Dr. Vijay Ramanan

Description:Background Acquired aplastic anemia (AA) is an immune-mediated hematopoietic disorder. It is characterized by pancytopenia and hypocellular bone marrow. The first-line treatment approach to AA includes immunosuppressive treatment (IST) using the combination of antithymocyte globulin (ATG) and cyclosporine A. Those patients who do not respond to this first-line treatment or have refractory disease succumb to bleeding or infections within five years following their diagnosis even after IST. Romiplostim, a thrombopoietin (TPO) receptor antagonist, promotes trilineage hematopoiesis in patients with AA. A retrospective study assessed the safety and effectiveness of romiplostim, as monotherapy among patients with refractory AA in Indian settings. Methods The case record forms of patients diagnosed with refractory AA and receiving treatment with weekly doses of 250 mg romiplostim and concomitant medications were reviewed at Yashoda Hematology Clinic, India. The primary outcome was to evaluate the increase in platelet count/percentage and the safety of romiplostim in these patients. The secondary outcomes were a change in total leucocyte count (TLC) and hemoglobin (Hb) levels from baseline after romiplostim therapy. Results Data from 28 patients diagnosed with AA and having received romiplostim subcutaneously in a dose of 250 mg weekly were analyzed. There was a significant improvement in platelet count which increased by 0.064 × 109/L units (95% CI: 0.021-0.107) at a 100-day interval from the initial measurement. The TLCs also increased by 0.022 × 109/L units (95% CI: 0.002-0.042). The mean Hb levels increased from 7.61 gm/L to 13.38 gm/L (95% CI, p < 0.001). No severe adverse events were reported. Conclusion Romiplostim demonstrated clinically significant outcomes with a favorable safety profile in patients with refractory AA.

Description:We planned to assess iron overload in young transfusion-dependent thalassemia (TDT) patients with T2* MRI and correlate with serum ferritin. This study included young TDT patients aged 3 to 38 years on regular transfusion in a tertiary care facility from July 2017 to December 2018. T2* MRI was performed on all patients and correlated with serum ferritin values. Out of 193 cases over a period of one and half year, 26 (13.4%) cases showed mild, 48 (24.8%) moderate, and 92 (47.6%) cases showed severe hepatic iron overload. Cardiac iron overload detected none in 129, mild in 21, moderate in 12, severe in 31 patients. Pancreatic iron overload was observed none in 67, mild 35, moderate in 43, severe in 33 patients and could not be done in 15 patients. There is strong negative correlation between serum ferritin level and liver T2*. Moderate negative correlation of serum ferritin was found with cardiac T2*. Statistically significant difference was observed between pancreas iron overload and age group (P-value = 0.001). The results of this study are comparable with those of several earlier studies In addition, there is a significant correlation between serum ferritin levels and iron overload determined by T2* MRI data.

Description:Inhibitor development is the most severe complication of hemophilia A (HA) care and is associated with increased morbidity and mortality. This study aimed to use a novel immunoglobulin G epitope mapping method to explore the factor VIII (FVIII)-specific epitope profile in the SIPPET cohort population and to develop an epitope mapping-based inhibitor prediction model. The population consisted of 122 previously untreated patients with severe HA who were followed up for 50 days of exposure to FVIII or 3 years, whichever occurred first. Sampling was performed before FVIII treatment and at the end of the follow-up. The outcome was inhibitor development. The FVIII epitope repertoire was assessed by means of a novel random peptide phage-display assay. A least absolute shrinkage and selection operator (LASSO) regression model and a random forest model were fitted on posttreatment sample data and validated in pretreatment sample data. The predictive performance of these models was assessed by the C-statistic and a calibration plot. We identified 27 775 peptides putatively directed against FVIII, which were used as input for the statistical models. The C-statistic of the LASSO and random forest models were good at 0.78 (95% confidence interval [CI], 0.69-0.86) and 0.80 (95% CI, 0.72-0.89). Model calibration of both models was moderately good. Two statistical models, developed on data from a novel random peptide phage display assay, were used to predict inhibitor development before exposure to exogenous FVIII. These models can be used to set up diagnostic tests that predict the risk of inhibitor development before starting treatment with FVIII.

Description:Romiplostim is a Food and Drug Administration (FDA)-approved therapy for immune thrombocytopenia (ITP). Biosimilar is a biological product that has no clinical meaningful difference from an existing FDA-approved reference product. It has a potential of lowering health-care-related cost. Biosimilar of romiplostim can be made available to patients with ITP at a low cost and can be beneficial in providing the best therapy. Thus, the efficacy and safety of biosimilar romiplostim (ENZ110) was compared with innovator romiplostim (Nplate) with respect to platelet response in patients with chronic ITP. This was a prospective, multicenter, randomized, and double-blind clinical trial. Patients with chronic ITP, aged 18-65 years, were enrolled in a study and were randomized to receive either ENZ110 or Nplate in a 3:1 ratio for a treatment period of 12 weeks, respectively. After completion of the treatment period, the patients were followed-up for one week to evaluate the platelet response and to monitor the adverse events (AEs). Over the duration of 12 weeks, platelet response of > 50 × 109/L was achieved in 85.3% patients treated with ENZ110 and in 75.0% patients treated with Nplate in per protocol population. In intent-to-treat population, 83.8% patients with ENZ110 and 76.9% patients with Nplate achieved a platelet response of > 50 × 109/L. In the ENZ110 group, 111 AEs were recorded in 66.7% patients, while 18 AEs were reported in 61.5% patients in the Nplate group. The study demonstrated non-inferiority with comparable efficacy and safety between biosimilar romiplostim and innovator romiplostim in patients with chronic ITP. Trial registration number and date of registration: CTRI/2019/04/018614.

Description:Background: There is a need to identify patients with haemophilia who have a very low or high risk of developing inhibitors. These patients could be candidates for personalized treatment strategies. Objective: The aim of this study was to externally validate a previously published prediction model for inhibitor development and to develop a new prediction model that incorporates novel predictors. Methods: The population consisted of 251 previously untreated or minimally treated patients with severe haemophilia A enrolled in the SIPPET study. The outcome was inhibitor formation. Model discrimination was measured using the C-statistic, and model calibration was assessed with a calibration plot. The new model was internally validated using bootstrap resampling. Results: Firstly, the previously published prediction model was validated. It consisted of three variables: family history of inhibitor development, F8 gene mutation and intensity of first treatment with factor VIII (FVIII). The C-statistic was 0.53 (95% CI: 0.46-0.60), and calibration was limited. Furthermore, a new prediction model was developed that consisted of four predictors: F8 gene mutation, intensity of first treatment with FVIII, the presence of factor VIII non-neutralizing antibodies before treatment initiation and lastly FVIII product type (recombinant vs. plasma-derived). The C-statistic was 0.66 (95 CI: 0.57-0.75), and calibration was moderate. Using a model cut-off point of 10%, positive- and negative predictive values were 0.22 and 0.95, respectively. Conclusions: Performance of all prediction models was limited. However, the new model with all predictors may be useful for identifying a small number of patients with a low risk of inhibitor formation.