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

doi:10.21203/rs.3.rs-5328975/v1

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

https://doi.org/10.21203/rs.3.rs-5328975/v1

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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

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.

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) < 0.5×10⁹/L, platelet count (PLT) < 20×10⁹/L, absolute reticulocyte count (ARC) < 20×10⁹/L. VSAA is defined as meeting the SAA criteria and ANC < 0.2×10⁹/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 > 1.5×10⁹/ L, and PLT > 100×10⁹/L; Partial response (PR) was defined as: HGB > 70g/L, ANC > 0.5×10⁹/ L, and PLT > 20×10⁹/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.

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 (×10⁹/L)	0.36 (0 ~ 1.27)	0.44 (0 ~ 1.3)	0.168
ARC (×10⁹/L)	15.9 (2.3 ~ 60.8)	19.7 (0.2 ~ 68.4)	0.294
ALC (×10⁹/L)	1.33 (0.08 ~ 3.16)	1.46 (0.21 ~ 4.62)	0.482
PLT (×10⁹/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 100×10⁹/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.

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.

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.

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No competing interests reported.

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

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Abstract

Figures

Introduction

Methods

Study design

Treatment

Hetrombopag and eltrombopag

IST regimen

Hematologic response criteria

Statistical analysis

Results

Patients

Hematologic Response

Predictors of Hematologic Response

Adverse events

Follow-up and survival

Discussion

Declarations

References

Additional Declarations

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