 19 (28.8%) in CAD/CAS and mAIHA, respectively. Clinical splenomegaly was present in 21.2% of wAIHA (primary: 14.0%; secondary: 30.2%) and 22.7% of mAIHA. Cardiac failure was present in 3.9% of patients and coronary insufficiency in 1.2%. The hemoglobin level was 71 g/L (Q1-Q3: 59-85) in wAIHA, 77 g/L (Q1-Q3: 66-94) in mAIHA, and 87 g/L (Q1-Q3: 76-99) in CAD/CAS. The levels of hemolytic markers were similar between groups. In the overall population, the lactate dehydrogenase level was 450 U/L (Q1-Q3: 338-666), the total bilirubinemia level was 38 µmol/L (Q1-Q3: 22-60), and the total haptoglobin level was 0.08 g/L (Q1-Q3: 0.00-0.10). We identified 126 secondary wAIHA (44.5% of wAIHA), 27 CAS (42.2% in CAD/CAS group), and 20 secondary mAIHA (30.3% of mAIHA). B cell clonal lymphoproliferative diseases were predominant in all AIHA subtypes (wAIHA: 55.6%; CAS: 44.4%; mAIHA 70.0%). In secondary wAIHA, the most frequent cause was chronic lymphocytic leukemia (23.0%) followed by marginal zone lymphoma (12.7%). Other autoimmune diseases were found in up to 25.4 % of wAIHA. Infections were the second causes of CAS (33.3%) including 5 (18.5%) patients with Mycoplasma pneumoniae infection. In secondary wAIHA, 10.3% of patients had systemic lupus erythematosus and 6.3% had antiphospholipid syndrome. Drug-induced wAIHA concerned 12 patients (n=5 immune checkpoint inhibitors; n=3 antibiotics). During the first week after AIHA diagnosis, wAIHA patients mostly received corticosteroids: 226 (80.0%) versus 28 (42.4%) and 10 (15.6%) in mAIHA and CAD/CAS, respectively. Red blood cell transfusion was required in 99 (35.0%) wAIHA patients, 20 (31.3%) CAD/CAS patients, and 16 (24.2%) mAIHA patients. During this early period, rituximab was introduced in 34 (12.0%) wAIHA patients, 6 (9.1%) mAIHA patients, and 3 (4.7%) CAD/CAS patients. Erythropoietin was scarcely used in all subtypes (wAIHA: 6.0%; CAD/CAS: 7.8%; mAIHA: 9.1%).In conclusion, age at AIHA diagnosis was similar between subtypes. AIHA was a severe disease with red blood cell transfusion requested at diagnosis in one quarter to one third of patients. The hemoglobin level was higher in cAIHA than in wAIHA and mAIHA. Rituximab was used early after wAIHA diagnosis in 12% of patients.

Background: Fostamatinib, a spleen tyrosine kinase inhibitor, has been marketed in France for the management of adult chronic immune thrombocytopenia (ITP) in October 2021. French health authority recommended the use fostamatinib in case of failure or contraindication to eltrombopag, romiplostim (the two thrombopoietin receptor agonists – TPO-RAs – available in France), rituximab and splenectomy, even if every hematologist or internist is allowed to prescribe the drug. The French national health authority also requested a prospective three-year registry to include and follow as many treated patients as possible to provide real-world evidence. We herein present the results of this registry, assessing the use, the effectiveness and the safety of fostamatinib in adult patients with ITP in the real world in France after three years of availability of the drug. Methods: The source of study population was the French fostamatinib registry, appended to the CARMEN-France registry of the French referral network for autoimmune cytopenias, that prospectively includes adult patients with a new diagnosis of ITP in 50 centers. Adult patients were included in the fostamatinib registry 1) if they were previously included in the CARMEN-France registry and initiated fostamatinib or 2) if they were not already in the registry but initiated fostamatinib. In that latter case, a retrospective assessment of ITP history was recorded. Patients who initiated fostamatinib between October 2021 and October 2024 were selected for the present analysis. We described the patients' characteristics, response rate on treatment (defined by an ongoing exposure to fostamatinib and a platelet count ≥30 x 109/L with no rescue in the previous 4 weeks) at M3, M6, M12 and M24, bleeding during fostamatinib, drug discontinuations, adverse drug reactions (ADRs, judged related to fostamatinib by the investigators), and other events of interest, i.e. thrombosis, infection, fracture, cancer and death. Results: During the study period, 164 patients were included in the registry, corresponding to 44.3% of exposed patients in the whole of France, as determined by the national dispensing database. Median age was 59 years and 55.5% were women. Thirty-eight percent had ≥1 comorbidity according to the Charlson Comorbidity Index and 29.7% had chronic arterial hypertension. The median lowest platelet count before fostamatinib was 11 x 109/L and 84.1% patients had experienced bleeding. Thirty patients had secondary ITP. The median ITP duration was 7.2 years and 146 (89.0%) patients had chronic ITP. The median number of previous exposures to ITP treatments was 6 (min-max: 1-13). Seventy-height percent of patients had been exposed to eltrombopag, 74.4% to romiplostim, 86.0% to rituximab, 48.8% to mycopenolate or azathioprine, and 28.0% were splenectomized. A concomitant exposure to another ITP treatment at fostamatinib initiation was present in 65.2% of patients. 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. Combination treatment (mostly with TPO-RA) was observed 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 the exposure to fostamatinib, 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%), transaminitis (n=7) and neutropenia (n=4). Seven (4.3%) thrombosis and 40 infections (including 12 serious) in 25 (15.2%) patients were reported mostly in patients with known risk factors. One fracture was reported (in an 87-year-old woman exposed to corticosteroids), two cancers (1 lymphoma and 1 adenocarcinoma considered not related to fostamatinib because diagnosed within the weeks following the exposure), and 5 deaths (47 to 82 year-old patients 3 related to infection, 1 to myocardial infarction, 1 of unknown cause). Conclusion: Fostamatinib was used in previously very heavily treated patients, with response rates of 44.0% at M3 and of 20.0% at M24. Combination therapy with TPO-RA is an option to consider in this population. No new safety signal was observed.

Introduction: There is still an unmet medical need for patients with low riskmyelodysplastic syndrome (MDS) who are refractory or relapsing to erythropoietin stimulating agents and transfusion dependent. Transfusion burden leads to iron overload needing iron chelation therapy. In vitro data from our team demonstrate that low dose of deferasirox (DFX) (3µM) induced MDS erythroid progenitors proliferation by decreasing oxidative stress (Meunier al, Oncotarget 2017). Several case reports from patients under iron chelation therapy have already shown an improvement of hemoglobin level. Thus, we initiated a multicenter study named LODEFI, prospectively assessing the potential benefit of low dose deferasirox on transfusion burden for low risk MDS patients. Methods: This is a single arm, multi-center, open-label, Phase II trial for patients with very low, low and intermediate myelodysplastic syndrome according to IPSS-R and WHO 2016 classification, refractory or relapsing to erythropoietin stimulating agents, with low transfusion burden and ferritin level under 1000 µg/l.Deferasirox 3.5mg/kg was given orally every day for 12 months. Baseline patient characteristics and biology including iron metabolism data were collected. Primary endpoint was the efficiency of low dose DFX on transfusion dependence at one year from the beginning of DFX, defined by the need of 2 and more red blood cells units per 8 weeks on 3 time periods of 8 weeks (24 weeks), from the 6th to the 12th month of the beginning of DFX. Some of the secondary endpoints were to assess the impact of low dose DFX on transfusion dependance (TD) defined as a transfusion burden of more than 4 red blood cells units every 8 weeks on an evaluation period of 24 weeks and to evaluate the clinical and biological tolerability of low dose of DFX in this population of patients. Results: Between February 2018 and April 2023,thirty-eight patients were enrolled with a median age of 73.5 years (interquartile range (IR): 69.0-78.0 years). Of these, 57.9% were male and the median Charlson index was 4 (IR: 3-5). MDS subtype were: MDS-SLD (8), MDS-RS (14), MDS-MLD (8), CMML-1 (1), MDS EB-1 (3) and MDS-U (4). The IPSS-R categories for the patients were very low (16), low (19) and intermediate (1), NA (2). The median hemoglobin level at inclusion was 86 g/L (IR: 81- 97) and the median ferritin level was 547µg/L (IR: 399; 849). The baseline biological parameters in MDS-RS versus the other MDS subtypes were: a lower median hemoglobin level (84g/L vs 88g/L), a higher median transferrin saturation (80% vs 50%, p=0.005) with a tendency for higher median non-transferrin-bound iron (NTBI) level (1.49 vs 1.00µmol/L), and a lower median hepcidin level (3.5ng/ml vs 16.4ng/ml, p=0.007). The majority of patients (86.8%) were considered non-TD according to IWG 2018 and 13.2% were low transfusion burden. All patients had received ESA prior to deferasirox. All patients received DFX at inclusion at 3.5mg/kg. Residual dosages of DFX were done at month 1 (M1) to adapt the dosage at M3 to reach around 3µM. The dosage of DFX was decreased in 26.3% of patients (mainly in MDS-RS patients) and increased in 15.8% of them. The primary objective was met: we observed a transfusion independence (TI) at 12 months in 47.4% (CI-95%: 31.0%; 64.2%) of the patients treated by DFX. If we used a more stringent definition of transfusion dependence described in secondary endpoints, we observed a TI at 12 months in 68.4% (CI 95%: 51.3%; 82.5%) of the patients treated by DFX. TI rate according to primary endpoint was numerically lower in MDS-RS than in the other types of MDS (28.6% vs 58.3%). Low dose DFX was also well tolerated (mainly grade 1 to 3 digestive, auditive renal adverse reactions), with only one diabetic patient having overdose of DFX and renal and hepatic impairment leading to DFX discontinuation. Conclusion: Low dose DFX induces 47.4% of transfusion independency at M12 in low risk MDS anemic patients refractory or relapsing to ESA, with a favorable tolerance profile. It could be a potential treatment option for anemia in selected MDS patients who are refractory or relapsing to ESA and with low transfusion burden.

ABSTRACT:In an open prospective, multicenter study enrolling 48 selected patients with chronic immune thrombocytopenia who achieved complete response for 1 year on thrombopoietin receptor agonists, half of the patients maintained a sustained response off treatment 4 years after treatment discontinuation.

BACKGROUND Most lower risk MDS patients (pts) with anemia currently receive frontline ESA in Europe, but when ESA should be started in those pts (i.e., before or when RBC transfusion dependence (TD) occurs) is not clearly established. In a retrospective study, we found that early onset of treatment with an ESA, within 6 months of diagnosis, in non-TD anemic lower-risk MDS, significantly delayed the time to RBC TD and therefore possibly slowed disease evolution (Park et al , Leuk Res 2010 PMID: 20580086). METHODS In this open-label, randomized, multicenter, phase III EPO-PRETAR trial (NCT03223961), we prospectively compared, in non-RBC TD lower-risk MDS with anemia, the time to RBC TD between early and delayed onset of ESA. Lower-risk MDS patients (pts) (IPSS-R<4) with baseline Hb between 9 and 10.5g/dL were randomized to receive EPO Alfa 60000 UI/week for at least 12 weeks at inclusion (early onset arm) or at the Hb threshold prospectively chosen for RBC transfusions for each pt (based on age, comorbidities, but which should be < 9g/dL) (late onset arm). TD was defined by 2 transfusion episodes during an 8-week interval after inclusion (early onset arm), or after at least 12 weeks of ESA (late onset arm). Baseline Cytokines, DNA -Seq and RNA-seq were performed in pts having received ESA. RESULTS Between February 2018 and Dec 2022, 121 pts were screened of which 84 fulfilled inclusion criteria, and 37 were screen failures. 43 were assigned to the early onset and 41 to the late onset arm. 40 pts started ESA in the early onset arm (3 withdrew consent), and 23 (56%) in the late onset arm had started ESA by 8 th July 2024, closing date of the study, after a median interval of 10.4 mo. Median age was 84 years, with 54% males. 75% of the pts had cardio-vascular comorbidities, 46% had sideroblastic and 54% non-sideroblastic lower risk MDS. Median time between diagnosis and inclusion was 4.1 mo (range 2.1-11). IPSS-R was very low or low in 88%. Median baseline Hb level was 10.2 g/dL (range 8.8-10.5), and median sEPO level 37 IU/L (range 5-335). Median follow-up was 34 months. Of the 84 included pts, 14 (32%) and 18 (44%) became RBC TD after inclusion in the early and late onset arms, respectively (p=0.28). Of the 63 pts who received at least 12 weeks of ESA, HI-E (Hematologic improvement-erythroid, IWG 2018 criteria) was 79.5% in the early onset arm and 54% in the late onset arm ( p =0.03). HI-E duration was longer in the early onset than in the late onset arm (median 30.6 months and 12.7 months respectively) (p=0.02). However, median time to RBC TD was similar (36.4 mo, 95% CI [28,3-NA] in the early arm, 36.4 months ,95% CI [22.4-44,1] in the late arm)) (p= 0.3). 13 and 10 pts progressed to higher risk MDS or AML in the early and late arms respectively (9.5 % in both arms for AML). Median PFS from inclusion was 60.6 mo in the early onset and not reached in the late onset arm (p=0.4). Median OS from inclusion was 49.6 and 55 months, respectively (p=0.3). No significant differences in changes in the every-12 weeks QOL FACT-An and EQ5D questionnaires were seen between the 2 arms. The number of cardio-vascular events was also similar. In the whole series of pts who received ESA, HI-E was associated with lower sEPO level (88% if < 50IU/L and 46% if> 50IU/L) (p=0.0003), lower IPSS-M (median IPSS-M: -0.603 in non- responders (NR) and -1.07 in responders (R )) (p=0.007), SF3B1 mutation: 81.8% HI-E in SF3B1 pos and 56.7% in SF3B1neg) (p=0.01). Time to TD was longer in IPSS-M lower risk (42.8 mo vs 28.3 mo) (p=0.002). TGFbeta-1 and IL6 plasma levels were lower in responders. Differentially expressed genes analysis (log2FC > I1I, BH-adjusted P-value <0.05) at baseline showed the activation of adaptive and innate immunity pathways (T cell activation, IL2/IL4 signaling and IFN alfa/IFN beta signalling) in responders. The expression level of a set of genes including erythropoiesis markers (ALAS2, ERFE, GDF15, BCL2L1), allowed the hierarchical clustering of non-responders (NR) vs responders and, within the NR pts, the segregation of TD vs non-TD pts. CONCLUSIONS Early introduction of ESA in lower risk MDS patients with anemia increased HI-E and its duration but not the time to RBC TD from inclusion, and had no effect on PFS, AML transformation, quality of life and survival. IPSS-M also predicted HI-E and duration of response to ESA.

The aim of this study was to assess the prevalence and the burden of difficult-to-treat primary ITP (pITP), defined by the need for another ITP treatment after romiplostim and eltrombopag. Adult patients were selected in the prospective, real-world CARMEN-France registry up to December 2021. Out of 821 adult patients with pITP, 29 had difficult-to-treat ITP (3.5%; 95% confidence interval [CI]: 2.3%–4.8% in total; 7.6%; 95% CI: 4.9%–10.2% of patients needing ≥2nd line treatment). The 3-year cumulative incidence of bleeding, infection and thrombosis was 100%, 24.1% and 13.8% respectively. The median cumulative duration of hospital stays was 31 days (median follow-up: 30.3 months).

Sustained response off-treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in ITP. This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response on TPO-RAs. The primary endpoint was the proportion of patients achieving SROT (platelet count > 30x109/L and no bleeding) at W24 with no other ITP-specific medications. Secondary endpoints included the proportion of sustained complete response off-treatment (SCROT, platelet count > 100x109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with median (IQR) age 58.5 years (41-73.5); 30/48 (63%) had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27/48 (56.2%, 95% CI, 41.2-70.5) achieved SROT; 15/48 (31.3%; 95% CI, 18.9-44.5) achieved SCROT at W24, and 25/48 (52.1%; 95% CI, 37.2-66.7) achieved respectively SROT and 14/48 (29.2%; 95% CI, 17.2-42.3) SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients re-challenged with TPO-RA, 11/12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA-seq revealed enrichment of a "TNFα signaling via NF-κB" signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based of progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. Clinical trial number: NCT03119974

Topic: 13. Myeloma and other monoclonal gammopathies - Biology & Translational Research Background: We report here the case of an 82-year-old patient, Caucasian, with no notable history, presenting a long-standing thrombocytopenia (107 G/L) and a low-level IgA kappa monoclonal gammopathy. CLINICALLY, the patient only complained of fatigue. We note the existence of trophic lesions of the distal extremities with chilblains (fingers and toes) without evidence for an underlying autoimmune disease. A first bone marrow aspiration shows some signs of DYSGRANULOPOIESIS, DYSERYTHROPOIESIS and 8% of DYSTROPHIC PLASMA CELLS. IMAGING (whole-body MRI) does not show suspicious bone lesions, except for a degenerative spine. CGH array analysis and FISH on sorted plasma cells, objectified recurrent abnormalities in the Multiple Myeloma (MM): a 1q21 gain; a gain of chromosomes 9 and 19 and a loss of chromosome 13; deletion of the long arms of a chromosome 14. No deletion of TP53 was demonstrated. Ten months later, because of the progression of thrombocytopenia and the occurrence of normochromic macrocytic non regenerative anemia and neutropenia, a new bone marrow aspiration is performed, this time finding a 20% dystrophic plasma cell infiltration associated with MDS with dysplasia concerning the 3 lineages, without excess blasts. CONVENTIONAL KARYOTYPING, out of 21 mitosis, returns to normal. The serum free light chains kappa/lambda ratio is 2.207. The Next Generation Sequencing (NGS) Myeloid Panel study detects two ASXL1 mutations, providing a clonality argument for a myeloid hemopathy, in this case, Myelodysplasia (MDS) (1). The patient does not respond to treatment with recombinant erythropoietin (EPO) combined with short-time corticosteroid therapy for one week. THE EVOLUTION was marked by the occurrence in October 2022 of a febrile delirium. The complete blood count now shows very dystrophic circulating plasma cells (approximately 165/mm3). Analysis of Cerebrospinal Fluid (CSF) shows the presence of Listeria monocytogenes, and cytologically a contingent of atypical plasma cells. Recently, the patient was hospitalized again for an ischemic stroke (3). Aims:Methods: Results:Summary/Conclusion: The simultaneous diagnosis of MM and MDS without a history of chemotherapy and/or radiotherapy is rarely reported in the literature. Further research is needed to elucidate the underlying mechanisms predisposing to a coexistence of MM and MDS. The contribution of new generation diagnostic tools have now become essential for difficult and complex cases as illustrated in that case. Other similar cases and additional studies are necessary to establish therapeutic recommendations which still remain uncodified in this type of case. Keywords: Multiple myeloma, Thrombosis, ASXL1, Myelodysplasia

The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0]; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23], P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73], P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP.

A significant proportion of older patients with immune thrombocytopenia (ITP) also have clinical indications for treatment of cardiovascular disease with antiplatelet agents. Ollier and colleagues sought to determine the frequency of bleeding in patients with ITP on aspirin therapy, finding that the pattern of bleeding, segregated by platelet count, is similar to that observed in other adults with ITP not on aspirin. They show that a platelet count of <20 × 109/L is associated with most bleeding in ITP patients on antiplatelet agents.

Topic: 32. Platelet disorders Background: Fostamatinib, a spleen tyrosine kinase inhibitor, has been marketed in France for the management of adult chronic immune thrombocytopenia (ITP) in October 2021. French authorities recommended the use fostamatinib in case of failure or contraindication to eltrombopag, romiplostim (the two thrombopoietin receptor agonists – TPO-RAs – available in France), rituximab and splenectomy, after validation by a referral center. Aims: To assess the use, the effectiveness and the safety of fostamatinib in adult patients with ITP in the real world in France after one year of availability of the drug. Methods: The source of study population was the French fostamatinib registry, appended to the CARMEN-France registry since fostamatinib marketing in France. The CARMEN-France registry is the registry of the French referral network for autoimmune cytopenias, that prospectively includes adult patients with a new diagnosis of ITP. Adult patients were included in the fostamatinib registry 1) if they were previously included in the CARMEN-France registry and started fostamatinib or 2) if they were not already in the registry but initiated fostamatinib. In that latter case, a retrospective assessment of ITP history was recorded. Patients who initiated fostamatinib between October 2021 and October 2022 were selected in the present interim analysis. We described the patients’ characteristics, the duration of exposure to fostamatinib, the achievement of response (platelet count ≥30 × 109/L with no other concomitant treatment), the withdrawal of concomitant ITP treatment at fostamatinib initiation, the need of treatment rescue, fostamatinib discontinuation and adverse drug reactions (ADRs, reported by investigators, with a World Health Organization causality score at least as “possible”). Results: Sixty-one patients were prospectively included. Mean age at ITP diagnosis was 51.3 years; 36 (59.1%) were women; 21 (37.8%) had ≥1 comorbidity of the Charlson Comorbidity Index; 14 (23.0%) had chronic arterial hypertension. At ITP diagnosis, the median platelet count was 10 x 109/L and 29 (47.5%) patients had bleeding. Six patients had secondary ITP. Median ITP duration was 6.5 years. The median number of previous exposures to ITP treatments was 5; 86.9% of patients had been exposed to TPO-RA, 86.9% to rituximab and 37.7% were splenectomized. Thirty-seven (61.7%) had a concomitant exposure to another ITP treatment at fostamatinib initiation. The median duration of exposure to fostamatinib at the time of data extraction was 2.2 months. Out of 50 patients with assessable data, 15 (30.0%) had a response without any concomitant ITP medication (8/26, i.e. 30.8% in patients with a duration of fostamatinib ≥12 weeks). A concomitant exposure to corticosteroids at fostamatinib initiation was withdrawn in 4/18 patients, to intravenous immunoglobulin (IVIg) in 2/7 patients and to TPO-RAs in 13/25. Twenty-six (42.6%) patients had at least one rescue treatment. Twenty-eight patients (45.9%) stopped fostamatinib, including 10 for ineffectiveness (only 1 had an exposure <12 weeks) and 12 for ADR. Thirty-two ADRs were reported in 24 (32.4%) patients, mostly diarrhea (n=6) and arterial hypertension (n=6). One thrombosis and 6 infections in 4 patients were reported (not considered as ADRs; all had other risk factors of thrombosis/infections). Summary/Conclusion: Fostamatinib was used in previously very heavily treated patients. One third of patients had ADRs but generally not serious, and >50% of patients were still treated with fostamatinib at the time of the analysis. Keywords: Real world data, Immune thrombocytopenia (ITP)

Introduction: Adults treated for immune thrombocytopenia (ITP) usually respond to 1 st-line therapy but the majority of them eventually relapse and need a second-line treatment to spare corticosteroids. Dapsone is an antibiotic drug with immunomodulatory properties that has shown some efficacy in various autoimmune diseases including ITP in several retrospective studies. The aim of this study was to assess the efficacy and the safety of dapsone given as second-line for primary ITP. Methods DAPS-ITP was a prospective multicenter randomized open-label controlled trial aimed to assess the efficacy and safety of dapsone as a second-line option in adult ITP. Adult patients with primary and newly diagnosed or persistent ITP with previous transient response to corticosteroids and/or IVIg and a platelet count ≤30x10 9/L (or <50x10 9/L with bleeding manifestations) were eligible. After randomization (1/1 ratio), patients received either dapsone at 100 mg/day in combination with prednisone for 3 weeks (arm A) or just the 3 weeks course of prednisone (arm B). The primary outcome was the overall response rate (R + CR) in intention to treat at week 52 in the absence of any rescue therapy after week 6 and/or any other treatment for ITP over the study period. Complete response (CR) was defined by a platelet count >100x 10 9/L on dapsone (arm A) or off treatment (arm B) and response (R) by a platelet count >30x10 9/L with a least a doubling of the baseline count. We also conducted a single-arm, emulated trial in the prospective, multicenter CARMEN-France registry to provide real world evidence about the efficacy and the safety of dapsone in ITP. The CARMEN-France is a prospective, multicenter registry of adult patients with a new diagnosis of ITP in France. We selected the patients included in the registry between 2013 and 2022 with a primary ITP, exposed to dapsone, who met the inclusion criteria of the DAPS-ITP trial. We assessed the same outcomes than in the DAPS-ITP trial. Results In total, 93 patients (51% of females, median age 51 years [range: 33-66]) were included and randomized (46 in arm A and 47 in arm B) in DAPS-ITP trial. Median platelet count at inclusion was 25x 10 9/L [17-36], median ITP duration was 0.31 years [0.18-0.90]. Forty-two (arm A) and 45 patients (arm B) were followed up to week 52. In intention to treat (see figure), the overall response-rate (ORR) was respectively 8.70% [2.78%-18.93%] (arm A) and 4.26% [0.78%-12.81%] (arm B) at week 52 (primary outcome, p value = 0.78)). At week 24, the ORR was 25% [11.06%-41.78%] in arm A and 12.77% [5.18%-23.89%] in arm B (p value = 0.57). One death (intracranial hemorrhage) occurred in arm A, none in arm B; 36/46 patients (78%) from arm A had to discontinue prematurely dapsone, mostly for inefficacy with the need of other ITP treatment (n =10/36, 27.7%) or for various safety issues (n=26/36, 72%) including anemia ± gastro-intestinal manifestations (n=6); high methemoglobinemia (n=4); toxidermia (n=3) and others miscellaneous causes (n =13). In the CARMEN registry, 127 patients were exposed to dapsone. Among them, 50 met the inclusion criteria of the DAPS-ITP trial and had a 52-week follow-up after the initiation of dapsone. Patients characteristics were similar to those included in the DAPS-ITP trial. Three patients had no platelet count measured at W52 ± 4 weeks and were withdrawn from the primary outcome assessment. Overall, 5/47 achieved R or CR at W52 without any concomitant ITP treatment, resulting in an ORR of 10.6%; 95% CI: 3.5-23.1. At W24, 9/45 patients achieved R or CR (ORR: 20.0%; 95% CI: 9.6 -34.6; 5 patients had no platelet count at W24 ± 4 weeks in the real world). Seventeen (34.0%) experienced 19 adverse drug reactions (ADRs) including 8 hemolytic anemia, 4 methemoglobinemia and 3 cutaneous rash. Twelve patients discontinued dapsone due to an ADR. Conclusion Among adult patients with primary ITP and a platelet count <30 x 10 9/L treated with dapsone as a second-line treatment, only a minority of patients achieved a sustained response at W52. The low rate of durable response may be at least in part due to an unexpectedly high rate of early discontinuation observed in the dapsone arm (DAPS-ITP trial) due to the occurrence of ADRs, some of which could have been easily manageable outside a clinical trial. Further studies are needed to better define who are the few patients who may still benefit from dapsone, in a cost-effectiveness perspective.

Background: MDS-RS are associated with a low risk of Acute Myeloid Leukemia (AML) progression and prolonged survival in most cases, but recurring anemia whose treatments, including Erythropoiesis Stimulating Agent (ESA), Lenalidomide, hypomethylating agents (HMAs), Luspatercept, and experimental drugs generally have transient effect and/or are not widely available. MDS-RS patients thus eventually have regular Red Blood Cells (RBC) transfusion dependency (TD) associated with mean low hemoglobin levels, and chronic anemia responsible for reduced quality of life, cardiovascular complications, and iron overload with organ dysfunction. We performed a retrospective observational study to describe transfusion characteristics and costs, along with clinical events, in a French population of RBC TD MDS-RS patients. Methods: Adult RBC-TD patients with MDS-RS from 12 hematology departments of the GFM were included. The number of RBC concentrates transfused was assessed over the last 6 months (during which no other treatment than transfusions was received), and patients categorized in low transfusion burden (LTB: 3 to 7 RBC/16 weeks) and high transfusion burden (HTB: ≥8 RBC concentrates /16 weeks). Data about iron chelation, full time hospitalization (differing from day care facility stays for programmed transfusions), causes of hospitalization, treatment of anemia before inclusion and transfusion costs was collected. Results: 100 patients MDS-RS were included, with a median time from diagnosis of 5 years (1 to 21 years). Median age was 78 years (57 to 99). Patients had received a median of 2 lines of treatment (including an ESA in 97% of them). 21% had LTB and 79% HTB. HTB patients had a longer disease duration, more frequent iron chelation (82% versus 50% in LTB patients, p=0.0052) and higher serum ferritin at inclusion (median 1958 µg/l versus 1176 µg/l, p=0.03). During the 6-month study period, 22% of the patients required full time hospitalization (in addition to day care facility for transfusions), including 25% of patients with HTB and 15% with LTB, and 43% during overall disease follow-up. Causes of full time hospitalization (figure) were symptomatic anemia (41%), general condition degradation (5%) or cardiac disease (8%), to both of which anemia potentially contributed, infection (23%), bleeding (8%), pulmonary (2%), 13% for other reasons. 15 HTB patients versus 1 LTB patient were hospitalized for symptomatic anemia. The 6-months average transfusion costs, including cost of the day care facility for RBC transfusion, transportation to and from the hospital, lab tests and iron chelation were $21459/patient, excluding costs of full-time hospitalization for complications. The average cost in HTB and LTB patients was $22829 and $7586/patient, respectively. Conclusion: Most MDS-RS patients currently become RBC-TD, often during several years, and most have high transfusion burden. The average cost of RBC transfusions and iron chelation was $21459/ 6 months. During this short observation time, 22% of the patients required full time hospitalization, due to complications of anemia in at least 50% of the cases, which also increased costs (comparison with rates of hospitalization in an age and sex matched general population will be presented). Poor quality of life associated with chronic anemia should also be taken into account in those RBC-TD patients. Widely available treatments, capable of avoiding RBC transfusion dependence and improving mean hemoglobin levels, are required in those MDS-RS patients. Disclosures Cony-Makhoul: BMS: Speakers Bureau; Incyte Biosciences: Speakers Bureau; BMS: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Thepot:astellas: Honoraria; novartis: Honoraria; sanofi: Honoraria; celgene: Honoraria. Cluzeau:Celgene: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Menarini: Consultancy; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Stamatoulas Bastard:Takeda: Consultancy; Pfizer: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria. Fenaux:Jazz: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Park:Pfizer: Other: Travel expenses; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees.

Background Hairy cell leukemia (HCL) is a rare chronic B cell malignancy, characterized by infiltration of bone marrow, blood and spleen by typical “hairy cells” that bear the BRAFV600E mutation. However, in addition to the intrinsic activation of the MAP kinase pathway as a consequence of the BRAFV600E mutation, the potential participation of other signaling pathways to the pathophysiology of the disease remains unclear as the precise origin of the malignant hairy B cells. Materials and methods Using mRNA gene expression profiling based on the Nanostring technology and the analysis of 290 genes with crucial roles in B cell lymphomas, we defined a 17 gene expression signature specific for HCL. Results Separate analysis of samples from classical and variant forms of hairy cell leukemia showed almost similar mRNA expression profiles apart from overexpression in vHCL of the immune checkpoints CD274 and PDCD1LG2 and underexpression of FAS . Our results point to a post-germinal memory B cell origin and in some samples to the activation of the non-canonical NF-κB pathway. Conclusions This study provides a better understanding of the pathogenesis of HCL and describes new and potential targets for treatment approaches and guidance for studies in the molecular mechanisms of HCL.