Adding eltrombopag to intensive immunosuppressive therapy helps adult patients catch up pediatric patients in severe aplastic anemia

doi:10.21203/rs.3.rs-4826832/v1

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Adding eltrombopag to intensive immunosuppressive therapy helps adult patients catch up pediatric patients in severe aplastic anemia

https://doi.org/10.21203/rs.3.rs-4826832/v1

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Direct comparison of immunosuppressive therapy (IST), especially after the addition of thrombopoietin receptor agonist (TPO-RA), between adult and paediatric patients with severe aplastic anaemia (SAA) has not been enunciated. The aim of this study was to evaluate differences in efficacy and survival between adults and children receiving IST ± eltrombopag (EPAG). Baseline characteristics, haematological response, overall survival (OS), event-free survival (EFS), relapse, and clonal evolution were compared in 366 patients (141 adults, 197males, median age 11 years). For IST alone, adults had a similar overall response rate (ORR) but a lower complete response rate (CRR) than did children at 12 months. Moreover, adults had lower OS and EFS. After adding EPAG, the ORR was greater in adults, and the CRR was similar between the two groups. OS and EFS in adults improved significantly and were similar to those in children. Adults had similar relapse rates but higher clonal evolution rates than children, with or without EPAG. Adults had greater clonal evolution, regardless of the addition of EPAG. Adding EPAG to intensive IST improved the ORR, CRR, OS and EFS in adults more than it did in children, bridged the gap previously existed between adult and paediatric patients.

Health sciences/Diseases/Haematological diseases/Anaemia

Biological sciences/Immunology/Haematopoiesis/Erythropoiesis/Haematopoietic stem cells

Aplastic anaemia

intensive immunosuppressive therapy

eltrombopag

adult patients

paediatric patients

Aplastic anaemia (AA) is a bone marrow failure disease characterized by a decrease in blood cells and anaemia, recurrent infections and bleeding [1]. The mechanism of acquired AA is associated with immunologic deregulation from the expansion of cytotoxic T cells, a decrease in regulatory T cells and an increase in inflammatory TH-1-related cytokines and proteins [2–3]. For patients with severe aplastic anaemia (SAA), intensive immunosuppressive therapy (IST), including antithymocyte globulin (ATG) and cyclosporin A (CsA), is typically recommended as the preferred treatment option for those who are not suitable candidates for haematopoietic stem cell transplantation (HSCT) [1]. Previous studies have shown that age is an independent factor influencing the efficacy of IST treatment alone and that overall survival of patients on IST is generally greater in children than in adults [4–6].

Thrombopoietin receptor agonist (TPO-RA) is an oral small-molecule drug that can initiate signalling cascades through interaction with the transmembrane structural domain of thrombopoietin receptors, as well as promote the proliferation and differentiation of bone marrow progenitor cells, consequently inducing haematopoiesis [7–8]. In recent years, with the application of TPO-RAs such as eltrombopag (EPAG) in the treatment of AA, the haematologic response has improved, and the 6-month response rate to the IST approach has reached 80% [9–10]. Similarly, the addition of TPO-RA to IST has been reported to significantly enhance the effectiveness of this therapy in patients with SAA [11–13]. However, most of the patients enrolled in these trials were adults; for paediatric patients, the benefits of adding TPO-RA are somewhat uncertain [14–16]. To date, there has been no direct comparison of IST treatment, especially after the addition of TPO-RA, between adult and paediatric patients. Therefore, the aim of this study was to evaluate differences in efficacy and survival between adults and children receiving IST ± EPAG. This study retrospectively analysed the clinical data of adult and paedia25tric patients with newly diagnosed SAA who had been treated with IST alone or with IST + EPAG and compared the differences in haematological response and long-term prognosis. Moreover, factors that may influence treatment efficacy were also analysed.

Patients and data collection

Data were collected and reviewed from patients newly diagnosed with SAA in the period from February 2013 to March 2022 at Peking Union Medical College Hospital (PUMCH) or Beijing Children's Hospital affiliated with Capital Medical University who had been treated with standard IST alone or IST + EPAG. Those patients did not undergo allogeneic HSCT due to the absence of HLA-matched sibling donors, age or personal preference. Patients who met the following criteria were included in the final analysis: (1) newly diagnosed with acquired SAA; (2) having been treated with rabbit ATG with CsA or rabbit ATG with CsA and EPAG; and (3) had a last follow-up date of September 30th, 2023, with all surviving patients followed for at least 12 months before enrolment. Patients who were diagnosed with hereditary bone marrow failure syndrome, myelodysplastic syndrome (MDS) or flaer-negative granulocytes larger than 50% with uncontrolled infection or severe liver or kidney impairment before treatment were excluded. Paroxysmal nocturnal haemoglobinuria (PNH) clones were detected by flow cytometry, and a PNH clone was considered to be present when the percentage of flaer-negative granulocytes exceeded 1%.

This study was approved by the Ethics Committee of Peking Union Medical College Hospital (Ethics No. K5283) and Beijing Children's Hospital of Capital Medical University (Ethics No. 2019-k-276). Informed consent was waived for retrospective studies.

Clinical data, including sex, age, baseline assessments (such as blood cell count, reticulocyte count, liver and kidney function, serum ferritin (SF), PNH clone, bone marrow smear and trephine biopsy, chromosomal karyotype and genetic mutations), time from diagnosis to ATG treatment, and treatment regimens, including the ATG dosage, CsA dose and trough concentration, EPAG dosage and duration, were recorded.

Criteria for diagnosis and response

The diagnosis of SAA and haematological response assessment were performed according to the Guidelines for the Diagnosis and Treatment of Aplastic Anaemia (2016 edition) [17]. For patients younger than 50 years, chromosome breakage tests, comet tests, telomere length tests, cytogenetic analyses and myeloid gene sequencing were conducted to exclude congenital bone marrow failure disorders. SAA was defined as a blood count that met at least two of the following three criteria: absolute neutrophil count (ANC) < 0.5×10⁹/L, platelet count (PLT) < 20×10⁹/L, and reticulocyte count (RET) < 20×10⁹/L. Cases with ANC < 0.2×10⁹/L were defined as very severe aplastic anaemia (VSAA).

The haematologic response was evaluated, including the overall response rate (ORR) and complete response rate (CRR), at 3, 6 and 12 months after standard IST or IST + EPAG treatments and at the end of follow-up. The definition of response was as follows: (1) complete response (CR) was defined as a haemoglobin (Hb) level reaching the normal range for that sex and age group, ANC > 1.0×10⁹/L, and PLT > 100×10⁹/L; (2) partial response (PR) was defined as transfusion independence and no longer meeting the SAA diagnostic criteria; (3) no response (NR) was defined as still meeting the diagnostic criteria for SAA; and (4) overall response (OR) was defined as achieving at least a PR (PR + CR) [17].

Possible predictive factors for the ORR and CRR at 6 months, such as sex, age, time from diagnosis to treatment (months), baseline neutrophil count, lymphocyte count, haemoglobin, platelet count, reticulocyte count, SAA or VSAA, the presence of PNH clones, the presence of chromosomal karyotype abnormalities, the presence of myeloid mutations and the use of EPAG, were analysed.

Clonal evolution, overall survival (OS) and event-free survival (EFS) were also documented.

Overall survival (OS): OS was calculated from the first day of IST treatment until the date of death or the last known survival.

Event-free survival (EFS) was defined as the time interval from the start of IST ± EPAG treatment to the occurrence of an event (death, relapse, clonal evolution, haematopoietic stem cell transplantation, or loss to follow-up).

Relapse was defined as the recurrence of lower peripheral blood cell counts after effective IST therapy which required second-line therapy, such as adding EPAG to those with IST alone or HSCT for those with IST + EPAG.

PNH clonal evolution was defined as the absence of PNH clones with subsequent presentation of PNH clones or as the expansion of PNH clones during follow-up.

Clonal evolution, which is the progression to myeloid cancer, was defined as the progression to myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) [18].

Possible influencing factors for OR, CR, OS and EFS, such as sex, age, time from diagnosis to treatment (months), baseline neutrophil count, lymphocyte count, haemoglobin, platelet count, reticulocyte count, SAA or VSAA, the presence of PNH clones, the presence of chromosomal karyotype abnormalities, the presence of myeloid mutations and the use of EPAG, were analysed.

Treatment regimen

IST ATG: rabbit ATG (rATG, Sanofi, France) 3–5 mg/(kg·d) for 5 days. Methylprednisolone was given to prevent serum sickness. CsA was started at 3–5 mg/kg twice a day, and the plasma trough concentration was maintained at 100–200 ng/ml. After the optimal efficacy was reached, the drug was continued for at least 6 months before the dose was tapered. The total duration of treatment was 2–3 years (Fig. 1).

TPO-RAs: Adult group: EPAG at a dosage of 100–150 mg qd. Children: EPAG at a dosage of 2.5 mg/kg qd for those aged 2–5 years, 50–75 mg qd for those aged 6–12 years, and 100 mg qd for those > 12 years (Fig. 1).

Supportive therapy: Patients were given anti-infective treatment, transfusion, and granulocyte colony-stimulating factor if needed. No other concomitant medications were given.

Statistical analysis

SPSS 24.0 statistical software (IBM SPSS, Somers, NY, USA) was used. Nonnormally distributed data are presented as medians (interquartile ranges, IQRs), whereas count data are expressed as cases (%). Differences between groups were evaluated via chi-square tests and Kruskal‒Wallis rank‒sum tests for categorical variables. Chi-square tests, Kruskal‒Wallis rank-sum tests and logistic regression were used to identify the factors that influenced treatment efficacy, and factors with P < 0.2 in the univariate analysis were included in the multivariate regression analysis. The Kaplan‒Meier method was used to estimate OS and EFS, and the OS and EFS of subgroups were compared via the log-rank test. Multivariable Cox proportional hazard regression models were used to analyse the factors influencing both OS and EFS. All the statistical tests were two-sided, and P values of < 0.05 were considered significant.

Patient characteristics

A total of 366 patients were enrolled in this study. The median age was 11 years (IQR 5–36), with a male/female ratio of 1.16:1. Among them, 222 (60.7%) patients had SAA, and 144 (39.3%) had VSAA. There were 141 (38.5%) adult patients and 225 (61.5%) paediatric patients. The median age of the adults was 40 years (IQR 26–52); 53.2% of these adults were male, 90 (63.8%) had SAA, and 51 (36.2%) had VSAA. The median age of the paediatric patients was 6 years (IQR 4–10); 54.2% of these children were male, 132 (58.7%) had SAA, and 93 (41.3%) had VSAA.

Patients were further classified into IST + EPAG (54 and 152 patients in the adult and paediatric groups, respectively) and IST alone groups (87 and 73 patients in the adult and paediatric groups, respectively), baseline clinical characteristics, including blood cell counts, severity, PNH clone, chromosomal karyotype and myeloid gene mutation were examined (Table 1) .With the exception of age, adult and paediatric patients had similar baseline characteristics either with IST alone or with IST + EPAG (P>0.05, Table 1).

Response

For all 366 SAA patients, an ORR of 61%, 75%, and 76% and a CRR of 14%, 29%, and 45% were observed at 3, 6, and 12 months after the initial IST with or without EPAG, respectively. For the IST alone group, there was no significant difference in the ORR at 3, 6 and 12 months between the adult and paediatric groups, with 3-month ORRs of 52% vs. 59% (P = 0.426), 6-month ORRs of 69% vs. 74% (P = 0.599) and 12-month ORRs of 76% vs. 75% (P = 1.000) in the adult and paediatric groups, respectively. Similarly, no significant difference was found in the 3- and 6-month CRRs, with 3-month CRRs of 3% vs. 11% (P = 0.113) and 6-month CRRs of 21% vs. 22% (P = 0.849) in the adult and paediatric groups, respectively. However, the 12-month CRR in the adult group was lower than that in the paediatric group (31% vs. 48%, P = 0.048; Table 2).

For the IST + EPAG groups, there was no significant difference in the ORR or CRR at 3 and 6 months, with 3-month ORRs of 67% vs. 64% (p = 0.868) and 6-month ORRs of 83% vs. 76% (P = 0.567), 3-month CRRs of 13% vs. 21% (p = 0.229) and 6-month CRRs of 25% vs. 38% (p = 0.124) in the adult and paediatric groups, respectively. However, at 12 months, the ORR was greater in adults than in children (89% vs. 73%, P = 0.027), and the CRR was not significantly different between the two cohorts (54% vs. 50%, P = 0.614; Table 2). These data indicate that the addition of EPAG induces an improvement in haematological response in adult more than in paediatric patients.

Analysis of factors affecting response

Since the difference between adults and children occurred mainly at 12 months after IST, we further analysed factors that may affect the ORR and CRR at 12 months. For the whole cohort, no predictive factor was found for the ORR or CRR. Subgroup analysis revealed that for the adult cohort, a higher baseline platelet count (P = 0.034) and the application of EPAG (P = 0.007) were the independent favourable factors for the ORR, whereas EPAG (P = 0.015) was the only independent favourable factor for the CRR; for the child cohort, younger age (P = 0.048) was associated with a greater ORR. No predictive factors were found for the CRR in children. These data suggest that baseline platelet count, EPAG and age play important roles in haematological response.

4-year OS, EFS

With a median follow-up of 42 (IQR 21–81) months, the 4-year OS was 92.9%±1.5%, and the 4-year EFS was 71.9%±2.7% for the whole cohort (Fig. 2A and 3B). For the IST alone group, the 4-year OS and 4-year EFS were significantly lower in adults than in children (OS 84.9 ± 3.9% vs. 96.9 ± 2.2%, P = 0.007; Fig. 2C; EFS 66.4 ± 5.1% vs. 79.7 ± 5.3%, P = 0.047; Fig. 2D). However, after adding EPAG to the IST, there was no statistically significant difference in 4-year OS or 4-year EFS between the adult and paediatric groups (OS 91.4 ± 4.2% vs. 96.7 ± 1.8%, P = 0.081; Fig. 2E; EFS 75.1 ± 6.3% vs. 72.3 ± 4.7%, P = 0.834; Fig. 2F). These results indicate that the addition of EPAG has a greater improvement in survival for adult compared to paediatric patients.

Relapse and clonal evolution

OR was obtained in 82.2% (301 of 366) of the whole cohort, with a total of 13.3% (40/301) of relapses. With a similar follow-up time in the IST alone group [82(49–100) months in adults vs. 91(79–101) months in children, P = 0.139] and the IST + EPAG group [35(23–46) months in adults vs. 32(21–42) months in children, P = 0.114], the relapse rates were similar in adult and paediatric patients treated with IST alone (15.5% vs. 13.1%, P = 0.806) and those treated with IST + EPAG (10.4% vs. 13.2%, P = 0.797).

A total of 3.3% (12/366) of patients had clonal evolution (PNH + MDS/AML evolution) at the end of follow-up. Adult patients had a significantly greater clonal evolution rate than did paediatric patients not only in the IST alone group (9.2% vs. 1.4%, P = 0.040) but also in the IST + EPAG group (5.5% vs. 0%, P = 0.017). However, subgroup analysis revealed that adult patients were similar to paediatric patients in terms of both PNH evolution [IST alone (4.6% vs. 0%, P = 0.126); IST + EPAG (1.8% vs. 0%, P = 0.262)] and MDS/AML progression [IST alone (4.6% vs. 1.4%, P = 0.337); IST + EPAG (3.7% vs. 0%, P = 0.068), Table 2], probably due to the relatively small number of patients in each subgroup.

Possible factors affecting 4-year OS and EFS

For the whole cohort, the application of EPAG was the only independent factor for better OS (P = 0.006). No predictive factor was found for EFS. Subgroup analysis revealed that for the adult group, the use of EPAG (P = 0.022) was an independent factor for OS, but no independent factor was found for EFS. For the paediatric group, no independent factor was found for OS, but the time from diagnosis to treatment (P = 0.004) and the baseline reticulocyte count (P = 0.031) were independent factors for EFS.

There are many studies analysing IST combined with TPO-RA in adult and paediatric SAA patients separately. However, comparisons of adult and paediatric patients treated with IST with or without TPO-RA are rare. Our investigation is a parallel cohort study with currently the largest number of both adult and paediatric patients to address the issue of whether there are differences in the efficacy and survival of EPAG application between children and adult patients with SAA.

Our study revealed that when patients were treated with IST alone, the 12-month ORR in adults was similar to that in children, and the CRR was lower than that in children. After the addition of EPAG, the ORR of adults improved and exceeded that of children at 12 months, and the CRR increased to a level similar to that of children, which was lower with IST alone. Many studies on the efficacy of standard IST in adult patients have shown that age remains a strong predictor of response and survival [4, 6, 19]. In first-line IST-alone therapy patients, the only factor associated with a better response was age younger than 40 years [5]. In recent years, efforts to improve the efficacy of IST-only therapy have been largely unsuccessful until TPO-RAs, such as EPAG, were added to IST therapy [10]. The addition of EPAG improved the rate, rapidity, and strength of the haematologic response among previously untreated SAA patients [9]. With the application of TPO-RA, the 6-month ORR increased to approximately 65% [9, 11–12]. Many meta-analyses have confirmed that TPO-RAs can significantly improve the haematological response of adult SAA patients, not only by raising the ORR and CRR but also by increasing the reaction depth and speed [20–23]. With respect to children, studies from the National Institutes of Health (NIH) have shown that EPAG does not improve outcomes in children [15], whereas other studies have shown contrasting results. Previous publications from Harry et al. have shown that the addition of EPAG to standard IST results in a satisfactory haematological response at 6 and 12 months in children [15]. A randomized controlled trial showed that compared with standard IST, the addition of EPAG significantly improves the CRR of paediatric patients [16]. Similarly, many studies have confirmed this result and have shown that EPAG increases the speed of haematological reactions and improves the CRR but does not significantly improve the ORR in paediatric patients [24–27]. A meta-analysis including adults and children suggested that EPAG + IST is more effective than IST alone in adult patients with SAA; however, for paediatric patients, the addition of EPAG may not improve the efficacy. The possible reason for this finding was that paediatric patients responded better than adult patients did, and the response rate was already high with IST alone in children [28]. Although still controversial, these studies on adults and children concur that adults benefit more from the addition of EPAG than paediatric patients do, which is in accordance with our direct comparison of adults and paediatric patients. Interestingly, more adults than children achieved CR between 6 and 12 months after IST + EPAG treatment (CRR increase from 25–54% in adult patients vs. from 38–50% in paediatric patients), indicating that EPAG yields a later response in adults.

When the possible predictive factors for the 12-month OR and CR were analysed, no predictive factors were found in the whole cohort. However, subgroup analysis revealed that baseline platelet count and application of EPAG were related to a better ORR, whereas EPAG treatment resulted in a better CRR in adults, which agreed with our findings that EPAG was beneficial for adult patients and was also proven by previous studies [9–13]. For children, age was the only favourable independent factor for a higher ORR, and no other factors were found for either the ORR or the CRR. A paediatric study indicated that younger children had lower response rates than did adolescents among patients receiving EPAG combined with IST [14], indicating that younger children benefit less than older children do, which agreed with our findings. A previous study involving adults and children with SAA revealed that a higher reticulocyte count, a lower thrombopoietin and a higher neutrophil count were the factors contributing to the haematological response in the IST combined with TPO-RA group, and the addition of EPAG markedly improved the overall response in subjects with an absolute reticulocyte count between 10 and 30 ×10⁹/L, ranging from 60–91% [29]. These findings indicate that age and residual haematopoiesis may remain the key factors for the response to IST + TPO-RA therapy.

On the other hand, we found that when the patients were treated with IST alone, OS and EFS were lower in adults than in children. This result was consistent with previous research, which showed that younger age was associated with better survival [4–6]. However, after the addition of EPAG, the OS and EFS in adults increased to levels similar to those in children. The application of EPAG significantly bridged the gap between OS and EFS that previously existed between adult and paediatric patients treated with standard IST. In other words, the addition of EPAG compensated for the objective disparity in bone marrow hematopoietic function that existed between adults and children due to different ages at IST alone era. Previous studies in adults have shown that EPAG therapy can improve OS and EFS [5, 9–11], and the improvement in EFS is more pronounced in individuals over the age of 40 years [5]. For paediatric patients, many studies have suggested that EPAG has no effect on OS or EFS [15–16, 24–25]. Our direct comparison further confirmed these findings.

The relapse rate was similar to that of children in both the IST alone group and the IST + EPAG group. Several studies have confirmed that EPAG does not affect the relapse rate either in adults or in children [10, 15, 30–32]. Clonal evolution remains a significant long-term complication in SAA patients [18, 33]. Our research revealed that, whether treated with IST alone or IST + EPAG, adult patients had a greater incidence of clonal evolution than paediatric patients did. This result was consistent with a previous study that revealed that older individuals, especially those over 48 years old, are more prone to clonal evolution [30]. The incidence rate of MDS in elderly patients was also significantly higher than that in young patients, which has been confirmed by previous studies [34–35]. There are concerns that the addition of TPO-RA may lead to a higher rate of malignant clonal evolution, but these concerns have not been verified by previous studies [33–34] and were not found in our study either. Indeed, our study showed that adding EPAG did not change the differences in clonal evolution between adults and children.

Regarding predictive factors for the OS, addition of EPAG was the only independent factor for both the whole group and adults but not for the children. No EFS-predicting factors were found for either the whole group or the adult group. However, the time from diagnosis to treatment and the baseline reticulocyte count were independent factors for children. Because of the very significant improvement in OS in adults after the addition of EPAG, it is reasonable that EPAG treatment status can predict OS in both adults and the whole cohort. Very few studies are available to predict OS and EFS in cohorts, including both adults and children with EPAG or without EPAG. In a study, Stephen reported that posttreatment status and age were associated with long-term prognosis in patients receiving IST alone [19]. A study conducted by Régis revealed that groups with or without EPAG had similar OS rates at the 2-year follow-up and that older age was the only risk factor for OS in IST alone and IST + EPAG patients. Older age and disease severity are risk factors for EFS [9]. However, the above researchers mainly enrolled patients who were older than 15 years. On the other hand, the difference may also be due to the diversity of follow-up times between the two groups. The follow-up time in our study was much longer than that in Régis' study (35 months vs. 23 months in the IST + EPAG group and 82 months vs. 24 months in the IST alone group). For the paediatric cohort alone, Meixin Fang’s study revealed that no significant factors affected OS in paediatric patients [36], which is similar to our results. Overall, the long-term prognosis of adults but not children could be improved by the addition of EPAG, whereas the degree of bone marrow impairment may affect EFS in children.

Our study also has several limitations. First, this was a retrospective study, which may have shortcomings such as the patient selection, treatment regimens and follow-up duration variations, and these limitations may have caused bias in the data analysis. Second, the number of patients was limited, making further age stratification and other subgroup analyses difficult. However, this study included 366 patients with a wide age range and a relatively long follow-up time (the median follow-up duration was 42 months), which is rare.

Our findings suggested that the addition of EPAG led to a significant improvement in the response and survival of adult patients which were inferior to those of children previously receiving IST alone. However, adding EPAG did not overcome relapse or clonal evolution in adult patients. Considering the high cost of EPAG, the value of EPAG in children needs further evaluation.

Author contributions

BXY, LYW, LLF and MC participated in study execution, data acquisition and drafting. MC, JM and BH designed the study, revised and critically reviewed the article. All authors gave final approval of the article version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was supported by CAMS Innovation Fund for Medical Sciences（CIFMS, 2023-12M-C&T-B-013），National Natural Science Foundation (82370121), National High Level Hospital Clinical Research Funding (2022-PUMCH-C-026, 2022-PUMCH-D-002).

Competing interests

The authors declare no competing interests.

Data availability statement

All the data are available in the main text. All the detailed metadata are available upon reasonable request from the corresponding author.

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Table 1 and 2 are available in the Supplementary Files section.

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Adding eltrombopag to intensive immunosuppressive therapy helps adult patients catch up pediatric patients in severe aplastic anemia

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