Efficacy and Safety of Avatrombopag in Combination with Standard Immunosuppressive Therapy for Severe Aplastic Anemia

Efficacy and Safety of Avatrombopag in Combination with Standard Immunosuppressive Therapy for Severe Aplastic Anemia | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and Safety of Avatrombopag in Combination with Standard Immunosuppressive Therapy for Severe Aplastic Anemia Jianping Li, Weiru Liang, Huihui Fan, Kang Zhou, Yuan Li, Wenrui Yang, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4927350/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 3 You are reading this latest preprint version Abstract Background: Severe aplastic anemia (SAA) is a life-threatening bone marrow failure disease. The addition of eltrombopag to immunosuppressive therapy (IST) improves the response rate and response quality of SAAs, but its hepatotoxicity is concerning. Avatrombopag (AVA), another small-molecule thrombopoietin receptor agonist without hepatotoxicity, has unknown efficacy in SAA treatment. Methods: This retrospective study compared clinical outcomes of 42 SAA patients treated with IST and AVA as first-line treatment (Group A) to a historical cohort of 84 patients who received IST alone (Group B) using propensity score matching (PSM). Results: The median age was 31.5 (6.0-67.0) years old in Group A and 26 (16.0-45.0) years old in Group B. At 3 months, Group A showed higher complete response (CR) and overall response (OR) rates than Group B (CR: 19.0% vs. 4.8%, P = 0.024; OR: 54.8% vs. 39.3%, P =0.145). Higher CR and OR rates were also found at 6 months in Group A than in Group B (CR 31.0% vs. 14.3%, P =0.145; OR 71.4% vs. 51.2%, P =0.048). In multivariate analysis of Group A, a shorter interval from disease onset to ATG treatment (≤6 months) ( P =0.005) predicted better responses rate at 6 months. Event free survival was also improved in Group A (60.7% vs. 49.6%). AVA was well-tolerated, with no hepatic injury observed during treatment, even in those with pre-existing hepatic impairment. Conclusion: The addition of AVA to IST improves both the response rate and response quality in SAA patients while ensuring safety. severe aplastic anemia immunosuppressive therapy avatrombopag thrombopoietin receptor agonist Figures Figure 1 Figure 2 Figure 3 Key Points 1. Avatrombopag added to standard immunosuppressive therapy was safe and effective in the first-line treatment for severe aplastic anemia, even in patients with hepatic impairment. 2. Patients with a short interval from disease onset to ATG treatment (≤6 months) has a higher hematologic response rate to immunosuppressive therapy. 1. Introduction Acquired aplastic anemia (AA) is immune-mediated bone marrow failure disease characterized by pancytopenia and hypoplastic bone marrow( 1 ). Severe AA (SAA) is life-threatening due to infection and bleeding. Immunosuppressive therapy (IST) based on antithymocyte globulin (ATG) and cyclosporine (CSA) is effective for SAA, but only 50–70% of patients achieve hematologic response( 2 , 3 ). Eltrombopag, an oral thrombopoietin receptor agonist (TPO-RA), has shown promising results in improving the quality and rapidity of hematologic responses in SAA patients( 3 – 6 ). In the first-line treatment, eltrombopag demonstrated an overall response (OR) rate of 59–80%, with a complete response (CR) rate of 22–30% at 6 months, without increasing clonal evolution during long-term follow-up. Currently, eltrombopag combined with IST is recommended as the first-line treatment for SAA patients who are not suitable candidates for transplantation. However, hepatotoxicity had been recorded in 12–18% of patients receiving eltrombopag, and most individuals taking doses higher than 150 mg/day experienced slate-grey pigmentation( 6 , 7 ). Therefore, there is a need for a TPO-RA that offers comparable effectiveness while minimizing toxicity when treating SAA. Avatrombopag (AVA), another oral TPO-RA with a distinct molecular structure, has been approved for the treatment of thrombocytopenia( 8 ). AVA is a suitable option for patients with liver injury due to its non-hepatotoxic nature( 9 , 10 ). Recent studies have demonstrated the efficacy of AVA in various conditions, including newly diagnosed and persistent immune thrombocytopenia (ITP), chronic primary ITP, and thrombocytopenia post hematopoietic stem-cell transplantation( 11 – 13 ). In non-severe AA patients who were refractory, relapsed, or intolerant to immunosuppressants and eltrombopag, 56% responded to AVA within 3 months( 14 ). AVA also exhibited safety and efficacy in SAA patients with hepatic dysfunction in a small Chinese case series( 15 ). Therefore, we can expect that AVA may have good efficacy in treating SAA patients. Currently, there is few data of AVA and IST as first-line treatment for SAA. So we conducted a single-center, retrospective study to investigate the efficacy and safety of adding AVA to standard IST as first-line treatment for SAA and reported the results here. 2. Patients and Methods This is a retrospective study on the clinical outcomes of a cohort of ATG-naïve SAA patients who received IST and AVA treatment. A historical cohort of patients who received ATG and CSA as first-line treatment was matched as control. The primary endpoint was to assess the benefit of adding AVA to IST as first-line therapy. This study was approved by the Ethical Committee of the Institute of Hematology and Blood Diseases Hospital. Informed consent was obtained from patients and/or their legal guardians in accordance with the Declaration of Helsinki. The study was part of registered NICHE cohort at www.clincialtrials.gov as # NCT04645199. 2.1 Patients The diagnosis of AA was made according to the criteria set by the International Granulocytosis and Aplastic Anemia Study Group( 16 ). SAA was defined as bone marrow hypoplasia (< 30%) in the absence of an abnormal infiltrate or marrow fibrosis on bone marrow biopsy, and meeting two out of three following criteria: absolute neutrophile count (ANC) < 0.5×10 9 /L, platelet count (PLT) < 20×10 9 /L and absolute reticulocyte count (ARC) < 20×10 9 /L. SAA with ANC < 0.2×10 9 /L was classified as very severe AA (VSAA)( 17 ). Paroxysmal nocturnal hemoglobinuria (PNH) cells were detected using flowcytometry. Patients with inherited bone marrow failure syndromes (IBMFS), hemolytic PNH, and myelodysplastic syndromes (MDS) did not receive IST treatment and were excluded through case histories, clinical manifestations, bone marrow examination, cytogenetics, mitomycin C test and blood tests. From April 2021 to April 2022, a total of 42 SAA patients received ATG, CSA and AVA as first-line treatment (Group A, AVA + IST group) at the Anemia Therapeutic Center, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences. To minimize potential confounders and selection bias, we performed a Propensity score matching (PSM) analysis to match patients from Group A with those who received ATG and CSA only from a historical cohort. From January 2015 through December 2019, 84 SAA patients (Group B, IST) were matched from a total of 537 consecutive SAA patients who were treated with standard IST. 2.2 Treatment AVA was orally administered at the dose of 40 mg (20mg for children ≤ 12 years) daily within 14 days of ATG treatment and continued for at least 3 months. Porcine ATG (Yujin Bio-Pharma Wuhan CNBG Co., LTD.) was given at a dose of 20 mg/kg/day for five consecutive days. CSA was given at 3–5 mg/kg/day in divided dose from the first day of ATG administration, and the blood trough concentration was maintained between 150 and 250 ng/mL. CSA was used for at least 6 months, and gradually tapered after achieving best hematologic response. Granulocyte stimulating factor (G-CSF, 5mg/kg/day) was administered when ANC < 0.5×10 9 /L. Hemoglobin levels were maintained above 60 g/L, and platelets were kept above 10×10 9 /L. Prophylactic antimicrobials were not routinely administered. 2.3 Hematological response criteria and outcome variables Complete response (CR) was defined as haemoglobin > 100 g/L, ANC > 1.5×10 9 /L, and platelet count > 100×10 9 /L. Partial response (PR) was defined as achieving transfusion independence but not meet criteria for CR. Overall response (OR) was the sum of CR and PR. No response (NR) was defined as not meeting the criteria for PR. Death or loss of follow-up within 6 months after ATG treatment were classified as NR. The haematological response was assessed at 3 and 6 months from the first day of ATG treatment. Relapse was defined as a substantial decrease in blood counts requiring transfusions or further intensive immunotherapy in responders. Overall survival (OS) was measured from the first day of ATG until death from any cause or the date of last follow-up. Event-free survival (EFS) was measured from the first day of ATG until any event (NR, HSCT, death, relapse, repeat IST or any additional AA treatment, transformation to PNH and malignant clonal evolution) or the date of last follow-up. 2.4 Statistical analysis Continuous variables were presented as medians and interquartile ranges (25th-75th). Categorical variables were expressed as frequencies and percentages. The Mann–Whitney U test, chi-square test and Fisher’s exact test were used to test for differences between groups for continuous and categorical variables, respectively. In this study, we implemented the 1:2 nearest neighbour PSM without replacement to match cases, and the logit of the propensity score was a caliper width of 0.2 of the standard deviation. Absolute standardized differences were used to compare covariates between pre- and post-matching cohorts, and absolute standardized difference less than 10% were considered optimally matched. Long-term endpoints were illustrated by Kaplan-Meier survival curves (OS, EFS) or cumulative incidence curves, with the Gehan-Breslow-Wilcoxon and log-rank tests for arms’ comparison respectively. Factors related to the 6-month haematological response were examined through binary Logistic regression. R version 4.3.1 and RStudio Version 1.4.1717 were used for statistical analysis. 3. Results 3.1 Baseline characteristics A total of 42 SAA patients received ATG, CSA and AVA as first-line treatment (Group A). There were 20 VSAA and 22 SAA patients, with a median age of 31.5 (20.25, 54.75) years old. The median ANC was 0.21×10 9 /L, ARC was 11.2×10 9 /L, and PLT was 6×10 9 /L. Three (7.9%) patients had chromosomal abnormalities including two -Y and one trisomy 8. Eight patients (19.0%) carried PNH clones (clone size≥1%) without evidence of hemolysis. Eleven (26.19%) patients had a long interval between disease onset and the initiation of ATG (interval Dis-ATG＞6 months). There were 13 patients had substantial liver disease, including 5 (11.9%) patients with hepatitis-associated AA (HAAA), 2 (4.8%) patients with chronic/active hepatitis B, and 6 (14.3%) patients with drug-related liver injury before IST. Four patients had grade 1-2 bilirubin elevation, and two had grade 3 transaminase elevation and bilirubin elevation according to Common Toxicity Criteria for Adverse Events (ver. 5). The details were shown in Table S1. Data from 537 patients who received standard IST were used to match patients in Group A. Compared to Group A, those patients were more likely to have a younger age, and lower proportion of VSAA patients. To avoid bias, 84 patients (Group B) were finally identified using PSM analysis. Covariates were well balanced between Group A and Group B (Table 1 and Figure 1). 3.2 Hematologic responses Patients in Group A have better haematological responses compared to patients in Group B (Table S2). The OR rate was 54.8% at 3 months and 71.4% at 6 months in Group A compared to that of 39.3% at 3 months ( P =0.145) and 51.2% at 6 months in Group B ( P =0.048). The CR rates in Group A were also higher than in Group B at 3 months (19.0% vs 4.8%, P = 0.024) and 6 months (31.0% vs 14.3%, P =0.048). At 12 months, the CR rate increased to 42.9% in Group A and 27.7% in Group B. Using the logistic regression analysis, AVA was associated with increased CR rate at 3 and 6 months, and increased OR rate at 6 months (Table 2). We further analysed the response rates according to disease severity (SAA and VSAA). At 3 months, SAA patients in group A had a CR rate of 18.2% and an OR rate of 54.5%, while VSAA patients had a CR rate of 20.0% ( P =1.000) and an OR rate of 55.0% ( P =1.000), respectively. At 6 months, the CR rate was 27.3% in SAAs and 35.0% in VSAAs ( P =0.836), and the OR rate was 63.6% and 80.0%, respectively ( P =0.406) (Figure 2A). The VSAA patients showed better CR ( P =0.006) and OR ( P =0.005) rate at 6 months in Group A compared to Group B (Table S3). We also analysed subgroups, according to age and PNH clone sizes. The AVA group showed increased 3 months CR rate in patients with PNH clone than those without PNH clone ( P =0.025). In the subgroup of age <40 years, patients in the AVA group had a better CR rate at 6 months than the IST group ( P =0.029) (Table S3). 3.1 Hematologic response related factors of Avatrombopag Multivariate regression analysis was used to explore the factors related to hematologic response of avatrombopag. We found that the interval between disease onset and the initiation of ATG (interval Dis-ATG) was the only factor significantly related to hematologic response at 6 months ( P =0.005). We further analyzed the response rate at 3 and 6 months according to the interval Dis-ATG. Patients with the interval Dis-ATG >6 months had a much lower OR rate at 3 months (36.4% vs. 61.3%, P=0.283) and 6 months (36.4% vs. 83.9%, P =0.009). The CR rates were also lower in the group with long interval Dis-ATG at 6 months (9.1% vs. 38.7%, P =0.148) (Figure 2B). Furthermore, we analysed data from 31 patients with a short interval Dis-ATG (≤6 months), including 16 SAA and 15 VSAA patients. We found that a reticulocyte count ≥10×10 9 /L showed better CR and OR rate than those with lower reticulocyte count both at 3 month (CR: 6.2% vs. 40.0%, P =0.069; OR: 37.5% vs. 86.7%, P =0.029) and at 6 month (CR: 18.8% vs. 60.0%, P =0.047; OR: 68.8% vs. 100.0%, P =0.061). (Figure 3C). 3.4 Safety The AVA treatment was well-tolerated, and no patient discontinued due to side effects. There was no exacerbation of the primary liver function abnormality. In patients with pre-existing abnormal liver function, liver parameters returned to normal during IST treatment and maintained normal. The HBV viral load stayed below 1000 copies per millilitre in the 2 patients with chronic hepatitis B. Thrombotic complications and gastrointestinal adverse reactions were not observed. One patient experienced a headache when taking 40mg AVA, which resolved upon reducing the dosage to 20mg/day. After one week, the dosage was increased to 40 mg/day without recurrence of headaches. 3.5 Outcomes Patients were followed up for 14 (12.2-25.7) months in Group A, and 20 (12.2-25.9) months in Group B. By the end of follow-up, the OR rate was 76.2% and the CR rate was 50.0% in Group A. The median duration of AVA intake was 12 (9-12) months. One patient died within 3 months. Eight patients who did not achieve hematologic response at 6 months discontinued taking AVA. One patient accepted hematopoietic stem cell transplantation (HSCT) and maintained CR. Another patient discontinued AVA treatment after achieving PR at 3 months but later experienced a relapse. Responders who tapered AVA after 3 months of ATG treatment did not experience relapse. Fifteen patients who achieved CR or stable PR had ceased AVA by the last follow-up. Clonal evolution was not observed in this study, including haemolytic PNH, myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML). Prior to treatment, 8 patients had PNH clones, and 6 of them achieved a hematologic response. Among the responders, the size of PNH clone decreased in 2 patients and disappeared in 3 patients. The OS was similar between Group A and Group B (2-year OS, 97.6% vs. 92.8%, P =0.270) (Figure 3A). The event-free survival (EFS) rate was higher in the AVA group compared to the IST group, although the difference was insignificant (2-year EFS 60.7% vs. 49.6%, P =0.108) (Figure 3B). 4. Discussion Eltrombopag has shown good therapeutic effect in AA. But there is limited data on the clinical use of AVA, a second-generation TPO-RA, for newly diagnosed AA( 18 – 21 ). A phase II trial of AVA in combination with immunosuppressive therapy in treatment-naïve and relapsed/refractory SAA are underway( 22 ). Here we conducted a retrospective analysis of the clinical outcomes of 42 SAA patients who received AVA, ATG and CSA as first-line treatment and compared to 84 patients treated by IST alone by PSM. It is currently the largest cohort of study on the use of AVA in SAA. This study showed that AVA was active and well-tolerated as first-line treatment for SAA. Higher hematological response rate and response quality were found both at 3 and 6 months than patients who received standard IST alone. These results are similar to that reported in first-line treatment using eltrombopag and IST. In this cohort, SAA patients received AVA of 40mg/d within 14 days of ATG treatment and continued for at least 3 months. We found a sharp increase in the complete response rate at 3, 6 and 12 months in the AVA group compared with the IST group (4.8%→19.0% at 3 months; 14.3%→31.0% at 6 months; 27.7%→42.9% at 12 months). The OR and CR rate at 6 months in patients received AVA and IST was similar with the results of eltrombopag in the RACE study (CR rate, 31.0% vs. 32%; PR rate, 40.4% vs. 37%)( 4 ). There results indicated that similar to eltrombopag, the addition of AVA could improve the quality of hematological responses, decrease transfusion burden and infectious risks of patients after IST therapy. Since the current study was a retrospective study, patients were routinely visited every three months after ATG, and blood test results were not provided at other time points, it was difficult to compare the median response time with or without AVA. But based on the higher OR rates at 3 and 6 months in the AVA group, we considered that the application of AVA can narrow the time to response. This earlier hematologic recovery also may translate into fewer patients having to switch to early HSCT. Previous study both from Bacigalupo A and our center showed that longer interval between AA diagnosis and ATG treatment was a negative predictor for response at 6 months( 23 , 24 ). Recent years in our center, most patients diagnosed with SAA were given ATG treatment within 2–4 weeks. Simply calculating the time from diagnosis to treatment would not be appropriate to show the real medical history. The regression analysis in this study identified the longer interval between disease onset (cytopenia) and ATG treatment (Interval Dis-ATG) as predictors of worse hematological response in SAA by 6 months. Only 4 out of 11 V/SAA patients with a long interval Dis-ATG (> 6 months) achieved hematologic response at 6 months. Although disease progression may be slow in these patients, the prolonged autoimmune attack may impair residual hematopoiesis and the bone marrow microenvironment, leading to poor ORR and OS( 25 ). Patients with shorter interval Dis-ATG, higher reticulocyte count (≥ 10×10 9 /L) achieved higher hematological response, consistent with previous findings of IST combined with eltrombopag ( 5 , 26 ). Thus, there was less chance to achieve hematological response after the treatment of TPO-RA and IST for patients with longer interval Dis-ATG and lower reticulocyte count, and HSCT treatment should be recommended as a priority. The risk of clonal evolution is also concerned for the application of TPO-RAs because of their stem-cell stimulatory properties( 27 ). It has been reported that the combination of TPO-RAs to IST does not increase high-risk evolution and hemolytic PNH conversion rate in SAA patients( 5 , 6 , 28 ). In our cohort, bone marrow and chromosome were routinely reexamined at 3, 6 and 12 months after treatment, and no patients were found at high risk of progression. Eight patients with PNH clones showed stable disease, and no clonal enlargement or hemolysis observed. There results indicated that AVA may not increase the risk of clonal progression in SAA patients in the short period. However, longer follow-up time and regular genetic examinations are required to further evaluate the risk of myeloid malignant transformation, which usually appears in 10–15% of patients 5–10 years after diagnosis( 29 , 30 ). As for long-term survival and relapse, the addition of AVA to IST did not result in evidently improved OS in SAA patients. Consistent to the improved response rate at 6 months, the EFS rate was improved (2-year EFS%: 49.6%→67.5%) in the AVA group although there was no statistical significance. These findings are consistent with the RACE study, in which the addition of eltrombopag increased EFS from 34–46% at 2 years( 4 ). However, the reintroduction of eltrombopag was common in RACE. While in our cohort, most patients treated with AVA have tapped and stopped taking the drugs without disease relapse. Only one patient with immediate discontinuation experienced a relapse. The metabolism of AVA is mainly carried out by two liver enzymes, CYP3A and CYP2C which do not increase bilirubin levels( 8 ). The drug does not have metal ion chelation and taking it with food may result in better absorption( 31 ). No drug-related liver function abnormalities were found in the phase I-III clinical study of AVA ( 10 , 29 , 30 ). Age, weight, gender, ethnicity, any grade of liver impairment, and mild to moderate renal impairment have no significant effect on the pharmacokinetics of avatrombopag( 31 , 32 ). In our study, all patients tolerated avatrombopag well, and no adverse events associated with liver function was reported. Only one patient reported headache which was relived after dose tapering. Compared to more commonly reported adverse liver events associated with eltrombopag treatment, adding AVA to IST may provide better safety for treating SAA, especially those who initially experienced liver damage. In summary, the combination of avatrombopag and IST is safe and effective as first-line treatment for SAA patients, even in patients with initial liver damage. Patients with a long interval Dis-ATG (> 6 months) and lower reticulocyte count (< 10×10 9 /L ) has a poor response to IST, so HSCT should be considered as soon as possible. Declarations Funding information: This study was supported by Grant 2023NCRCA0119 of Clinical Research Funding of National Clinical Research Center for Blood Diseases; Grant 2022-PUMCH-C-026 of National High Level Hospital Clinical Research Funding; Grant 2022YFA1103300 of National Key R&D Program of China. Data availability statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Conflict of interest disclosure: The authors have no competing financial interests to declare. Ethics approval statement and consent to participate: The study was approved by the Ethics Committee and Institutional Review Board of Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, and conducted in concordance with the Declaration of Helsinki. All legal guardians of pediatric patients signed written informed consent before participation in the trial. All procedures performed in the study were in accordance with the ethical standards of this research committee. Author Contribution Jianping Li and Weiru Liang collected and analyzed data, draft the manuscript; Yuan Li, Wenrui Yang, Xiangrong Hu, Baohang Zhang, Huihui Fan, Liping Jing, Li Zhang, Kang Zhou, Lei Ye, Yang Yang, Youzhen Xiong treated patients and collected the clinical data; Weiping Yuan and Jun Shi reviewed and edited the manuscript; Fengkui Zhang and Xin Zhao were involved in the study design, data analysis and manuscript writing. All authors reviewed the data analyses, contributed to data interpretation and approved the final version of the submitted report. References Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108(8):2509–19. Olnes MJ, Scheinberg P, Calvo KR, Desmond R, Tang Y, Dumitriu B, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367(1):11–9. Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017;376(16):1540–50. De Peffault R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, et al. Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. N Engl J Med. 2022;386(1):11–23. Zaimoku Y, Patel BA, Shalhoub R, Groarke EM, Feng X, Wu CO, et al. Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag. Haematologica. 2021;107(1):126–33. Patel BA, Groarke EM, Lotter J, Shalhoub R, Gutierrez-Rodrigues F, Rios O, et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood. 2022;139(1):34–43. Gill H, Wong RSM, Kwong YL. From chronic immune thrombocytopenia to severe aplastic anemia: recent insights into the evolution of eltrombopag. Ther Adv Hematol. 2017;8(5):159–74. Shirley M. Avatrombopag: First Global Approval. Drugs. 2018;78(11):1163–8. Terrault N, Chen YC, Izumi N, Kayali Z, Mitrut P, Tak WY, et al. Avatrombopag Before Procedures Reduces Need for Platelet Transfusion in Patients With Chronic Liver Disease and Thrombocytopenia. Gastroenterology. 2018;155(3):705–18. Jurczak W, Chojnowski K, Mayer J, Krawczyk K, Jamieson BD, Tian W, et al. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018;183(3):479–90. Zhou M, Qi J, Gu C, Wang H, Zhang Z, Wu D, et al. Avatrombopag for the treatment of thrombocytopenia post hematopoietic stem-cell transplantation. Ther Adv Hematol. 2022;13:20406207221127532. Mei H, Zhou H, Hou M, Sun J, Zhang L, Luo J, et al. Avatrombopag for adult chronic primary immune thrombocytopenia: a randomized phase 3 trial in China. Res Pract Thromb Haemost. 2023;7(6):102158. Virk ZM, Leaf RK, Kuter DJ, Goodarzi K, Connell NT, Connors JM, et al. Avatrombopag for adults with early versus chronic immune thrombocytopenia. Am J Hematol. 2024;99(2):155–62. Wan Z, Chen M, Han B. Avatrombopag, a promising novel thrombopoietin receptor agonist for refractory/relapsed/intolerant non-severe aplastic anemia: a phase 2 single-arm clinical trial. Ann Med. 2023;55(1):2224044. Li JP, Yang WR, Li Y, Xiong YZ, Ye L, Fan HH, et al. [Avatrombopag combined with standard immunosuppressive therapy in the treatment of severe aplastic anemia with hepatic impairment in six patients]. Zhonghua Xue Ye Xue Za Zhi Zhonghua Xueyexue Zazhi. 2022;43(11):952–5. Camitta BM, Thomas ED, Nathan DG, Santos G, Gordon-Smith EC, Gale RP, et al. Severe Aplastic Anemia: A Prospective Study of the Effect of Early Marrow Transplantation on Acute Mortality. Blood. 1976;48(1):63–70. Bacigalupo A, Hows J, Gluckman E, Nissen C, Marsh J, Van Lint MT, et al. Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA): a report of the EBMT SAA working party. Br J Haematol. 1988;70(2):177–82. Chi Y, Hu Q, Yang C, Chen M, Han B. Avatrombopag is effective in patients with chemoradiotherapy-induced aplastic anemia: a single-center, retrospective study. Exp Hematol. 2023;117:62–8. Wang H, He G, Jia J, Liu M, Liu H, Wang T, et al. Efficacy and safety of avatrombopag in aplastic anemia patients with liver disease. J Transl Intern Med. 2023;11(1):90–3. Zhang Z, Hu Q, Yang C, Chen M, Han B. Comparison of eltrombopag and avatrombopag in the treatment of refractory/relapsed aplastic anemia: a single-center retrospective study in China. Ther Adv Hematol. 2023;14:20406207231191310. Liu X, Yang H, LI R. Avatrombopag for the treatment of SAA with abnormal hepatic and renal function: favorable efficacy and well tolerated. Chin J Pract Intern Med. 2021;(41):863–88. McQuilten Z, Heritier S, Fox L, Fox V, Young L, Blombery P, et al. Efficacy and safety of avatrombopag in combination with immunosuppressive therapy in treatment-naïve and relapsed/refractory severe aplastic anaemia: protocol for the DIAAMOND-Ava-FIRST and DIAAMOND-Ava-NEXT Bayesian Optimal Phase II trials. BMJ Open. 2024;14(1):e076246. Liu L, Zhao X, Miao M, Zhang Y, Jiao W, Lei M, et al. Inefficacy of Immunosuppressive Therapy for Severe Aplastic Anemia Progressing From Non-SAA: Improved Outcome After Allogeneic Hematopoietic Stem Cell Transplantation. Front Oncol. 2021;11:739561. Bacigalupo A, Oneto R, Schrezenmeier H, Hochsmann B, Dufour C, Kojima S, et al. First line treatment of aplastic anemia with thymoglobuline in Europe and Asia: Outcome of 955 patients treated 2001–2012. Am J Hematol. 2018;93(5):643–8. Giudice V, Selleri C. Aplastic anemia: Pathophysiology. Semin Hematol. 2022;59(1):13–20. Li R, Zhou J, Liu Z, Chen X, Long Q, Yang Y, et al. Predicting Response of Severe Aplastic Anemia to Rabbit-Antithymocyte Immunoglobulin Based Immunosuppressive Therapy Combined With Eltrombopag. Front Immunol. 2022;13:884312. Ghanima W, Cooper N, Rodeghiero F, Godeau B, Bussel JB. Thrombopoietin receptor agonists: ten years later. Haematologica. 2019;104(6):1112–23. Yang W, Zhao X, Liu X, Xiong Y, Fan H, Zhang L, et al. Hetrombopag plus porcine ATG and cyclosporine for the treatment of aplastic anaemia: early outcomes of a prospective pilot study. Exp Hematol Oncol. 2023;12(1):16. Rosenfeld S, Follmann D, Nunez O, Young NS. Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA. 2003;289(9):1130–5. Socié G, Rosenfeld S, Frickhofen N, Gluckman E, Tichelli A. Late clonal diseases of treated aplastic anemia. Semin Hematol. 2000;37(1):91–101. Kuter DJ. The structure, function, and clinical use of the thrombopoietin receptor agonist avatrombopag. Blood Rev. 2022;53:100909. Kuter DJ, Allen LF. Avatrombopag, an oral thrombopoietin receptor agonist: results of two double-blind, dose-rising, placebo-controlled Phase 1 studies. Br J Haematol. 2018;183(3):466–78. Terrault NA, Hassanein T, Howell CD, Joshi S, Lake J, Sher L, et al. Phase II study of avatrombopag in thrombocytopenic patients with cirrhosis undergoing an elective procedure. J Hepatol. 2014;61(6):1253–9. Bussel JB, Kuter DJ, Aledort LM, Kessler CM, Cuker A, Pendergrass KB, et al. A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia. Blood. 2014;123(25):3887–94. Nomoto M, Pastino G, Rege B, Aluri J, Ferry J, Han D, Pharmacokinetics. Pharmacodynamics, Pharmacogenomics, Safety, and Tolerability of Avatrombopag in Healthy Japanese and White Subjects. Clin Pharmacol Drug Dev. 2018;7(2):188–95. Tables Table 1 Baseline Characteristics of AVA+IST Group and IST Group Categories Group A: AVA+IST (n=42) Group B: IST only (n=84) Before PSM (n=537) ASD After PSM (n=84) ASD Demographic Gender, males, n (%) 24 (57.1) 296 (55.1) 0.041 46 (54.8) 0.048 Age (years) 31.50 [20.25, 54.75] 26.00 [16.00, 45.00] 0.343 33.00 [19.75, 52.25] 0.049 Disease severity, n (%) 0.161 0.048 SAA 22 (52.4) 324 (60.3) 42 (50.0) VSAA 20 (47.6) 213 (39.7) 42 (50.0) Laboratory values, median (IQR) WBC, ×10 9 /L 1.47 [0.86, 2.02] 1.51 [0.99, 2.09] 0.133 1.41 [0.64, 2.16] 0.017 ANC, ×10 9 /L 0.21 [0.09, 0.47] 0.29 [0.08, 0.46] 0.007 0.20 [0.04, 0.49] 0.037 Hb, g/L 61.50 [54.25, 71.25] 60.00 [53.00, 66.00] 0.242 63.00[54.50, 73.25] 0.003 PLT, ×10 9 /L 6.00 [3.25, 12.00] 9.00 [5.00, 12.00] 0.364 7.00[3.00, 10.00] 0.028 ARC, ×10 9 /L 11.20 [4.90, 24.80] 10.40 [4.30, 22.60] 0.085 9.25[3.40, 20.40] 0.042 LYM, ×10 9 /L 1.25 [0.88, 1.53] 1.18 [0.72, 1.80] 0.018 0.96 [0.38, 1.90] 0.022 PNH clone ≥1%, n (%) 8 (19.0) 107 (19.9) 0.022 15 (17.9) 0.031 Abbreviations: ALC, absolute lymphocyte count; ANC, absolute neutrophil count; ARC, absolute reticulocyte count; AVA, avatrombopag; ASD, average squared deviation; Hb, hemoglobin; Interval Dis-ATG, interval from disease onset to ATG treatment; IST, immunosuppressive therapy; IQR, interquartile range; LYM, lymphocyte; OR, odds ratio; PLT, platelet; PNH, paroxysmal nocturnal hemoglobinuria; PSM, propensity score matching; WBC, white blood cell. Table 2. Association between AVA therapy and hematological response at 3-month and 6-month Outcomes OR and 95% CI P value Complete response at 3-month, n (%) Group A: IST only Reference Group B: AVA+IST 4.70(1.39-18.62) 0.016 Overall response at 3-month, n (%) Group A: IST only Reference Group B: AVA+IST 1.87(0.89-3.99) 0.101 Complete response at 6-month, n (%) Group A: IST only Reference Group B: AVA+IST 2.69(1.10-6.67) 0.030 Overall response at 6-month, n (%) Group A: IST only Reference Group B: AVA+IST 2.38(1.09-5.42) 0.032 Abbreviations: AVA, avatrombopag; CI, confidence interval; IST, immunosuppressive therapy; OR, odds ratio. Table 3. Prognostic factors that may affect the six-month overall response in the AVA group Characteristics* Univariate analysis Multivariate analysis OR (95%CI) P value OR (95%CI) P value Gender Males 0.934(0.241-3.625) 0.921 0.866(0.860-27.748) 0.859 Females 1.000 Age at diagnose ≥40years 0.244(0.055-1.074) 0.062 0.753(0.149-3.760) 0.723 Disease severity VSAA 2.286(0.565-9.253) 0.247 SAA 1.000 Hb >60g/L 1.714(0.452-6.506) 0.428 ANC >0.5×109/L 0.571(0.101-3.224) 0.526 ALC >1×109/L 0.451(0.119-1.710) 0.552 PLT >10×109/L 2.694(0.676-10.739) 0.160 ARC >10×109/L 4.772(1.068-20.885) 0.041 3.424(0.672-25.902) 0.167 PNH clone size ≥1% 1.25(0.215-7.281) 0.804 Chromosomal abnormalities, n (%) 0.393(0.023-6.848) 0.522 Interval Dis-ATG >6 months 0.110(0.023-0.522) 0.005 0.074(0.009-0.391) 0.005 *All the values were baseline Abbreviations: ALC, absolute lymphocyte count; ANC, absolute neutrophil count; ARC, absolute reticulocyte count; AVA, avatrombopag; CI, confidence interval; Hb, hemoglobin; Interval Dis-ATG, interval from disease onset to ATG treatment; OR, odds ratio; PLT, platelet; PNH, paroxysmal nocturnal hemoglobinuria; SAA, severe aplastic anemia; VSAA, very severe aplastic anemia. Additional Declarations No competing interests reported. Supplementary Files SupplementalMaterials.docx Cite Share Download PDF Status: Under Review Version 1 posted Editor assigned by journal 18 Aug, 2024 Submission checks completed at journal 17 Aug, 2024 First submitted to journal 16 Aug, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4927350","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":341695101,"identity":"9dcea7e5-2152-4b30-890b-50aa4e6429ce","order_by":0,"name":"Jianping Li","email":"","orcid":"","institution":"National Clinical Research Center for Blood Diseases, State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology \u0026 Blood Diseases 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Hospital","correspondingAuthor":true,"prefix":"","firstName":"Xin","middleName":"","lastName":"Zhao","suffix":""}],"badges":[],"createdAt":"2024-08-17 01:14:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4927350/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4927350/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":66549740,"identity":"b00a19de-56df-4324-8569-ef2bfd91d98e","added_by":"auto","created_at":"2024-10-14 08:54:58","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":266597,"visible":true,"origin":"","legend":"\u003cp\u003eLove plot for covariates between pre- and post-matching cohorts.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4927350/v1/81c0627c9141a4a559d26489.jpg"},{"id":66548639,"identity":"8f464756-08f8-4074-a193-4d39393029f2","added_by":"auto","created_at":"2024-10-14 08:46:58","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":616180,"visible":true,"origin":"","legend":"\u003cp\u003eA\u0026amp;B, hematological response rates by 3 months and 6 months in different groups divided by disease severity (fig. 2A), interval Dis-ATG(fig. 2B). Fig. 2C, hematological response rates by 3 months and 6 months in different groups divided by acute reticulocyte count in patients with a short interval Dis-ATG (≤6 months).\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4927350/v1/45f07750b76181717094b806.jpg"},{"id":66548641,"identity":"d9fecf95-d4e8-4e24-b6aa-4672dbd39bae","added_by":"auto","created_at":"2024-10-14 08:46:58","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":863033,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation between AVA therapy and Long-term Overall Survival and Event-free Survival.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4927350/v1/dc0ee07961c79bb2274b8b5b.jpg"},{"id":66550524,"identity":"17bc30ba-7cc4-4a30-ad81-dbe2bd94ced6","added_by":"auto","created_at":"2024-10-14 09:02:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2396443,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4927350/v1/e2f906d1-48db-41bb-96a1-6c00e5fe3458.pdf"},{"id":66548638,"identity":"38a45507-a85d-40bb-9942-9e76f238d998","added_by":"auto","created_at":"2024-10-14 08:46:58","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":30113,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalMaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-4927350/v1/9938c89f943364de840b6fa5.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and Safety of Avatrombopag in Combination with Standard Immunosuppressive Therapy for Severe Aplastic Anemia","fulltext":[{"header":"Key Points","content":"\u003cp\u003e1. Avatrombopag added to standard immunosuppressive therapy was safe and effective in the first-line treatment for severe aplastic anemia, even in patients with hepatic impairment.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e2. Patients with a short interval from disease onset to ATG treatment (\u0026le;6 months) has a higher hematologic response rate to immunosuppressive therapy.\u0026nbsp;\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eAcquired aplastic anemia (AA) is immune-mediated bone marrow failure disease characterized by pancytopenia and hypoplastic bone marrow(\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Severe AA (SAA) is life-threatening due to infection and bleeding. Immunosuppressive therapy (IST) based on antithymocyte globulin (ATG) and cyclosporine (CSA) is effective for SAA, but only 50\u0026ndash;70% of patients achieve hematologic response(\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Eltrombopag, an oral thrombopoietin receptor agonist (TPO-RA), has shown promising results in improving the quality and rapidity of hematologic responses in SAA patients(\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). In the first-line treatment, eltrombopag demonstrated an overall response (OR) rate of 59\u0026ndash;80%, with a complete response (CR) rate of 22\u0026ndash;30% at 6 months, without increasing clonal evolution during long-term follow-up. Currently, eltrombopag combined with IST is recommended as the first-line treatment for SAA patients who are not suitable candidates for transplantation. However, hepatotoxicity had been recorded in 12\u0026ndash;18% of patients receiving eltrombopag, and most individuals taking doses higher than 150 mg/day experienced slate-grey pigmentation(\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). Therefore, there is a need for a TPO-RA that offers comparable effectiveness while minimizing toxicity when treating SAA.\u003c/p\u003e \u003cp\u003eAvatrombopag (AVA), another oral TPO-RA with a distinct molecular structure, has been approved for the treatment of thrombocytopenia(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). AVA is a suitable option for patients with liver injury due to its non-hepatotoxic nature(\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Recent studies have demonstrated the efficacy of AVA in various conditions, including newly diagnosed and persistent immune thrombocytopenia (ITP), chronic primary ITP, and thrombocytopenia post hematopoietic stem-cell transplantation(\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In non-severe AA patients who were refractory, relapsed, or intolerant to immunosuppressants and eltrombopag, 56% responded to AVA within 3 months(\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). AVA also exhibited safety and efficacy in SAA patients with hepatic dysfunction in a small Chinese case series(\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Therefore, we can expect that AVA may have good efficacy in treating SAA patients.\u003c/p\u003e \u003cp\u003eCurrently, there is few data of AVA and IST as first-line treatment for SAA. So we conducted a single-center, retrospective study to investigate the efficacy and safety of adding AVA to standard IST as first-line treatment for SAA and reported the results here.\u003c/p\u003e"},{"header":"2. Patients and Methods","content":"\u003cp\u003eThis is a retrospective study on the clinical outcomes of a cohort of ATG-na\u0026iuml;ve SAA patients who received IST and AVA treatment. A historical cohort of patients who received ATG and CSA as first-line treatment was matched as control. The primary endpoint was to assess the benefit of adding AVA to IST as first-line therapy. This study was approved by the Ethical Committee of the Institute of Hematology and Blood Diseases Hospital. Informed consent was obtained from patients and/or their legal guardians in accordance with the Declaration of Helsinki. The study was part of registered NICHE cohort at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ewww.clincialtrials.gov\u003c/span\u003e\u003cspan address=\"http://www.clincialtrials.gov\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e as # NCT04645199.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Patients\u003c/h2\u003e \u003cp\u003eThe diagnosis of AA was made according to the criteria set by the International Granulocytosis and Aplastic Anemia Study Group(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). SAA was defined as bone marrow hypoplasia (\u0026lt;\u0026thinsp;30%) in the absence of an abnormal infiltrate or marrow fibrosis on bone marrow biopsy, and meeting two out of three following criteria: absolute neutrophile count (ANC)\u0026thinsp;\u0026lt;\u0026thinsp;0.5\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, platelet count (PLT)\u0026thinsp;\u0026lt;\u0026thinsp;20\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L and absolute reticulocyte count (ARC)\u0026thinsp;\u0026lt;\u0026thinsp;20\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L. SAA with ANC\u0026thinsp;\u0026lt;\u0026thinsp;0.2\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L was classified as very severe AA (VSAA)(\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). Paroxysmal nocturnal hemoglobinuria (PNH) cells were detected using flowcytometry. Patients with inherited bone marrow failure syndromes (IBMFS), hemolytic PNH, and myelodysplastic syndromes (MDS) did not receive IST treatment and were excluded through case histories, clinical manifestations, bone marrow examination, cytogenetics, mitomycin C test and blood tests.\u003c/p\u003e \u003cp\u003eFrom April 2021 to April 2022, a total of 42 SAA patients received ATG, CSA and AVA as first-line treatment (Group A, AVA\u0026thinsp;+\u0026thinsp;IST group) at the Anemia Therapeutic Center, Institute of Hematology \u0026amp; Blood Diseases Hospital, Chinese Academy of Medical Sciences. To minimize potential confounders and selection bias, we performed a Propensity score matching (PSM) analysis to match patients from Group A with those who received ATG and CSA only from a historical cohort. From January 2015 through December 2019, 84 SAA patients (Group B, IST) were matched from a total of 537 consecutive SAA patients who were treated with standard IST.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Treatment\u003c/h2\u003e \u003cp\u003eAVA was orally administered at the dose of 40 mg (20mg for children\u0026thinsp;\u0026le;\u0026thinsp;12 years) daily within 14 days of ATG treatment and continued for at least 3 months.\u003c/p\u003e \u003cp\u003ePorcine ATG (Yujin Bio-Pharma Wuhan CNBG Co., LTD.) was given at a dose of 20 mg/kg/day for five consecutive days. CSA was given at 3\u0026ndash;5 mg/kg/day in divided dose from the first day of ATG administration, and the blood trough concentration was maintained between 150 and 250 ng/mL. CSA was used for at least 6 months, and gradually tapered after achieving best hematologic response.\u003c/p\u003e \u003cp\u003eGranulocyte stimulating factor (G-CSF, 5mg/kg/day) was administered when ANC\u0026thinsp;\u0026lt;\u0026thinsp;0.5\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L. Hemoglobin levels were maintained above 60 g/L, and platelets were kept above 10\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L. Prophylactic antimicrobials were not routinely administered.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Hematological response criteria and outcome variables\u003c/h2\u003e \u003cp\u003eComplete response (CR) was defined as haemoglobin\u0026thinsp;\u0026gt;\u0026thinsp;100 g/L, ANC\u0026thinsp;\u0026gt;\u0026thinsp;1.5\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, and platelet count\u0026thinsp;\u0026gt;\u0026thinsp;100\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L. Partial response (PR) was defined as achieving transfusion independence but not meet criteria for CR. Overall response (OR) was the sum of CR and PR. No response (NR) was defined as not meeting the criteria for PR. Death or loss of follow-up within 6 months after ATG treatment were classified as NR. The haematological response was assessed at 3 and 6 months from the first day of ATG treatment.\u003c/p\u003e \u003cp\u003eRelapse was defined as a substantial decrease in blood counts requiring transfusions or further intensive immunotherapy in responders. Overall survival (OS) was measured from the first day of ATG until death from any cause or the date of last follow-up. Event-free survival (EFS) was measured from the first day of ATG until any event (NR, HSCT, death, relapse, repeat IST or any additional AA treatment, transformation to PNH and malignant clonal evolution) or the date of last follow-up.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Statistical analysis\u003c/h2\u003e \u003cp\u003eContinuous variables were presented as medians and interquartile ranges (25th-75th). Categorical variables were expressed as frequencies and percentages. The Mann\u0026ndash;Whitney U test, chi-square test and Fisher\u0026rsquo;s exact test were used to test for differences between groups for continuous and categorical variables, respectively.\u003c/p\u003e \u003cp\u003eIn this study, we implemented the 1:2 nearest neighbour PSM without replacement to match cases, and the logit of the propensity score was a caliper width of 0.2 of the standard deviation. Absolute standardized differences were used to compare covariates between pre- and post-matching cohorts, and absolute standardized difference less than 10% were considered optimally matched.\u003c/p\u003e \u003cp\u003eLong-term endpoints were illustrated by Kaplan-Meier survival curves (OS, EFS) or cumulative incidence curves, with the Gehan-Breslow-Wilcoxon and log-rank tests for arms\u0026rsquo; comparison respectively. Factors related to the 6-month haematological response were examined through binary Logistic regression. R version 4.3.1 and RStudio Version 1.4.1717 were used for statistical analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cstrong\u003e3.1\u0026nbsp;Baseline characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 42 SAA patients received ATG, CSA and AVA as first-line treatment (Group A).\u0026nbsp;There were 20 VSAA and 22 SAA patients, with a median age of 31.5 (20.25, 54.75) years old. The median ANC was 0.21\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L,\u0026nbsp;ARC was 11.2\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, and PLT was 6\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L.\u0026nbsp;Three (7.9%) patients had chromosomal abnormalities including two -Y and one trisomy 8. Eight patients (19.0%) carried PNH clones (clone size\u0026ge;1%) without evidence of hemolysis. Eleven (26.19%) patients had a long interval between disease onset and the initiation of ATG (interval Dis-ATG＞6 months). There were 13 patients had substantial liver disease, including 5 (11.9%) patients with hepatitis-associated AA (HAAA), 2 (4.8%) patients with chronic/active hepatitis B, and 6 (14.3%) patients with drug-related liver injury before IST. Four patients had grade 1-2 bilirubin elevation, and two had grade 3 transaminase elevation and bilirubin elevation according to Common Toxicity Criteria for Adverse Events (ver. 5). The details were shown in Table S1.\u003c/p\u003e\n\u003cp\u003eData from 537 patients who received standard IST were used to match patients in Group A. Compared to Group A, those patients were more likely to have a younger age, and lower proportion of VSAA patients. To avoid bias, 84 patients (Group B) were finally identified using PSM analysis. Covariates were well balanced between Group A and Group B (Table 1 and Figure 1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.2\u0026nbsp;Hematologic responses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients in Group A have better haematological responses compared to patients in Group B (Table S2). The OR rate was 54.8% at 3 months and 71.4% at 6 months in Group A compared to that of 39.3% at 3 months (\u003cem\u003eP\u003c/em\u003e=0.145) and 51.2% at 6 months in Group B (\u003cem\u003eP\u003c/em\u003e=0.048). The CR rates in Group A were also higher than in Group B at 3 months (19.0% vs 4.8%, \u003cem\u003eP\u003c/em\u003e = 0.024) and 6 months (31.0% vs 14.3%, \u003cem\u003eP\u003c/em\u003e=0.048). At 12 months, the CR rate increased to 42.9% in Group A and 27.7% in Group B. Using the logistic regression analysis, AVA was associated with increased CR rate at 3 and 6 months, and increased OR rate at 6 months (Table 2).\u003c/p\u003e\n\u003cp\u003eWe further analysed the response rates according to disease severity (SAA and VSAA).\u0026nbsp;At 3 months, SAA patients in group A had a CR rate of 18.2% and an OR rate of 54.5%, while VSAA patients had a CR rate of\u0026nbsp;20.0% (\u003cem\u003eP\u003c/em\u003e=1.000) and an OR rate of 55.0% (\u003cem\u003eP\u003c/em\u003e=1.000), respectively. At 6 months, the CR rate was 27.3% in SAAs and 35.0% in VSAAs (\u003cem\u003eP\u003c/em\u003e=0.836), and the OR rate was 63.6% and 80.0%, respectively (\u003cem\u003eP\u003c/em\u003e=0.406) (Figure 2A).\u0026nbsp;The VSAA patients showed better CR (\u003cem\u003eP\u003c/em\u003e=0.006) and OR (\u003cem\u003eP\u003c/em\u003e=0.005) rate at 6 months in Group A compared to Group B (Table S3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe also analysed subgroups, according to age and PNH clone sizes. The AVA group showed increased 3 months CR rate in patients with PNH clone than those without PNH clone (\u003cem\u003eP\u003c/em\u003e=0.025). In the subgroup of age \u0026lt;40 years, patients in the AVA group had a better CR rate at 6 months than the IST group (\u003cem\u003eP\u003c/em\u003e=0.029) (Table S3). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.1\u0026nbsp;Hematologic response related factors of Avatrombopag\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultivariate regression analysis was used to explore the factors related to hematologic response of avatrombopag. We found that the interval between disease onset and the initiation of ATG (interval Dis-ATG) was the only factor significantly related to hematologic response at 6 months (\u003cem\u003eP\u003c/em\u003e=0.005). We further analyzed the response rate at 3 and 6 months according to the interval Dis-ATG. Patients with the interval Dis-ATG \u0026gt;6 months had a much lower OR rate at 3 months (36.4% vs. 61.3%, P=0.283) and 6 months (36.4% vs. 83.9%, \u003cem\u003eP\u003c/em\u003e=0.009). The CR rates were also lower in the group with long interval Dis-ATG at 6 months (9.1% vs. 38.7%, \u003cem\u003eP\u003c/em\u003e=0.148) (Figure 2B).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFurthermore, we analysed data from 31 patients with a short interval Dis-ATG (\u0026le;6 months), including 16 SAA and 15 VSAA patients. We found that a reticulocyte count\u0026nbsp;\u0026ge;10\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L\u0026nbsp;showed better CR and OR rate than those with lower reticulocyte count\u0026nbsp;both\u0026nbsp;at 3 month (CR: 6.2% vs. 40.0%, \u003cem\u003eP\u003c/em\u003e=0.069; OR: 37.5% vs. 86.7%, \u003cem\u003eP\u003c/em\u003e=0.029) and at 6 month (CR: 18.8% vs. 60.0%, \u003cem\u003eP\u003c/em\u003e=0.047; OR: 68.8% vs. 100.0%, \u003cem\u003eP\u003c/em\u003e=0.061). (Figure 3C).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.4 Safety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe AVA treatment was well-tolerated, and no patient discontinued due to side effects.\u0026nbsp;There was no exacerbation of the primary liver function abnormality. In patients with pre-existing abnormal liver function, liver parameters returned to normal during IST treatment and maintained normal.\u0026nbsp;The HBV viral load stayed below 1000 copies per millilitre in the 2 patients with chronic hepatitis B. Thrombotic complications and gastrointestinal adverse reactions were not observed. One patient experienced a headache when taking 40mg AVA, which resolved upon reducing the dosage to 20mg/day. After one week, the dosage was increased to 40 mg/day without recurrence of headaches.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e3.5\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePatients were followed up for 14 (12.2-25.7) months in Group A, and 20 (12.2-25.9) months in Group B. By the end of follow-up, the OR rate was 76.2% and the CR rate was 50.0% in Group A. The median duration of AVA intake was 12 (9-12) months.\u0026nbsp;One patient died within 3 months. Eight patients who did not achieve hematologic response at 6 months discontinued taking AVA. One patient accepted hematopoietic stem cell transplantation (HSCT) and maintained CR. Another patient discontinued AVA treatment after achieving PR at 3 months but later experienced a relapse. Responders who tapered AVA after 3 months of ATG treatment did not experience relapse. Fifteen patients who achieved CR or stable PR had ceased AVA by the last follow-up.\u003c/p\u003e\n\u003cp\u003eClonal evolution was not observed in this study, including haemolytic PNH, myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML).\u0026nbsp;Prior to treatment, 8 patients had PNH clones,\u0026nbsp;and 6 of them achieved a hematologic response. Among the responders, the size of PNH clone decreased in 2 patients and disappeared in 3 patients.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe OS was similar between Group A and Group B (2-year OS, 97.6% vs. 92.8%, \u003cem\u003eP\u003c/em\u003e=0.270) (Figure 3A). The event-free survival (EFS) rate was higher in the AVA group compared to the IST group, although the difference was insignificant (2-year EFS 60.7% vs. 49.6%, \u003cem\u003eP\u003c/em\u003e=0.108) (Figure 3B).\u0026nbsp;\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eEltrombopag has shown good therapeutic effect in AA. But there is limited data on the clinical use of AVA, a second-generation TPO-RA, for newly diagnosed AA(\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). A phase II trial of AVA in combination with immunosuppressive therapy in treatment-na\u0026iuml;ve and relapsed/refractory SAA are underway(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). Here we conducted a retrospective analysis of the clinical outcomes of 42 SAA patients who received AVA, ATG and CSA as first-line treatment and compared to 84 patients treated by IST alone by PSM. It is currently the largest cohort of study on the use of AVA in SAA. This study showed that AVA was active and well-tolerated as first-line treatment for SAA. Higher hematological response rate and response quality were found both at 3 and 6 months than patients who received standard IST alone. These results are similar to that reported in first-line treatment using eltrombopag and IST.\u003c/p\u003e \u003cp\u003eIn this cohort, SAA patients received AVA of 40mg/d within 14 days of ATG treatment and continued for at least 3 months. We found a sharp increase in the complete response rate at 3, 6 and 12 months in the AVA group compared with the IST group (4.8%\u0026rarr;19.0% at 3 months; 14.3%\u0026rarr;31.0% at 6 months; 27.7%\u0026rarr;42.9% at 12 months). The OR and CR rate at 6 months in patients received AVA and IST was similar with the results of eltrombopag in the RACE study (CR rate, 31.0% vs. 32%; PR rate, 40.4% vs. 37%)(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). There results indicated that similar to eltrombopag, the addition of AVA could improve the quality of hematological responses, decrease transfusion burden and infectious risks of patients after IST therapy. Since the current study was a retrospective study, patients were routinely visited every three months after ATG, and blood test results were not provided at other time points, it was difficult to compare the median response time with or without AVA. But based on the higher OR rates at 3 and 6 months in the AVA group, we considered that the application of AVA can narrow the time to response. This earlier hematologic recovery also may translate into fewer patients having to switch to early HSCT.\u003c/p\u003e \u003cp\u003ePrevious study both from Bacigalupo A and our center showed that longer interval between AA diagnosis and ATG treatment was a negative predictor for response at 6 months(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). Recent years in our center, most patients diagnosed with SAA were given ATG treatment within 2\u0026ndash;4 weeks. Simply calculating the time from diagnosis to treatment would not be appropriate to show the real medical history. The regression analysis in this study identified the longer interval between disease onset (cytopenia) and ATG treatment (Interval Dis-ATG) as predictors of worse hematological response in SAA by 6 months. Only 4 out of 11 V/SAA patients with a long interval Dis-ATG (\u0026gt;\u0026thinsp;6 months) achieved hematologic response at 6 months. Although disease progression may be slow in these patients, the prolonged autoimmune attack may impair residual hematopoiesis and the bone marrow microenvironment, leading to poor ORR and OS(\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). Patients with shorter interval Dis-ATG, higher reticulocyte count (\u0026ge;\u0026thinsp;10\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L) achieved higher hematological response, consistent with previous findings of IST combined with eltrombopag (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Thus, there was less chance to achieve hematological response after the treatment of TPO-RA and IST for patients with longer interval Dis-ATG and lower reticulocyte count, and HSCT treatment should be recommended as a priority.\u003c/p\u003e \u003cp\u003eThe risk of clonal evolution is also concerned for the application of TPO-RAs because of their stem-cell stimulatory properties(\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). It has been reported that the combination of TPO-RAs to IST does not increase high-risk evolution and hemolytic PNH conversion rate in SAA patients(\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). In our cohort, bone marrow and chromosome were routinely reexamined at 3, 6 and 12 months after treatment, and no patients were found at high risk of progression. Eight patients with PNH clones showed stable disease, and no clonal enlargement or hemolysis observed. There results indicated that AVA may not increase the risk of clonal progression in SAA patients in the short period. However, longer follow-up time and regular genetic examinations are required to further evaluate the risk of myeloid malignant transformation, which usually appears in 10\u0026ndash;15% of patients 5\u0026ndash;10 years after diagnosis(\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs for long-term survival and relapse, the addition of AVA to IST did not result in evidently improved OS in SAA patients. Consistent to the improved response rate at 6 months, the EFS rate was improved (2-year EFS%: 49.6%\u0026rarr;67.5%) in the AVA group although there was no statistical significance. These findings are consistent with the RACE study, in which the addition of eltrombopag increased EFS from 34\u0026ndash;46% at 2 years(\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). However, the reintroduction of eltrombopag was common in RACE. While in our cohort, most patients treated with AVA have tapped and stopped taking the drugs without disease relapse. Only one patient with immediate discontinuation experienced a relapse.\u003c/p\u003e \u003cp\u003eThe metabolism of AVA is mainly carried out by two liver enzymes, CYP3A and CYP2C which do not increase bilirubin levels(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). The drug does not have metal ion chelation and taking it with food may result in better absorption(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e). No drug-related liver function abnormalities were found in the phase I-III clinical study of AVA\u003c/p\u003e \u003cp\u003e(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Age, weight, gender, ethnicity, any grade of liver impairment, and mild to moderate renal impairment have no significant effect on the pharmacokinetics of avatrombopag(\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). In our study, all patients tolerated avatrombopag well, and no adverse events associated with liver function was reported. Only one patient reported headache which was relived after dose tapering. Compared to more commonly reported adverse liver events associated with eltrombopag treatment, adding AVA to IST may provide better safety for treating SAA, especially those who initially experienced liver damage.\u003c/p\u003e \u003cp\u003eIn summary, the combination of avatrombopag and IST is safe and effective as first-line treatment for SAA patients, even in patients with initial liver damage. Patients with a long interval Dis-ATG (\u0026gt;\u0026thinsp;6 months) and lower reticulocyte count (\u0026lt;\u0026thinsp;10\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L ) has a poor response to IST, so HSCT should be considered as soon as possible.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding information:\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003eThis study was supported by Grant 2023NCRCA0119 of Clinical Research Funding of National Clinical Research Center for Blood Diseases; Grant 2022-PUMCH-C-026 of National High Level Hospital Clinical Research Funding; Grant 2022YFA1103300 of National Key R\u0026amp;D Program of China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u0026nbsp;\u003c/strong\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest disclosure:\u003c/strong\u003e The authors have no competing financial interests to declare.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval statement and consent to participate:\u0026nbsp;\u003c/strong\u003eThe study was approved by the Ethics Committee and Institutional Review Board of Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences \u0026amp; Peking Union Medical College, and conducted in concordance with the Declaration of Helsinki. All legal guardians of pediatric patients signed written informed consent before participation in the trial. All procedures performed in the study were in accordance with the ethical standards of this research committee.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJianping Li and Weiru Liang collected and analyzed data, draft the manuscript; Yuan Li, Wenrui Yang, Xiangrong Hu, Baohang Zhang, Huihui Fan, Liping Jing, Li Zhang, Kang Zhou, Lei Ye, Yang Yang, Youzhen Xiong treated patients and collected the clinical data; Weiping Yuan and Jun Shi reviewed and edited the manuscript; Fengkui Zhang and Xin Zhao were involved in the study design, data analysis and manuscript writing. All authors reviewed the data analyses, contributed to data interpretation and approved the final version of the submitted report.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYoung NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108(8):2509\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOlnes MJ, Scheinberg P, Calvo KR, Desmond R, Tang Y, Dumitriu B, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367(1):11\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTownsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017;376(16):1540\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDe Peffault R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, et al. Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. N Engl J Med. 2022;386(1):11\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZaimoku Y, Patel BA, Shalhoub R, Groarke EM, Feng X, Wu CO, et al. Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag. Haematologica. 2021;107(1):126\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatel BA, Groarke EM, Lotter J, Shalhoub R, Gutierrez-Rodrigues F, Rios O, et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood. 2022;139(1):34\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGill H, Wong RSM, Kwong YL. From chronic immune thrombocytopenia to severe aplastic anemia: recent insights into the evolution of eltrombopag. Ther Adv Hematol. 2017;8(5):159\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShirley M. Avatrombopag: First Global Approval. Drugs. 2018;78(11):1163\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTerrault N, Chen YC, Izumi N, Kayali Z, Mitrut P, Tak WY, et al. Avatrombopag Before Procedures Reduces Need for Platelet Transfusion in Patients With Chronic Liver Disease and Thrombocytopenia. Gastroenterology. 2018;155(3):705\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJurczak W, Chojnowski K, Mayer J, Krawczyk K, Jamieson BD, Tian W, et al. Phase 3 randomised study of avatrombopag, a novel thrombopoietin receptor agonist for the treatment of chronic immune thrombocytopenia. Br J Haematol. 2018;183(3):479\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou M, Qi J, Gu C, Wang H, Zhang Z, Wu D, et al. Avatrombopag for the treatment of thrombocytopenia post hematopoietic stem-cell transplantation. Ther Adv Hematol. 2022;13:20406207221127532.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMei H, Zhou H, Hou M, Sun J, Zhang L, Luo J, et al. Avatrombopag for adult chronic primary immune thrombocytopenia: a randomized phase 3 trial in China. Res Pract Thromb Haemost. 2023;7(6):102158.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVirk ZM, Leaf RK, Kuter DJ, Goodarzi K, Connell NT, Connors JM, et al. Avatrombopag for adults with early versus chronic immune thrombocytopenia. Am J Hematol. 2024;99(2):155\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWan Z, Chen M, Han B. Avatrombopag, a promising novel thrombopoietin receptor agonist for refractory/relapsed/intolerant non-severe aplastic anemia: a phase 2 single-arm clinical trial. Ann Med. 2023;55(1):2224044.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi JP, Yang WR, Li Y, Xiong YZ, Ye L, Fan HH, et al. [Avatrombopag combined with standard immunosuppressive therapy in the treatment of severe aplastic anemia with hepatic impairment in six patients]. Zhonghua Xue Ye Xue Za Zhi Zhonghua Xueyexue Zazhi. 2022;43(11):952\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCamitta BM, Thomas ED, Nathan DG, Santos G, Gordon-Smith EC, Gale RP, et al. Severe Aplastic Anemia: A Prospective Study of the Effect of Early Marrow Transplantation on Acute Mortality. Blood. 1976;48(1):63\u0026ndash;70.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBacigalupo A, Hows J, Gluckman E, Nissen C, Marsh J, Van Lint MT, et al. Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA): a report of the EBMT SAA working party. Br J Haematol. 1988;70(2):177\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChi Y, Hu Q, Yang C, Chen M, Han B. Avatrombopag is effective in patients with chemoradiotherapy-induced aplastic anemia: a single-center, retrospective study. Exp Hematol. 2023;117:62\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang H, He G, Jia J, Liu M, Liu H, Wang T, et al. Efficacy and safety of avatrombopag in aplastic anemia patients with liver disease. J Transl Intern Med. 2023;11(1):90\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang Z, Hu Q, Yang C, Chen M, Han B. Comparison of eltrombopag and avatrombopag in the treatment of refractory/relapsed aplastic anemia: a single-center retrospective study in China. Ther Adv Hematol. 2023;14:20406207231191310.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu X, Yang H, LI R. Avatrombopag for the treatment of SAA with abnormal hepatic and renal function: favorable efficacy and well tolerated. Chin J Pract Intern Med. 2021;(41):863\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcQuilten Z, Heritier S, Fox L, Fox V, Young L, Blombery P, et al. Efficacy and safety of avatrombopag in combination with immunosuppressive therapy in treatment-na\u0026iuml;ve and relapsed/refractory severe aplastic anaemia: protocol for the DIAAMOND-Ava-FIRST and DIAAMOND-Ava-NEXT Bayesian Optimal Phase II trials. BMJ Open. 2024;14(1):e076246.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu L, Zhao X, Miao M, Zhang Y, Jiao W, Lei M, et al. Inefficacy of Immunosuppressive Therapy for Severe Aplastic Anemia Progressing From Non-SAA: Improved Outcome After Allogeneic Hematopoietic Stem Cell Transplantation. Front Oncol. 2021;11:739561.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBacigalupo A, Oneto R, Schrezenmeier H, Hochsmann B, Dufour C, Kojima S, et al. First line treatment of aplastic anemia with thymoglobuline in Europe and Asia: Outcome of 955 patients treated 2001\u0026ndash;2012. Am J Hematol. 2018;93(5):643\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGiudice V, Selleri C. Aplastic anemia: Pathophysiology. Semin Hematol. 2022;59(1):13\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi R, Zhou J, Liu Z, Chen X, Long Q, Yang Y, et al. Predicting Response of Severe Aplastic Anemia to Rabbit-Antithymocyte Immunoglobulin Based Immunosuppressive Therapy Combined With Eltrombopag. Front Immunol. 2022;13:884312.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhanima W, Cooper N, Rodeghiero F, Godeau B, Bussel JB. Thrombopoietin receptor agonists: ten years later. Haematologica. 2019;104(6):1112\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang W, Zhao X, Liu X, Xiong Y, Fan H, Zhang L, et al. Hetrombopag plus porcine ATG and cyclosporine for the treatment of aplastic anaemia: early outcomes of a prospective pilot study. Exp Hematol Oncol. 2023;12(1):16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosenfeld S, Follmann D, Nunez O, Young NS. Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA. 2003;289(9):1130\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoci\u0026eacute; G, Rosenfeld S, Frickhofen N, Gluckman E, Tichelli A. Late clonal diseases of treated aplastic anemia. Semin Hematol. 2000;37(1):91\u0026ndash;101.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuter DJ. The structure, function, and clinical use of the thrombopoietin receptor agonist avatrombopag. Blood Rev. 2022;53:100909.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKuter DJ, Allen LF. Avatrombopag, an oral thrombopoietin receptor agonist: results of two double-blind, dose-rising, placebo-controlled Phase 1 studies. Br J Haematol. 2018;183(3):466\u0026ndash;78.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTerrault NA, Hassanein T, Howell CD, Joshi S, Lake J, Sher L, et al. Phase II study of avatrombopag in thrombocytopenic patients with cirrhosis undergoing an elective procedure. J Hepatol. 2014;61(6):1253\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBussel JB, Kuter DJ, Aledort LM, Kessler CM, Cuker A, Pendergrass KB, et al. A randomized trial of avatrombopag, an investigational thrombopoietin-receptor agonist, in persistent and chronic immune thrombocytopenia. Blood. 2014;123(25):3887\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNomoto M, Pastino G, Rege B, Aluri J, Ferry J, Han D, Pharmacokinetics. Pharmacodynamics, Pharmacogenomics, Safety, and Tolerability of Avatrombopag in Healthy Japanese and White Subjects. Clin Pharmacol Drug Dev. 2018;7(2):188\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1 Baseline Characteristics of AVA+IST Group and IST Group\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 44.058%;\"\u003e\n \u003cp\u003eCategories\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width: 15.2043%;\"\u003e\n \u003cp\u003eGroup A: AVA+IST\u003c/p\u003e\n \u003cp\u003e(n=42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 34.2097%;\"\u003e\n \u003cp\u003eGroup B: IST only\u003c/p\u003e\n \u003cp\u003e(n=84)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\n \u003cp\u003eBefore PSM\u003c/p\u003e\n \u003cp\u003e(n=537)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\n \u003cp\u003eASD\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.1634%;\"\u003e\n \u003cp\u003eAfter PSM\u003c/p\u003e\n \u003cp\u003e(n=84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1948%;\"\u003e\n \u003cp\u003eASD\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44.058%;\"\u003e\n \u003cp\u003eDemographic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12.1634%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.1948%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44.058%;\"\u003e\n \u003cp\u003eGender, males, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\n \u003cp\u003e24 (57.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\n \u003cp\u003e296 (55.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\n \u003cp\u003e0.041\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.1634%;\"\u003e\n \u003cp\u003e46 (54.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1948%;\"\u003e\n \u003cp\u003e0.048\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44.058%;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\n \u003cp\u003e31.50 [20.25, 54.75]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\n \u003cp\u003e26.00 [16.00, 45.00]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\n \u003cp\u003e0.343\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.1634%;\"\u003e\n \u003cp\u003e33.00 [19.75, 52.25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1948%;\"\u003e\n \u003cp\u003e0.049\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44.058%;\"\u003e\n \u003cp\u003eDisease severity, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\n \u003cp\u003e0.161\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.1634%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1948%;\"\u003e\n \u003cp\u003e0.048\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44.058%;\"\u003e\n \u003cp\u003eSAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\n \u003cp\u003e22 (52.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\n \u003cp\u003e324 (60.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 12.1634%;\"\u003e\n \u003cp\u003e42 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.1948%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 44.058%;\"\u003e\n \u003cp\u003e\u0026nbsp; VSAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\n \u003cp\u003e20 (47.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\n \u003cp\u003e213 (39.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 12.1634%;\"\u003e\n \u003cp\u003e42 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 5.1948%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 35.8568%;\"\u003e\n \u003cp\u003eLaboratory values, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 34.2097%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8841%;\"\u003e\n \u003cp\u003eWBC, \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\n \u003cp\u003e1.47 [0.86, 2.02]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\n \u003cp\u003e1.51 [0.99, 2.09]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\n \u003cp\u003e0.133\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.1634%;\"\u003e\n \u003cp\u003e1.41 [0.64, 2.16]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1948%;\"\u003e\n \u003cp\u003e0.017\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8841%;\"\u003e\n \u003cp\u003eANC, \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\n \u003cp\u003e0.21 [0.09, 0.47]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\n \u003cp\u003e0.29 [0.08, 0.46]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.1634%;\"\u003e\n \u003cp\u003e0.20 [0.04, 0.49]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1948%;\"\u003e\n \u003cp\u003e0.037\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8841%;\"\u003e\n \u003cp\u003eHb, g/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\n \u003cp\u003e61.50 [54.25, 71.25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\n \u003cp\u003e60.00 [53.00, 66.00]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\n \u003cp\u003e0.242\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.1634%;\"\u003e\n \u003cp\u003e63.00[54.50, 73.25]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1948%;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8841%;\"\u003e\n \u003cp\u003ePLT, \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\n \u003cp\u003e6.00 [3.25, 12.00]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\n \u003cp\u003e9.00 [5.00, 12.00]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\n \u003cp\u003e0.364\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.1634%;\"\u003e\n \u003cp\u003e7.00[3.00, 10.00]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1948%;\"\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8841%;\"\u003e\n \u003cp\u003eARC, \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\n \u003cp\u003e11.20 [4.90, 24.80]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\n \u003cp\u003e10.40 [4.30, 22.60]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\n \u003cp\u003e0.085\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.1634%;\"\u003e\n \u003cp\u003e9.25[3.40, 20.40]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1948%;\"\u003e\n \u003cp\u003e0.042\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8841%;\"\u003e\n \u003cp\u003eLYM, \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\n \u003cp\u003e1.25 [0.88, 1.53]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\n \u003cp\u003e1.18 [0.72, 1.80]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\n \u003cp\u003e0.018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.1634%;\"\u003e\n \u003cp\u003e0.96 [0.38, 1.90]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1948%;\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 37.8841%;\"\u003e\n \u003cp\u003ePNH clone \u0026ge;1%, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 15.2043%;\"\u003e\n \u003cp\u003e8 (19.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.7833%;\"\u003e\n \u003cp\u003e107 (19.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.0681%;\"\u003e\n \u003cp\u003e0.022\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 12.1634%;\"\u003e\n \u003cp\u003e15 (17.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 5.1948%;\"\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e ALC, absolute lymphocyte count; ANC, absolute neutrophil count; ARC, absolute reticulocyte count; AVA, avatrombopag; ASD, average squared deviation; Hb, hemoglobin; Interval Dis-ATG, interval from disease onset to ATG treatment; IST, immunosuppressive therapy; IQR, interquartile range; LYM, lymphocyte; OR, odds ratio; PLT, platelet; PNH, paroxysmal nocturnal hemoglobinuria; PSM, propensity score matching; WBC, white blood cell.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Association between AVA therapy and hematological response at 3-month and 6-month\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"96%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"43.75%\" style=\"width: 34.9631%;\"\u003e\n \u003cp\u003eOutcomes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.75%\" style=\"width: 34.9631%;\"\u003e\n \u003cp\u003e\u0026nbsp;OR and 95% CI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.5%\" style=\"width: 10.095%;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 69.9261%;\"\u003e\n \u003cp\u003eComplete response at 3-month, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.095%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.9631%;\"\u003e\n \u003cp\u003eGroup A: IST only\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.9631%;\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.095%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.9631%;\"\u003e\n \u003cp\u003eGroup B: AVA+IST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.9631%;\"\u003e\n \u003cp\u003e4.70(1.39-18.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.095%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.016\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 69.9261%;\"\u003e\n \u003cp\u003eOverall response at 3-month, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.095%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.9631%;\"\u003e\n \u003cp\u003eGroup A: IST only\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.9631%;\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.095%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.9631%;\"\u003e\n \u003cp\u003eGroup B: AVA+IST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.9631%;\"\u003e\n \u003cp\u003e1.87(0.89-3.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.095%;\"\u003e\n \u003cp\u003e0.101\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 69.9261%;\"\u003e\n \u003cp\u003eComplete response at 6-month, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 10.095%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.9631%;\"\u003e\n \u003cp\u003eGroup A: IST only\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.9631%;\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.095%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.9631%;\"\u003e\n \u003cp\u003eGroup B: AVA+IST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.9631%;\"\u003e\n \u003cp\u003e2.69(1.10-6.67)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.095%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.030\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 69.9261%;\"\u003e\n \u003cp\u003eOverall response at 6-month, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.095%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.9631%;\"\u003e\n \u003cp\u003eGroup A: IST only\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.9631%;\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.095%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 34.9631%;\"\u003e\n \u003cp\u003eGroup B: AVA+IST\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 34.9631%;\"\u003e\n \u003cp\u003e2.38(1.09-5.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.095%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.032\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u0026nbsp;\u003c/strong\u003eAVA, avatrombopag; CI, confidence interval; IST, immunosuppressive therapy; OR, odds ratio.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Prognostic factors that may affect the six-month overall response in the AVA group\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" rowspan=\"2\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003eCharacteristics*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.612244897959183%\" colspan=\"2\" valign=\"top\" style=\"width: 44.3955%;\"\u003e\n \u003cp\u003eUnivariate analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.632653061224488%\" colspan=\"2\" valign=\"top\" style=\"width: 18.5942%;\"\u003e\n \u003cp\u003eMultivariate analysis\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003eOR (95%CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"34.92063492063492%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003eOR (95%CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.285714285714286%\" valign=\"top\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Males\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e0.934(0.241-3.625)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e0.921\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e0.866(0.860-27.748)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e0.859\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Females\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003eAge at diagnose \u0026ge;40years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e0.244(0.055-1.074)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e0.062\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e0.753(0.149-3.760)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e0.723\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003eDisease severity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;VSAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e2.286(0.565-9.253)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e0.247\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;SAA\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003eHb \u0026gt;60g/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e1.714(0.452-6.506)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e0.428\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003eANC \u0026gt;0.5\u0026times;109/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e0.571(0.101-3.224)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e0.526\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003eALC \u0026gt;1\u0026times;109/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e0.451(0.119-1.710)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e0.552\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003ePLT \u0026gt;10\u0026times;109/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e2.694(0.676-10.739)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e0.160\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003eARC \u0026gt;10\u0026times;109/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e4.772(1.068-20.885)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.041\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e3.424(0.672-25.902)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e0.167\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003ePNH clone size \u0026ge;1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e1.25(0.215-7.281)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e0.804\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003eChromosomal abnormalities, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e0.393(0.023-6.848)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e0.522\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"35.714285714285715%\" valign=\"top\" style=\"width: 33.4407%;\"\u003e\n \u003cp\u003eInterval Dis-ATG \u0026gt;6 months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.428571428571427%\" style=\"width: 30.9903%;\"\u003e\n \u003cp\u003e0.110(0.023-0.522)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.005\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"22.448979591836736%\" valign=\"top\" style=\"width: 13.261%;\"\u003e\n \u003cp\u003e0.074(0.009-0.391)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.183673469387756%\" style=\"width: 5.3332%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e0.005\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e*All the values were baseline\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAbbreviations:\u003c/strong\u003e ALC, absolute lymphocyte count; ANC, absolute neutrophil count; ARC, absolute reticulocyte count; AVA, avatrombopag; CI, confidence interval; Hb, hemoglobin; Interval Dis-ATG, interval from disease onset to ATG treatment; OR, odds ratio; PLT, platelet; PNH, paroxysmal nocturnal hemoglobinuria; SAA, severe aplastic anemia; VSAA, very severe aplastic anemia.\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"experimental-hematology-and-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"exho","sideBox":"Learn more about [Experimental Hematology \u0026 Oncology](http://ehoonline.biomedcentral.com)","snPcode":"40164","submissionUrl":"https://submission.nature.com/new-submission/40164/3","title":"Experimental Hematology \u0026 Oncology","twitterHandle":"@SN_Oncology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"severe aplastic anemia, immunosuppressive therapy, avatrombopag, thrombopoietin receptor agonist","lastPublishedDoi":"10.21203/rs.3.rs-4927350/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4927350/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eSevere aplastic anemia (SAA) is a life-threatening bone marrow failure disease. The addition of eltrombopag to immunosuppressive therapy (IST) improves the response rate and response quality of SAAs, but its hepatotoxicity is concerning. Avatrombopag (AVA), another small-molecule thrombopoietin receptor agonist without hepatotoxicity, has unknown efficacy in SAA treatment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis retrospective study compared clinical outcomes of 42 SAA patients treated with IST and AVA as first-line treatment (Group A) to a historical cohort of 84 patients who received IST alone (Group B) using propensity score matching (PSM).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe median age was 31.5 (6.0-67.0) years old in Group A and 26 (16.0-45.0) years old in Group B. At 3 months, Group A showed higher complete response (CR) and overall response (OR) rates than Group B (CR: 19.0% vs. 4.8%, \u003cem\u003eP\u003c/em\u003e = 0.024; OR: 54.8% vs. 39.3%, \u003cem\u003eP\u003c/em\u003e=0.145). Higher CR and OR rates were also found at 6 months in Group A than in Group B (CR 31.0% vs. 14.3%, \u003cem\u003eP\u003c/em\u003e=0.145; OR 71.4% vs. 51.2%, \u003cem\u003eP\u003c/em\u003e=0.048). In multivariate analysis of Group A, a shorter interval from disease onset to ATG treatment (≤6 months) (\u003cem\u003eP\u003c/em\u003e=0.005) predicted better responses rate at 6 months. Event free survival was also improved in Group A (60.7% vs. 49.6%). AVA was well-tolerated, with no hepatic injury observed during treatment, even in those with pre-existing hepatic impairment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The addition of AVA to IST improves both the response rate and response quality in SAA patients while ensuring safety.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Avatrombopag in Combination with Standard Immunosuppressive Therapy for Severe Aplastic Anemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-14 08:46:53","doi":"10.21203/rs.3.rs-4927350/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorAssigned","content":"","date":"2024-08-18T12:23:26+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-17T15:07:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"Experimental Hematology \u0026 Oncology","date":"2024-08-17T01:12:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"experimental-hematology-and-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"exho","sideBox":"Learn more about [Experimental Hematology \u0026 Oncology](http://ehoonline.biomedcentral.com)","snPcode":"40164","submissionUrl":"https://submission.nature.com/new-submission/40164/3","title":"Experimental Hematology \u0026 Oncology","twitterHandle":"@SN_Oncology","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"165de38d-3879-4903-9e38-8e9ecdad58a4","owner":[],"postedDate":"October 14th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2024-10-14T08:46:54+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-14 08:46:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4927350","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4927350","identity":"rs-4927350","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}