Abstract

Hydroxyurea and low dose thalidomide are low-cost, easily accessible Hb F inducing agents that have been found to decrease transfusion dependency among transfusion-dependent thalassemia patients. However, these drugs have not much been explored in a randomized controlled setting. The objective of this study was to determine the efficacy and safety of hydroxyurea and low dose thalidomide in adult transfusion dependent β thalassemia. A total of 39 transfusion dependent β thalassemia patients were randomized into three arms: Arm A (Hydroxyurea 500 mg/day), Arm B (thalidomide 50 mg/day), and Control Arm. The primary outcome was rise in haemoglobin at 24-weeks from the baseline levels. The mean age of the cohort was 26.9 ± 4.7 years. Total 13 patients (33.3%) were splenectomised. The mean rise of haemoglobin at the end of 24 weeks was 0.18 ± 0.645 g/dl, 0.56 ± 1.343 g/dl, and - 0.31 ± 0.942 g/dl in Arm A, Arm B and control arm, respectively, p = 0.127. The mean volume of blood transfused per unit body weight in 24 weeks was significantly less in the thalidomide arm compared with the control arm (p = 0.035). Abdominal pain (Grade 1-2, 23.1%) and pruritus (Grade 1, 15.4%) were the main adverse events in hydroxyurea arm, whereas somnolence was the main side effect noted in the thalidomide arm (Grade 1-2, 78.3%). Single agent hydroxyurea or thalidomide is ineffective in increasing haemoglobin and decreasing transfusion burden among majority of the adult transfusion dependent thalassemia patients. SUPPLEMENTARY INFORMATION The online version contains supplementary material available at 10.1007/s12288-022-01620-3.

Abstract

BACKGROUND Non-transfusion-dependent β-thalassaemia (NTDβT) is a subset of inherited haemoglobin disorders characterised by reduced production of the β-globin chain of haemoglobin leading to anaemia of varying severity. Although blood transfusion is not a necessity for survival, it may be required to prevent complications of chronic anaemia, such as impaired growth and hypercoagulability. People with NTDβT also experience iron overload due to increased iron absorption from food sources which becomes more pronounced in those requiring blood transfusion. People with a higher foetal haemoglobin (HbF) level have been found to require fewer blood transfusions, thus leading to the emergence of treatments that could increase its level. HbF inducers stimulate HbF production without altering any gene structures. Evidence for the possible benefits and harms of these inducers is important for making an informed decision on their use. OBJECTIVES To compare the effectiveness and safety of the following for reducing blood transfusion for people with NTDβT: 1. HbF inducers versus usual care or placebo; 2. single HbF inducer with another HbF inducer, and single dose with another dose; and 3. combination of HbF inducers versus usual care or placebo, or single HbF inducer. SEARCH METHODS We used standard, extensive Cochrane search methods. The latest search date was 21 August 2022. SELECTION CRITERIA We included randomised controlled trials (RCTs) or quasi-RCTs comparing single HbF inducer with placebo or usual care, with another single HbF inducer or with a combination of HbF inducers; or comparing different doses of the same HbF inducer. DATA COLLECTION AND ANALYSIS We used standard Cochrane methods. Our primary outcomes were blood transfusion and haemoglobin levels. Our secondary outcomes were HbF levels, the long-term sequelae of NTDβT, quality of life and adverse events. MAIN RESULTS We included seven RCTs involving 291 people with NTDβT, aged two to 49 years, from five countries. We reported 10 comparisons using eight different HbF inducers (four pharmacological and four natural): three RCTs compared a single HbF inducer to placebo and seven to another HbF inducer. The duration of the intervention lasted from 56 days to six months. Most studies did not adequately report the randomisation procedures or whether and how blinding was achieved. HbF inducer against placebo or usual care Three HbF inducers, HQK-1001, Radix Astragali or a 3-in-1 combined natural preparation (CNP), were compared with a placebo. None of the comparisons reported the frequency of blood transfusion. We are uncertain whether Radix Astragali and CNP increase haemoglobin at three months (mean difference (MD) 1.33 g/dL, 95% confidence interval (CI) 0.54 to 2.11; 1 study, 2 interventions, 35 participants; very low-certainty evidence). We are uncertain whether Radix Astragali and CNP have any effect on HbF (MD 12%, 95% CI -0.74% to 24.75%; 1 study, 2 interventions, 35 participants; very low-certainty evidence). Only medians on haemoglobin and HbF levels were reported for HQK-1001. Adverse effects reported for HQK-1001 were nausea, vomiting, dizziness and suprapubic pain. There were no prespecified adverse effects for Radix Astragali and CNP. HbF inducer versus another HbF inducer Four studies compared a single inducer with another over three to six months. Comparisons included hydroxyurea versus resveratrol, hydroxyurea versus thalidomide, hydroxyurea versus decitabine and Radix Astragali versus CNP. No study reported our prespecified outcomes on blood transfusion. Haemoglobin and HbF were reported for the comparison Radix Astragali versus CNP, but we are uncertain whether there were any differences (1 study, 24 participants; low-certainty evidence). Different doses of the same HbF inducer Two studies compared two different types of HbF inducers at different doses over two to six months. Comparisons included hydroxyurea 20 mg/kg/day versus 10 mg/kg/day and HQK-1001 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day and 40 mg/kg/day. Blood transfusion, as prespecified, was not reported. In one study (61 participants) we are uncertain whether the lower levels of both haemoglobin and HbF at 24 weeks were due to the higher dose of hydroxyurea (haemoglobin: MD -2.39 g/dL, 95% CI -2.80 to -1.98; very low-certainty evidence; HbF: MD -10.20%, 95% CI -16.28% to -4.12%; very low-certainty evidence). The study of the four different doses of HQK-1001 did not report results for either haemoglobin or HbF. We are not certain if major adverse effects may be more common with higher hydroxyurea doses (neutropenia: risk ratio (RR) 9.93, 95% CI 1.34 to 73.97; thrombocytopenia: RR 3.68, 95% CI 1.12 to 12.07; very low-certainty evidence). Taking HQK-1001 20 mg/kg/day may result in the fewest adverse effects. A combination of HbF inducers versus a single HbF inducer Two studies compared three combinations of two inducers with a single inducer over six months: hydroxyurea plus resveratrol versus resveratrol or hydroxyurea alone, and hydroxyurea plus l-carnitine versus hydroxyurea alone. Blood transfusion was not reported. Hydroxyurea plus resveratrol may reduce haemoglobin compared with either resveratrol or hydroxyurea alone (MD -0.74 g/dL, 95% CI -1.45 to -0.03; 1 study, 54 participants; low-certainty evidence). We are not certain whether the gastrointestinal disturbances, headache and malaise more commonly reported with hydroxyurea plus resveratrol than resveratrol alone were due to the interventions. We are uncertain whether hydroxyurea plus l-carnitine compared with hydroxyurea alone may increase mean haemoglobin, and reduce pulmonary hypertension (1 study, 60 participants; very low-certainty evidence). Adverse events were reported but not in the intervention group. None of the comparisons reported the outcome of HbF. AUTHORS' CONCLUSIONS We are uncertain whether any of the eight HbF inducers in this review have a beneficial effect on people with NTDβT. For each of these HbF inducers, we found only one or at the most two small studies. There is no information on whether any of these HbF inducers have an effect on our primary outcome, blood transfusion. For the second primary outcome, haemoglobin, there may be small differences between intervention groups, but these may not be clinically meaningful and are of low- to very low-certainty evidence. Data on adverse effects and optimal doses are limited. Five studies are awaiting classification, but none are ongoing.

Abstract

Immune thrombocytopenic purpura (ITP) is an acquired antibody or cell-mediated platelet damage or decreased platelet production. Steroids, IV immunoglobulins (IVIG), and Rho-anti-D antibodies are the commonly used initial treatments for ITP. However, many ITP patients either do not respond or do not maintain a response to initial therapy. Splenectomy, rituximab, and thrombomimetics are the commonly used second-line treatment. More treatment options include tyrosine kinases inhibitors (TKI), including spleen tyrosine kinase (Syk) and Bruton's tyrosine kinase (BTK) inhibitors. This review aims to assess the safety and efficacy of TKIs. Methods: Literature was searched on PubMed, Embase, WOS, and clinicaltrials.gov using keywords, "tyrosine kinase" and "idiopathic thrombocytopenic purpura". PRISMA guidelines were followed. Results: In total, 4 clinical trials were included with 255 adult patients with relapsed/refractory ITP. In all, 101 (39.6%) patients were treated with fostamatinib, 60 (23%) patients with rilzabrutinib, and 34 (13%) with HMPL-523. Patients treated with fostamatinib achieved a stable response (SR) and overall response (OR) in 18/101 (17.8%) and 43/101 (42.5%) of the patients, respectively, while SR and OR were achieved in 1/49 (2%) and 7/49 (14%) of the patients, respectively, in the placebo group. Patients treated with HMPL-523 (300 mg dose expansion) achieved an SR and OR in 5/20 (25%) and 11/20 (55%) of the patients, respectively, while SR and OR were achieved in 1/11 (9%) of the patients treated with the placebo. Patients treated with rilzabrutinib achieved an SR in 17/60 (28%) patients. Dizziness (1%), hypertension (2%), diarrhea (1%), and neutropenia (1%) were serious adverse events in fostamatinib patients. Rilzabrutinib or HMPL-523 patients did not require a dose reduction due to drug-related adverse effects. Conclusions: Rilzabrutinib, fostamatinib, and HMPL-523 were safe and effective in the treatment of relapsed/refractory ITP.

Abstract

INTRODUCTION Eptacog beta is a new recombinant activated human factor VII bypassing agent approved in the United States for the treatment and control of bleeding in patients with haemophilia A or B with inhibitors 12 years of age or older. AIM: To prospectively assess in a phase 3 clinical trial (PERSEPT 2) eptacog beta efficacy and safety for treatment of bleeding in children <12 years of age with haemophilia A or B with inhibitors. METHODS Using a randomised crossover design, subjects received initial doses of 75 or 225 μg/kg eptacog beta followed by 75 μg/kg dosing at predefined intervals (as determined by clinical response) to treat bleeding episodes (BEs). Treatment success criteria included a haemostasis evaluation of 'excellent' or 'good' without use of additional eptacog beta, alternative haemostatic agent or blood product, and no increase in pain following the first 'excellent' or 'good' assessment. RESULTS Treatment success proportions in 25 subjects (1-11 years) who experienced 546 mild or moderate BEs were 65% in the 75 μg/kg initial dose regimen (IDR) and 60% in the 225 μg/kg IDR 12 h following initial eptacog beta infusion. By 24 h, the treatment success proportions were 97% for the 75 μg/kg IDR and 98% for the 225 μg/kg IDR. No thrombotic events, allergic reactions, neutralising antibodies or treatment-related adverse events were reported. CONCLUSION Both 75 and 225 μg/kg eptacog beta IDRs provided safe and effective treatment and control of bleeding in children <12 years of age.

Abstract

WHAT IS KNOWN AND OBJECTIVE To evaluate the efficacy and safety of intravenous iron supplementation in patients with renal anaemia. METHODS We searched the PubMed, Embase, Cochrane Library, and Web of Science from their inception until 17 September 2021, for randomized controlled trials (RCTs) to evaluate the efficacy and safety of intravenous iron at different frequencies. The observed efficacy indicators included transfer saturation (TSAT), serum ferritin (SF) and haemoglobin (HGB). Outcomes of interest included allergies, infections, all-cause mortality and cardiovascular events. RESULTS AND DISCUSSION Of the 751 eligible studies, 7 RCTs met the inclusion criteria. The RCTs showed that there were no significant differences between the low-frequency high-dose group (1-2 doses, >200 mg/dose) and the high-frequency low-dose group (4-5 doses, ≤200 mg/dose) in the increase in TSAT (WMD = 1.90; 95% CI = -2.04 to 5.84; I(2) = 0%), SF (WMD = 15.70; 95% CI = -32.20 to 70.61; I(2) = 0%) and HGB (WMD = -0.00; 95% CI = -0.43 to 0.42; I(2) = 0%). There was also no significant difference in the occurrence of outcome events, including allergies (RR = 1.84; 95% CI = 0.95 to 3.57; I(2) = 45%), infections (RR = 0.61; 95% CI = 0.20-1.86; I(2) = 0%), cardiovascular events (RR = 0.88; 95% CI = 0.67-1.15; I(2) = 48%) and all-cause mortality (RR = 0.74; 95% CI = 0.40-1.35; I(2) = 0%). WHAT IS NEW AND CONCLUSION Frequencies of intravenous iron supplementation with similar doses share similar safety and efficacy in patients with renal anaemia. However, a single dose or two doses of intravenous iron are more cost-effective and patient friendly. These findings may provide evidence for the clinical application of intravenous iron supplementation for patients with renal anaemia.

Abstract

BACKGROUND To systematically evaluate the clinical efficacy, drug safety and health-related quality of life (HRQoL) of Romiplostim in adult and child immune thrombocytopenia (ITP) patients. METHODS PubMed, EMBASE and Cohrane library databases were searched for all randomized controlled trials published until 2022, and the Review Manager 5.3 was used for meta-analysis. RESULTS A total of 9 randomized controlled trials were included in this study. The results of meta-analysis showed that the total platelet response rate and long-term platelet response rate in treatment group were significantly higher than those in control group (P<0.05). There was no statistical significance in the side effects, serious side effects, bleeding events and serious bleeding events between 2 groups (P>0.05). Compared with control group, the HRQoL in ITP adults and children, and parents of ITP children had no statistical significance (P>0.05). CONCLUSION Romiplostim has a certain clinical efficacy in ITP adults and children, and relatively small adverse drug reactions. The improvement of Romiplostim on HRQoL in ITP adults and children is not clear.

Abstract

The Kasabach-Merritt phenomenon (KMP) in kaposiform hemangioendothelioma (KHE) is characterized by life-threatening thrombocytopenia and consumptive coagulopathy. This study compared the efficacy and safety of sirolimus plus prednisolone versus sirolimus monotherapy as treatment strategies for KHE with KMP in the largest cohort to date. Participants were randomized to receive either sirolimus in combination with a short course of prednisolone or sirolimus monotherapy for at least 12 months. The primary outcome was defined as achievement of a durable platelet response (platelet count >100×109/L) at week 4. Participants completed efficacy assessments 2 years after the initial treatment. At week 4, a durable platelet response was achieved by 35 of 37 patients given sirolimus and prednisolone compared with 24 of 36 patients given sirolimus monotherapy (difference 27.9%; 95% CI, 10.0% to 44.7%). Compared with the sirolimus monotherapy group, the combination treatment group showed improvements in terms of measures of durable platelet responses at all points during the initial 3-week treatment period, median platelet counts during weeks 1 to 4, increased numbers of patients achieving fibrinogen stabilization at week 4, and objective lesion responses at month 12. Patients receiving combination therapy had fewer blood transfusions and a lower total incidence of disease sequelae than patients receiving sirolimus alone. The frequencies of total adverse events and grade 3-4 adverse events during treatment were similar in both groups. The responses seen in patients with KHE with KMP were profound and encouraging, suggesting that sirolimus plus prednisolone should be considered a valid treatment for KHE with KMP. ClinicalTrial.gov, number NCT03188068.

Abstract

INTRODUCTION To conduct a network meta-analysis to assess the efficacy and incidence of treatment related adverse events (TRAEs) of eltrombopag, romiplostim, avatrombopag, recombinant human thrombopoietin (rhTPO) and hetrombopag for adult immune thrombocytopenia (ITP). METHODS Randomized controlled trails (RCTs) of the five therapies from inception to June 1, 2022 were included. The efficacy outcome was the rate of platelet response, defined as the achievement of platelet counts above 50 x 109/L. Pairwise odds ratios (ORs) and 95% confidence intervals (CIs) were caculated. The surface under the cumulative ranking (SUCRA) was used to rank the included therapies for each outcome. RESULTS In total, 1,360 participants were analyzed in 14 eligible RCTs. All of the therapies showed a significantly better platelet response than the placebo, and avatrombopag (OR, 7.42; 95% CI, 1.74-31.69) and rhTPO (OR, 3.86; 95%CI, 1.62-9.18) were better than eltrombopag. Regarding TRAEs, no significant differences were found between patients receiving eltrombopag, romiplostim, and avatrombopag. Avatrombopag carried the highest platelet response rate with SUCRA value of 87.5, and carried the least TRAEs risk with SUCRA value of 37.0. CONCLUSIONS These findings indicated that avatrombopag appeared to be the optimal choice as the second-line therapy of adult ITP.

Abstract

INTRODUCTION Current treatment of severe haemophilia A includes prophylaxis with factor VIII (FVIII) replacement. The supply of plasma-derived FVIII is short in China. PURPOSE To evaluate the efficacy and safety of a new B-domain deleted (BDD) recombinant FVIII (TQG202) produced by human-derived cells for prophylaxis in severe haemophilia A patients and compare the bioequivalence with Xyntha. METHODS This multicentre, clinical trial consisted of an open-label, randomized, two-period cross-over trial assessing single-dose pharmacokinetics (PK), and a single-arm clinical trial evaluating the efficacy and safety of 24 weeks of TQG202 prophylaxis, and repeated PK were assessed after prophylaxis phase. The single-dose was 50 IU/kg in PK assessment, and the initial dose was 30 ± 5 IU/kg for prophylaxis. The primary endpoints of prophylaxis were the annualized bleeding rate (ABR) and the incremental recovery rate of the first administration. Adverse events (AEs) were recorded. RESULTS Twenty-six participants were enrolled in the PK assessment and 81 participants in the prophylaxis phase. Mean age was 25.9 ± 10.8 years and all participants were male. The results of PK assessment showed TQG202 is bioequivalent to Xyntha. The total ABR was 2.0 (95% CI: 1.2-2.9) in prophylaxis phase. The mean incremental recovery rate of the first administration was .027 (95% CI: .026-.028) (IU/ml)/(IU/kg). AEs occurred in 42 participants, with an incidence of 51.9%. One severe AE not related to TQG202 occurred. No participants developed FVIII inhibitors. CONCLUSION TQG202 shows bioequivalence with Xyntha. The promising efficacy and tolerability in the severe haemophilia A prophylaxis support the use of TQG202in clinical practice.

Abstract

Hemophilia A, the most common hereditary disorder, is caused by clotting factor deficiency. Challenges encountered in the current treatment of hemophilia A [factor VIII (FVIII) replacement therapy] due to inhibitor development have caused ineffective treatment as well as morbidity and mortality among patients. However, there are no studies comparing the two types of FVIII treatments in terms of inhibitor development rate. Therefore, we conducted this systematic review to devise a better treatment option with a lower risk of inhibitor development. The systematic review was conducted using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and by searching several databases. Data extraction on study characteristics and outcomes was conducted. Reviewers also conducted a risk of bias assessment on all studies. All eligible studies for quantitative analysis were then processed using RevMan 5.4.1 and the data was extrapolated into cumulative outcomes and expressed in forest and funnel plots. Nine studies were included in the meta-analysis, involving a total of 2,531 hemophilia A patients who were followed up from birth until death. A higher incidence of inhibitor development was found to be associated with recombinant FVIII (rFVIII) [odds ratio (OR)=1.57, 95% confidence interval (CI): 0.95-2.59; hazard ratio (HR)=1.89, 95% CI: 1.15-3.12]. The same trend was also found for high-responding inhibitors (OR=1.38, 95% CI: 0.70-2.70; HR=1.42, 95% CI: 0.84-2.39). rFVIII is associated with a higher risk of overall and high-responding inhibitor development compared to plasma-derived FVIII (pdFVIII).