Transfusion-dependent Non-severe Aplastic Anemia Research Articles

The Efficacy of Hetrombopag Combined with Cyclosporine a in Patients with Transfusion-Dependent Non-Severe Aplastic Anemia

Objective: Thetherapeutic approach for transfusion-dependent non-severe aplastic anemia (TD-NSAA) is undetermined. Though the British guideline recommended intensive immunosuppressive therapy (IST) as front-line therapy for TD-NSAA ( Killick SB, et al. British Journal of Haematology. 2016; 172(2): 187-207), the cost and risk were relatively high. Hetrombopag is a thrombopoietin receptor agonist approved for IST-refractory severe aplastic anemia (SAA) by the China Food and Drug Administration in 2021 ( Peng G, et al. Ther Adv Hematol. 2022; 13: 20406207221085197). This study aimed to evaluate the efficacy of hetrombopag plus cyclosporine A (CsA) for TD-NSAA. Methods: 24 eligible patients receiving hetrombopag plus CsA from September 2021 to July 2023 were collected by prospective registration (ChiCTR2100045895) in the Chinese Eastern Collaboration Group of Anemia (CECGA). A historical cohort (n=79) receiving CsA alone from December 2013 to January 2017 in the CECGA was used as a comparator (Table 1). Primary endpoint was overall response at 24 weeks, defined as hematologic response in ≥ 1 lineage. Secondary endpoints were overall response at 12 and 48 weeks, complete response at 48 weeks, overall survival, transformation to SAA and treatment-related adverse events. Results: At 24 weeks, the overall response rate was 74% in hetrombopag plus CsA cohort and 16% in CsA cohort (odds ratio [OR]: 14.7; 95% confidence interval [CI]: 4.1 ~ 52.4; p＜0.001). The overall response rates at 12 and 48 weeks were also significantly higher in hetrombopag plus CsA cohort than those in CsA cohort (43% vs 8%, OR: 9.1, 95% CI: 2.7 ~ 31.1, p＜0.001; 85% vs 30%, OR: 13.0, 95% CI: 2.5 ~ 66.2, p = 0.001, respectively). At 48 weeks, the complete response rate was 23% in hetrombopag plus CsA cohort and 2% in CsA cohort (OR: 13.8; 95% CI: 1.3 ~ 146.8; p = 0.029). The median time to initial response was 11.6 [95% CI: 2.9~20.3] weeks in hetrombopag plus CsA cohort, significantly shorter than that in CsA cohort (hazard ratio: 5.0; 95% CI: 2.1 ~ 12.1; p＜0.0001) (Figure 1). The median time to erythroid, platelet and neutrophil responses in hetrombopag plus CsA cohort were 20.6 [95% CI: 9.1 ~ 32.0], 16.4 [95% CI: 3.0 ~ 29.9] and 23.0 [95% CI: 10.6 ~ 35.4] weeks, respectively. The 1-year survival rates in hetrombopag plus CsA cohort and in CsA cohort were similar (90% vs 94%; hazard ratio: 1.9; 95% CI: 0.2 ~ 15; p = 0.5). The percentage of patients transforming to SAA was 8% in hetrombopag plus CsA cohort and 34% in CsA cohort (OR: 0.2; 95% CI: 0.0 ~ 0.8; p = 0.018). Treatment-related hepatic or renal injury occurred in 7 patients (29%) in hetrombopag plus CsA cohort with only one ≥ Grade 3; all gained remission after dose reduction or discontinuation. Multivariate analysis of clinical parameters of all patients from both cohorts revealed that adding hetrombopag to therapy was strongly correlated with response (OR: 43; 95% CI: 4 ~ 528; p = 0.003), as was lower lymphocyte count (OR: 0.5; 95% CI: 0.3 ~ 0.8; p = 0.011). Conclusion: The combination of hetrombopag with CsA improved the rate, rapidity, and strength of hematologic response among patients with TD-NSAA, and lowered their risks of transforming to SAA. Disclosure: This study is supported by National Natural Science Foundation of China (81900109). The authors declare that there is no conflict of interest.

Adding Hetrombopag to Cyclosporine a to Patients with Newly Diagnosed Transfusion-Dependent Non-Severe Aplastic Anemia-a Prospective Phase 2 Study

Abstract Objective: To investigate the efficacy and safety of adding hetrombopag to cyclosporin A (CsA) in patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA). Methods: This was a single center, prospective phase 2 study. Eligible patients were aged 18 years or older, were diagnosed as TD-NSAA within 6 months and treatment-naïve. Enrolled patients were treated with hetrombopag and CsA. Hetrombopag was started at 10mg/day with possible titration up to 15mg/day, and tapered gradually when the optimal response was achieved. CsA was given at 3-5mg/kg/d for at least 6 months, and tapered after the optimal response was reached. The primary endpoint was the overall response rate (ORR) and safety at 6 months. Patients who had been followed-up for at least 6 months were included in the analysis. A history cohort with compatible baseline characters treated with CsA alone were analyzed as control. The trial was registered with ClinicalTrails.gov NCT05018936. Result: Between Oct 2021 to Oct 2022, 28 patients were enrolled, comprising 13 men and 15 women, median age 46(range: 18-81). The ORR was 68.2% at 6 months. The most frequently reported adverse events were gastrointestinal discomfort grade 1 or 2. No grade 3 or 4 treatment-emergent adverse events were reported. There were 30 patients enrolled in the history control cohort with compatible baseline characters including age, sex ratio, complete blood cell count (P>0.05). After a median follow-up of 15 (range: 9-22) vs 16 (range:9-24) months(P>0.05), the ORR at 3, 6 months and the end of follow-up were 57.1% vs 16.7% (P=0.001), 68.2% vs 30.0% (P=0.006) and 90.9% vs 46.6%(P<0.001) in hetrombopag plus CsA group and CsA alone group, respectively. The complete response rate (CRR) at 3, 6 months and the end of follow-up were 10.7% vs 0% (P=0.068), 22.7% vs 10.0% (P=0.217) and 36.4% vs 16.6% (P=0.109) in both groups, respectively. Adverse effects were reported in 13 (46.4%) patients in hetrombopag plus CsA group and 15 (50%) patients of CsA alone group (P>0.05). 1 (3.6%) vs 8 (26.6%) patient relapsed (P=0.038) at 6 month in both groups. Clone evolution were noticed in no patients in hetrombopag plus CsA group and 2 (6.7%) patients in CsA alone group at 12 and15 months, respectively (P=0.225). Conclusion: Adding hetrombopag to CsA can improve the ORR for newly diagnosed TD-NSAA, with good tolerance and lower relapse rate. Keywords: Transfusion-dependent aplastic anemia, Hetrombopag, Cyclosporin A, efficacy, relapse.

Differences between Peripheral and Bone Marrow Lipidomics in Patients with Severe Aplastic Anemia and Its Finding in Predicting the Early Immunosuppressive Therapy Response

Aplastic anemia (AA) is a common clinical hematological disease, which is characterized by pancytopenia due to bone marrow hematopoietic failure. AA can be divided into severe AA (SAA) and non-severe AA (NSAA) based on disease severity. Anti-thymoglobulin (ATG)-based immunosuppressive treatment (IST) is recommended as the main first-line treatment for AA patients when stem cell transplantation is not available. The mechanism of AA has not been fully clarified. When considering role of the bone marrow microenvironment, current studies showed that the abnormal of quantity, function, and differentiation of mesenchymal stem cells (MSCs) were involved in the occurrence and development of AA, including the boost of adipocyte. Han, et al. [PMID: 35445952] found that the peripheral serum lipid profile may have great meaning in the differentiation diagnosis between transfusion-dependent non-severe AA and hypo- myelodysplastic syndrome (MDS), as well as in predicting their response to cyclosporine (CsA). Our previous study [PMID: 36192750] also revealed that the higher apolipoprotein-A is a potential prognostic biomarker for severe AA patients treated with ATG-based IST. However, the understanding of peripheral serum lipid metabolism may not fully represent the changes in bone marrow. Herein, we try to investigate the difference of lipid metabolomic profile between bone marrow and peripheral serum in SAA patients, and explore its meaning in predicting early IST response. In this study, a total of 11 SAA patients and 15 age and sex matched healthy donors were enrolled. Among them, six SAA received ATG based IST (Table. 1). An orthogonal partial least-squares discrimination analysis (OPLS-DA) model was established to analyze the differences between the subgroups and overfitting was accessed by permutation test (Fig A, B). The following volcano map (Fig. C) and heat map (Fig. D) confirmed that there were differences in subgroups to a certain degree. To explain the difference, we firstly compared lipid metabolism profile between patients (P) and donors (D) in peripheral serum (ps) (P ps Vs D ps) and bone marrow (bm) serum (P bm Vs D bm), and found that the difference in bone marrow was more distinct than that in peripheral serum, which suggested bone marrow may be more reliable as clinical samples in studies (Fig. E). Secondly, bone marrow serum and peripheral serum (P bm Vs P ps) in SAA patients were compared, fatty acids were upregulated (Fig. F), which indicated that there may be hyperproduction or transport disorder of fatty acid in bone marrow than in peripheral serum. Thirdly, comparing patients' baseline bone marrow lipid metabolites with donors' bone marrow lipid metabolites and with patients' bone marrow after treatment respectively, and analyzing the intersections of differences in two comparison groups, there were 11 common different metabolites, including 4 sphingolipids, 2 glycerides, 2 glycerophospholipids, 2 glycolipids, and 1 steroid lipid. Pathway analysis illustrated those metabolites were involved mainly in metabolism of sphingolipid, glycerophospholipid and glycerophospholipid, indicating that IST may restore homeostasis of bone marrow by affecting those pathways. Finally, we compared the bone marrow serum lipidomics between the SAA patients achieved 3-months response (CR/PR) and no response (NR). The difference of lipid metabolism was reduced after 3 months, while the differences in glucuronolipid (GlcADG) and phosphatidylinositol (PI) were significantly increased (Fig. G). In summary, difference of lipid metabolism between SAA and donors was more obvious in bone marrow, and the lipid metabolism process of bone marrow was less affected by external factors. IST may restore the homeostasis of lipid metabolism in the bone marrow by affecting metabolism of sphingolipid and glycerophospholipid, and GlcADG and PI may be used as new predictors for early IST response in SAA patients.

Comparison of anti-thymocyte globulin-based immunosuppressive therapy and allogeneic hematopoietic stem cell transplantation in patients with transfusion-dependent non-severe aplastic anaemia: a retrospective study from a single centre

Objectives The selection and timing of anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) or allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA) pose significant clinical challenges. This study aims to compare the efficacy and long-term outcomes of the two treatments in TD-NSAA. Methods Patients who underwent ATG-based IST or allo-HSCT between July 2011 and December 2019 were reviewed. We gathered their clinical information, treatment response, survival data, and subsequently analysed the associated risk factors. Results A total of 97 TD-NSAA patients were reviewed, and 55 patients who underwent either ATG-based IST (n = 27) or allo-HSCT (n = 28) were enrolled. We observed a significant disparity in the 12-month overall response rate (ORR) (48.1% in IST vs 78.6% in HSCT, p < 0.05), but not in five-year overall survival (OS) and event-free survival (EFS). Multivariate Cox regression analysis identified the transfusion of ≥78.75 units of red blood cells (RBCs) as the sole independent risk factor for OS (HR: 17.04, p = 0.039) in the IST group. For the HSCT group, disease duration (DD) ≥20 months and transfusion of ≥78.75 units of RBCs predicted an adverse EFS. Frontline IST exhibited superior 12-month ORR (68.8% vs 18.2%, p = 0.018) and five-year EFS when compared to non-frontline. Patients with a DD ranging from 6 to 20 months displayed a better EFS (p = 0.016) in HSCT group than those in the ATG-based IST group. Conclusions Prior treatment history, disease duration, and serum ferritin levels should be carefully weighed when making the choice between ATG-based IST and allo-HSCT for TD-NSAA.

Transfusion-dependent non-severe aplastic anemia: characteristics and outcomes in the clinic.

Transfusion-dependent non-severe aplastic anemia (TD-NSAA) is a rare condition of bone marrow failure that can persist for a long time or develop into severe aplastic anemia (SAA). Little is known about the clinical and laboratory characteristics, and disease prognosis and outcomes in TD-NSAA patients. The clinical and laboratory data of 124 consecutive TD-NSAA patients in the Chinese Eastern Collaboration Group of Anemia from December 2013 and January 2017 were analyzed retrospectively. In 124 TD-NSAA patients, the median age was 32 years (range: 3-80) and the median disease course was 38 months (range: 3-363). Common complications were iron overload (53/101, 52.5%), liver and kidney dysfunction (42/124, 33.9%), diabetes mellitus/impaired glucose tolerance (24/124, 19.4%), and severe infection (29 cases, 23.4%). 58% of patients (57/124) developed severe aplastic anemia with a median progression time of 24 months (range: 3-216). Patients with absolute neutrophil count (ANC) <0.5×109/L, severe infection, or iron overload had a higher probability of progression to SAA (P=0.022, P=0.025, P=0.001). Patients receiving antithymocyte globulin (ATG) plus Cyclosporin A (CsA) had a higher overall response rate compared to those receiving CsA alone (56.7% vs 19.3%, P < 0.001). The addition of ATG was the favorable factor for efficacy (P=0.003). Fourteen patients developed secondary clonal hematologic disease: eleven patients with paroxysmal nocturnal hemoglobinuria, two patients with myelodysplastic syndromes, and one patient with acute myeloid leukemia, respectively. Ten patients (8.1%) died with a median follow-up of 12 months (range: 3- 36 months). Patients with TD-NSAA usually have a prolonged course of disease, and are prone to be complicated with important organ damage and disease progression to SAA. Intensive immunosuppressive therapy based on ATG might be an appropriate approach for TD-NSAA. Clinical trial registration: http://www.chictr.org.cn/edit.aspx?pid=125480&htm=4, identifier ChiCTR2100045895.

Effect of Eltrombopag on Response to Immunosuppressive Therapy in Patients with Transfusion-Dependent Non-Severe Aplastic Anemia

To compare the efficacy of eltrombopag combined with cyclosporine A (CsA) and CsA alone in patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA). The clinical data of 76 patients with treatment-naive TD-NSAA in Ningde Municipal Hospital of Ningde Normal University and Affiliated Hospital of Nantong University from December 2017 to June 2021 were retrospectively analyzed. Among them, 45 cases were treated with eltrombopag combined with CsA, and 31 patients with compatible baseline characters were treated with CsA alone. The efficacy of patients between the two groups was compared, and the factors affecting the curative effects were also analyzed. There were significant differences in hematological response (HR) and complete response(CR) rates between the two groups at 3, 6, 12 months, and follow-up endpoint of treatment (P<0.05). With the prolongation of eltrombopag treatment time, the curative effect increased gradually, and the patients achieved more CR and HR rates by the end of the follow-up period. Simultaneously, with the increase in the maximum stable dose of eltrombopag, the HR rate increased gradually. The megakaryocyte count in eltrombopag group was higher than that in control at 6 and 12 months (P<0.05). Compared with the control group, the median time of platelet transfusion independence in eltrombopag group was more shorter (P=0.018), and the median platelets transfusion volume was lower (P=0.009). At 3, 6, 12 months after eltrombopag, the change of platelet in eltrombopag group was higher than that in the control group (P<0.05). Analysis of related factors affecting the efficacy showed that sex, age, iron overload, platelet count before treatment had no effect on the efficacy, and the median maximum stable dosage and the administration period for eltrombopag were related to the curative effect. The patients of eltrombopag group experienced adverse events of varying degrees, but the reactions were mild and mostly tolerated. Eltrombopag can effectively improve the hematopoietic response and promote platelet recovery for TD-NSAA patients with relatively more residual hematopoietic cells, and it is safe and well tolerated.

Comparison of ATG-Based Immunosuppressive Treatment and Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Transfusion-Dependent Non-Severe Aplastic Anemia: A Single Center, Retrospective Analysis

Transfusion-dependent non-severe aplastic anemia (TD-NSAA) refers to aplastic anemia (AA) that is dependent on blood transfusion but does not fulfilling the criteria for severe AA (SAA). It has been clear that allogeneic hematopoietic stem cell transplantation (HSCT) and anti-thymocyte globulin (ATG)-based immunosuppressive therapy (IST) is the front line for the treatment of SAA, but there is no consensus on the treatment timing and strategy for TD-NSAA. The natural history observation reported that the progress-free survival (PFS) of TD-NSAA at 60 months after diagnosis is around 62%, but decreased significantly to 22% at 120 months. In China, the practical guideline recommends cyclosporine-based IST with or without hematopoietic stimulating regimes (such as androgens) as initial treatment, and further treated as SAA if no response was observed after 6 months management. As reported, the hematopoietic response of ATG-based IST was much better than CsA-based IST (75% Vs. 55.8%, 6-month) for TD-NSAA, however, the relapse and clonal expansion are still the unavoidable events. For HSCT, the long-term PFS is much better than IST for SAA, but the complications (including graft versus host disease, various infection, etc.), transplantation related mortality, as well as donor availability still limited its application. At present, there is limited data compared the efficiency of HSCT and IST for TD-NSAA. With the development of haplo-identical transplantation in China, most TD-NSAA own a donor, and we also performed HSCT for those young patients after informed consent. Herein, we respectively compared the efficiency of ATG-based IST and HSCT for TD-NSAA, and also analyzed the risk factors that contribute to the overall survival (OS) as well as event free survival (EFS). During Jul 2011 to Dec 2019, 97 TD-NSAA patients were diagnosed in our cohort, among them, 5 only received supportive treatment, 30 received CsA-based IST with or without androgen, and the other 62 patients received HSCT or ATG-based IST therapy. We further analyzed the efficiency and prognosis of 55 patients aged 16-60 years old who received HSCT or ATG-based IST therapy. Among them, 27 (49.09%) patients received ATG-based IST, and the others performed HSCT (including 14 from sibling donor, 7 from haplo-identical donor and 7 from unrelated donor) (the baseline information showed in Table1). Results showed that the 12-month overall response rate (ORR) of ATG-based IST and HSCT were 48.1% (with 18.52% CR) and 78.57% (with 60.71% CR), respectively (P=0.04, Fig A). The median time of achieving transfusion-free was 94(35-205) and 24(11-139) days, respectively in ATG-based IST and HSCT group (P<0.001, Fig B). The 5-year OS and EFS rates were 54.9±13.3% and 34.5±12.1% in ATG-based IST group respectively, and 70.0±9.0% and 62.6±9.6% in HSCT group, while no statistically differences was observed (Fig C and D). To explore the possible influencing factors of 5-year OS and EFS, we performed COX regression analysis based on age, disease duration, baseline absolute neutrophil count (ANC), hemoglobin (HB), platelet count (PLT), serum ferritin (SF), lymphocyte percentage, and CD4/CD8 ratio. Univariate analysis showed that disease duration, baseline HB, SF, and ANC may affect OS and EFS of patients in ATG-based IST group (Table 2), and multivariate analysis showed that SF≧1000ng/ml was an independent risk factor for OS in ATG-based IST group. While in the HSCT group, patients with disease duration≧20 months had a higher risk of events (Table 3). The subgroup analysis showed that in HSCT group, patients with disease duration of 6 to 20 months had a lower risk of events (HR=0.196, 95%CI: 0.046-0.832); the HR of the group <6 months and ≥20 months were not statistically significant (Fig E). TD-NSAA patients with disease duration between 6 months and 20 months had a higher EFS rate in HSCT group than that in ATG-based IST group (Fig F). The subgroup analysis of mortality was not statistically significant (Fig G). To conclusion, TD-NSAA patients should be actively treated, patients with shorter disease duration and no iron overload may achieve a better response. The 12-month ORR in the HSCT group was higher than that in the IST group, but there was no significant difference in OS rate and EFS rate, even there is a great difference tendency. For TD-NSAA patients with a disease duration between 6 to 20 months, HSCT has a higher EFS rate than IST, which may be a better choice. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

P827: EFFICACY AND SAFETY OF ROMIPLOSTIM ADDED TO IMMUNOSUPPRESSIVE THERAPY AS A FIRST-LINE TREATMENT IN PATIENTS WITH APLASTIC ANEMIA: A PHASE 2/3 CLINICAL TRIAL

Background: Romiplostim, a thrombopoietin (TPO) mimetic protein, has been shown to promote tri-lineage hematopoiesis in patients with acquired aplastic anemia (AA) refractory to immunosuppressive therapy (IST) or eltrombopag; however, its effectiveness in the combination therapy with antithymocyte globulin (ATG) plus cyclosporine (CsA) as a first-line treatment remains unknown. Aims: To clarify this issue, we conducted a phase 2/3 clinical trial to evaluate the efficacy and safety of romiplostim combined with rabbit ATG plus CsA in patients with AA requiring transfusions who had not been exposed to IST. Methods: This study was a multi-national, open-label study with romiplostim in IST-naïve adult patients with AA (NCT03957694). 10 µg/kg of romiplostim was started on day 1 of ATG therapy (2.5mg/kg/day for 5 days) and was weekly given for the first 4 weeks. The dose was adjusted from 5 to 20 µg/kg according to the prespecified dose adjustment procedure. Treatment lasted until Week 26. For those who intend to continue treatment, romiplostim administration was extended to Week 52. The primary endpoint was the hematological response rate (HRR) at Week 27 based on the response assessment criteria (Table 1). The secondary endpoints included the HRR at Week 14; the time to the hematological response; the proportion of patients who achieved transfusion independence or who showed a reduction of transfusion requirement among patients who had received a transfusion within 8 weeks prior to the first romiplostim administration. The bone marrow and cytogenetic analyses were performed prior to enrollment and at Week 27 and 53. Results: Twenty-six patients were screened, of which 17 (9 Japan, 7 Korea, and 1 Taiwan; 5 transfusion dependent non-severe AA, 6 severe AA (SAA) and 6 very SAA) were enrolled in the study. The median age was 44.0 years (range: 25-70). Two patients discontinued romiplostim before Week 27. The HRR (CR or PR) at Week 27 was 76.5% (95% CI: 50.10%, 93.13%), of which 6 (35.3%) achieved CR. The HRR at Week 14 was 41.2% (95% CI: 18.44%, 67.03%). The median day to achieve the first hematological response was 93.0 (range: 63-181). Of the 16 patients who depended on platelet transfusion before romiplostim administration, 14 (87.5%) achieved transfusion independence or showed a reduction of transfusion requirement at Week 27. In addition, of 16 who required erythrocyte transfusion at baseline, 13 (81.3%) achieved transfusion independence or showed a reduction of transfusion requirement at Week 27. The frequently reported adverse events (AEs) were constipation (41.2%) followed by headache (35.6%). The frequently reported drug-related AEs were headache (12.9%) followed by muscle spasms (9.7%), alanine aminotransferase increased, fibrin D dimer increased, malaise, and pain in extremity (each 6.5%). In bone marrow examination, increases of reticuline grade (grade 1 to 2) were observed in 3 patients at Week 27 and 1 patient at Week 53. No chromosomal abnormality or transformation into MDS and/or AML was observed. Image:Summary/Conclusion: This is the first clinical trial of romiplostim combined with rabbit ATG plus CsA in patients with acquired AA requiring transfusions who were previously untreated with IST. This regimen produced higher HRR at Week 27 (76.5%) than those of historical control received rabbit ATG plus CsA (approximately 50% at 6 months), with manageable AEs, and could therefore serve as a new first-line treatment option in patients with AA.

The efficacy of eltrombopag plus cyclosporine A in patients with transfusion-dependent non-severe aplastic anemia: a retrospective study from single center

The main purpose of our study was to evaluate the efficacy and safety of eltrombopag plus cyclosporine A (CsA) in transfusion-dependent non-severe aplastic anemia(TD-NSAA). The clinical characteristics of 13 TD-NSAA patients who received initial treatment of eltrombopag plus CsA from 2019 to 2021 were retrospectively analyzed. The 3-month overall hematological response (OR) rate was 12/13. Until the end of follow-up, 12 patients responded, among whom 2 patients reached complete response (CR) and 9 patients reached partial response (PR) and 1 with HR. Paroxysmal nocturnal hemoglobinuria (PNH) developed in one patient at 6 months after treatment. Five of thirteen patients reported mild adverse reactions, which were all manageable. Compared with historical data, the combination of eltrombopag with CsA is an effective regimen in patients with TD-NSAA.

Cyclosporine Monotherapy in Pediatric Patients With Non-severe Aplastic Anemia: A Retrospective Analysis.

ObjectiveThe management of children with non-severe aplastic anemia (NSAA) is undefined and the efficacies and benefits of immunosuppressive therapy remain inconsistent. The study aimed to investigate the efficacy of Cyclosporine (CsA) monotherapy for pediatric NSAA.MethodsClinical data of children with NSAA who had been treated with CsA monotherapy at the outpatient department of Beijing Children's Hospital, Capital Medical University, National Children's Medical Center from January 2017 to March 2021 was collected retrospectively. Patients who had been treated <1 years until the end of follow-up were excluded. Transfusion-independent NSAA was further divided into moderate NSAA and mild NSAA according to the degree of cytopenia. Progression was defined as the development of transfusion-dependent AA or SAA and relapse was considered when treatment failed after initial response.ResultsA total of 95 pediatric patients with NSAA were enrolled in this study with 49 (51.6%) patients confirmed as mild NSAA, 38 (40%) as moderate NSAA and 8 (8.4%) as transfusion-dependent NSAA. The median treatment time of CsA was 22 (12–44) months. The overall response rate (ORR) was 57.9%, with 30.5% CR and 27.4% PR. Unexpectedly, patients with mild NSAA acquired lowest ORR (46.9%), then patients with moderate NSAA (63.2%), while 8 patients who were transfusion-dependent all had an active response to CsA. The granulocyte and megakaryocyte response was 46.9 and 55.8% respectively, while the erythrocyte response rate was as low as 22.5%. Univariate analyses revealed that patients with lower platelet count and higher interleukin 10 level predict an active response to CsA while higher level of fetal hemoglobin (HbF) tended to be a negative factor. Data of Treg cells before and after 1 year's treatment was available in a total number of 40 patients. Paired comparison found that the percentage of Treg cells in CD4+ T cells was decreased after 1 year's treatment of CsA (6.78 ± 2.72 vs. 5.23 ± 2.06, P = 0.001),both in responders and non-responders. The degree of decline in Treg cells between two distinctive response groups had no significant difference (P>0.05). With a median follow-up time of 22 months, 10.9% of responders relapsed and maintained NSAA while 27.5% of non-responders progressed to SAA or became transfusion-dependent. The overall progression rate was 11.6%.ConclusionCsA monotherapy had heterogeneous effects in the treatment of children NSAA Treatment approaches should be hierarchical and individual in clinical. Patients with lower platelet count and higher interleukin 10 level predicted an active response to CsA. While higher level of fetal hemoglobin (HbF) tended to be a negative factor. The percentage of Treg cells in CD4+ T cells was decreased broadly after treatment.

Efficacy of Rabbit Antithymocyte Globulin as a First-line Therapy in Children With Aplastic Anemia.

The efficacy, safety, and outcome of rabbit antihuman thymocyte globulin (rATG) as initial therapy for children aplastic anemia (AA) were evaluated. Sixty-one children with AA were retrospectively analyzed, including 43 patients with severe AA and 18 patients with transfusion-dependent nonsevere AA. All patients received rATG in combination with cyclosporine A between September 2005 and January 2015. The overall response rates were 55.7%, 68.9%, and 68.9% at 6, 12, and 18 months, respectively. Surprisingly, the overall complete response rate kept increasing from 9.8% at 12 months to 39.3% at 18 months, indicating a delayed response for rATG. Overall survival at 5 and 10 years was 72.1% and 67.2%, respectively. The overall survival of patients who responded between 3 and 12 months was significantly higher than that of nonresponders (71.4% vs. 47.4%).Antithymocyte globulin-related adverse reactions were significantly higher in severe AA (83.7%) than in nonsevere AA (55.6%) and these reactions were controllable and not life threatening with comprehensive measures. This retrospective study shows an encouraging response and survival results in children with AA treated with rATG. Prolonged assessments were needed to evaluate the delayed responses to rATG. rATG could be used as an alternative in the first-line treatment of childhood AA.

Prognostic factors of cyclosporine A combined with androgen in the treatment of transfusion dependent non-severe aplastic anemia

目的调查影响环孢素A（CsA）联合雄激素方案治疗输血依赖非重型再生障碍性贫血(TD-NSAA)获得血液学反应的因素。方法回顾性分析2010–2013年连续收治的77例TD-NSAA患者临床资料，单因素和多因素分析影响CsA联合雄激素治疗方案获得血液学反应患者的基线临床和血液学特征。结果77例TD-NSAA患者治疗后6个月和12个月获得血液学反应分别为43例（55.8％）和53例（68.8％），单因素分析基线血小板计数［19（6～61）×109/L对13.5（5～45）×109/L，P＝0.001］是影响6个月获得血液学反应的唯一因素；基线血小板计数［18（6～61）×109/L对10.5（5～45）×109/L，P<0.001］、网织红细胞绝对值［0.03（0.01～0.06）×1012/L对0.03（0.02～0.06）×1012/L，P＝0.043］、血小板输注依赖（P＝0.007）和红细胞及血小板输注依赖（P＝0.012）为治疗后12个月能否获得血液学反应相关因素。多因素分析显示基线血小板水平为获得血液学反应独立影响因素（P值分别为0.010和0.009）。受试者工作特征曲线（ROC曲线）方法显示基线PLT界值为15.5×109/L。结论TD-NSAA患者初诊时较高的血小板基线水平、网织红细胞基线水平和不伴血小板输注依赖均提示预后较好，血小板水平≥15.5×109/L时可以考虑采用CsA联合雄激素治疗。

Real-World Effectiveness and Safety of Eltrombopag in Patients with Aplastic Anemia: A Chinese Nationwide Survey

Immunosuppressive therapy (IST) based on antithymoglobin (ATG) and cyclosporin (CsA) is the first-line treatment for severe aplastic anemia (SAA) patients who are unfit for transplantation,and the overall response rate (ORR) is about 70%.The utility of eltrombopag (EPAG),a TPO receptor agonist, achieved robust hematologic response in refractory and treatment-naïve SAA patients in clinical trials and some other studies. However, only a few data came from Asia countries where higher incidence of AA has been reported. A retrospective study on the use of EPAG in AA was conducted in mainland China. Aplastic anemia (transfusion dependent non-severe, severe, and very severe) patients who started eltrombopag before Feb 2019 and continued for at least 3 months either as first-line treatment or as rescue treatment, were enrolled. The maximum daily dosage of EPAG used continuously for at least 2 weeks is defined as the stable dosage. Response criteria were referred to that used in previous reports (Townsley DM, NEJM 2017; BCSH, BJH 2016). Fifty-six patients from eleven centers were enrolled in this study, including 26 males and 30 females at the median age of 39 (7-80) years. All patients were transfusion-dependent by the time of EPAG administration, and there were 14 VSAA, 24 SAA and 18 transfusion dependent non-severe aplastic anemia (TD-NSAA). Nineteen treatment-naïve patients received EPAG and IST (ATG+CsA, n=10; CsA/CsA+androgen, n=9) as first-line treatment. Thirty-seven patients were refractory to IST. Eltrombopag was administered at a median dose of 75 (25-150) mg per day for 7 (3-31) month. The median follow-up time was 9 (3-40) months. The overall response rate in patients receiving EPAG as first-line therapy was 78.9% (15/19), and most patients achieved complete response (CR) (10/15). Among the 10 patients receiving ATG+CsA, 6 patients achieved hematologic response (HR) at 3 months post-treatment, including 3 CR. Six patients were diagnosed as VSAA and three achieved HR. For the 9 patients treated with CsA/CsA+androgen, 8 achieved HR (88.9%) and 4 were CR (44.4%) at 3 months. By last follow-up, the cumulative HR rate was 70% in ATG+CsA group and 89% in CsA/CsA+ androgen group. Among the 14 responders, 11 patients receiving EPAG at a stable dosage ≤75mg/d and achieved HR at 3 months. The overall response rate in IST-refractory patients was 46% (17/37), with trilineage response in 27% patients at 3 months. For the 18 ATG+CsA refractory SAA patients,trilineage HR occurred in 4 patients (22.2%, 4/18), bi-lineage HR in one patient and single lineage HR in one patient. Thus, the total HR was 33.3% (6/18) at 3 months and increased to 44% (8/18) by last follow-up. Among the 19 CsA/CsA+ androgen refractory patients, 6 (31.5%, 6/19) achieved trilineage HR, one achieved bi-lineage HR and 4 achieved single lineage response. Total HR rate was 57.9% (11/19) at 3 months after EPAG initiation and 68% (13/19) by last follow-up, including 9 patients with trilineage HR. Among 17 responders, 13 received a stable EPAG dose of≤75mg/d. Most patients tolerated EPAG well. Adverse events occurred in 29 patients (52%) and most were mild to moderate, including gastrointestinal symptom (n=15, e.g. abdominal pain, nausea), impaired liver function (n=5), skin changes (n=7, e.g. skin pruritus and rash) and musculoskeletal pain (n=6), and venous thrombus (n=2). Eltrombopag dosage was reduced in 2 patients due to severe digestive symptoms at 100 mg/d and discontinued in one patient who suffered from upper limb venous thrombus. In conclusion, EPAG is effective and safe in treating Chinese AA patients at a daily dose of 75mg and less. The real-world result of EPAG in Chinese patients is similar to those reported in Western countries. Disclosures No relevant conflicts of interest to declare.

Clinical Efficacy of Therapies for Transfusion-Dependent Non-Severe Aplastic Anemia: A Retrospective Cohort Study in Multiple Hospitals

BACKGROUND: This study aims to evaluate the clinical efficacy and prognosis of currently popular treatments for patients with transfusion-dependent non-severe aplastic anemia (TD-NSAA).METHODS: Medical records of patients with TD-NSAA were collected from three hospitals and divided into four groups based on their treatment. Treatment efficacy was evaluated at 6 months after treatment, with subgroup analysis based on patients' disease courses. Adverse events and 3-year survival status were also reviewed.RESULTS: A total of 175 patients' records were collected in this study. The analysis of treatment efficacy indicated that the most effective treatment was allo-hematopoietic stem cell transplant (HSCT) with the response rate of 84.62%, which was followed by Anti thymocyte globulin and ciclosporin A (ATG + CsA) (68.52%), CsA + androgen (26.92%), and androgen (0%), respectively. The subgroup analysis showed that for patients with less than 6-month disease courses, ATG + CsA treatment could achieve similar response rate as allo-HSCT (84.00%). Besides, ATG + CsA showed better efficacy than CsA + androgen in all stratified arms (P<0.05). Three-year event-free survival rates were higher in patients treated with ATG + CsA (83.3%) than with CsA + androgen (64.4%) (P=0.013).CONCLUSIONS: Therefore, we concluded that ATG+ CsA could achieve better efficacy to treat TS-NSAA than did CsA+ androgen. DisclosuresNo relevant conflicts of interest to declare.

Treatment of transfusion-dependent nonsevere aplastic anemia with cyclosporine A plus ATG/ALG versus cyclosporine A plus androgens: a retrospective single center study

目的比较抗人胸腺／淋巴细胞球蛋白（ATG/ALG）联合环孢素A (CsA）与CsA联合雄激素一线治疗输血依赖非重型再生障碍性贫血（TD-NSAA）疗效。方法回顾性分析2007年8月至2014年9月125例TD-NSAA患者临床资料，比较一线采用ATG/ALG联合CsA与CsA联合雄激素治疗的血液学反应及生存情况。结果125例TD-NSAA患者中，男70例，女55例，男女比为1.27∶1；中位年龄27 (6~66）岁。其中48例一线接受ATG/ALG联合CsA治疗，77例一线接受CsA联合雄激素治疗，两组早期死亡率分别为2.1%（1/48）及0 (0/77）（P=0.384）。ATG/ALG联合CsA组患者治疗后3个月总体血液学反应率（70.8％对45.5%，P=0.006）和良好血液学反应率（27.1％对10.4%，P=0.015）均高于CsA联合雄激素组；两组治疗后6个月总体血液学反应率（75.0％对55.8%，P＝0.031）与良好血液学反应率（41.7％对22.1%，P=0.020）差异亦有统计学意义，治疗后6个月ATG/ALG联合CsA组脱离血制品输注依赖的中位时间为36.5 (0~149) d，明显短于CsA联合雄激素组的98 (14~180）d（P<0.001）。ATG/ALG联合CsA组与CsA联合雄激素组患者3年总生存率（97.9％对100.0%，P=0.227）和无事件生存率（71.2％对59.5%，P=0.227）差异无统计学意义。结论一线采用CsA联合雄激素治疗TD-NSAA血液学反应率和血液学反应质量均不及ATG/ALG联合CsA，两组患者短期生存率相同，应优选ATG/ALG联合CsA方案治疗TD-NSAA。

Interim Results of a Multi-Center Observational Study of Current Treatment Patterns for Patients with Severe Aplastic Anemia (SAA), Very Severe Aplastic Anemia (VSAA) and Transfusion-Dependent Non-Severe Aplastic Anemia (TD-NSAA) in China

BackgroundIn China, the incidence of aplastic anemia (AA) is about 0.74/105, with 0.14/105 of severe aplastic anemia (SAA). Most of these SAA patients are treated in big medical centers or traditional Chinese medicine (TCM) hospitals, which could stand for the current practices in China. Despite the China Aplastic Anemia Consensus, published in 2010, recommended that the immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT) were the standard treatment for SAA, very severe aplastic anemia (VSAA) and transfusion-dependent non-severe aplastic anemia (TD-NSAA), the current treatment options for patients with these diseases are diverse, including antithymocyte globulin (ATG)/antilymphocyte globulin (ALG) + cyclosporin A (CsA), CSA + androgen, CSA or androgen alone, only supportive care, TCM, etc. This national disease registry study aimed to describe the current clinical practice and treatment patterns for SAA, VSAA and TD-NSAA patients in China and understand their IST patterns as well as the supportive care measures.MethodsIn this prospective, multi-center, observational study, adult or pediatric patients diagnosed as acquired aplastic anemia within 3 months and met the guideline criteria of SAA, VSAA or TD-NSAA were enrolled from October 2012 to April 2014. All enrolled patients will be followed at least for one year. Each subject will be visited every 3 months in the first year and every 6 months from the second year until the patients withdraw the ICF or study close. The main evaluation criteria is the treatment patterns of SAA, VSAA and TD-NSAA which will be specified as: IST (ATG + CsA, CsA + androgen, CsA and others), HSCT, TCM, androgen, supportive care and others. The response of SAA/VSAA and TD-NSAA after each treatment, and serious adverse events, will also be evaluated by the investigators. An interim analysis is planned when all patients have been enrolled (target N=350) and will focus on their baseline characteristics and first treatment choice. This study was sponsored by Sanofi.ResultsA total of 352 patients were enrolled at 29 sites in China (SAA 221 pts; VSAA 84 pts; TD-NSAA 47 pts). The median age was 21 years (range, 0-84) and 65.1% were adults. 51.7% were male and 71.6% had ECOG PS <2. The vast majority of enrolled patients (344/352 pts, 97.7%) had no previous AA-related history. The most common onset symptom at baseline was anemia (92.9%), followed by hemorrhage (72.2%), infection (56.8%) and others (3.4%). TD-NSAA patients had less infections than SAA or VSAA patients (25.5% vs. 57.9%/71.4%). Cytogenetic abnormality were detected in 6.1% of the 245 patients who received cytogenetic test at baseline. The analysis of the primary endpoint showed 74.1% and 4.3% of the total patients received IST and HSCT at baseline, respectively. Among the patients with IST treatment, the standard ATG + CsA treatment was only applied in 26.4% of them (SAA 25.5%; VSAA 42.4%; TD-NSAA 5.4%). The other IST regimens were CsA + androgen (31.0%), CsA (31.4%) and others (11.1%). Three different brands of ATG/ALG were used in patients with IST: Rabbit ATG (75.0%), ATG-Fresenius (2.1%) and ALG-Porcine (22.9%). TCM therapy were applied in 12.8% of the total patients and were more common in SAA/VSAA patients (15.8% & 10.7%, respectively) than in TD-NSAA patients (2.1%). 2.8% of the patients received androgen therapy alone at baseline. 8 patients (2.3%) had switched their treatment pattern within 3 months before the enrolment because of unsatisfying efficacy (5 pts) or personal reasons (3 pts). Supportive care was applied in 95.7% of the total patients. The supportive care measures included blood transfusion (97.9%), antibiotics (64.1%), hematopoietic growth factors (58.8%), protective isolation (46.6%), iron chelators (0.3%) and others (2.7%). When the study initiated, the first treatment choice for all patients were IST (74.1%), HSCT (3.4%) and others (22.4%). There were no substantial difference of the first treatment pattern among SAA, VSAA and TD-NSAA groups.ConclusionsChinese AA patients received diverse treatments in real life clinical practice. Based on this interim analysis, 74.1% of the SAA, VSAA and TD-NSAA patients in China received IST. But only 26.4% of them received the standard ATG + CsA therapy. TCM therapy still played a role in the treatment, especially for SAA and VSAA patients in China. Final results including efficacy and safety profiles will be reported later. DisclosuresOff Label Use: Anti-thymocyte globulin-Fresenius is used as an immunosuppressive therapy for the treatment of aplastic anemia.

Prospective Phase II Pilot Study of Rabbit Antithymocyte Globulin (ATG, Thymoglobuline) with Ciclosporin for Patients with Acquired Aplastic Anemia and Matched Pair Analysis with Patients Treated with Horse ATG (Lymphoglobuline) and Ciclosporin: A Study From the EBMT Severe Aplastic Anemia Working Party (RATGAA07)

Abstract 2408 BackgroundPreviously, horse antithymocyte globulin (hATG) with ciclosporin (CSA) was the standard immunosuppressive therapy (IST) for patients with aplastic anemia (AA) ineligible for HSCT, with response rates of 60–75% within 3–4 months. Rabbit ATG (rATG, Thymoglobuline, Genzyme) was reserved for non-response or relapse after a course of hATG. Following the withdrawal of hATG (Lymphoglobuline) from the market, the use of rATG as first line IST has been evaluated prospectively with hATG (ATGAM, Pfizer) in a randomised study from NIH (Scheinberg et al, NEJM, 2011), reporting significantly lower response rate and worse outcome after rATG. We report here the results of a multicenter, EBMT, phase II pilot study of 35 patients with AA enrolled between August 2008 and August 2010 at 10 centres (EUdraCT number 2007–000902–55). Patients enrolled were ineligible for matched sibling HSCT, had not received prior ATG or CSA and included both severe AA (SAA) and transfusion dependent non-severe AA (NSAA). The median age was 36 years (range 17–75). Six (17%) patients had very severe AA, 20 (57%) SAA and 9 (26%) had NSAA. Primary endpoint was response at 6 months. Dose of rATG was 3.75mg/kg daily for 5 days. CSA dose was 5mg/kg daily from day +1. For prevention of serum sickness, prednisolone was given at 1–2mg/kg daily from day 1–5, then the dose halved every 5 days. Results were compared in a 3: 1 ratio with 105 historical patients from the EBMT registry, matched for categorised age and disease severity, and who had been treated with hATG (Lymphoglobuline, Genzyme) and CSA. The study was designed to demonstrate a 25% difference in total response to rATG, with 80% power at a 5% level of significance. The median follow up for all patients treated with rATG is 285 days (6–781). ResultsAt 3 months, no patients had achieved a complete response (CR). Partial response (PR) occurred in 11 (34%). Two patients died, on day +6 and +9, and one was lost to follow up. At 6 months, CR rate was 7% (n=2) and PR rate 32% (n=11). One patient relapsed at 59 days. Five patients underwent unrelated donor HSCT for non-response to rATG, at day +153, 168, 321, 322 and 460 post rATG. Infections occurred in 22 (63%), elevated liver function in 10 (29%), rash in 8 (23%), haemorrhage in 7 (20%), hypertension in 6 (17%), abnormal renal function in 6 (17%), arthralgia in 5 (14%), avascular bone necrosis in one. There were 10 deaths after rATG (28.5%) and one following subsequent HSCT. Infections were the main cause of death in 9/10 patients. For rATG, overall survival at 2 yr was 56%, compared to 78% for hATG, p=0.001. Overall survival after censoring HSCT patients was 39% for rATG and 72% for hATG, p=0.0005. On multivariate analysis, rATG (RR = 3.4, p=0.003) and age > 37 years (RR = 3.8, p=0.002), were independent adverse risk factors for survival. Disease severity and time from diagnosis to treatment were not significant risk factors. CR at a given time was 11% for rATG and 44% for hATG, and PR for rATG was 43% and 23% for hATG. There were 19/105 (18%) deaths after hATG.Changes in CD4+ T-cells were analysed in a subset of 5 patients from a single center, prior to rATG (n=5) and post rATG (n=8). The relevant (preliminary) findings are:pre-ATG therapy, number of Tregs was significantly lower in AA compared to healthy age-matched controls (p=0.009), while Th17 (p=0.014), Th1 cells (p=0.014) and Th2/Tregs ratio (p=0.025) were higher in AA patients. Following treatment with ATG, the frequency of Th1 (p=0.002) and B-cells (p=0.007) was reduced but there was no significant change in the frequency of Tregs, Th17/Tregs or T-helpers/Tregs ratios. However, the frequency of cytokine secreting non-Tregs (CD4+ CD25high CD45 RA− Foxp3low) studied in 5 patients was significantly increased in post treatment samples (p=0.02) and there was a trend for a higher frequency in non-responders compared to responders. ConclusionsWe report significantly inferior response and survival with rATG (Thymoglobuline) compared to hATG (Lymphoglobuline), and a high incidence of serious infections with rATG, in association with significant changes in CD4+ T-cell subsets. These results have major implications for future treatment algorithms for AA and improve further our understanding of the mechanism of action of rATG in AA. Disclosures:Marsh:Genzyme: Consultancy, Research Funding. Off Label Use: ATG used in treatment of aplastic anemia. Schrezenmeier:Genzyme: Research Funding. Risitano:Genzyme: Honoraria. Dufour:Pfizer: Research Funding. Elebute:Alexion: Honoraria. Mufti:Celgene: Consultancy, Research Funding; Genzyme: Research Funding. Bacigalupo:Genzyme: Speakers Bureau; Pfizer: Research Funding.