S184: SAFETY AND OUTCOMES FOLLOWING IMMUNOSUPPRESSIVE THERAPY WITH ATG/CYCLOSPORIN +/- ELTROMBOPAG FOR OLDER PATIENTS WITH SEVERE APLASTIC ANEMIA
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SUBMITTER: Prabahran A
PROVIDER: S-EPMC10428470 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
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Project description:Since the approval of horse antithymocyte globulin (ATG) decades ago, there was a long hiatus in therapies with activity in severe aplastic anemia (SAA). This scenario changed in 2014 when eltrombopag, a thrombopoietin receptor agonist, was approved for SAA after an insufficient response to initial immunosuppressive therapy (IST). The basis for this approval was the observation of single-agent activity of eltrombopag in this patient population, where 40% to 50% recovered blood counts at times involving >1 lineage. The achievement of transfusion independence confirmed the clinical benefit of this approach. Increase in marrow cellularity and CD34+ cells suggested a recovery to a more functioning bone marrow. Further in its development, eltrombopag was associated with standard horse ATG plus cyclosporine in first line, producing increases in overall (at about 90%) and complete response rates (at about 40%) and leading to transfusion independence and excellent survival. Interestingly, best results were observed when all drugs were started simultaneously. The cumulative incidence of clonal cytogenetic abnormalities to date has compared favorably with the vast experience with IST alone in SAA. Longer follow-up will help in define these long-term risks. In this review, the development of eltrombopag in SAA will be discussed.
| S-EPMC6234374 | biostudies-literature
Project description:Since the approval of horse antithymocyte globulin (ATG) decades ago, there was a long hiatus in therapies with activity in severe aplastic anemia (SAA). This scenario changed in 2014 when eltrombopag, a thrombopoietin receptor agonist, was approved for SAA after an insufficient response to initial immunosuppressive therapy (IST). The basis for this approval was the observation of single-agent activity of eltrombopag in this patient population, where 40% to 50% recovered blood counts at times involving >1 lineage. The achievement of transfusion independence confirmed the clinical benefit of this approach. Increase in marrow cellularity and CD34+ cells suggested a recovery to a more functioning bone marrow. Further in its development, eltrombopag was associated with standard horse ATG plus cyclosporine in first line, producing increases in overall (at about 90%) and complete response rates (at about 40%) and leading to transfusion independence and excellent survival. Interestingly, best results were observed when all drugs were started simultaneously. The cumulative incidence of clonal cytogenetic abnormalities to date has compared favorably with the vast experience with IST alone in SAA. Longer follow-up will help in define these long-term risks. In this review, the development of eltrombopag in SAA will be discussed.
| S-EPMC6245975 | biostudies-literature
Project description:Background and objectiveImmunosuppressive therapy (IST) is the first choice for severe aplastic anemia (SAA) patients with hematopoietic stem cell transplantation (HSCT) limitation, and the main factor limiting its efficacy is too few residual hematopoietic stem/progenitor cells (HSPC). Eltrombopag (EPAG), as a small molecule thrombopoietin receptor agonist, can stimulate the proliferation of residual HSPC and restore the bone marrow hematopoietic function of patients. In recent years, many studies have observed the efficacy and safety of IST combined with EPAG in the treatment of SAA, but the results are still controversial. The aim of this study is to systematically evaluate the efficacy and safety of IST combined with or without EPGA in the treatment of SAA.MethodsWe conducted a systematic review of all relevant literature published up to January 19, 2024. Pooled odds ratio (OR) was calculated to compare the rates, along with 95% confidence intervals (CI) and p value to assess whether the results were statistically significant by Review Manager 5.4.1. The p values for the interactions between each subgroup were calculated by Stata 15.1. The Newcastle-Ottawa Scale and the Cochrane bias risk assessment tools were respectively used to evaluate the quality of the literature with cohort studies and randomized controlled trials. The Review Manager 5.4.1 and Stata 15.1 were used to assess bias risk and perform the meta-analysis.ResultsA total of 16 studies involving 2148 patients were included. The IST combined with the EPAG group had higher overall response rate (ORR) than the IST group at 3 months (pooled OR = 2.10, 95% CI 1.58-2.79, p < 0.00001) and 6 months (pooled OR = 2.13, 95% CI 1.60-2.83, p < 0.00001), but the difference between the two groups became statistically insignificant at 12 months (pooled OR = 1.13, 95% CI 0.75-1.72, p = 0.55). The results of complete response rate (CRR) (pooled OR at 3 months = 2.73, 95% CI 1.83-4.09, p < 0.00001, 6 months = 2.76, 95% CI 2.08-3.67, p < 0.00001 and 12 months = 1.38, 95% CI 0.85-2.23, p = 0.19) were similar to ORR. Compared with the IST group, the IST combined with the EPAG group had better overall survival rate (OSR) (pooled OR = 1.70, 95% CI 1.15-2.51, p = 0.008), but there were no statistically significant differences in event-free survival rate (EFSR) (pooled OR = 1.40, 95% CI 0.93-2.13, p = 0.11), clonal evolution rate (pooled OR = 0.68, 95% CI 0.46-1.00, p = 0.05) and other adverse events between the two groups. The results of subgroup analysis showed that different ages were a source of heterogeneity, but different study types and different follow-up times were not. Moreover, all p-values for the interactions were greater than 0.05, suggesting that the treatment effect was not influenced by subgroup characteristics.ConclusionEPAG added to IST enables patients to achieve earlier and faster hematologic responses with a higher rate of complete response. Although it had no effect on overall EFSR, it improved OSR and did not increase the incidence of clonal evolution and other adverse events.
| S-EPMC10993616 | biostudies-literature
Project description:Addition of eltrombopag (E-PAG) to intensive immunosuppressive therapy (IST) contributes to restoring hematopoiesis in patients with severe aplastic anemia (SAA). Used at relatively low doses in the East Asian population, the efficacies of E-PAG and the predictors for efficacy are not clear. We conducted a retrospective, multicenter study to analyze the efficacy and the possible predicting factors at 6 months in 58 adult SAA patients with rabbit ATG-based IST and E-PAG. The response rate and complete response rate at 6 months were 76% and 21%, respectively. The baseline reticulocyte percentage [area under a curve (AUC)=0.798, 95% confidence interval (CI) 0.640-0.956, P=0.006], absolute reticulocyte count (ARC) (AUC =0.808, 95%CI 0.647-0.970, P=0.004), red cell distribution width - coefficient of variation (RDW-CV) (AUC=0.722, 95%CI 0.494-0.950, P=0.040), and absolute lymphocyte count (ALC) (AUC=0.706, 95%CI 0.522-0.890, P=0.057) were highly predictive of response at 6 months. The tipping values of reticulocyte percentage, ARC, RDW-CV, and ALC were 0.45%, 7.36×109/L, 11.75%, and 1.06×109/L, respectively. The sensitivity and specificity of reticulocyte percentages were 81.6% and 66.7%; ARC were 86.8% and 66.7%, RDW-CV were 94.7% and 55.6%; ALC were 55.3% and 88.9%. At a median follow-up of 15.5 months, the 2-year cumulative overall survival was 92%. The baseline reticulocyte percentage, ARC, RDW-CV, and ALC were potential factors in predicting a favorable effect of rabbit-ATG based IST plus E-PAG in SAA patients of East Asia (ChiCTR2100045895).Clinical trial registrationhttp://www.chictr.org.cn/edit.aspx?pid=125480&htm=4, identifier ChiCTR2100045895.
| S-EPMC9204341 | biostudies-literature
Project description: Not available
| S-EPMC10228467 | biostudies-literature
Project description:BackgroundEltrombopag (EPAG), an oral thrombopoietin receptor agonist (TPO-RA), has been proven to improve the hematologic response without increasing toxic effects as a first-line therapy combined with standard immunosuppressive treatment (IST) in adults with severe aplastic anemia (SAA). Nevertheless, the clinical evidence on the efficacy of EPAG in children with acquired aplastic anemia is limited and controversial.MethodsWe performed a single-center, retrospective study to analyze the clinical outcomes of fifteen patients aged ≤18 years with newly diagnosed acquired SAA who received first-line IST and EPAG (EPAG group) compared with those of forty-five patients who received IST alone (IST group) by propensity score matching (PSM).ResultsThere was no difference in the overall response (OR) rate between the EPAG group and IST group (53.3% vs. 46.7% at 3 months, P = 0.655; 66.7% vs. 57.8% at 6 months, P = 0.543), but the complete response (CR) rate was statistically significant (20.0% vs. 4.4% at 3 months, P = 0.094; 46.7% vs. 13.3% at 6 months, P = 0.012). The median time to achieve a hematological response in the EPAG and IST groups was 105 days and 184 days, respectively. No difference was observed in the event-free survival (EFS) or overall survival (OS) rates.ConclusionAdding EPAG to standard IST as the first-line treatment for children with acquired SAA improved the rapidity of hematological response and the CR rate but did not improve the OR or EFS rates.
| S-EPMC9872003 | biostudies-literature
Project description:For patients with severe aplastic anemia (SAA) in China who have had an insufficient response to the first-line treatment with hematopoietic stem cell transplantation or immunosuppressive therapy, there is no established standard of care other than transfusion support and treatment of infections. This non-randomized, open-label, Phase II multicenter trial investigated the efficacy and safety of eltrombopag in 20 adult Chinese patients with refractory or relapsed (r/r) SAA. The primary endpoint of hematologic response rate at Week 26, defined as the proportion of patients who met any of the International Working Group criteria, was observed in 70% (14/20) of patients, with more than 50% of these having at least bi-lineage response. Reduced red blood cell and platelet transfusion at Week 26 were observed in 57% (8/14) and 80% (8/10) of patients, respectively. Safety findings were consistent with the established safety profile of eltrombopag and no new safety signals were reported. None of the patients discontinued eltrombopag because of safety concerns. Although the sample size was small, this is the first prospective study to show that eltrombopag is efficacious and has a favorable safety profile in a Chinese patient population with r/r SAA.Trial registration: This trial is registered on ClinicalTrials.gov (NCT03988608); registered 17 June 2019.
| S-EPMC10622422 | biostudies-literature
Project description:BackgroundThe immune-mediated destruction of hematopoietic stem cells is implicated in the pathophysiology of aplastic anemia (AA). Immunosuppressive therapy (IST) using antithymocyte globulin and cyclosporine is successful in this setting. Eltrombopag is active in patients with refractory AA, presumably by increasing the bone marrow progenitors.MethodsThis phase 2 trial initially was designed to evaluate standard IST in newly diagnosed patients with severe AA and later was amended to add eltrombopag to simultaneously address immune destruction and stem cell depletion. The primary outcome was the overall response rate (ORR) at 3 months and 6 months.ResultsA total of 38 patients were enrolled: 17 (45%) received IST alone and 21 (55%) received additional eltrombopag. The ORR was 74%. Patients receiving IST plus eltrombopag had a similar ORR (76% vs 71%; P = .72), complete remission rate (38% vs 29%; P = .73), and median time to response (84 days vs 57 days; P = .30) compared with those receiving IST alone. The 2-year overall survival rate in the IST group was 91% compared with 82% for those patients treated with IST plus eltrombopag (P = .82). No cumulative toxicities were noted after the addition of eltrombopag.ConclusionsThe addition of eltrombopag to standard IST was well tolerated and resulted in similar responses.
| S-EPMC6800043 | biostudies-literature
Project description:Predictors, genetic characteristics, and long-term outcomes of patients with SAA who clonally evolved after immunosuppressive therapy (IST) were assessed. SAA patients were treated with IST from 1989-2020. Clonal evolution was categorized as "high-risk" (overt myeloid neoplasm [meeting WHO criteria for dysplasia, MPN or acute leukemia] or isolated chromosome-7 abnormality/complex karyotype without dysplasia or overt myeloid neoplasia) or "low-risk" (non-7 or non-complex chromosome abnormalities without morphological evidence of dysplasia or myeloid neoplasia). Univariate and multivariate analysis using Fine-Gray competing risk regression model determined predictors. Long-term outcomes included relapse, overall survival (OS) and hematopoietic stem cell transplant (HSCT). Somatic mutations in myeloid cancer genes were assessed in evolvers and in 407 patients 6 months after IST. Of 663 SAA patients, 95 developed clonal evolution. Pre-treatment age >48 years and ANC > 0.87 × 109/L were strong predictors of high-risk evolution. OS was 37% in high-risk clonal evolution by 5 years compared to 94% in low-risk. High-risk patients who underwent HSCT had improved OS. Eltrombopag did not increase high-risk evolution. Splicing factors and RUNX1 somatic variants were detected exclusively at high-risk evolution; DNMT3A, BCOR/L1 and ASXL1 were present in both. RUNX1, splicing factors and ASXL1 somatic mutations detected at 6 months after IST predicted high-risk evolution.
| S-EPMC9701554 | biostudies-literature
Project description:This study prospectively compared the efficacy and safety between matched related donor-hematopoietic stem cell transplantation (MRD-HSCT) (n = 108) and immunosuppressive therapy (IST) plus eltrombopag (EPAG) (IST + EPAG) (n = 104) to determine whether MRD-HSCT was still superior as a front-line treatment for patients with severe aplastic anemia (SAA). Compared with IST + EPAG group, patients in the MRD-HSCT achieved faster transfusion independence, absolute neutrophil count ≥ 1.0 × 109/L (P < 0.05), as well as high percentage of normal blood routine at 6-month (86.5% vs. 23.7%, P < 0.001). In the MRD-HSCT and IST + EPAG groups, 3-year overall survival (OS) was 84.2 ± 3.5% and 89.7 ± 3.1% (P = 0.164), whereas 3-year failure-free survival (FFS) was 81.4 ± 4.0% and 59.1 ± 4.9% (P = 0.002), respectively. Subgroup analysis indicated that the FFS of the MRD-HSCT was superior to that of the IST + EPAG among patients aged < 40 years old (81.0 ± 4.6% vs. 63.7 ± 6.5%, P = 0.033), and among patients with vSAA (86.1 ± 5.9% vs. 54.9 ± 7.9%, P = 0.003), while the 3-year OS of the IST + EPAG was higher than that of the MRD-HSCT among the patient aged ≥ 40 years old (100.0 ± 0.0% vs. 77.8 ± 9.8%, P = 0.036). Multivariate analysis showed that first-line MRD-HSCT treatment was associated favorably with normal blood results at 6-month and FFS (P < 0.05). These outcomes suggest that MRD-HSCT remains the preferred first-line option for SAA patients aged < 40 years old or with vSAA even in the era of EPAG.
| S-EPMC9373485 | biostudies-literature