Deferasirox treatment of iron-overloaded chelation-naïve and prechelated patients with myelodysplastic syndromes in medical practice: results from the observational studies eXtend and eXjange

EXtend and eXjange were prospective, 1‐yr, non‐interventional, observational, multicentre studies that investigated deferasirox, a once‐daily oral iron chelator, in iron‐overloaded chelation‐naïve and prechelated patients with myelodysplastic syndromes (MDS), respectively, treated in the daily‐routine setting of office‐based physicians. No inclusion or exclusion criteria or additional monitoring procedures were applied. Deferasirox was administered as recommended in the European Summary of Product Characteristics. Haematological parameters and adverse events (AEs) were collected at two‐monthly intervals. Data from 123 chelation‐naïve patients with MDS (mean age 70.4 yrs) with median baseline serum ferritin level of 2679 (range 184–16 500) ng/mL, and 44 prechelated patients with MDS (mean age 69.6 yrs) with median baseline serum ferritin level of 2442 (range 521–8565) ng/mL, were assessed. The mean prescribed daily dose of deferasirox at the first visit was 15.7 and 18.7 mg/kg/d, respectively. Treatment with deferasirox produced a significant reduction in median serum ferritin levels in chelation‐naïve patients with MDS from 2679 to 2000 ng/mL (P = 0.0002) and a pronounced decrease in prechelated patients with MDS from 2442 to 2077 ng/mL (P = 0.06). The most common drug‐related AEs were gastrointestinal, increased serum creatinine levels and rash. These studies demonstrate that deferasirox used in physicians’ medical practices is effective in managing iron burden in transfusion‐dependent patients with MDS.     

Long-term results of a sirolimus-eluting stent with biodegradable polymer (RAPSTROM™) in de novo coronary stenoses

ObjectivesTo report long-term results of a novel sirolimus-eluting stent with biodegradable polymerBackgroundNewer generation drug-eluting stents are characterized by thin struts, improved platform design and highly biocompatible polymer carrying the antiproliferative drug. The RapstromTM stent, sharing these features, showed promising outcomes in preclinical models and in a first-in-man trial.MethodsThe present study is a multicenter, non-randomized post-market registry, including patients with de novo coronary artery disease treated with implantation of one or more Rapstrom stents. Primary endpoint of the study was the rate of major adverse cardiac events (MACE) at three-year follow-up.Results1073 patients were enrolled, with a high prevalence of diabetes (35%) and acute coronary syndrome at presentation (82%); at three-year follow up, MACE rate was 14.8%, with a low incidence of definite or probable stent thrombosis (0.75%).ConclusionsThese data confirm the good clinical performance of the Rapstrom stent, supporting the concept that the combination of thin struts and biodegradable polymer is associated with positive clinical outcomes.     

Do patients with de novo hypertension differ from patients with previously known hypertension when malignant phase hypertension occurs?

Malignant phase hypertension (MHT) represents the most severe form of hypertension, and many consider that this condition only occurs in poorly managed patients with previously known hypertension. To investigate this further, we studied 350 patients with MHT on the West Birmingham MHT database: 195 (55.7%) of these presented de novo, without any known past history of hypertension (Group 1), and 146 (41.7%) were previously known hypertensives (Group 2), of whom 86 were receiving antihypertensive therapy; in 9 patients, the status was uncertain. Median duration of clinical followup was similar in both groups (36.0 v 37.5 months, Mann-Whitney test P = .795). Patients presenting de novo with MHT (Group 1) were younger, with a predominance of whites and men. Nevertheless, the clinical features, blood pressures, and renal function at presentation were similar to MHT patients with previously known hypertension. Renal function at follow-up was also similar in both groups. There was an excess of women and nonwhites in MHT patients with previously known hypertension (Group 2), who also had higher mean follow-up blood pressures. On univariate life-table analysis, there was no statistically significant difference in survival time between Groups 1 and 2 (mean 57.5 v 63.5 months, median 36.0 v 37.0 months; log-rank test, P = .456). Using a multivariate Cox analysis of baseline variables, the independent predictors of outcome (death or dialysis) were age at presentation (P = .0019), diastolic blood pressure (P = .0466), serum urea (P = .006), and serum creatinine (P < .001). Whether the patient had presented de novo, without any known history of hypertension (Group 1) or had previously known hypertension (Group 2) did not independently predict outcome (P = .6549). We suggest that MHT can occur de novo in patients without previously known hypertension, and the clinical characteristics and prognosis in such patients were similar to MHT patients with previously known hypertension.     

Flow cytometric analysis of patients with hereditary spherocytosis – an Indian scenario

Objectives: Flow cytometry osmotic fragility test (FC-OFT) was a recently introduced screening test for hereditary spherocytosis (HS). This study was conducted to evaluate the utility of FC-OFT in all newly diagnosed cases of HS, to compare its diagnostic value with conventional OFT and to correlate with clinical disease severity.

Methods: In this study, the percentage of residual red cells (%RRC) was measured using flow cytometer after creating a red cell suspension. Subsequently, this was spiked with deionized water for FC-OFT in all cases of HS (n?=?40), healthy subjects (n?=?40) and beta-thalassemia traits (BTT) (n?=?20).

Results: The receiver operator curve analysis defined the optimal cut-offs for FC-OFT-derived indices, such as %RRC value (≤16.29%) and %RRC ratio (>1.72), for HS cases when compared with healthy subjects and BTT (p?p?=?0.001) and %RRC values (p?=?0.0486). No significant correlation was observed between %RRC value (p?=?0.8934), %RRC ratio (p?=?0.6348) and HS disease severity score.

Conclusion: Our results suggest that FC-OFT could be the better screening test for HS cases in developing countries if flow cytometer is available.     

Dose tapering of biologic agents in patients with rheumatoid arthritis—results from a cohort study in Germany

Clinical Rheumatology - To assess the association of demographic and clinical factors with the clinical decision of tapering biologic disease modifying antirheumatic drugs (bDMARDs) in patients...     

Comparison of five prognostic scoring systems, the French–American–British (FAB) and World Health Organization (WHO) classifications in patients with myelodysplastic syndromes: results of a single-center analysis

We retrospectively studied 89 consecutive patients diagnosed with primary myelodysplastic syndrome (MDS) over a period of 10 years to (1) identify prognostic factors for overall survival (OS) and leukemia-free survival (LFS); (2) to assess and compare the Bournemouth-, Spanish-, Düsseldorf-, Lille-, and the International prognostic scoring systems (IPSS); and to (3) compare the French–American–British (FAB) and World Health Organization (WHO) classifications. The median age of patients was 63 years (range, 26–85). Karyotype analyses were done in 85 patients (96%). Median OS was 3 years; 67 patients (75%) have died, and 28 (31%) had progression to acute myeloid leukemia (AML). Major independent prognostic variables for both OS and LFS (multivariate analysis) were percentage of bone marrow (BM) blasts (P<0.0001), and in patients with cytogenetic data available, cytogenetic risk groups by Lille-score (OS, P=0.031/LFS, P=0.002) and IPSS (OS, P=0.024). All five prognostic scoring systems successfully discriminated risk groups as regards OS and LFS, but in patients with cytogenetic data available, the major independent prognostic score for OS (P<0.0001) and LFS (P=0.006) was the IPSS. The FAB and WHO classifications also successfully discriminated between risk groups. The new WHO subgroups [refractory cytopenia with multilineage dysplasia (RCMD), with (RCMD-RS) or without ringed sideroblasts] showed a significantly (P=0.0454) different prognosis for OS, but not for LFS (P=0.0839), in comparison to the subgroups having erythroid dysplasia only (RA/RARS). Risk stratification into refractory anemia with excess blast-I (RAEB-I) and RAEB-II tended to yield different prognoses for OS and LFS. The 5q-minus syndrome strongly predicted for a good prognosis. In patients treated with the demethylating agent decitabine (n=24), IPSS “poor risk” cytogenetics were unable to predict for the expected worse prognosis when compared to “intermediate-risk” cytogenetics. In conclusion, we confirm in a single-center patient cohort that the use of the WHO classification improves the predictive value of the FAB classification and that, in patients with cytogenetic data available, the IPSS can be used for clinical decision-making.     

Management of anti-HBc-positive patients with rheumatic diseases treated with disease-modifying antirheumatic drugs—a single-center analysis of 2054 patients

Hepatitis B virus (HBV) reactivation is a common complication of immunosuppressive treatment in high prevalence countries. Biological disease-modifying antirheumatic drugs (bDMARDs) cause this adverse event more often than conventional immunosuppressants. The incidence of HBV reactivation during treatment for rheumatic diseases in Germany is unclear. Furthermore, it remains open how to treat and monitor patients at risk during immunosuppressive therapy with bDMARDs. We examined 2054 patients from a German tertiary rheumatology center in order to analyze the prevalence of HBc-antibody-positivity and the incidence of HBV reactivation in German rheumatology patients treated with immunosuppressants. Of 1317 patients treated with bDMARDs and 737 conventional synthetic DMARD (csDMARDs) patients between 2008 and 2017, 86 had a history of HBV infection (anti-HBc positive). Only two patients were suffering from chronic infection (HBsAg positive). Three patients were treated pre-emptively with entecavir, and eight patients after HBV DNA reappearance. No liver failure occurred due to HBV reactivation. Compared to anti-HBc-positive patients without reactivation, the reactivation group included more patients exposed to three or more classes of bDMARDs (p =?0.017). The median HBs antibody titer was significantly lower in the reactivation group (15.0 IU/l vs. 293.5 IU/l; p =?0.001). This study shows that bDMARDs and csDMARDs can safely be administered to patients with a history of HBV, provided they are closely monitored. Low titers of anti-HBs antibodies and a history of ≥?3 classes of immunosuppressants increase the risk of HBV reactivation. These data highlight major differences to high prevalence regions.     

Study of nucleophosmin (NPM) gene mutation in patients with acute myeloid leukemia and myelodysplastic syndromes

Objective To investigate nucleophosmin (NPM) gene mutations in patients with de novo acute myeloid leukemia (AML) with normal cytogenetics and primary myelodysplastic syndromes (MDS). Methods Genomic DNA corresponding to exon 12 of NPM gene was amplified by polymerase chain reaction (PCR) in 40 AML patients (28 case untreated and 12 in first remission) and     

Management of patients with higher-risk myelodysplastic syndromes after failure of hypomethylating agents: What is on the horizon?

The hypomethylating agents (HMA) azacitidine (AZA) and decitabine (DAC) are the standard of care for frontline treatment of patients with higher-risk myelodysplastic syndromes (MDS). As complete responses to HMAs are rare and typically not durable, HMA failure is a common clinical dilemma and associated with very short survival in most patients. Salvage therapies with various agents such as novel HMAs (guadecitabine, CC-486), and CTLA-4/PD1-type immune checkpoint inhibitors (ICPIs) have yielded mixed and only modest results at best in MDS patients with HMA failure. Thanks to advances in the understanding of the molecular and biologic pathogenesis of MDS, several novel targeted agents such as the BCL-2 inhibitor venetoclax, TP-53 refolding agent APR-246, IDH1/2 inhibitors, and novel ICPIs such as magrolimab and sabatolimab have been developed and demonstrated activity in combination with HMA in the frontline setting. However, clinical testing of these agents post HMA failure has been limited to date. Furthermore, the biology of HMA failure remains poorly defined which significantly limits rationale drug development. This highlights the importance of optimization of frontline therapy to avoid/delay HMA failure in addition to development of more effective salvage therapies.     

Leflunomide in the treatment of patients with early rheumatoid arthritis—results of a prospective non-interventional study

Leflunomide is effective and well tolerated in the treatment of rheumatoid arthritis (RA), however, data on its use in early RA are scarce. This study seeks to evaluate effectiveness and safety of leflunomide in the treatment of early RA in daily practice. This prospective, open-label, non-interventional, multi-center study was carried out over 24 weeks including adults with early RA (≤1 year since diagnosis). Leflunomide treatment was according to label instructions. Three hundred thirty-four patients were included. Disease activity score in 28 joints (DAS28) response (reduction in DAS28 of >1.2 or reduction of >0.6 and a DAS28 of ≤5.1) was 71.9% at week?12 and 84.6% at week 24. 25.0% of patients achieved clinical remission (DAS28?≤?2.6). Most frequently reported adverse drug reactions (ADR) were diarrhea (3.0%), nausea (2.4%), hypertension (1.8%), and headache (1.5%). Serious ADR were reported in four patients (1.2%). Leflunomide showed the effectiveness which was to be expected from controlled studies without revealing any new or hitherto unknown side effects. Onset of action was quick and significant improvement of disease was seen after 12 weeks of therapy and at even higher rates after 24 weeks irrespective of the use of a loading dose. Interestingly, the DAS28-remission rate achieved was similar to the rate seen with methotrexate or biologic therapy in other studies.     

Anti-TNF therapy in patients with HBV infection—analysis of 87 patients with inflammatory arthritis

This study aims to investigate the incidence of hepatitis B virus (HBV) reactivation in inflammatory arthritis (IA) patients with HBV infection using anti-tumor necrosis factor (TNF) agents and evaluate the efficacy of antiviral therapy in reducing the risk of viral reactivation in chronic HBV infection. IA patients using anti-TNF agents from six centers were enrolled. Their HBV infection conditions and ALT and HBV-DNA levels were monitored periodically. Among the six chronic hepatitis B patients, HBV reactivation was found in two patients without antivirus prophylaxis and no viral replication was detected in the other four patients with antivirus prophylaxis. In the 31 inactive carriers, the increase of viral load was detected in 6 of 22 (27.3 %) patients without antiviral prophylaxis, and there was no viral reactivation in the other 9 patients with antiviral prophylaxis. HBV reactivation was not found in the 50 patients with resolved HBV infection. It is suggested that anti-TNF therapy might increase the risk of HBV reactivation in patients with chronic HBV infection, and antiviral prophylaxis could effectively decrease the risk. Anti-TNF agents seem to be safe in patients with resolved HBV infection.     

Does cytogenetic evolution have any prognostic relevance in myelodysplastic syndromes? A study on 153 patients from a single institution

The present study was designed to establish the incidence of cytogenetic evolution (CE), defined as the acquisition of chromosomal defects during the course of MDS, in order to correlate it with the WHO classification and IPSS score, and to assess its impact on overall survival (OS) and risk of MDS/AML evolution (progression-free interval, PFI) by means of Cox models for time-dependent covariates. Adjustments for known risk factors were achieved by performing a bivariable analysis. The study was carried out in 153 MDS patients who were followed for a median period of 45.2 months. Disease progression occurred in 42.4% of patients after a 65.2-month median PFI, while CE occurred in 30.7% of patients. Our study shows that (1) CE was more common in advanced than in early MDS, and advanced MDS presented secondary chromosomal defects distinct from those of early MDS; (2) CE significantly affected OS and PFI independently of other prognostic variables; (3) del(7)(q31q34) was the only secondary chromosomal defect which significantly affected PFI; trisomy 8 had only a moderate influence.     

Treatment of anal fistula with FiLaC®: results of a 10-year experience with 175 patients

Techniques in Coloproctology - Treatment of fistula-in-ano with fistula laser closure (FiLaC®) is a sphincter-saving procedure indicated for patients with complex anal fistulas. The aim of our...     

Daily practice management of myelodysplastic syndromes in France: data from 907 patients in a one-week cross-sectional study by the Groupe Francophone des My��lodysplasies

Background

There is little published information on the everyday clinical management of myelodysplastic syndromes in real world practice.

Design and Methods

We conducted a cross-sectional study of all patients with myelodysplastic syndromes attending 74 French centers in a 1-week period for inpatient admission, day-hospital care or outpatient visits.

Results

Nine hundred and seven patients were included; 67.3% had lower-risk myelodysplastic syndromes (International Prognostic Scoring System: low or intermediate-1). Karyotype had been analyzed in 82.5% of the cases and was more often of intermediate or poor risk in patients under 65 years old compared with those who were older. Red blood cell transfusions accounted for as many as 31.4% of the admissions. Endogenous erythropoietin level was less than 500 IU/L in 88% of the patients tested. Erythroid stimulating agents had been or were being used in 36.8% of the lower risk patients, iron chelation in 31% of lower risk patients requiring red blood cell transfusions and lenalidomide in 41% of lower risk patients with del 5q. High-dose chemotherapy, hypomethylating agents, low dose cytarabine and allogeneic stem cell transplantation had been or were being used in 14.8%, 31.1%, 8.8% and 5.1%, respectively, of higher-risk patients.

Conclusions

Karyotype is now assessed in most patients with myelodysplastic syndromes, and patients under 65 years old may have more aggressive disease. Apart from erythroid-stimulating agents and, in higher-risk myelodysplastic syndromes, hypomethylating agents, specific treatments are used in a minority of patients with myelodysplastic syndromes and red blood cell transfusions still represent the major reason for hospital admission.