Unrelated donor hematopoietic stem cell transplantation compared to immunosuppressive therapy plus eltrombopag as first-line treatment for adults with severe aplastic anemia.
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SUBMITTER: Wu L
PROVIDER: S-EPMC10914753 | biostudies-literature | 2024 Mar
REPOSITORIES: biostudies-literature
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Unrelated donor hematopoietic stem cell transplantation compared to immunosuppressive therapy plus eltrombopag as first-line treatment for adults with severe aplastic anemia.
Wu Liangliang L Liu Limin L Zhao Xin X Zhou Ming M Fu Andie A Zhang Yuping Y Yang Wenrui W Chen Xiaowei X Mo Wenjian W Wang Caixia C Li Yumiao Y Xu Shilin S Pan Shiyi S Zhou Ruiqing R Meng Fankai F Zhang Fengkui F Wu Depei D Wang Shunqing S
Blood cancer journal 20240306 1
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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
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: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:ImportanceTelomeres protect chromosome ends and are markers of cellular aging and replicative capacity.ObjectiveTo evaluate the association between recipient and donor pretransplant leukocyte telomere length with outcomes after unrelated donor allogeneic hematopoietic cell transplantation (HCT) for patients with severe aplastic anemia.Design, participants, and settingThe study included 330 patients (235 acquired, 85 Fanconi anemia, and 10 Diamond-Blackfan anemia) and their unrelated donors who had pre-HCT blood samples and clinical and outcome data available at the Center for International Blood and Marrow Transplant Research. Patients underwent HCT between 1989 and 2007 in 84 centers and were followed-up to March 2013.ExposuresRecipient and donor pre-HCT leukocyte telomere length classified into long (third tertile) and short (first and second tertiles combined) based on donor telomere length distribution.Main outcomes and measuresOverall survival, neutrophil recovery, and acute and chronic graft-vs-host disease, as ascertained by transplant centers through regular patient follow-up.ResultsLonger donor leukocyte telomere length was associated with higher survival probability (5-year overall survival, 56%; number at risk, 57; cumulative deaths, 50) than shorter donor leukocyte telomere length (5-year overall survival, 40%; number at risk, 71; cumulative deaths, 128; P = .009). The association remained statistically significant after adjusting for donor age, disease subtype, Karnofsky performance score, graft type, HLA matching, prior aplastic anemia therapy, race/ethnicity, and calendar year of transplant (hazard ratio [HR], 0.61; 95% CI, 0.44-0.86). Similar results were noted in analyses stratified on severe aplastic anemia subtype, recipient age, HLA matching, calendar year of transplant, and conditioning regimen. There was no association between donor telomere length and neutrophil engraftment at 28 days (cumulative incidence, 86% vs 85%; HR, 0.94; 95% CI, 0.73-1.22), acute graft-vs-host disease grades III-IV at 100 days (cumulative incidence, 22% vs 28%; HR, 0.77; 95% CI, 0.48-1.23), or chronic graft-vs-host disease at 1-year (cumulative incidence, 28% vs 30%; HR, 0.81; 95% CI, 0.53-1.24) for long vs short, respectively. Pretransplant leukocyte telomere length in the recipients was not associated with posttransplant survival (HR, 0.91; 95% CI, 0.64-1.30).Conclusions and relevanceLonger donor leukocyte telomere length was associated with increased 5-year survival in patients who received HCT for severe aplastic anemia. Patient leukocyte telomere length was not associated with survival. The results of this observational study suggest that donor leukocyte telomere length may have a role in long-term posttransplant survival.
| S-EPMC4388056 | biostudies-literature
Project description:Eltrombopag, an FDA-approved non-peptidyl thrombopoietin receptor agonist, is clinically used for the treatment of aplastic anemia, a disease characterized by hematopoietic stem cell failure and pancytopenia, to improve platelet counts and stem cell function. Eltrombopag treatment results in a durable trilineage hematopoietic expansion in patients. Some of the eltrombopag hematopoietic activity has been attributed to its off-target effects, including iron chelation properties. However, the mechanism of action for its full spectrum of clinical effects is still poorly understood. Here, we report that eltrombopag bound to the TET2 catalytic domain and inhibited its dioxygenase activity, which was independent of its role as an iron chelator. The DNA demethylating enzyme TET2, essential for hematopoietic stem cell differentiation and lineage commitment, is frequently mutated in myeloid malignancies. Eltrombopag treatment expanded TET2-proficient normal hematopoietic stem and progenitor cells, in part because of its ability to mimic loss of TET2 with simultaneous thrombopoietin receptor activation. On the contrary, TET inhibition in TET2 mutant malignant myeloid cells prevented neoplastic clonal evolution in vitro and in vivo. This mechanism of action may offer a restorative therapeutic index and provide a scientific rationale to treat selected patients with TET2 mutant-associated or TET deficiency-associated myeloid malignancies.
| S-EPMC8843742 | 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-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: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:BackgroundAcquired aplastic anemia results from immune-mediated destruction of bone marrow. Immunosuppressive therapies are effective, but reduced numbers of residual stem cells may limit their efficacy. In patients with aplastic anemia that was refractory to immunosuppression, eltrombopag, a synthetic thrombopoietin-receptor agonist, led to clinically significant increases in blood counts in almost half the patients. We combined standard immunosuppressive therapy with eltrombopag in previously untreated patients with severe aplastic anemia.MethodsWe enrolled 92 consecutive patients in a prospective phase 1-2 study of immunosuppressive therapy plus eltrombopag. The three consecutively enrolled cohorts differed with regard to the timing of initiation and the duration of the eltrombopag regimen (cohort 1 received eltrombopag from day 14 to 6 months, cohort 2 from day 14 to 3 months, and cohort 3 from day 1 to 6 months). The cohorts were analyzed separately. The primary outcome was complete hematologic response at 6 months. Secondary end points included overall response, survival, relapse, and clonal evolution to myeloid cancer.ResultsThe rate of complete response at 6 months was 33% in cohort 1, 26% in cohort 2, and 58% in cohort 3. The overall response rates at 6 months were 80%, 87%, and 94%, respectively. The complete and overall response rates in the combined cohorts were higher than in our historical cohort, in which the rate of complete response was 10% and the overall response rate was 66%. At a median follow-up of 2 years, the survival rate was 97%; one patient died during the study from a nonhematologic cause. Marked increases in bone marrow cellularity, CD34+ cell number, and frequency of early hematopoietic progenitors were noted. Rates of relapse and clonal evolution were similar to our historical experience. Severe rashes occurred in two patients, resulting in the early discontinuation of eltrombopag.ConclusionsThe addition of eltrombopag to immunosuppressive therapy was associated with markedly higher rates of hematologic response among patients with severe aplastic anemia than in a historical cohort. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT01623167 .).
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Project description: Not available
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