The clinical epidemiology of immune thrombocytopenia (ITP) is not well known in adults. This study was aimed at assessing the clinical epidemiology of incident ITP adults, the factors associated with ...chronicity and exposure to treatments. This study was conducted in the CARMEN registry, a multicentric prospective cohort aimed at including all newly diagnosed ITP adults in the French Midi‐Pyrénées region, South of France (3 million inhabitants) from June 2013. Descriptive analyses and multivariate logistic regression models were conducted. Out of 121 newly diagnosed ITP until December 2014, 113 patients were followed in the region and gave informed consent. Median age was 65 years. Half of the patients were female, 20.3% had a secondary ITP, 50.4% had a Charlson's score ≥1, median platelet count was 17 × 109/L; 50.9% had bleeding symptoms, including 2 severe gastrointestinal tract and 1 intracranial bleedings; 21.4% had another autoimmune disease and 20.3% experienced an infection within the six weeks before ITP onset. Persistency and chronicity rates were 68.2% and 58.7%, respectively. Antinuclear antibodies were associated with chronicity (OR: 2.89, 95% CI: 1.08‐7.74). Sixty‐eight (60.2%) patients were treated during the week following the diagnosis. Factors associated with the use of intravenous corticosteroids were secondary ITP and high bleeding score. Those associated with the use of intravenous immunoglobulin (IVIg) were a high bleeding score and low platelet count. In conclusion, severe bleeding is rare at ITP onset. Associated autoimmune diseases and recent infections were frequent. Antinuclear antibodies seem predictors of chronicity. Intravenous corticosteroids and IVIg were frequently used.
Background: The clinical epidemiology of immune thrombocytopenia (ITP) is not well known. Some issues (bleeding events at diagnosis, association to other autoimmune diseases, rate of infection prior ...to ITP onset) are not well described in adults. Little is known as regards first-line treatment choice in the real-life practice.
Aim: The aims of this study were to assess i) the clinical epidemiology of incident ITP adults; ii) the use of first-line treatments in this population; and iii) the factors associated with the initial use of intravenous (IV) corticosteroids (CS) and of intravenous immunoglobulin (IVIg) in a real-life setting. This study was carried out on behalf of the French national center for autoimmune cytopenia and the French national center for rare diseases in immunohematology.
Methods: Study population was the patients included between June 2013 and December 2014 in the CARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) multicenter registry. This multicenter registry is carried out on behalf of the French national center for autoimmune cytopenia and the French national center for rare diseases in immunohematology. The originalities of this registry are: the prospective follow-up of newly diagnosed ITPs, aimed at completeness of recording in the French Midi-Pyrénées region, South of France (3 million inhabitants), and the detailed recording of ITP treatment exposures. All the physicians in charge of ITP patients in the region, belonging to the netwotk of the regional center for autoimmune cytopenia, prospectively follow every patient newly diagnosed for ITP during routine visit or hospital stay. ITP is defined in accordance with French guidelines: platelet count <150 x 109/L and exclusion of other causes of thrombocytopenia. In this study, we assessed the clinical epidemiology at ITP onset, as well as ITP treatment use during the week following the diagnosis. Logistic regression models were performed to assess the factors associated with the use of IV CS and of IVIg. The following covariates were included: age, gender, Charlson's comorbidity score, secondary vs. primary ITP, bleeding score and platelet count.
Results: Out of 121 newly diagnosed ITP, 113 patients were followed in the region and gave informed consent. Median age was 65 years (range: 18-95). Half of the patients were female, 24 (21.3%) had a secondary ITP, 57 (50.4%) had a Charlson's score ≥1, median platelet count was 17 x109/L (range: 1-126); 57 (50.9%) had bleeding symptoms, including 2 severe gastro-intestinal tract and 1 intracranial bleeding. Median Khellaf's bleeding score was 5 (range: 0-35). Twenty-five (21.4%) patients had another autoimmune disease (mostly: Hashimoto's thyroiditis, n=6, Sjögren syndrome, n=5, Evans syndrome, n=3) and 23 (20.3%) experienced an infection within the six weeks before ITP onset (including 8 influenza-like and 3 gastro-enteritis like syndromes, the others being various bacterial infections). Sixty-eight (60.2%) patients were treated during the week following the diagnosis. Among them, 66 (98.5%) received CS (median dose: 0.99 mg/kg/d), including 21 (31.3%) IV CS, 29 (43.3%) IVIg, 8 (11,9%) platelet transfusion, 2 romiplostim and 1 rituximab. The factors associated with the use of IV CS were secondary ITP (OR: 5.91; 95% CI: 1.78-19.71) and Khellaf's bleeding score >8 (OR: 4.09; 95% CI 0.96-17.35). Those associated with the use of IVIg were Khellaf's bleeding score >8 (OR: 7.30; 95% CI 1.36-32.27) and platelet count <10 x 109/L (OR: 3.95; 95% CI 1.77-13.29).
Conclusions: This prospective cohort of newly diagnosed ITP adults confirms that severe bleeding is rare at ITP onset. Associated autoimmune diseases and recent infections are frequent. IVIg and IV CS were frequently used, particularly in case of severe bleeding.
Godeau:Roche: Research Funding; Amgen: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Adoue:LFB: Other: Symposium presentations ; OCTAPHARMA: Other: Symposium presentations ; ACTELION: Other: Symposium presentations ; PFIZER: Other: Symposium presentations ; AMGEN: Other: Symposium presentations ; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Other: Symposium presentations.
We report a multicenter controlled trial comparing renal recovery and tolerance profile of doublet versus triplet bortezomib-based regimens in patients with initial myeloma cast nephropathy (CN) and ...acute kidney injury (AKI) without need for dialysis.
After symptomatic measures and high-dose dexamethasone, patients were randomly assigned to receive bortezomib plus dexamethasone (BD), or BD plus cyclophosphamide (C-BD). In patients with < 50% reduction of serum free light chains (sFLCs) after 3 cycles, chemotherapy was reinforced with either cyclophosphamide (BD group) or thalidomide (C-BD group).
Ninety-two patients were enrolled in each group. At random assignment, characteristics of the 2 groups were similar, including median age (68 years) and serum creatinine level (305.5 and 273.5 µmol/L in BD and C-BD group, respectively). At 3 months, renal response rate (primary end point) was not different (41
47 responders in the BD and C-BD groups, respectively; relative risk RR, 0.87;
= .46). Very good partial response (free light chain reduction ≥ 90%) or more was achieved in 36 and 47 patients, respectively (RR, 0.76;
= .10). After 1 cycle of chemotherapy, 69 in the BD group and 67 patients in the C-BD group had achieved sFLC level ≤ 500 mg/L. Serious adverse events were recorded in 30 and 40 patients, respectively. At 12 months, 19 patients had died (9 in the BD group
10 in the C-BD group), including 10 (6 in the BD group and 4 in the C-BD group) from myeloma progression and 3 (0 in the BD group and 3 in the C-BD group) from infection. Within median follow-up of 27 months, 43 and 42 patients switched to new therapy, respectively. Overall, 50 patients (24 in the BD group and 26 in the C-BD group) had died.
This randomized study did not show any benefit of C-BD compared with BD on renal recovery of patients with initial CN not requiring dialysis. Adding cyclophosphamide did not sufficiently improve the efficacy-toxicity balance. Patients with myeloma with AKI are fragile, and indication for doublet or triplet regimen should be adapted to frailty.
Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are associated with systemic inflammatory or autoimmune diseases in 10-20 % of cases. Among them, immune thrombocytopenia ...(ITP) has been reported but large studies assessing this association are missing. Whether such patients have a particular phenotype and require particular management is unclear. This study analyzes the clinical spectrum, outcome and therapeutic management of patients with ITP associated with MDS or CMML, in comparison (i) to patients with primary ITP without MDS/CMML and (ii) to patients with MDS/CMML without ITP. Forty-one MDS/CMML-associated ITP patients were included, with chronic ITP in 26 (63%) patients, low-risk myelodysplasia in 30 (73%) patients and CMML in 24 (59%) patients. An associated autoimmune disease was noted in 10 (24%) patients. In comparison to primary ITP patients, MDS/CMML-associated ITP patients had a higher occurrence of severe bleeding despite similar platelet counts at diagnosis. First-line treatment consisted of glucocorticoids (98%) and intravenous immunoglobulin (IVIg) (56%). Response achievement with IVIg was more frequent in primary ITP than in MDS/CMML-associated ITP patients. Response rates to second-line therapies were not statistically different between primary ITP and MDS/CMMLassociated ITP patients. Ten percent (n=4) of patients with MDS/CMML-associated ITP had multirefractory ITP versus none in primary ITP controls. After a median follow-up of 60 months, there was no difference in overall survival between MDS/CMML-associated ITP and primary ITP patients. Leukemia-free-survival was significantly better in MDS/CMMLassociated ITP patients than in MDS/CMML without ITP MDS/CMML-associated ITP have a particular outcome with more severe bleeding and multirefractory profile than primary ITP, similar response profile to primary ITP therapy except for IVIg, and less progression toward acute myeloid leukemia than MDS/CMML without ITP.
Summary
Data about the presentation and the management of primary immune thrombocytopenia (ITP) in very elderly patients (VEPs; aged ≥80 years) are lacking. The aim of the present study was to ...describe ITP in this subgroup. The data source was the prospective CARMEN‐France registry. Patients included between 2013 and 2018 were selected. ITP presentation and management in VEPs was compared to elderly patients (EPs; aged 65–79 years). We assessed factors associated with bleeding at ITP onset in VEPs. Of 541 patients, 184 were included: 87 in the VEP group and 97 in the EP group. The mean age was 85·7 years in the VEP group. Comorbidities were more frequent in the VEP group (67·4% vs. 47·9%). The median platelet count at ITP onset was similar but severe bleeding tended to be more frequent in VEPs (10·3% vs. 4·1%, P = 0·1) as well as mortality. Exposure to ITP drugs, response to first‐line treatment, need of second‐line treatment, evolution towards persistency, occurrence of bleeding, infection and thrombosis did not differ between groups. In VEPs, factors associated to bleeding were female sex odds ratio (OR) 4·75, 95% confidence interval (CI) 1·31–17·32 and platelet count of <20 × 109/l (OR 10·05, 95% CI 4·83–67·39). Exposure to anticoagulants was strongly associated with severe bleeding (OR 7·61, 95% CI 1·77–32·83).
Introduction:There are discrepancies across recommendations about the indication of bone marrow smear in adults diagnosed for immune thrombocytopenia (ITP). The 2011 American Society of Hematology ...guidelines do not recommend bone marrow smear in case of typical ITP. In contrast, the 2010 international consensus and the 2017 French guidelines recommend systematic bone marrow smear in adults aged >60 years even in case of typical ITP to detect a blood cancer, particularly myelodysplastic syndrome. This recommendation is driven from expert consensus. Data are lacking about the positivity rate of this examination in older patients with typical ITP. The aim of this study was to assess the positivity rate of bone marrow smear at ITP diagnosis in >60-year-old patients with no other clinical or biological sign of hematological malignancy.
Methods:Data source was theCARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) registry. All adult patients with an incident diagnosis of ITP in the French Midi-Pyrénées region (South of France, 3 million inhabitants) are prospectively enrolled since June 2013 in the multicenter CARMEN registry. ITP is defined by international guidelines (platelet count <100 x 109/L and exclusion of other causes of thrombocytopenia). Investigations performed at ITP diagnosis in a real-life basis, including bone marrow smear, are recorded with their results. Study population was selected among the patients included in the CARMEN registry from June 2013 to December 2018. Inclusion criteria were: age>60 years; absence of clinical signs of hematological malignancy (lymphadenopathy, hepatomegaly, splenomegaly); isolated thrombocytopenia on blood count; bone marrow smear performed at ITP diagnosis. We described patients with abnormal bone marrow smear and implications for ITP management.
Results:We identified 114patients (66 men and 48 women) satisfying all inclusion criteria. Mean age at ITP diagnosis was 76 years (standard deviation - SD: 9 years). Platelet count at diagnosis was 32.7 x 109/L (SD: 27.7 x 109/L) and 58 patients presented with bleeding: skin bleeding only (n=33), oral bleeding (n=17), epistaxis (n=10) and hematuria (n=3). Only one patient had an abnormal bone marrow smear corresponding to a characterized hematological disease: a myelodysplastic syndrome. It was a 62-year-old man without medical history who presented in 2014 with extensive skin bleeding, and isolated thrombocytopenia (6 x 109/L). Other blood count parameters were: hemoglobin: 15.2 g/dL; MCV: 83 fL; leukocytes: 5.3 x 109/L; polynuclear neutrophils: 3.5 x 109/L; lymphocytes: 1.0 x 109/L; monocytes: 0,3 x 109/L . Bone marrow smear revealed normal cellularity. The megakaryocytic lineage was normally represented with significant number of megakaryocytes with multiple separated nuclei. Significant dysgranulopoiesis was also observed with pseudo-Pelger-Huët anomaly and cytoplasmic hypogranulation. Some erythroblasts with defective haemoglobination or cytoplasmic vacuolation were present. This aspect was compatible with the diagnosis of myelodysplastic syndrome with multilineage dysplasia (MDS-MLD). Karyotype was normal. The patient was initially treated for ITP with steroids and intravenous immunoglobulins (with partial response), then with danazol (complete response), eltrombopag (after loss of response to danazol and ocular bleeding, resulting in complete response) and more recently romiplostim (after loss of response to eltrombopag, resulting in complete response). He was treated in 2019 by rituximab to spare exposure to thrombopoietin receptor agonists, without efficacy. Before Rituximab, another bone marrow smear was performed (4 years after the first one) with the same cytologic and cytogenetic features (MLD-MDS with normal caryotype).
Conclusions:Diagnosis of hematological malignancy is very uncommon in >60 year-old patients who present with typical ITP. Myelodysplastic syndrome was found in 1 (0.8%) patient in this series, and did not impact the management or the evolution of the patient with a five-year follow-up. Overall, this study sustains guidelines that does not recommend systematic testing for bone marrow examination in >60 year-old patients with typical ITP.
Comont:BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees. Recher:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; Macrogenics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Beyne-Rauzy:Novartis: Research Funding; Cellgene: Research Funding. Moulis:CSL Behring: Research Funding; Amgen pharma: Research Funding, Speakers Bureau; Novartis pharma: Research Funding, Speakers Bureau.
Introduction: Bleeding is a main cause of morbidity and mortality in adult immune thrombocytopenia (ITP). Treatment is indicated in case of bleeding or of low platelet count. However, the threshold ...of platelet count associated with bleeding and therefore to initiation of treatment is debated. Most of guidelines recommend the threshold of <30 x 109/L. However, some authors recommend other thresholds, as low as 10 x 109/L. Moreover, the risk factors for bleeding are not well known in ITP. The aim of this study is to assess the risk of bleeding by platelet count and to identify these risk factors.
Methods: We studied all the patients included between June 2013 and December 2016 in the CARMEN (Cytopénies Auto-immunes : Registre Midi-PyréneEN) registry. This multicenter registry is aimed at the prospective follow-up of all incident ITP adults in the French Midi-Pyrénées region (South-West of France, 3 million inhabitants). Each investigator follows every patient newly diagnosed for ITP in routine visit or hospital stay and detailed information on patients' characteristics and management of ITP are recorded prospectively. We also included all adult patients newly diagnosed for ITP at the French National Referral Center for autoimmune cytopenias (Créteil) from November 2015 to December 2016 where data are prospectively recorded in the same database. ITP was defined by platelet count <100 x 109/L and exclusion of other causes of thrombocytopenia. We described the frequency of any bleeding, of mucosal bleeding and of severe bleeding (defined by macroscopic hematuria, gastrointestinal or central nervous system bleedings) at ITP onset by platelet count and by subgroups of interest: age groups (according to quartiles: ≤45, 45-64, 65-79 and ≥80 years), sex, arterial hypertension, history or current symptoms of gastroduodenal ulcer, Charlson's comorbidity score, exposure to non-steroidal anti-inflammatory drugs (NSAIDs), antiplatelet drugs, anticoagulant drugs and serotonin reuptake inhibitors (SRIs). Lastly, we assessed in the whole cohort the factors associated with any bleeding, mucosal bleeding and severe bleeding using multivariate logistic regression analysis.
Results: 302 newly diagnosed ITP adults were prospectively included in the study. Median age was 66 years, 49.7% were females, 46.8% had a Charlson's score ≥1, 3.7% had a history or current symptoms of gastroduodenal ulcer, 16.0% had secondary ITP, 19.5% were exposed to antiplatelet drugs, 7.6% to anticoagulant drugs, 7.6% to NSAIDs and 6.6 to SRIs at the time of diagnosis. Median platelet count was 18 x109/L. At diagnosis, 57.9% experienced any bleeding symptom, 30.1% mucosal bleeding, and 6.6% severe bleeding (including 4 central nervous system bleedings).
The rates of bleeding, mucosal bleeding and severe bleeding by platelet count is shown in Figure 1. The rate of any bleeding was >50% if platelet count was <20 x109/L. The rate of mucosal bleeding was >40% if platelet count was <10 x109/L. In contrast, a similar risk of severe bleeding was observed with all platelet count categories. Only slight differences were observed in other subgroups, except an increased frequency of any bleeding in case of exposure to NSAIDs, as well as an increased rate of severe bleeding in elderly and patients exposed to anticoagulant drugs and SRIs.
In multivariate analysis, the factors associated with any bleeding at ITP diagnosis were a low platelet count (<10 x109/L vs. >20 x109/L: OR, 46.3, 95% CI: 19.4-110.6; between 10 and 19 x109/L vs. >20 x109/L: OR, 5.1, 95% CI: 2.3-11.2), female sex (OR for males, 0.4, 95%CI: 0.2-0.8) and exposure to NSAIDs (OR, 4.4, 95 %CI: 1.1-18.7). Only a low platelet count was associated with mucosal bleeding (<10 x109/L vs. >20 x109/L: OR, 6.2, 95% CI: 3.4-11.6; between 10 and 19 x109/L vs. >20 x109/L: OR, 2.6, 95% CI: 1.1-6.1). Lastly, only exposure to anticoagulant drugs was associated with severe bleeding (OR, 4.5, 95% CI: 1.4-14.4). Analyses restricted to primary ITPs led to similar results.
Conclusion: Platelet counts <20 x109/L and <10 x109/L were thresholds with major increased risk for both any and mucosal bleedings. Platelet count, female sex and exposure to NSAIDs should be considered to assess the risk of any bleeding. In contrast, severe bleeding seemed not linked to platelet count but to individual factors, particularly exposure to anticoagulant.
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No relevant conflicts of interest to declare.
The CARMEN-France registry is a prospective, multicenter registry in France including adult patients with a new diagnosis of immune thrombocytopenia or of autoimmune immune hemolytic anemia (2402 ...patients included in December 31, 2023). The recording of clinical, biological and treatment data allows detailed epidemiological and pharmacoepidemiological real-world studies. This review summarizes the CARMEN-France registry protocol, gives examples of studies conducted in the registry, and indicates future directions such as inclusion of patient reported outcomes, linkage with the French national health insurance database and linkage with other registries in Europe.
Le registre CARMEN-France est un registre prospectif multicentrique en France, qui suit des patients adultes avec un purpura thrombopénique immunologique ou une anémie hémolytique auto-immune nouvellement diagnostiqués (2402 patients inclus au 31 décembre 2023). Le recueil des données cliniques, biologiques et des expositions thérapeutiques permet des études épidémiologiques et pharmaco-épidémiologiques détaillées « de vraie vie ». Cet article résume le protocole du registre CARMEN-France, donne des exemples d’études déjà conduites avec génération de « preuves de vraie vie », et indique les futures directions du registre avec implémentation de données rapportées par le patient, chaînage avec les données du système national des données de santé et avec d’autres registres de cytopénies auto-immunes en Europe.
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