Comparison of Hetrombopag and Eltrombopag added to first-line immunosuppressive therapy in severe aplastic anemia

Comparison of Hetrombopag and Eltrombopag added to first-line immunosuppressive therapy in 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 Comparison of Hetrombopag and Eltrombopag added to first-line immunosuppressive therapy in severe aplastic anemia Baohang Zhang, Wenrui Yang, Rui Kang, Yimeng Shi, Xiangrong Hu, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5328975/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The addition of thrombopoietin receptor agonists (TPO-RAs) to immunosuppressive therapy (IST) improves the hematologic response rate and quality in patients with severe aplastic anemia (SAA). However, no studies have yet reported on whether there are differences in the efficacy of TPO-RAs. Here we analyzed the clinical data of SAA patients who received hetrombopag (HPAG) or eltrombopag (EPAG) as part of first-line standard IST between March 2020 and June 2022 to compare the efficacy of HPAG and EPAG in SAA patients. Sixty-seven patients were enrolled in the HPAG group and 42 patients in the EPAG group, with a similar proportion of very severe aplastic anemia (VSAA) patients between the two groups (26.9% vs 33.3%, P = 0.613). The overall hematologic response (OR) rates of the HPAG group at 3 and 6 months after IST were 50.7% and 65.6%, respectively, close to that of the EPAG group (50%, P = 0.973; 73.8%, P = 0.494). The rates of complete response (CR) at 3 and 6 months were 13.4% and 31.3% in the HPAG group, respectively, which were like those in the EPAG group (11.9% and 28.6%), with no statistical difference ( P = 1.00 and 0.59). The median time to first response (3.0 months vs 3.2 months, P = 0.79) was similar in HPAG and EPAG. We further analyzed data of VSAA patients. The OR rate, CR rate and the time to obtain first response in VSAAs were comparable between the two groups. The median follow-up time of HPAG group was 22.38 (3-33.27) months, and that of EPAG group was 33.9 (9.4–49.2) months. The overall survival (OS) rates were 91.0% and 92.8% in HPAG group and EPAG group ( P = 0.53), respectively. Monosomy 7 was detected in 1 patient in EPAG group and her disease transformed to acute myelocytic leukemia (AML) at 25 months after ATG treatment. One patient in HPAG had trisomy 8 at 9 months of ATG treatment, and bone marrow examination showed no disease progression. Conclusion : The addition of HPAG to standard IST in SAA patients showed similar response rates and response quality to that of EPAG. HPAG could be an alternative of EPAG for the first-line treatment of SAA patients. Hetrombopag Eltrombopag Immunosuppressive therapy Aplastic anemia Thrombopoietin receptor agonist Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Aplastic anemia (AA) is an immune-mediated bone marrow failure disorder characterized by a reduction in the hematopoietic stem/progenitor cell pool[1]. Severe AA (SAA) is life-threatening with significant cytopenia. Standard immune suppressive therapy (IST) based on antithymocyte globulin (ATG), cyclosporine (CSA), with TPO-RAs, is first-line treatment option for SAA patients who are not suitable for hematopoietic stem cell transplantation (HSCT)[1, 2]. Eltrombopag is a small molecular non-peptide thrombopoietin receptor agonist (TPO-RA). It promotes proliferation and differentiation of hematopoietic stem/progenitor cells [3-5], and enables 40-50% of IST-refractory SAA patients to achieve hematological response (OR) [5-7]. An open-label, nonrandomized, phase II study from NIH showed that EPAG in combination with standard horse ATG and CSA had efficacy in untreated SAA patients with complete hematological response (CR) rate of 39% and OR rate of 81% at 6 months[8, 9]. A prospective, randomized study comparing triple therapy including EPAG and standard IST in SAA showed higher CR and OR rates both at 3 and 6 months in EPAG group [7]. Thus, addition of EPAG to IST provide patients with earlier hematologic response and higher response rates. Hetrombopag (HPAG) is another small molecule TPO-RA, and its effectiveness in stimulating hematopoietic stem/progenitor cells was similar to EPAG with higher potency in preclinical mouse experiments [10, 11]. Our previous data showed that HPAG had efficacy in IST-refractory SAA patients [12], and improved the OR and CR(68.7% and 34.4%) at 6 months in untreated SAA patients[13]. But its efficacy compared to EPAG has not been reported. Therefore, this study aims to evaluate the treatment efficacy of SAA patients who received HPAG or EPAG combined with IST as first-line therapy. Methods Study design Newly diagnosed SAA patients who received standard IST (ATG + CSA) combined with HPAG or EPAG in Blood Diseases Hospital between March 2020 and June 2022 were enrolled. The study was complied with the Helsinki Declaration and approved by the Ethics Committee of the Blood Diseases Hospital. Written consents were provided by patients and/or their legal guardians. Diagnosis of SAA refers to previous reports[ 14 – 16 ]. SAA is defined as bone marrow proliferation less than 30% of normal, and blood routine meets two of the following three criteria: absolute neutrophil count (ANC) < 0.5×10 9 /L, platelet count (PLT) < 20×10 9 /L, absolute reticulocyte count (ARC) < 20×10 9 /L. VSAA is defined as meeting the SAA criteria and ANC < 0.2×10 9 /L. The FLAER-based screening was used to detect paroxysmal nocturnal hemoglobinuria (PNH) clones with a positive threshold of 1%. Treatment Hetrombopag and eltrombopag HPAG/EPAG was administered orally for at least 3 months. The dose of HPAG was 15mg per day, except for four patients (10mg) and one 6-year-old child (5mg). The dose of EPAG was 75-150mg per day, except for two adults (50mg) and one 10-year-old patient (37.5mg). IST regimen Rabbit ATG (r-ATG) was administered for five consecutive days at a dosage of 3.0mg/kg/d. Porcine ATG (p-ATG) was used at a dose of 20mg/kg/d. CSA was administered orally at 3-5mg/kg/d in divided doses and adjusted to maintain a serum trough concentration between 150–250 ng/mL. Hematologic response criteria CR was defined as: hemoglobin (HGB) > 100g/L, ANC > 1.5×10 9 / L, and PLT > 100×10 9 /L; Partial response (PR) was defined as: HGB > 70g/L, ANC > 0.5×10 9 / L, and PLT > 20×10 9 /L. No response (NR) was defined as not meeting the criteria of PR. Overall response rate (OR) was defined as PR plus CR. The time to first response is defined as the interval between ATG initiation and the time achieving PR. The time to CR is defined as the interval between ATG initiation and the time achieving CR. Statistical analysis SPSS software (version 26.0) (IBM Corp., Armonk, NY, USA) and R 4.2.2 were used for statistical analysis and chart plotting. The comparison of categorical variables between the two groups was performed using the chi-square test or Fisher’s exact test. The comparison of continuous variables was performed using the Mann-Whitney U test. Kaplan‒Meier curves were used to compare the cumulative hematological response rate, and differences were tested using the Gehan-Breslow and log-rank tests. P value < 0.05 was considered statistically significant. Results Patients A total of 109 patients were included in this study, with a median age of 38 (range 6–70) years. There were 53 males and 56 females. Among them, 67 patients received HPAG and 42 patients received EPAG. The proportion of VSAA was similar ( P = 0.613). There was no significant difference between the two groups in clinical characteristics and baseline parameters, except for the ATG type they received (Table 1 ). One (4.8%) patient in the EPAG group had chromosomal abnormality of -Y at baseline. Two patients (4.5%) in the HPAG group had chromosomal abnormalities, including one with -Y and another with 45,XX,t(11;12)(q13;p13),-13. Table 1 Baseline Characteristics of the Patients by Treatment Group Characteristics Median (range); n (%) EPAG + IST (n = 42) HPAG + IST (n = 67) P -value Age, years 35.6(10 ~ 68) 40.4 (6 ~ 70) 0.183 Sex: Male Female 25(59.5%) 17(40.5%) 28(41.8%) 39(58.2%) 0.108 Interval Onset-ATG, month Median (range) 3.8 (1 ~ 48) 11.3 (0.25 ~ 240) 0.128 Severity of AA Severe Very severe 28(66.7%) 14(33.3%) 49(73.1%) 18(26.9%) 0.613 ANC (×10 9 /L) 0.36 (0 ~ 1.27) 0.44 (0 ~ 1.3) 0.168 ARC (×10 9 /L) 15.9 (2.3 ~ 60.8) 19.7 (0.2 ~ 68.4) 0.294 ALC (×10 9 /L) 1.33 (0.08 ~ 3.16) 1.46 (0.21 ~ 4.62) 0.482 PLT (×10 9 /L) 8.6 (1 ~ 25) 6.8 (1 ~ 21) 0.075 PNH clone (> 1%) 11(26.2%) 11(34.4%) 0.613 ATG type p-ALG r-ATG 28(66.7%) 14(33.3%) 64(95.5%) 3(4.5%) < 0.001 EPAG, eltrombopag; HPAG, Hetrombopag; IST, immunosuppressive therapy; AA, aplastic anemia; PNH, paroxysmal nocturnal hemoglobinuria; ARC: absolute reticulocyte count; ANC: absolute neutrophil count; ALC: absolute lymphocyte count; Interval Onset-ATG, the interval between disease onset to the initiation of ATG treatment Hematologic Response At 3 months, 50.7% of patients in the HPAG group achieved hematologic response, close to that of 50% in the EPAG group ( P = 0.973, Fig. 1 ). The CR rate at 3 months was 13.4% in the HPAG group and 11.9% in the EPAG group ( P = 1.00). In total, 65.6% of patients in HPAG group achieved hematologic response at 6 months, while 73.8% of patients in the EPAG group achieved hematologic response ( P = 0.494). There was no significant difference in CR rate at 6 months (31.3% in HPAG group vs. 28.6% in EPAG group, P = 0.59). We further analyzed the efficacy according to severity of the disease. Among SAA patients, the OR rate at 3 months in the HPAG and EPAG group was 61.2% and 57.1% respectively, and that increased to 77.6% and 82.1% at 6 months ( P = 0.883 and 0.557). The CR rate was 14.3% vs. 10.7% between the two groups at 3 months and 36.7% vs. 28.6% at 6 months ( P = 1.000 and 0.486). There were 18 VSAA patients in HPAG group and 14 VSAA patients in EPAG group. Among the VSAA patients, the OR rate (22.2% vs. 35.7% at 3 months; 33.3% vs. 57.1% at 6 months, P = 0.671 and 0.404) and CR rate (11.1% vs. 14.3% at 3 months and 16.7% vs. 28.6% at 6 months, P = 1.000 and 1.000) were comparable between the HPAG and EPAG groups. The median time to the first response was similar in the HPAG and EPAG groups (3.0 months vs. 3.2 months, P = 0.79). The median time to achieving platelet counts of 100×10 9 /L was 5.63 months in the HPAG group and 7.27 months in the EPAG group ( P = 0.66). The median time to CR was 5.63 months in the HPAG group and 8.37 months in the EPAG group ( P = 0.82, Fig. 2 ). In SAA patients, median time to achieve the first response in the HPAG group was similar to that in the EPAG group (3 months vs. 3.2 months, P = 0.2). In VSAA patients, median time to achieved first response in the HPAG group was also similar to that in the EPAG group (3.3 months vs. 3.2 months, P = 0.13). Predictors of Hematologic Response We first used univariate analysis to obtain factors that related to OR, and all variables with P < 0.2 in the univariate analysis were included in the multivariate analysis. Given its clinical significance and association with efficacy in previous studies[ 17 ], ALC was also included in the multivariate analysis. In the multivariable analysis (Fig. 3 ), OR at 6 months was correlated with HGB, PLT, presence of PNH clone, disease severity and ALC levels, and not related to TPO-RA types. Patients with higher HGB levels, higher PLT count, presence of PNH clone, less severe disease and lower ALC levels had better OR. Baseline PLT counts were the only predictive factor for the 6-month OR in EPAG group. The acquisition of OR in HPAG group was negatively correlated with disease severity and ALC levels, and positively correlated with presence of PNH clone. Different types of ATG (r-ATG or p-ATG) had no effect on the OR and CR rates. Adverse events We focused on the adverse events in liver functions. Among the 42 patients in the EPAG group, 38 (90%) had elevated bilirubin, with 25 (59.52%) having grade 2 elevation and 5 (11.90%) having grade 3 elevation. Four patients (9.52%) had elevated transaminases, 3 (7.14%) grade 1 and 1 (2.38%) grade 2. One patient (2.38%) had skin pigmentation and 1 patient (2.38%) had pruritus. In the 67 patients of HPAG group, 16 (23.88%) patients had elevated bilirubin, with 6 (8.96%) cases being grade 2 elevation and no grade 3 elevation. Four (5.97%) patients had grade 1 elevated transaminases. Significant increases in indirect bilirubin levels were observed in patients using EPAG, but not found in the HPAG group. Even patients with high baseline indirect bilirubin levels gradually returned to normal levels when using HPAG. No thrombotic events or cataracts were noted. The adverse reactions in patients were tolerable without the need for adjusting drug dosage. Follow-up and survival The median follow-up time of HPAG group was 22.38 (3-33.27) months, and that of EPAG group was 33.9 (9.4–49.2) months. The OS rates were 91.0% and 92.8% in HPAG group and EPAG group respectively ( P = 0.53). By the end of follow-up, 4 non-responders in the HPAG group died due to infections or cerebral hemorrhage, 8 patients received HSCT and 2 of them died of complications of HSCT. Three SAA patients in HPAG group were lost follow-up since 2022, who were also non-responders, including one patient who carried monosomy 8 at 9 months after ATG treatment. Two patients in the HPAG group who had chromosomal abnormalities at baseline showed normal karyotype at last follow-up. There were 3 patients died in EPAG group. One is non-responder and died of infections. One patient achieved PR but transformed to acute myeloid leukemia with monosomy 7 at 24 months and died at 28 months after ATG treatment. One patient received HSCT and died of complications. One non-responder in EPAG group was lost follow-up. The CR rate and PR rate at last follow-up were 41.8% (28/67) and 26.9% (18/67) in HPAG, and 57.1% (24/42) and 21.4% (9/42) in EPAG group. Discussion Clinical trials have shown that EPAG combined with IST can significantly improve the hematologic response rate in treatment-naive SAA patients[ 7 , 18 ]. Therefore, EPAG combined with IST is recommended as the first-line treatment for SAA patients who are not suitable for transplantation[ 19 ]. HPAG, another small molecule TPO-RA, also showed effectiveness in IST-refractory SAAs and as first-line treatment in SAAs[ 12 , 13 ]. But the efficacy of these two TPO-RAs has not been compared. In this study, we analysed the efficacy and safety data of patients who used IST and EPAG/HPAG treatment and found that the hematological response rates were comparable between the two groups, whereas the incidence of adverse liver effect was lower in the HPAG group. Thus, the addition of HPAG to standard IST can achieve the similar efficacy as that of EPAG, with less hepatotoxicity in SAA patients. Previous research has indicated that both EPAG and HPAG could accelerate the acquisition of hematological response[ 7 , 13 ]. In this study, we found that the median time to achieve the response was similar in both treatment groups. The median time to obtain CR appeared to be shorter in the HPAG group than in the EPAG group, potentially due to the limitations of sample size. Additionally, we observed that there was no significant difference in the median time to response between HPAG and EPAG in patients with SAA and VSAA, suggesting that the hematopoietic stimulatory effects of these two drugs are similar in AA patients with varying degrees of residual hematopoiesis. Therefore, HPAG could serve as a viable alternative to EPAG for AA patients. We also analysed the predictors associated with response and showed that patients with higher baseline HGB and PLT, lower ALC, and less severe disease are more likely to achieve hematologic response (OR) after 6 months of treatment, regardless of the type of TPO-RA and ATG used. Consistent with previous findings[ 17 , 20 ], patients with more residual bone marrow hematopoietic stem cells are more likely to benefit from the three-drug combination regimen. Additionally, our research indicates that disease severity, PNH, and ALC are predictive factors for OR at 6 months in the HPAG group, with lower baseline ALC, less severe disease, and carrying PNH clone being associated with a higher likelihood of achieving OR. Furthermore, the multivariable analysis showed that only baseline PLT levels were correlated with OR at 6 months in the EPAG group. In conclusion, IST efficacy is still limited by residual hematopoiesis, regardless of which TPO-RA is used. Due to the limited sample size of this study, there may be some bias in the findings, which needs to be further confirmed by the large sample research. The OS rates were similarly between two groups. Thirty-one patients who responded at 6 months in the HPAG group had an OS of 100%, and 44 responders at 6 months in the EPAG group had an OS of 95.5%. There was no difference between the two groups ( P = 0.53). In the HPAG group, 23 patients did not achieve the hematologic response at 6 months, four of whom (17.4%) died at the last follow-up, and the OS in NR patients was 82.6%. Six non-responders at 6 months continued using CSA and HPAG and achieved HR at the last follow-up, including 4 PRs and 2 CRs. Other 7 non-responders switched to HSCT. In the EPAG group, eleven patients did not respond at 6 months, three of whom (27.3%) died at the last follow-up, and the OS was 72.7%. There was no difference between the two groups ( P = 0.53). In these non-responders. One patient received HSCT and died of related complications. One patient developed chromosomal abnormalities and transformed into AML and died. In V/SAA patients, there was no difference in survival. Consistent with previous studies[ 9 ], response at 6 months remains one of the factors affecting the survival of AA patients. Additionally, our study showed that the incidence of liver adverse effect in the HPAG group was lower than that in the EPAG group, and a decrease in bilirubin levels was observed in the HPAG group, suggesting that the liver toxicity of HPAG may be lower than that of EPAG. For patients with liver function abnormalities, HPAG may be preferable to EPAG. Overall, the HPAG joint standard IST protocol can provide SAA patients with similar efficacy to EPAG, while exhibiting less liver adverse effect and superior safety. Nonetheless, this study is a retrospective analysis with a limited number of cases, and thus, large-scale prospective clinical studies are necessary to confirm these findings. Declarations Author contribution Baohang Zhang and Wenrui Yang collected and analyzed the data, performed statistical analysis and drafted the manuscript. Rui Kang, Yimeng Shi and Xiangrong Hu collected data. Li Zhang and Liping Jing enrolled patients and edited the manuscript. Weiping Yuan, Jun Shi and Fengkui Zhang revised the manuscript. Xin Zhao analysed the data, performed statistical review and literature review, and revised the manuscript. All authors edited the final version of the manuscript, and approved the final article. Funding This study was supported by Grant 2022YFA1103300 of National Key R&D Program of China, and Grant 2022-PUMCH-C-026 of National High Level Hospital Clinical Research Funding. Ethics approval The approvals have been permitted by the Institutional Review Board and the Institutional Ethics Committee of the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College. Informed consent was signatured by patients before the study, following the Declaration of Helsinki. Conflict of interest The authors declare no competing interests. References Young NS. Aplastic Anemia. N Engl J Med. 2018;379:1643–56. Kulasekararaj A, Cavenagh J, Dokal I, et al. Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline. Br J Haematol. 2024;204:784–804. Sun H, Tsai Y, Nowak I, Liesveld J, Chen Y. Eltrombopag, a thrombopoietin receptor agonist, enhances human umbilical cord blood hematopoietic stem/primitive progenitor cell expansion and promotes multi-lineage hematopoiesis. Stem cell Res. 2012;9:77–86. Quintino de Oliveira B, Catto LFB, Santana BAA, et al. Eltrombopag preferentially expands haematopoietic multipotent progenitors in human aplastic anaemia. Br J Haematol. 2021;193:410–4. Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123:1818–25. Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367:11–9. Peffault de Latour R, Kulasekararaj A, Iacobelli S, et al. Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. N Engl J Med. 2022;386:11–23. Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017;376:1540–50. Patel BA, Groarke EM, Lotter J, et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood. 2022;139:34–43. Xie C, Zhao H, Bao X, Fu H, Lou L. 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Br J Haematol. 1988;70:177–82. Incidence of aplastic. anemia: the relevance of diagnostic criteria. By the International Agranulocytosis and Aplastic Anemia Study. Blood. 1987;70:1718–21. Zaimoku Y, Patel BA, Shalhoub R, et al. Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag. Haematologica. 2022;107:126–33. Yang WR, Han B, Chang H, et al. [Efficacy and safety of eltrombopag in aplastic anemia: A multi-center survey in China]. Zhonghua Xue Ye Xue Za Zhi. 2020;41:890–5. Kulasekararaj A, Cavenagh J, Dokal I, et al. Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline. Br J Haematol. 2024;204:784–804. Scheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol. 2009;144:206–16. Additional Declarations No competing interests reported. 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02:38:21","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5328975/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5328975/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":67660995,"identity":"6ca521bd-c3c7-4950-9d5f-f233cab0c021","added_by":"auto","created_at":"2024-10-28 12:59:35","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":245155,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHematological Response to First-line Treatment by EPAG/HPAG in different month\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eA.\u003c/strong\u003e Hematological Response to all the patients for treatment groups;\u003cstrong\u003e B. \u003c/strong\u003eHematological Response to the patients of SAA for treatment groups; \u003cstrong\u003eC.\u003c/strong\u003e Hematological Response to the patients of VSAA for treatment groups;\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-5328975/v1/cfa8c4e6de58a4b77fc537b0.jpeg"},{"id":67660993,"identity":"13b667ba-7074-46c7-9794-4f93a1edafe5","added_by":"auto","created_at":"2024-10-28 12:59:34","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":304660,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative Incidence of Hematologic Response by Treatment Group and Depending on the Severity of Aplastic Anemia\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-5328975/v1/52659d291c1fbf48a97938d4.png"},{"id":67660994,"identity":"c8d41e91-9889-474d-8ecd-8e7fb3c39ae7","added_by":"auto","created_at":"2024-10-28 12:59:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":238716,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eLogistic regression analysis for hematologic response\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"OnlineFigure3.png","url":"https://assets-eu.researchsquare.com/files/rs-5328975/v1/f18a034a48d9752966602e66.png"},{"id":67660992,"identity":"8385a267-e693-4ca9-8a0b-15a84ca063d2","added_by":"auto","created_at":"2024-10-28 12:59:34","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":40600,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe overall survival rate between two groups\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHPAG: Hetrombopag; EPAG: eltrombopag;\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"OnlineFigure4.png","url":"https://assets-eu.researchsquare.com/files/rs-5328975/v1/fa058f1c9ac72dd730fdd8df.png"},{"id":67938553,"identity":"871f0c13-6ce3-4f7d-8481-baa7d5f1c1ce","added_by":"auto","created_at":"2024-10-31 11:32:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1639504,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5328975/v1/f45ee0c1-dccf-4456-884b-1ee703b6d956.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of Hetrombopag and Eltrombopag added to first-line immunosuppressive therapy in severe aplastic anemia","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAplastic anemia (AA) is an immune-mediated bone marrow failure disorder characterized by a reduction in the hematopoietic stem/progenitor cell pool[1]. Severe AA (SAA) is life-threatening with significant cytopenia. Standard immune suppressive therapy (IST) based on antithymocyte globulin (ATG), cyclosporine (CSA), with TPO-RAs, is first-line treatment option for SAA patients who are not suitable for hematopoietic stem cell transplantation (HSCT)[1, 2].\u003c/p\u003e\n\u003cp\u003eEltrombopag is a small molecular non-peptide thrombopoietin receptor agonist (TPO-RA). It promotes proliferation and differentiation of hematopoietic stem/progenitor cells\u0026nbsp;[3-5], and enables 40-50% of IST-refractory SAA patients to achieve hematological response (OR)\u0026nbsp;[5-7].\u0026nbsp;An open-label, nonrandomized, phase II study from NIH showed that EPAG in combination with standard horse ATG and CSA had efficacy in untreated SAA patients with complete hematological response (CR) rate of 39% and OR rate of 81% at 6 months[8, 9].\u0026nbsp;A prospective, randomized study comparing triple therapy including EPAG and standard IST in SAA showed higher CR and OR rates both at 3 and 6 months in EPAG group\u0026nbsp;[7]. Thus, addition of EPAG to IST provide patients with earlier hematologic response and higher response rates. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHetrombopag (HPAG) is another small molecule TPO-RA, and its effectiveness in stimulating hematopoietic stem/progenitor cells was similar to EPAG with higher potency in preclinical mouse experiments [10, 11]. Our previous data showed that HPAG had efficacy in IST-refractory SAA patients [12], and improved the OR and CR(68.7% and 34.4%) at 6 months in untreated SAA patients[13]. But its efficacy compared to EPAG has not been reported. Therefore, this study aims to evaluate the treatment efficacy of SAA patients who received HPAG or EPAG combined with IST as first-line therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec2\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eNewly diagnosed SAA patients who received standard IST (ATG\u0026thinsp;+\u0026thinsp;CSA) combined with HPAG or EPAG in Blood Diseases Hospital between March 2020 and June 2022 were enrolled. The study was complied with the Helsinki Declaration and approved by the Ethics Committee of the Blood Diseases Hospital. Written consents were provided by patients and/or their legal guardians.\u003c/p\u003e \u003cp\u003eDiagnosis of SAA refers to previous reports[\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. SAA is defined as bone marrow proliferation less than 30% of normal, and blood routine meets two of the following three criteria: absolute neutrophil 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, absolute reticulocyte count (ARC)\u0026thinsp;\u0026lt;\u0026thinsp;20\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L. VSAA is defined as meeting the SAA criteria and ANC\u0026thinsp;\u0026lt;\u0026thinsp;0.2\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L. The FLAER-based screening was used to detect paroxysmal nocturnal hemoglobinuria (PNH) clones with a positive threshold of 1%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eTreatment\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003eHetrombopag and eltrombopag\u003c/h2\u003e \u003cp\u003eHPAG/EPAG was administered orally for at least 3 months. The dose of HPAG was 15mg per day, except for four patients (10mg) and one 6-year-old child (5mg). The dose of EPAG was 75-150mg per day, except for two adults (50mg) and one 10-year-old patient (37.5mg).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003eIST regimen\u003c/h3\u003e\n\u003cp\u003eRabbit ATG (r-ATG) was administered for five consecutive days at a dosage of 3.0mg/kg/d. Porcine ATG (p-ATG) was used at a dose of 20mg/kg/d. CSA was administered orally at 3-5mg/kg/d in divided doses and adjusted to maintain a serum trough concentration between 150\u0026ndash;250 ng/mL.\u003c/p\u003e\n\u003ch3\u003eHematologic response criteria\u003c/h3\u003e\n\u003cp\u003eCR was defined as: hemoglobin (HGB)\u0026thinsp;\u0026gt;\u0026thinsp;100g/L, ANC\u0026thinsp;\u0026gt;\u0026thinsp;1.5\u0026times;10\u003csup\u003e9\u003c/sup\u003e/ L, and PLT\u0026thinsp;\u0026gt;\u0026thinsp;100\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L; Partial response (PR) was defined as: HGB\u0026thinsp;\u0026gt;\u0026thinsp;70g/L, ANC\u0026thinsp;\u0026gt;\u0026thinsp;0.5\u0026times;10\u003csup\u003e9\u003c/sup\u003e/ L, and PLT\u0026thinsp;\u0026gt;\u0026thinsp;20\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L. No response (NR) was defined as not meeting the criteria of PR. Overall response rate (OR) was defined as PR plus CR. The time to first response is defined as the interval between ATG initiation and the time achieving PR. The time to CR is defined as the interval between ATG initiation and the time achieving CR.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSPSS software (version 26.0) (IBM Corp., Armonk, NY, USA) and R 4.2.2 were used for statistical analysis and chart plotting. The comparison of categorical variables between the two groups was performed using the chi-square test or Fisher\u0026rsquo;s exact test. The comparison of continuous variables was performed using the Mann-Whitney U test. Kaplan‒Meier curves were used to compare the cumulative hematological response rate, and differences were tested using the Gehan-Breslow and log-rank tests. \u003cem\u003eP\u003c/em\u003e value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatients\u003c/h2\u003e \u003cp\u003eA total of 109 patients were included in this study, with a median age of 38 (range 6\u0026ndash;70) years. There were 53 males and 56 females. Among them, 67 patients received HPAG and 42 patients received EPAG. The proportion of VSAA was similar (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.613). There was no significant difference between the two groups in clinical characteristics and baseline parameters, except for the ATG type they received (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). One (4.8%) patient in the EPAG group had chromosomal abnormality of -Y at baseline. Two patients (4.5%) in the HPAG group had chromosomal abnormalities, including one with -Y and another with 45,XX,t(11;12)(q13;p13),-13.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline Characteristics of the Patients by Treatment Group\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003cp\u003eMedian (range); n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEPAG\u0026thinsp;+\u0026thinsp;IST (n\u0026thinsp;=\u0026thinsp;42)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHPAG\u0026thinsp;+\u0026thinsp;IST (n\u0026thinsp;=\u0026thinsp;67)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35.6(10\u0026thinsp;~\u0026thinsp;68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40.4 (6\u0026thinsp;~\u0026thinsp;70)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.183\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex:\u003c/p\u003e \u003cp\u003eMale\u003c/p\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25(59.5%)\u003c/p\u003e \u003cp\u003e17(40.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e28(41.8%)\u003c/p\u003e \u003cp\u003e39(58.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.108\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInterval Onset-ATG, month\u003c/p\u003e \u003cp\u003eMedian (range)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.8 (1\u0026thinsp;~\u0026thinsp;48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.3 (0.25\u0026thinsp;~\u0026thinsp;240)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.128\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeverity of AA\u003c/p\u003e \u003cp\u003eSevere\u003c/p\u003e \u003cp\u003eVery severe\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28(66.7%)\u003c/p\u003e \u003cp\u003e14(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49(73.1%)\u003c/p\u003e \u003cp\u003e18(26.9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.613\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eANC (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.36 (0\u0026thinsp;~\u0026thinsp;1.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.44 (0\u0026thinsp;~\u0026thinsp;1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.168\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eARC (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15.9 (2.3\u0026thinsp;~\u0026thinsp;60.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19.7 (0.2\u0026thinsp;~\u0026thinsp;68.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.294\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eALC (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.33 (0.08\u0026thinsp;~\u0026thinsp;3.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.46 (0.21\u0026thinsp;~\u0026thinsp;4.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.482\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePLT (\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8.6 (1\u0026thinsp;~\u0026thinsp;25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6.8 (1\u0026thinsp;~\u0026thinsp;21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePNH clone (\u0026gt;\u0026thinsp;1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11(26.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11(34.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.613\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eATG type\u003c/p\u003e \u003cp\u003ep-ALG\u003c/p\u003e \u003cp\u003er-ATG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28(66.7%)\u003c/p\u003e \u003cp\u003e14(33.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e64(95.5%)\u003c/p\u003e \u003cp\u003e3(4.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eEPAG, eltrombopag; HPAG, Hetrombopag; IST, immunosuppressive therapy; AA, aplastic anemia; PNH, paroxysmal nocturnal hemoglobinuria; ARC: absolute reticulocyte count; ANC: absolute neutrophil count; ALC: absolute lymphocyte count; Interval Onset-ATG, the interval between disease onset to the initiation of ATG treatment\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eHematologic Response\u003c/h3\u003e\n\u003cp\u003eAt 3 months, 50.7% of patients in the HPAG group achieved hematologic response, close to that of 50% in the EPAG group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.973, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The CR rate at 3 months was 13.4% in the HPAG group and 11.9% in the EPAG group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.00). In total, 65.6% of patients in HPAG group achieved hematologic response at 6 months, while 73.8% of patients in the EPAG group achieved hematologic response (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.494). There was no significant difference in CR rate at 6 months (31.3% in HPAG group vs. 28.6% in EPAG group, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.59).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWe further analyzed the efficacy according to severity of the disease. Among SAA patients, the OR rate at 3 months in the HPAG and EPAG group was 61.2% and 57.1% respectively, and that increased to 77.6% and 82.1% at 6 months (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.883 and 0.557). The CR rate was 14.3% vs. 10.7% between the two groups at 3 months and 36.7% vs. 28.6% at 6 months (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.000 and 0.486). There were 18 VSAA patients in HPAG group and 14 VSAA patients in EPAG group. Among the VSAA patients, the OR rate (22.2% vs. 35.7% at 3 months; 33.3% vs. 57.1% at 6 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.671 and 0.404) and CR rate (11.1% vs. 14.3% at 3 months and 16.7% vs. 28.6% at 6 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.000 and 1.000) were comparable between the HPAG and EPAG groups.\u003c/p\u003e \u003cp\u003eThe median time to the first response was similar in the HPAG and EPAG groups (3.0 months vs. 3.2 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.79). The median time to achieving platelet counts of 100\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L was 5.63 months in the HPAG group and 7.27 months in the EPAG group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.66). The median time to CR was 5.63 months in the HPAG group and 8.37 months in the EPAG group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.82, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In SAA patients, median time to achieve the first response in the HPAG group was similar to that in the EPAG group (3 months vs. 3.2 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.2). In VSAA patients, median time to achieved first response in the HPAG group was also similar to that in the EPAG group (3.3 months vs. 3.2 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.13).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003ePredictors of Hematologic Response\u003c/h2\u003e \u003cp\u003eWe first used univariate analysis to obtain factors that related to OR, and all variables with \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.2 in the univariate analysis were included in the multivariate analysis. Given its clinical significance and association with efficacy in previous studies[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], ALC was also included in the multivariate analysis. In the multivariable analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), OR at 6 months was correlated with HGB, PLT, presence of PNH clone, disease severity and ALC levels, and not related to TPO-RA types. Patients with higher HGB levels, higher PLT count, presence of PNH clone, less severe disease and lower ALC levels had better OR. Baseline PLT counts were the only predictive factor for the 6-month OR in EPAG group. The acquisition of OR in HPAG group was negatively correlated with disease severity and ALC levels, and positively correlated with presence of PNH clone. Different types of ATG (r-ATG or p-ATG) had no effect on the OR and CR rates.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eAdverse events\u003c/h2\u003e \u003cp\u003eWe focused on the adverse events in liver functions. Among the 42 patients in the EPAG group, 38 (90%) had elevated bilirubin, with 25 (59.52%) having grade 2 elevation and 5 (11.90%) having grade 3 elevation. Four patients (9.52%) had elevated transaminases, 3 (7.14%) grade 1 and 1 (2.38%) grade 2. One patient (2.38%) had skin pigmentation and 1 patient (2.38%) had pruritus. In the 67 patients of HPAG group, 16 (23.88%) patients had elevated bilirubin, with 6 (8.96%) cases being grade 2 elevation and no grade 3 elevation. Four (5.97%) patients had grade 1 elevated transaminases. Significant increases in indirect bilirubin levels were observed in patients using EPAG, but not found in the HPAG group. Even patients with high baseline indirect bilirubin levels gradually returned to normal levels when using HPAG. No thrombotic events or cataracts were noted. The adverse reactions in patients were tolerable without the need for adjusting drug dosage.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eFollow-up and survival\u003c/h2\u003e \u003cp\u003eThe median follow-up time of HPAG group was 22.38 (3-33.27) months, and that of EPAG group was 33.9 (9.4\u0026ndash;49.2) months. The OS rates were 91.0% and 92.8% in HPAG group and EPAG group respectively (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.53). By the end of follow-up, 4 non-responders in the HPAG group died due to infections or cerebral hemorrhage, 8 patients received HSCT and 2 of them died of complications of HSCT. Three SAA patients in HPAG group were lost follow-up since 2022, who were also non-responders, including one patient who carried monosomy 8 at 9 months after ATG treatment. Two patients in the HPAG group who had chromosomal abnormalities at baseline showed normal karyotype at last follow-up. There were 3 patients died in EPAG group. One is non-responder and died of infections. One patient achieved PR but transformed to acute myeloid leukemia with monosomy 7 at 24 months and died at 28 months after ATG treatment. One patient received HSCT and died of complications. One non-responder in EPAG group was lost follow-up. The CR rate and PR rate at last follow-up were 41.8% (28/67) and 26.9% (18/67) in HPAG, and 57.1% (24/42) and 21.4% (9/42) in EPAG group.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eClinical trials have shown that EPAG combined with IST can significantly improve the hematologic response rate in treatment-naive SAA patients[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Therefore, EPAG combined with IST is recommended as the first-line treatment for SAA patients who are not suitable for transplantation[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. HPAG, another small molecule TPO-RA, also showed effectiveness in IST-refractory SAAs and as first-line treatment in SAAs[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. But the efficacy of these two TPO-RAs has not been compared. In this study, we analysed the efficacy and safety data of patients who used IST and EPAG/HPAG treatment and found that the hematological response rates were comparable between the two groups, whereas the incidence of adverse liver effect was lower in the HPAG group. Thus, the addition of HPAG to standard IST can achieve the similar efficacy as that of EPAG, with less hepatotoxicity in SAA patients.\u003c/p\u003e \u003cp\u003ePrevious research has indicated that both EPAG and HPAG could accelerate the acquisition of hematological response[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In this study, we found that the median time to achieve the response was similar in both treatment groups. The median time to obtain CR appeared to be shorter in the HPAG group than in the EPAG group, potentially due to the limitations of sample size. Additionally, we observed that there was no significant difference in the median time to response between HPAG and EPAG in patients with SAA and VSAA, suggesting that the hematopoietic stimulatory effects of these two drugs are similar in AA patients with varying degrees of residual hematopoiesis. Therefore, HPAG could serve as a viable alternative to EPAG for AA patients.\u003c/p\u003e \u003cp\u003eWe also analysed the predictors associated with response and showed that patients with higher baseline HGB and PLT, lower ALC, and less severe disease are more likely to achieve hematologic response (OR) after 6 months of treatment, regardless of the type of TPO-RA and ATG used. Consistent with previous findings[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], patients with more residual bone marrow hematopoietic stem cells are more likely to benefit from the three-drug combination regimen. Additionally, our research indicates that disease severity, PNH, and ALC are predictive factors for OR at 6 months in the HPAG group, with lower baseline ALC, less severe disease, and carrying PNH clone being associated with a higher likelihood of achieving OR. Furthermore, the multivariable analysis showed that only baseline PLT levels were correlated with OR at 6 months in the EPAG group. In conclusion, IST efficacy is still limited by residual hematopoiesis, regardless of which TPO-RA is used. Due to the limited sample size of this study, there may be some bias in the findings, which needs to be further confirmed by the large sample research.\u003c/p\u003e \u003cp\u003eThe OS rates were similarly between two groups. Thirty-one patients who responded at 6 months in the HPAG group had an OS of 100%, and 44 responders at 6 months in the EPAG group had an OS of 95.5%. There was no difference between the two groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.53). In the HPAG group, 23 patients did not achieve the hematologic response at 6 months, four of whom (17.4%) died at the last follow-up, and the OS in NR patients was 82.6%. Six non-responders at 6 months continued using CSA and HPAG and achieved HR at the last follow-up, including 4 PRs and 2 CRs. Other 7 non-responders switched to HSCT. In the EPAG group, eleven patients did not respond at 6 months, three of whom (27.3%) died at the last follow-up, and the OS was 72.7%. There was no difference between the two groups (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.53). In these non-responders. One patient received HSCT and died of related complications. One patient developed chromosomal abnormalities and transformed into AML and died. In V/SAA patients, there was no difference in survival. Consistent with previous studies[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], response at 6 months remains one of the factors affecting the survival of AA patients.\u003c/p\u003e \u003cp\u003eAdditionally, our study showed that the incidence of liver adverse effect in the HPAG group was lower than that in the EPAG group, and a decrease in bilirubin levels was observed in the HPAG group, suggesting that the liver toxicity of HPAG may be lower than that of EPAG. For patients with liver function abnormalities, HPAG may be preferable to EPAG.\u003c/p\u003e \u003cp\u003eOverall, the HPAG joint standard IST protocol can provide SAA patients with similar efficacy to EPAG, while exhibiting less liver adverse effect and superior safety. Nonetheless, this study is a retrospective analysis with a limited number of cases, and thus, large-scale prospective clinical studies are necessary to confirm these findings.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor contribution\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBaohang Zhang and Wenrui Yang collected and analyzed the data, performed statistical analysis and drafted the manuscript. Rui Kang, Yimeng Shi and Xiangrong Hu collected data. Li Zhang and Liping Jing enrolled patients and edited the manuscript. Weiping Yuan, Jun Shi and Fengkui Zhang revised the manuscript. Xin Zhao analysed the data, performed statistical review and literature review, and revised the manuscript. All authors edited the final version of the manuscript, and approved the final article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by Grant 2022YFA1103300 of National Key R\u0026amp;D Program of China, and Grant 2022-PUMCH-C-026 of National High Level Hospital Clinical Research Funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe approvals have been permitted by the Institutional Review Board and the Institutional Ethics Committee of the Institute of Hematology \u0026amp; Blood Diseases Hospital, Chinese Academy of Medical Sciences \u0026amp; Peking Union Medical College. Informed consent was signatured by patients before the study, following the Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eYoung NS. Aplastic Anemia. N Engl J Med. 2018;379:1643\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKulasekararaj A, Cavenagh J, Dokal I, et al. Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline. Br J Haematol. 2024;204:784\u0026ndash;804.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun H, Tsai Y, Nowak I, Liesveld J, Chen Y. Eltrombopag, a thrombopoietin receptor agonist, enhances human umbilical cord blood hematopoietic stem/primitive progenitor cell expansion and promotes multi-lineage hematopoiesis. Stem cell Res. 2012;9:77\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQuintino de Oliveira B, Catto LFB, Santana BAA, et al. Eltrombopag preferentially expands haematopoietic multipotent progenitors in human aplastic anaemia. Br J Haematol. 2021;193:410\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDesmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123:1818\u0026ndash;25.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOlnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367:11\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeffault de Latour R, Kulasekararaj A, Iacobelli S, et al. Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia. N Engl J Med. 2022;386:11\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTownsley DM, Scheinberg P, Winkler T, et al. Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia. N Engl J Med. 2017;376:1540\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePatel BA, Groarke EM, Lotter J, et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood. 2022;139:34\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXie C, Zhao H, Bao X, Fu H, Lou L. Pharmacological characterization of hetrombopag, a novel orally active human thrombopoietin receptor agonist. J Cell Mol Med. 2018;22:5367\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSyed YY, Hetrombopag. First Approval Drugs. 2021;81:1581\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePeng G, He G, Chang H, et al. A multicenter phase II study on the efficacy and safety of hetrombopag in patients with severe aplastic anemia refractory to immunosuppressive therapy. Ther Adv Hematol. 2022;13:20406207221085197.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang W, Zhao X, Liu X, 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;12:16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCamitta BM, Thomas ED. Severe aplastic anaemia: a prospective study of the effect of androgens or transplantation on haematological recovery and survival. Clin Haematol. 1978;7:587\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBacigalupo A, Hows J, Gluckman E, 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;70:177\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIncidence of aplastic. anemia: the relevance of diagnostic criteria. By the International Agranulocytosis and Aplastic Anemia Study. Blood. 1987;70:1718\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZaimoku Y, Patel BA, Shalhoub R, et al. Predicting response of severe aplastic anemia to immunosuppression combined with eltrombopag. Haematologica. 2022;107:126\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang WR, Han B, Chang H, et al. [Efficacy and safety of eltrombopag in aplastic anemia: A multi-center survey in China]. Zhonghua Xue Ye Xue Za Zhi. 2020;41:890\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKulasekararaj A, Cavenagh J, Dokal I, et al. Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline. Br J Haematol. 2024;204:784\u0026ndash;804.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eScheinberg P, Wu CO, Nunez O, Young NS. Predicting response to immunosuppressive therapy and survival in severe aplastic anaemia. Br J Haematol. 2009;144:206\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Hetrombopag, Eltrombopag, Immunosuppressive therapy, Aplastic anemia, Thrombopoietin receptor agonist","lastPublishedDoi":"10.21203/rs.3.rs-5328975/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5328975/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe addition of thrombopoietin receptor agonists (TPO-RAs) to immunosuppressive therapy (IST) improves the hematologic response rate and quality in patients with severe aplastic anemia (SAA). However, no studies have yet reported on whether there are differences in the efficacy of TPO-RAs. Here we analyzed the clinical data of SAA patients who received hetrombopag (HPAG) or eltrombopag (EPAG) as part of first-line standard IST between March 2020 and June 2022 to compare the efficacy of HPAG and EPAG in SAA patients. Sixty-seven patients were enrolled in the HPAG group and 42 patients in the EPAG group, with a similar proportion of very severe aplastic anemia (VSAA) patients between the two groups (26.9% vs 33.3%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.613). The overall hematologic response (OR) rates of the HPAG group at 3 and 6 months after IST were 50.7% and 65.6%, respectively, close to that of the EPAG group (50%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.973; 73.8%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.494). The rates of complete response (CR) at 3 and 6 months were 13.4% and 31.3% in the HPAG group, respectively, which were like those in the EPAG group (11.9% and 28.6%), with no statistical difference (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;1.00 and 0.59). The median time to first response (3.0 months vs 3.2 months, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.79) was similar in HPAG and EPAG. We further analyzed data of VSAA patients. The OR rate, CR rate and the time to obtain first response in VSAAs were comparable between the two groups. The median follow-up time of HPAG group was 22.38 (3-33.27) months, and that of EPAG group was 33.9 (9.4\u0026ndash;49.2) months. The overall survival (OS) rates were 91.0% and 92.8% in HPAG group and EPAG group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.53), respectively. Monosomy 7 was detected in 1 patient in EPAG group and her disease transformed to acute myelocytic leukemia (AML) at 25 months after ATG treatment. One patient in HPAG had trisomy 8 at 9 months of ATG treatment, and bone marrow examination showed no disease progression.\u003c/p\u003e \u003cp\u003e \u003cb\u003eConclusion\u003c/b\u003e: The addition of HPAG to standard IST in SAA patients showed similar response rates and response quality to that of EPAG. HPAG could be an alternative of EPAG for the first-line treatment of SAA patients.\u003c/p\u003e","manuscriptTitle":"Comparison of Hetrombopag and Eltrombopag added to first-line immunosuppressive therapy in severe aplastic anemia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-10-28 12:59:30","doi":"10.21203/rs.3.rs-5328975/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"165de38d-3879-4903-9e38-8e9ecdad58a4","owner":[],"postedDate":"October 28th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-31T11:24:42+00:00","versionOfRecord":[],"versionCreatedAt":"2024-10-28 12:59:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5328975","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5328975","identity":"rs-5328975","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}