Gaucher disease type 1 (GD1) is a rare genetic lysosomal storage disorder. Eliglustat is a first-line oral therapy for adult patients with GD1. The aim of the ELIPRO (ELIglustat Patient Reported ...Outcomes) study was to assess real-world outcomes of eliglustat treatment for over 1 year in patients with GD1, with a focus on patient-reported outcomes (PROs), including treatment adherence.
This was a non-interventional, prospective, multicentric study. Patients were stratified according to their previous time on eliglustat: >6 months (Group1) and ≤ 6 months (Group2). The primary endpoint was adherence to eliglustat, measured by the eight-items Morisky Medication Adherence Scale (MMAS-8; scale of 0–8) at 6 months in Group2. Secondary endpoints were quality of life (QoL) measured by patient input using the European Quality of Life five-dimensional three-level EQ-5D-3L questionnaire, fatigue and pain measured by numeric rating scale NRS; on a scale of 0–10, the evaluation of patient satisfaction level regarding eliglustat treatment measured by Likert scale scale of 0–7 and treatment adherence at 12 months in both groups. The study also evaluated the safety and effectiveness of eliglustat in the adult GD1 population.
Sixty patients with GD1 (approximatively 52% male, mean age: 46.6 ± 13.9 years) were analyzed: 29 in Group1 and 31 in Group2. GD1 was mostly of mild severity (90%) and 95% of patients had extensive CYP2D6 metabolizer phenotype. Fifty-seven patients had previously received treatment for GD1 (91% enzyme replacement therapy) and 15% were splenectomized. Groups1 and 2 were not necessarily matching for all characteristics. At 6 months, 58% of Group2 patients showed medium adherence (6 < MMAS-8 < 7.75) while 21% showed high adherence (MMAS-8: 8) (mean MMAS-8: 6.7 ± 1.0); similar results were obtained in Group1 (50% showed high compliance, 35% showed medium compliance; mean MMAS-8: 6.8 ± 1.4). The mean MMAS-8 for Group1 and Group2 were 7.1 ± 1.2 (vs 7.0 ± 1.0 at baseline) and 6.5 ± 1.0, respectively, at 12 months. At 12 months, the mean NRS scores in Group1 and Group2 were 72.0 ± 18.5 and 77.3 ± 13.7 for QoL (vs. 71.7 ± 18.4 and 80.2 ± 12.4, respectively at baseline), 4.8 ± 2.6 and 3.6 ± 2.7 for fatigue (vs. 4.6 ± 2.7 and 3.6 ± 2.6, respectively at baseline) and 3.3 ± 2.7 and 2.3 ± 2.3 for pain (vs. 3.3 ± 2.7 and 2.0 ± 2.4, respectively at baseline). GD1 assessments (biological, clinical and imaging parameters) remained stable during 12 months in both groups. At the end of the study, majority (97.4%) of patients were satisfied with their treatment with eliglustat (satisfaction score over 5 out of 7). Sixty-six percent of patients (n = 41) experienced mostly mild adverse events (AE) (including four study withdrawals), of whom 27.4% (n = 17) of patients experienced eliglustat-related AEs. Treatment adherence remained stable during 12 months in both groups.
Eliglustat treatment compliance was good and sustained, along with overall health state, fatigue and pain levels, which was consistent with overall patients' clinical status. Eliglustat was well tolerated, and had a good safety profile, aligned with a good patient satisfaction. Our study should encourage greater use of PROs for evaluation of impact of the GD treatment on patient's symptoms and well-being.
•ELIPRO was the first real-world observational study to assess compliance and other PROs of eliglustat in GD1.•Eliglustat treatment was well tolerated, and had a favorable safety profile, aligned with a good patient satisfaction level.•Eliglustat was associated with maintenance of good quality of life, and low levels of fatigue and pain.•The PROs remained stable during the 12 month study duration irrespective of duration of eliglustat exposure.•The study supports the use of PROs when evaluating the impact of GD treatment on patients' symptoms and well-being.
Abstract
Objective
To assess the safety and the efficacy of TNF-α antagonists and tocilizumab in patients with Takayasu arteritis (TAK).
Methods
A total of 209 patients with TAK median age 29 years ...(interquartile range 7–62), 186 (89%) females were included. They received either TNF-α antagonists n = 132 (63%) with 172 lines; infliximab (n = 109), adalimumab (n = 45), golimumab (n = 8), certolizumab (n = 6) and etanercept (n = 5) or tocilizumab n = 77 (37%) with 121 lines; i.v. and s.c. in 95 and 26 cases, respectively.
Results
A complete response at 6 months was evidenced in 101/152 (66%) patients on TNF-α antagonists and 75/107 (70%) patients on tocilizumab. Age ≥30 years odds ratio 2.09 (95% CI 1.09, 3.99) was associated with complete response, whereas vascular signs OR 0.26 (95% CI 0.1, 0.65), baseline prednisone ≥20 mg/day OR 0.51 (95% CI 0.28, 0.93) were negatively associated with the complete response to TNF-α antagonists or tocilizumab. During a median follow-up of 36 months, 103 relapses were noted. Supra-aortic branches and thoracic aorta involvement HR 2.44 (95% CI 1.06, 5.65) and 3.66 (1.18, 11.4), respectively and systemic signs at baseline HR 2.01 (95% CI 1.30, 3.11) were significantly associated with relapse. The cumulative incidence of treatment discontinuation and relapse were similar in TNF-α antagonists and tocilizumab. Fifty-eight (20%) adverse effects occurred on biologic targeted therapies 37 (21%) on TNF-α antagonists and 21 (17%) on tocilizumab (P = 0.4), respectively.
Conclusion
This large multicentre study shows high efficacy of biologic targeted treatments in refractory TAK. Efficacy, relapse and drug retention rate were equivalent with TNF-α antagonists and tocilizumab.
To develop and validate the prognostic prediction model DU-VASC to assist the clinicians in decision-making regarding the use of platelet inhibitors (PIs) for the management of digital ulcers in ...patients with systemic sclerosis. Secondly, to assess the incremental value of PIs as predictor.
We analysed patient data from the European Scleroderma Trials and Research group registry (one time point assessed). Three sets of derivation/validation cohorts were obtained from the original cohort. Using logistic regression, we developed a model for prediction of digital ulcers (DUs). C-Statistics and calibration plots were calculated to evaluate the prediction performance. Variable importance plots and the decrease in C-statistics were used to address the importance of the predictors.
Of 3710 patients in the original cohort, 487 had DUs and 90 were exposed to PIs. For the DU-VASC model, which includes 27 predictors, we observed good calibration and discrimination in all cohorts (C-statistic = 81.1% 95% CI: 78.9%, 83.4% for the derivation and 82.3% 95% CI: 779.3%, 85.3% for the independent temporal validation cohort). Exposure to PIs was associated with absence of DUs and was the most important therapeutic predictor. Further important factors associated with absence of DUs were lower modified Rodnan skin score, anti-Scl-70 negativity and normal CRP. Conversely, the exposure to phosphodiesterase-5 inhibitor, prostacyclin analogues or endothelin receptor antagonists seemed to be associated with the occurrence of DUs. Nonetheless, previous DUs remains the most impactful predictor of DUs.
The DU-VASC model, with good calibration and discrimination ability, revealed that PI treatment was the most important therapy-related predictor associated with reduced DU occurrence.
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).
Abstract Objective To assess the safety and the efficacy of TNF-α antagonists and tocilizumab in patients with Takayasu arteritis (TAK). Methods A total of 209 patients with TAK median age 29 years ...(interquartile range 7–62), 186 (89%) females were included. They received either TNF-α antagonists n = 132 (63%) with 172 lines; infliximab (n = 109), adalimumab (n = 45), golimumab (n = 8), certolizumab (n = 6) and etanercept (n = 5) or tocilizumab n = 77 (37%) with 121 lines; i.v. and s.c. in 95 and 26 cases, respectively. Results A complete response at 6 months was evidenced in 101/152 (66%) patients on TNF-α antagonists and 75/107 (70%) patients on tocilizumab. Age ≥30 years odds ratio 2.09 (95% CI 1.09, 3.99) was associated with complete response, whereas vascular signs OR 0.26 (95% CI 0.1, 0.65), baseline prednisone ≥20 mg/day OR 0.51 (95% CI 0.28, 0.93) were negatively associated with the complete response to TNF-α antagonists or tocilizumab. During a median follow-up of 36 months, 103 relapses were noted. Supra-aortic branches and thoracic aorta involvement HR 2.44 (95% CI 1.06, 5.65) and 3.66 (1.18, 11.4), respectively and systemic signs at baseline HR 2.01 (95% CI 1.30, 3.11) were significantly associated with relapse. The cumulative incidence of treatment discontinuation and relapse were similar in TNF-α antagonists and tocilizumab. Fifty-eight (20%) adverse effects occurred on biologic targeted therapies 37 (21%) on TNF-α antagonists and 21 (17%) on tocilizumab (P = 0.4), respectively. Conclusion This large multicentre study shows high efficacy of biologic targeted treatments in refractory TAK. Efficacy, relapse and drug retention rate were equivalent with TNF-α antagonists and tocilizumab.
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.
PDF
