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Avatrombopag for adult chronic primary immune thrombocytopenia: a randomized phase 3 trial in China
Mei, H., Zhou, H., Hou, M., Sun, J., Zhang, L., Luo, J., Jiang, Z., Ye, X., Xu, Y., Lu, J., et al
Research and practice in thrombosis and haemostasis. 2023;7(6):102158
Abstract
BACKGROUND Immune thrombocytopenia (ITP) is an autoimmune disorder with decreased platelet counts and increased bleeding risk. OBJECTIVES To evaluate the efficacy and safety of avatrombopag, a second-generation oral thrombopoietin receptor agonist, for the treatment of Chinese patients with chronic primary ITP. METHODS This multicenter, randomized, double-blind, placebo-controlled phase 3 study (CTR20210431) consisted of a 6-week double-blind core treatment phase followed by a 20-week, open-label extension phase. Chinese adults with chronic primary ITP for at least 12 months and a platelet count <30 × 10(9)/L were randomized (2:1) to receive avatrombopag (initial dose of 20 mg/day) or matched placebo. The primary endpoint was the proportion of subjects with a platelet count ≥50 × 10(9)/L at week 6 of the core treatment phase in absence of rescue therapy. RESULTS In total, 74 patients were randomized (avatrombopag: N = 48; placebo: N = 26) between March 5, 2021, and August 6, 2021; all of whom entered the extension phase (72 received avatrombopag up to 26 weeks). At week 6 of the core study, the platelet response (≥50 x 10(9)/L) rate was significantly higher in the avatrombopag group (77.1%; 95% CI, 62.7, 88.0) vs placebo (7.7%; 95% CI, 1.0, 25.1); the treatment difference was 69.4% (95% CI, 56.2, 86.3; P < .0001). During the 6-week core study, treatment-emergent adverse events were reported in 41 (85.4%) and 20 (76.9%) patients in the avatrombopag and placebo groups, respectively. The most common avatrombopag-related treatment-emergent adverse events were upper respiratory tract infection (14/48 [29.2%]), increased platelet count (13/48 [27.1%]) and headache (7/48 [14.6%]). CONCLUSION Avatrombopag was efficacious and generally well tolerated in Chinese patients with chronic primary ITP, with comparable efficacy and safety to previous reports in Western patients.
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A randomized controlled trial of thrice-weekly versus thrice-daily oral ferrous fumarate treatment in adult patients with iron-deficiency anemia
Jongkraijakra S, Doungngern T, Sripakdee W, Lekhakula A
Annals of hematology. 2023;102(6):1333-1340
Abstract
Iron deficiency anemia (IDA) is a common health problem in developing countries. Many studies have shown that low-dose oral iron could have similar efficacy and less gastrointestinal effects in iron deficiency without anemia. This prospective open-labeled randomized controlled study was designed to compare the response of 200 mg ferrous fumarate thrice-weekly (TIW) as not inferior to the thrice-daily (TID) regimen and to assess the incidence of adverse events (AEs) between two regimens in treating adult patients with IDA. The primary endpoint was either an increase in Hb ≥ 3 g/dL, having Hb of 12 g/dL in females or 13 g/dL in males at the 12th week of treatment. Secondary outcomes included adverse events (AEs), red blood cell indices, iron profiles, and patient compliance. Sixty-four patients were randomized: 32 in the TIW arm and the other 32 in the TID arm. The response rates were not different between two arms either with intention to treat analysis (72.0%, 95%CI 56.6-88.5 vs. 71.9%, 95%CI 53.3-86.3, p = 0.777); or per-protocol analysis (88.9%, 95%CI 70.8-97.6 vs. 88.5%, 95%CI 69.8-97.6, p = 1.0), respectively. The trial demonstrated non-inferiority at a margin of 23%. Although the iron profile response of the TID arm was earlier than the TIW arm, almost all patients recovered from anemic symptoms at week 4, and hematologic responses were not different at week 12. There were more gastrointestinal AEs in the TID arm. In conclusion, this study showed that the TIW was non-inferior to the TID iron treatment of IDA patients but less AEs and costs.
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Effectiveness of Pharmacokinetic-Guided Hydroxyurea Dose Individualization in Patients with Sickle Cell Anemia: A Mini-Review
Dos Santos Neres, J. S., Yahouédéhou, Scma, Goncalves, M. S.
Pharmaceuticals (Basel, Switzerland). 2023;16(6)
Abstract
Inconsistent therapeutic responses have been observed among patients with sickle cell anemia (SCA) undergoing hydroxyurea (HU) following the adoption of the standardized protocol. Moreover, this treatment regimen necessitates a prolonged period to reach the maximum tolerated dose in which beneficial therapeutic effects are observed in most SCA patients. To overcome this limitation, several studies have performed HU dose adjustments in SCA patients based on individualized pharmacokinetic profiles. The present systematic mini-review aims to select and analyze published data to present an overview of HU pharmacokinetics studies performed in SCA patients, as well as evaluate the effectiveness of the dose adjustment strategy. A systematic search was performed in the Embase, Pubmed, Scopus, Web of Science, Scielo, Google Scholar, and the Virtual Library of Health databases from December 2020 to August 2022, with a total of five studies included. Inclusion criteria consisted of studies in which the dose adjustment was performed in SCA patients based on pharmacokinetic parameters. Quality analyzes were performed using QAT, while data synthesis was performed according to the Cochrane Manual of Systematic Reviews of Interventions. Analysis of the selected studies revealed improved HU treatment effectiveness using personalized dosages in SCA patients. Moreover, several laboratory parameters were utilized as biomarkers of the HU response, and methods designed to simplify the adoption of this practice were presented. Despite the scarcity of studies on this topic, HU-personalized treatment based on individualized pharmacokinetic profiles represents a viable alternative for SCA patients who are candidates for HU therapy, especially for pediatric patients. Registration number: PROSPERO CRD42022344512.
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Risk of thrombotic events in immune thrombocytopenia patients treated with thrombopoietic agents: a systematic review and meta-analysis
Dong, Y., Xia, Z., Zhou, J., Hu, Y., Yue, M., Wang, Y., Hu, M.
Thrombosis journal. 2023;21(1):69
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Editor's Choice
Abstract
BACKGROUND Immune thrombocytopenia (ITP), which is a well-known hemorrhagic disorder characterized by low platelet counts, has been shown to be associated with the risk of thrombosis. Thrombopoietic agents (TAs) are extensively used as second-line treatments for ITP, effectively reducing the risk of hemorrhage. However, thrombosis, a potential adverse effect of TAs, raises clinical challenges. METHODS The MEDLINE(PubMed), Embase, and the Cochrane Library databases were systematically searched for relevant studies, including both single-arm trials and randomized controlled trials (RCTs), without language restrictions. RESULTS A total of 17 RCTs comprising 2,105 patients and 29 single-arm trials comprising 3,227 patients were included. In the single-arm meta-analysis, the pooled rate of overall thrombotic events in ITP patients receiving TAs was 2.2% (95% CI 1.0% - 3.7%). In RCTs, a higher incidence of thrombosis (33/1425 vs. 4/680) and higher risk ratios (RR) of overall, arterial, and venous thrombotic events (1.73, 95% CI [0.88, 3.39], P = 0.113; RR 1.98, 95% CI [0.80, 4.92], P = 0.141; RR 1.06, 95% CI [0.46, 2.41], P = 0.895, respectively) were observed in the TAs group than in the control group, although the differences were not significant. Subgroup analysis demonstrated that hetrombopag was the only TA with no increased thrombotic risk (rate 0.3% 95% CI [0.0 - 1.5%]; RR 0.76, 95% CI [0.03, 18.41], P = 0.864) compared to eltrombopag, avatrombopag, romiplostim, and rhTPO. Subgroup analyses also revealed that ITP patients with advanced age (3.7% vs. 1.3%, P = 0.132) or with a thrombotic history (3.0% vs. 1.4%, P = 0.257), and patients who received TAs therapy for a long duration (4.7% vs. 0.1%, P < 0.001) had an increased risk of thrombosis. CONCLUSION Our findings suggest ITP patients treated with TAs have a nonsignificantly higher risk of overall, arterial, and venous thrombotic events. Furthermore, hetrombopag is the recommended TA to avoid thrombophilia. Patients receiving long-term TAs, as well as elderly ITP patients or those with a history of thrombosis, face an increased thrombotic risk. In general, clinicians should consider potential thrombotic risks, address underlying risk factors, and ensure ongoing monitoring and follow-up when treating ITP patients with TAs.
PICO Summary
Population
Adult patients with immune thrombocytopenia (ITP), (17 randomised controlled trials (RCTs) and 29 single arm trials).
Intervention
Thrombopoietic agents (TAs) at any dosage, with or without combination therapy.
Comparison
Standard of care or placebo.
Outcome
In the single-arm meta-analysis, the pooled rate of overall thrombotic events was 2.2%; 95% CI [1.0%, 3.7%]. In RCTs, a higher incidence of thrombosis (33/1,425 vs. 4/680) and higher risk ratios (RR) of overall, arterial, and venous thrombotic events were observed in the TAs group than in the control group, although the differences were not significant. Hetrombopag was the only TA with no increased thrombotic risk compared to eltrombopag, avatrombopag, romiplostim, and recombinant human thrombopoietin (rhTPO). ITP patients with advanced age or with a thrombotic history, and patients who received TAs therapy for a long duration (4.7% vs. 0.1%) had an increased risk of thrombosis.
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Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study
Germing, U., Fenaux, P., Platzbecker, U., Buckstein, R., Santini, V., Díez-Campelo, M., Yucel, A., Tang, D., Fabre, S., Zhang, G., et al
Annals of Hematology. 2023;102(2):311-321
Abstract
Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients' baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, erythroid response, serum ferritin levels, and hemoglobin levels relative to baseline were evaluated. Through week 25, fewer RBC transfusion units and visits were observed in luspatercept-treated patients versus placebo, regardless of baseline transfusion burden. This continued through 144 weeks of luspatercept treatment, particularly in patients with low baseline transfusion burden. Sixty-eight patients were initial nonresponders at week 25 but continued treatment; most (81%) received the maximum dose of luspatercept (1.75 mg/kg). Sixteen percent achieved RBC-TI for ≥ 8 weeks during weeks 25-48, 26% had reduced RBC transfusion burden, 10% achieved an erythroid response, 44% had reduced serum ferritin, and hemoglobin levels increased an average of 1.3 g/dL from baseline. These data have implications for clinical practice, as transfusion units and visits are less in luspatercept-treated patients through week 25 regardless of baseline transfusion burden, and continuing luspatercept beyond week 25 can potentially provide additional clinical benefits for initial nonresponders. Trial registration: NCT02631070.
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Eltrombopag for Adults and Children with Immune-Refractory Thrombocytopenic Purpura: A Systematic Review
de Barros Torelli, D. F. H., Oliveira, C. B. S., Nai, G. A., Trindade, E. M., Prestes-Carneiro, L. E.
Journal of clinical medicine. 2023;12(12)
Abstract
Eltrombopag is an agonist that binds to the membrane-bound domain of the thrombopoietin receptor used in immune thrombocytopenic purpura (ITP). We conducted a meta-analysis of randomized controlled trials to assess the efficacy and safety of eltrombopag in adults and children with refractory ITP. Adults who received eltrombopag had a significantly better platelet response (relative risk [RR], 3.65; 95% confidence interval [CI], 2.39-5.55), but there were no differences in the incidence of bleeding (RR, 0.8; 95% CI, 0.52-1.22) and adverse effects (RR, 0.99; 95% CI, 0.55-1.78) compared with the placebo. In children, there was no difference between eltrombopag and placebo for a platelet response >50,000/mm(3) (RR, 3.93; 95% CI, 0.56-27.79) and the number of adverse events (RR, 0.99; 95% CI, 0.25-1.49); however, a lower incidence of bleeding was observed (RR, 0.47; 95% CI, 0.27-0.83). Treatment with eltrombopag protected adults and children from severe disease and death.
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Evaluation of collagen turnover biomarkers as an objective measure for efficacy of treatment with rurioctocog alfa pegol in Hemophilia A patients: a secondary analysis of a randomized controlled trial
Manon-Jensen, T., Tangada, S., Bager, C., Chowdary, P., Klamroth, R., von Drygalski, A., Windyga, J., Escobar, M., Frederiksen, P., Engl, W., et al
Journal of thrombosis and haemostasis : JTH. 2023
Abstract
BACKGROUND Hemophilia patients with recurrent hemarthroses develop hemophilic arthropathy (HA). Regular prophylaxis with factor VIII (FVIII) can reduce HA, but there is a need for objective outcome measures to evaluate treatment efficacy. METHODS Joint remodeling was assessed by analyzing serum levels of collagen remodeling products at baseline and months 3, 6, 9, and 12 in a 98 patient subset receiving pharmacokinetics-guided prophylaxis with rurioctocog alfa pegol, targeting FVIII trough levels of 1-3 IU/dL or 8-12 IU/dL (PROPEL study, NCT0285960). RESULTS Basement membrane metabolism-related type 4 collagen remodeling products (C4M and PRO-C4) decreased after 3 months at all time points by up to 25% at 1-3 IU/dL (p=.049, p<.0001) and 8-12 IU/dL FVIII trough levels (p=.0002, p<.0001). Interstitial tissue metabolism-related type 3 (C3M) and 5 (PRO-C5) collagen remodeling products decreased after 3 months, by up to 19% at 1-3 IU/dL FVIII trough level (p=.0001, p=.009) and 23% at 8-12 IU/dL FVIII trough level (p=.0002, p=.001). An increase of up to 12% was seen for cartilage metabolism-related type 2 collagen product (PRO-C2, not C2M) after 6 months at both trough levels (p=.01, p=.005). When stratified by prior treatment, changes in C3M (p=.03) and C4M (p=.02) levels were observed between trough levels for prior on-demand treatment but not for prophylaxis prior to study entry. CONCLUSION Joint improvement measured by collagen remodelling biomarkers specific to the basement membrane, interstitial matrix, and cartilage was seen with pharmacokinetics-guided prophylaxis. These collagen remodeling biomarkers warrant further exploration as biomarkers to guide treatment toward improvement in HA.
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Efficacy of Eltrombopag with Immunosuppressive Therapy Versus Immunosuppressive Therapy Alone on Severe Aplastic Anaemia: A Systematic Review and Meta-analysis
Zhang S, Wang Q, Cui K, Cheng B, Fan J, Hu S
Clinical drug investigation. 2023
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Editor's Choice
Abstract
BACKGROUND AND OBJECTIVE Severe aplastic anaemia (SAA) is a syndrome of bone marrow failure caused by T cell-mediated destruction of haematopoietic stem cells and progenitor cells. Whether patients with SAA should be treated with eltrombopag (EPAG) and immunosuppressive therapy (IST) or IST alone remains debatable. Therefore, we conducted this meta-analysis to compare the efficacy of eltrombopag + IST with that of IST alone in patients with SAA and to assess the difference in the efficacy of eltrombopag in adults and children. METHODS We performed this meta-analysis by retrieving studies that met the inclusion and exclusion criteria from PubMed, EMBASE, and the Cochrane Library up to 1 January 2023. We used a random-effects model to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for primary and secondary outcomes. I(2) statistics were used to evaluate the heterogeneity of the included studies. RESULTS Six studies involving a total of 699 patients were included. In terms of the primary outcomes, our pooled results indicated that patients treated with EPAG + IST had a higher 6-month overall response rate (OR = 2.25; 95% CI, 1.60-3.16; p < 0.00001), a higher 6-month complete response rate (OR = 2.61; 95% CI, 1.82-3.74; p < 0.00001), and a lower 6-month nonresponse rate (OR = 0.32; 95% CI, 0.19-0.52; p < 0.00001). However, there was no significant difference in the rate of 6-month partial response (OR = 0.94; 95% CI, 0.49-1.81; p = 0.85). CONCLUSION This meta-analysis indicated that patients treated with additional eltrombopag for IST may have a higher rate of haematological response.
PICO Summary
Population
Children and adults with severe aplastic anaemia (6 studies, n= 699).
Intervention
Eltrombopag (EPAG) and immunosuppressive therapy (IST), (n= 364).
Comparison
IST alone (n= 335).
Outcome
Patients treated with EPAG + IST had a higher 6-month overall response rate (odds ratio (OR), 2.25; 95% confidence interval (CI), [1.60, 3.16]), a higher 6-month complete response rate (OR, 2.61; 95% CI [1.82, 3.74]), and a lower 6-month non-response rate (OR, 0.32; 95% CI [0.19, 0.52]). There was no significant difference in the rate of 6-month partial response (OR, 0.94; 95% CI [0.49, 1.81]).
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Eltrombopag for Low-Risk Myelodysplastic Syndromes With Thrombocytopenia: Interim Results of a Phase-II, Randomized, Placebo-Controlled Clinical Trial (EQOL-MDS)
Oliva, E. N., Riva, M., Niscola, P., Santini, V., Breccia, M., Giai, V., Poloni, A., Patriarca, A., Crisà, E., Capodanno, I., et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023;:Jco2202699
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Editor's Choice
Abstract
PURPOSE In myelodysplastic syndromes (MDS), severe thrombocytopenia is associated with poor prognosis. This multicenter trial presents the second-part long-term efficacy and safety results of eltrombopag in patients with low-risk MDS and severe thrombocytopenia. METHODS In this single-blind, randomized, placebo-controlled, phase-II trial of adult patients with International Prognostic Scoring System low- or intermediate-1-risk MDS, patients with a stable platelet (PLT) count (<30 × 10(3)/mm(3)) received eltrombopag or placebo until disease progression. Primary end points were duration of PLT response (PLT-R; calculated from the time of PLT-R to date of loss of PLT-R, defined as bleeding/PLT count <30 × 10(3)/mm(3) or last date in observation) and long-term safety and tolerability. Secondary end points included incidence and severity of bleeding, PLT transfusions, quality of life, leukemia-free survival, progression-free survival, overall survival and pharmacokinetics. RESULTS From 2011 to 2021, of 325 patients screened, 169 patients were randomly assigned oral eltrombopag (N = 112) or placebo (N = 57) at a starting dose of 50 mg once daily to maximum of 300 mg. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients versus 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI, 2.3 to 14.9; P < .001). In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6% (95% CI, 46.0 to 81.2). Clinically significant bleeding (WHO bleeding score ≥ 2) occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI, 0.38 to 0.75; P = .0002). Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ(2) = 9.5, P = .002). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times. CONCLUSION Eltrombopag was effective and relatively safe in low-risk MDS with severe thrombocytopenia. This trial is registered with ClinicalTrials.gov identifier: NCT02912208 and EU Clinical Trials Register: EudraCT No. 2010-022890-33.
PICO Summary
Population
Adult patients with low-risk myelodysplastic syndromes and severe thrombocytopenia (n= 169).
Intervention
Oral eltrombopag (n= 112).
Comparison
Placebo (n= 57).
Outcome
Primary end points were duration of platelets response (PLT-R) and long-term safety and tolerability. PLT-R, with 25-week follow-up (IQR, 14-68) occurred in 47/111 (42.3%) eltrombopag patients vs. 6/54 (11.1%) in placebo (odds ratio, 5.9; 95% CI [2.3, 14.9]. In eltrombopag patients, 12/47 (25.5%) lost the PLT-R, with cumulative thrombocytopenia relapse-free survival at 60 months of 63.6%; 95% CI [46.0, 81.2]. Clinically significant bleeding occurred less frequently in the eltrombopag arm than in the placebo group (incidence rate ratio, 0.54; 95% CI [0.38, 0.75]. Although no difference in the frequency of grade 1-2 adverse events (AEs) was observed, a higher proportion of eltrombopag patients experienced grade 3-4 AEs (χ2= 9.5). AML evolution and/or disease progression occurred in 17% (for both) of eltrombopag and placebo patients with no difference in survival times.
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Targeting an elevated FVIII level using personalized rurioctocog alfa pegol prophylaxis in specific patient populations with hemophilia A: post hoc subanalysis of the randomized, phase 3 PROPEL study
Escuriola-Ettingshausen, C., Klamroth, R., Escobar, M., Stasyshyn, O., Tangada, S., Engl, W., Honauer, I., Lee, H. Y., Chowdary, P., Windyga, J.
Therapeutic advances in hematology. 2023;14:20406207231178596
Abstract
BACKGROUND The phase 3, prospective PROPEL study demonstrated that pharmacokinetic (PK)-guided prophylaxis targeting elevated factor VIII (FVIII) troughs in patients with hemophilia A resulted in lower annualized bleeding rates (ABRs) and a higher proportion of patients experiencing zero bleeds in the second 6 months of treatment when targeting a FVIII trough of 8-12% versus 1-3%. OBJECTIVE To investigate the benefit of PK-guided prophylaxis with rurioctocog alfa pegol targeting two FVIII trough levels in specific patient subgroups in a post hoc analysis using data from PROPEL. DESIGN This is a post hoc analysis of data from the PROPEL study. The design and primary outcomes of the prospective, randomized PROPEL study (NCT02585960) have been reported previously. METHODS This post hoc analysis reports data stratified by FVIII half-life (t(1/2)), hemophilic arthropathy status, number of target joints at screening, previous treatment regimen, and ABR range in the 12 months before study entry. RESULTS Targeting an elevated FVIII trough of 8-12% was associated with higher average FVIII levels over time, regardless of FVIII t(1/2) at baseline. The decrease in total ABR between the 8-12% and 1-3% arms was greatest in patients with a FVIII t(1/2) of 6 to <12 h (0.7 versus 3.5); a higher number of target joints, that is, at least four target joints, at baseline (0.2 versus 1.6); the presence of arthropathy (0.1 versus 1.7); and those previously treated on-demand (0.3 versus 1.8). CONCLUSION These results support the feasibility of targeting elevated FVIII levels using personalized rurioctocog alfa pegol prophylaxis. These benefits may be especially important in patients with a short FVIII t(1/2) and those receiving standard prophylaxis with frequent breakthrough bleeds, arthropathy, and target joints. REGISTRATION ClinicalTrials.gov Identifier: NCT02585960; https://clinicaltrials.gov/ct2/show/NCT02585960.