Myelodysplastic syndrome (MDS) represents a heterogeneous group of myeloid neoplasms, with approximately two-thirds identified as lower-risk MDS (LR-MDS). LR-MDS with thrombocytopenia is associated with poor prognosis, a high risk of life-threatening hemorrhage, and limited treatment options. We explored a prospective single-arm, single-center study on the combination of very-low-dose decitabine (VLD-DAC, 3.5 mg/m2/day from days 1 to 5 of a 28-day cycle) and recombinant human thrombopoietin (rhTPO, 1.5 million units/day from days 1 to 14) for treating LR-MDS with thrombocytopenia (platelet count < 50 × 109/L). The primary endpoint was the hematologic improvement-platelet (HI-P) rate. Among 20 patients, 19 completed at least two treatment cycles. Of these, 63

ObjectivesVEXAS syndrome is a recently characterized hemato-inflammatory disorder caused by somatic mutations in the X-linked UBA1 gene in hematopoietic cells, which remains poorly characterized in Chinese populations. This study aims to address this gap.MethodsWe retrospectively analyzed 4512 consecutive patients with hematologic abnormalities at a Chinese academic hospital between June 2023 and July 2024, identifying 16 male VEXAS patients (median age 61.5 years, range 30-74).ResultsAll patients presented with anemia and lymphopenia, with or without neutropenia and thrombocytopenia. Diagnoses included CCUS, MDS, MGUS, as well as novel phenotypes of primary myelofibrosis and a hemolysis-like disorder. Most patients (11/16, 69%) exhibited constitutional symptoms and typical autoinflammation-associated multiorgan involvement, including skin lesions, ear chondritis, pulmonary infiltration, and deep vein thrombosis, etc. Hypercellular bone marrow was commonly seen in core biopsies and 11 patients (68.8%) exhibited typical vacuoles in myeloid and erythroid progenitors. Canonical UBA1 pathogenic variants were detected in 81.3% (13/16) of patients, with p.M41V being the dominant mutation. Three infrequent variants were also identified: c.118-1G>C, p.S56P, and p.S621C. Corticosteroids and immunosuppressants commonly provided symptomatic relief, while variable hematologic responses were achieved with androgens and erythropoiesis-stimulating agents.ConclusionsAs a relatively large cohort of VEXAS syndrome characterizing Chinese patients, our findings demonstrate that VEXAS should be considered in those with cytopenia, regardless of systemic symptoms or multiorgan involvement. Increased awareness among hematologists is critical to facilitate early diagnosis via UBA1 testing. This can prevent unnecessary diagnostic procedures and guide appropriate treatment, including consideration of pre-emptive stem cell transplantation.

Non-severe aplastic anemia (NSAA) is a heterogeneous bone marrow failure syndrome with limited standardized treatment options. Cyclosporine A (CsA) monotherapy often yields suboptimal responses, highlighting an unmet clinical need for more effective therapies. Thrombopoietin receptor agonists (TPO-RAs) have shown satisfying outcomes in severe aplastic anemia (SAA), but data on their frontline use in NSAA remain scarce. We enrolled 54 adults with newly diagnosed NSAA, including 25 with transfusion-dependent NSAA (TD-NSAA) in the prospective, single-arm Phase 2 trial (NCT05660785) to evaluate the efficacy and safety of hetrombopag, an oral TPO-RA, in combination with CsA. At 24 weeks, the overall response rate (ORR) was 81.5% (44/54), comprising 72.2% partial responses and 9.3% complete responses (CRs). Notably, CR and robust partial response (robust PR) were achieved in 46.3% (25/54) of patients. In the TD-NSAA subgroup, the ORR was even higher at 88.0% (22/25) with substantial improvements in hematologic parameters and quality of life. Extending treatment from 16 to 24 weeks increased the CR and robust PR rate from 24.0% to 44.0%. The median time to achieve an initial response was 6, and 14 weeks for robust PR. Adverse events occurred in 35% of patients, predominantly Grade 1 or 2 and were manageable. Importantly, no clonal progression to myelodysplastic syndrome or leukemia was observed. These findings support hetrombopag plus CsA as a potential first-line therapeutic intervention for NSAA, especially in TD-NSAA patients.

Aplastic anemia (AA) is an immune-mediated bone marrow failure disorder with 15-20% risk of clonal evolution. We analyzed 371 patients with AA receiving immunosuppressive therapy (IST). All patients underwent PNH testing and 357 evaluable for cytogenetic analysis. Two hundred and thirty-seven received serial targeted sequencing. Clonal characteristics were compared before and after IST across age, disease severity, and hematological response. Among the 237 patients, somatic mutations were detected in 53 patients (22%) at baseline and 97 (41%) after IST. Distinct patterns of mutational dynamics were observed under IST, with newly acquired mutations defined as Pattern 2 being most common. High-risk mutations such as ASXL1 expanded persistently, whereas favorable clones like BCOR and PIGA often contracted or remained stable. Older age was associated with heavier mutational burden, and disease severity was associated with greater increase in mutations. Cytogenetic abnormalities were observed in 18 of 357 patients (5%) and rose to 37 (10%) post-treatment. PNH clones were present in 20% of patients at baseline and remained relatively stable during follow-up, 15 patients progressed to PNH syndrome. Six patients evolved to myeloid neoplasms, including myelodysplastic syndromes and chronic myelomonocytic leukemia. These findings highlight the importance of long-term molecular surveillance (ClinicalTrials.gov number, NCT04645199).

BACKGROUND:In patients with autoimmune hemolytic anemia (AIHA), the risk of relapse is high owing to persistent autoreactive B-cell activity. Multirefractory AIHA is a more advanced stage of disease that is defined by a lack of response to at least three lines of therapy. CD19-directed chimeric antigen receptor (CAR) T-cell therapy results in profound B-cell depletion and may be a useful approach to achieving drug-free remission in multirefractory AIHA. METHODS:We enrolled patients from a compassionate-use program and those from a phase 1 study who had primary multirefractory AIHA. Each patient received a single infusion of autologous CD19 CAR T cells. The primary objective was to assess the safety profile - the incidence, characteristics, and severity of adverse events, including cytokine-release syndrome and immune effector cell-associated neurotoxicity syndrome. Secondary objectives included efficacy and pharmacokinetic features. A complete response was defined by resolution of symptoms, an increased hemoglobin level, and normalization of hemolysis markers. B-cell reconstitution and the origin of relapse were analyzed with flow cytometry, single-cell RNA sequencing, and paired B-cell receptor sequencing. RESULTS:CD19 CAR T cells were administered to 11 patients - 5 in the compassionate-use program and 6 in the phase 1 study. The median follow-up was 12.2 months (range, 7.3 to 21.9). All patients had a complete response; the median time to a complete response was 45 days (range, 21 to 153). The median duration of drug-free remission was 11.5 months (range, 6.8 to 21.0). Cytokine-release syndrome of grade 1 or 2 in severity occurred in 9 patients, and immune effector cell-associated neurotoxicity syndrome of grade 1 occurred in 1 patient. A total of 15 infections occurred among 7 patients, with no infections of grade 4 or higher. One patient had immune effector cell-associated hematotoxicity of grade 3. In multi-omics assessments of sequential samples, naive B cells were predominant in the reconstituted B-cell population in patients with drug-free remission, and crosstalk between HLA-DRB5+ B cells, CD4+ T cells, and B-cell maturation antigen-expressing long-lived plasma cells contributed to a relapse-specific B-cell niche. CONCLUSIONS:CD19 CAR T-cell therapy had expected toxic effects and resulted in sustained remission in patients with multirefractory AIHA. (Funded by the National Key Research and Development Program of China and others; ClinicalTrials.gov number, NCT06231368.).

Background:Thrombopoietin receptor agonists combined with anti-thymocyte globulin (ATG) and cyclosporine (CsA) are the standard immunosuppressive therapy (IST) for severe/very severe aplastic anemia (SAA/VSAA). However, early response rates remain suboptimal. Cyclophosphamide (CTX) has shown efficacy in relapsed/refractory AA. Therefore, we designed a clinical trial to evaluate low-dose CTX combined with the standard IST as a first-line treatment for SAA/VSAA to improve early response rates. Methods:This study was a single-arm, prospective, phase II clinical trial using a Simon's two-stage design, and 43 patients were enrolled. The primary endpoint was the overall response rate (ORR) at 3 months. Newly diagnosed SAA/VSAA patients received a combination treatment as follows: porcine ATG at 25 mg/kg/day from days 1 to 5, CsA at 3-5 mg/kg/day continuously, hetrombopag at 15 mg/day starting from day 1 and continued for 6 months, low-dose CTX at 20 mg/kg/day on days 29-30 and days 43-44. Results:All 43 patients achieved the primary endpoint, demonstrating 3-month and 6-month ORR of 65.1% (28/43) and 69.8% (30/43) respectively. Complete response (CR) rates were 9.3% (4/43) at 3-month and 27.9% (12/43) at 6-month. CTX associated toxicities comprised 100% grade 1-2 gastrointestinal reactions, grade 3-4 neutropenia in 62.8% of patients (median duration 6 days, range 4-33). Infectious events occurred in 60.5% (26/43) of patients within the first 3 months of treatment, while no mortality observed during this period. Conclusions:Low-dose CTX combined with standard IST appears to improve the early response rate in SAA/VSAA patients with manageable toxicity.

ABSTRACT:We found that 8 of 10 patients with aplastic anemia experienced resolution of platelet transfusion refractoriness following daratumumab administration. Notably, 4 responders achieved hematopoietic recovery, including 3 participants who showed improvements in multilineage blood cell counts, even with daratumumab monotherapy. This trial was registered at www.clinicaltrials.gov as #NCT05832216.

Differentiating between immune thrombocytopenia (ITP), aplastic anemia (AA), and myelodysplastic syndromes (MDS) is critical due to the distinct treatment approaches required for each condition. This study investigates the role of serum thrombopoietin (TPO) levels as a potential biomarker to aid in the diagnosis of these hematological disorders. This retrospective cohort study analyzed serum TPO levels in patients diagnosed with ITP, AA, and MDS, using clinical records and stored serum samples collected from patients treated between September 2023 and May 2024. Statistical analyses were performed to determine cut-off values for TPO levels that effectively differentiate between these conditions. Additionally, machine learning models were utilized to enhance diagnostic accuracy based on clinical indicators, including TPO levels. Serum TPO levels were markedly elevated in AA (1369.19 ± 751.26 pg/ml) compared to ITP (263.57 ± 355.91 pg/ml), MDS (434.55 ± 551.56 pg/ml), and health control (71.64 ± 30.32 pg/ml) (P < 0.0001). Correlation analysis revealed a significant positive correlation between TPO levels and ITP, AA, and MDS (P < 0.0001), Linear regression analysis indicated that age was a significant predictor of TPO levels (P < 0.0001). The optimal cut-off value for TPO levels distinguishing ITP from AA was 302.43 pg/mL, yielding an AUC of 0.925 (sensitivity with 80.75

Background Incorporating thrombopoietin receptor agonists (TPO-RAs) into standard immunosuppressive therapy (IST) has significantly improved both the hematologic response rate and quality of remission in treatment-naïve patients with severe aplastic anemia (SAA). Romiplostim N01, a long-acting TPO-RA, has shown promising results in refractory aplastic anemia, achieving an overall hematologic response rate of 84%, with platelet responses in 65% of patients. Approximately 70% of patients experienced some degree of hematologic improvement within 3 months, highlighting its potential for frontline use. We therefore designed a single-arm, phase II clinical trial to evaluate the efficacy and safety of first-line romiplostim N01 in combination with intensified IST in patients with severe or very severe aplastic anemia (NCT 06613880). Methods This study employed Simon's optimal two-stage design to estimate the sample size. The primary endpoint was overall response rate (ORR) at week 27. Historical ORR for ATG plus cyclosporine is 45%; the expected ORR with the addition of romiplostim N01 is 65%. With a one-sided alpha of 0.05 and 80% power, 43 patients were required. Considering a 10% of drop-out rate, the final sample size is 48. The screening period was up to 4 weeks. Treatment consisted of porcine ATG (pALG) 25 mg/kg/day on days 1-5, continuous cyclosporine 3-5 mg/kg/day, and romiplostim N01 starting at 10 μg/kg/week on day 1, titrated up to 20 μg/kg/week based on platelet count and clinical response (in 5 μg/kg increments). Secondary endpoints included superior response (defined as HGB >80 g/L and PLT >50×10⁹/L), ORR and complete response (CR), time to hematologic response, and incidence of adverse events. Results A total of 48 patients were enrolled: 36 with SAA (75%) and 12 with very severe aplastic anemia (VSAA). One VSAA patient died of bacterial sepsis 3 days after pALG initiation, three patients were lost to follow-up at week 4, week 6 and week 22, respectively. Among the 45 evaluable patients at 3 months, the ORR was 80%, with a CR rate of 24.4% and 66.7% achieving superior responses. Among 34 evaluable SAA patients, 88.2% achieved hematologic response, including 29.4% with CR. In the VSAA subgroup (n=11), 54.5% achieved response and 9.1% achieved CR. At 6 months, 37 patients were evaluable: the ORR was 86.5%, CR rate 40.5%, and 86.4% achieved superior responses. The median time to hematologic response was 7.5 weeks (range: 4–20). Among 26 evaluable SAA patients, 92.3% achieved hematologic response, including 42.3% with CR. In the VSAA subgroup (n=11), 72.7% achieved response and the CR rate increased to 36.4%. Grade≥3 adverse events were reported in 9 patients, including infections (10.4%), allergic reactions (8.3%), liver dysfunction (2.1%), and acute coronary syndrome (2.1%). Conclusions First-line romiplostim N01 combined with intensified IST demonstrates high efficacy, rapid onset of response, and favorable remission quality in patients with SAA/VSAA, supporting its promising therapeutic potential. Keywords: Aplastic anemia, Romiplostim N01, Immunosuppressive therapy, Hematologic response

Objective There is a need for real-world studies in China to help address evidence gaps supporting precise clinical decision-making with respect to the ideal treatment options for patients with severe aplastic anemia (SAA). Accordingly, we objectively evaluated the efficacy of cyclosporine A (CsA) + antilymphocyte globulin (ALG) versus CsA + thrombopoietin receptor agonist (TPO-RA) for such patients.Methods A cost-utility analysis (CUA) was conducted to compare the quality-adjusted life years (QALY) and total costs associated with the two treatment regimens. Patient utility values were derived from the European Quality-of-Life 5 Dimensions 3 Level Version (EQ-5D-3L) using the Japanese time trade-off conversion method.Results Patients receiving the CsA + ALG regimen reported higher subjective well-being than those treated with the CsA + TPO-RA regimen from the time of hospital admission through 6 months of follow-up. In addition, the quality-of-life of patients in the CsA + ALG group was significantly higher than that of the patients in the CsA + TPO-RA group, with a difference of 0.08 QALY (P < 0.01). However, the total cost of the CsA + ALG regimen was nearly twice that of the CsA + TPO-RA regimen. The incremental cost per QALY gained with the CsA + ALG regimen relative to the CsA + TPO-RA regimen was 1.63 million yuan.Conclusions This study utilized CUA to comparatively assess the cost-effectiveness of CsA + ALG and CsA + TPO-RA regimens in the treatment of SAA. Although both regimens were found to be effective, the CsA + TPO-RA regimen presented a viable treatment option with assured therapeutic efficacy while reducing the financial burden, thereby offering greater benefits for patients with SAA and alleviating the societal healthcare costs.

Allogeneic stem cell transplant and immunosuppressive therapy (IST) are the current standard treatments for patients with aplastic anemia (AA). However, IST also carries significant risks and side effects, and up to 30-50% of patients experienced refractory or relapsed disease following IST. Treating AA remains challenging and novel efficient therapies are in critical need. The IL-2 inducible T-cell kinase (ITK) plays a crucial role in the T cell response and functions as a regulator of T cell activity. While ITK inhibition has shown promise in various immune-related disorders, its potential role in the pathophysiology of AA has not been thoroughly investigated. We observed elevated level of phosphorylated ITK in T cells from AA patients and AA mouse models. Moreover, we found that both treatment with an ITK inhibitor or conditional depletion of Itk in donor mice alleviated bone marrow hypoplasia, improved cytopenia, and extended survival rates. Notably, ITK inhibition orchestrates T cell quantity and function by reducing T cell infiltration and suppressing the secretion of key inflammatory cytokines in AA mice. Our data suggest that ITK inhibitor could potentially offer a new therapeutic strategy for AA.

T cell large granular lymphocytic leukemia (T-LGLL) is a clonal lymphoproliferative disorder, originated from mature effector memory CD8+ T cells. It is a challenge to define the leukemic T cell clones due to the lack of definite markers. Here, we decipher the heterogeneity of CD8+ T cells using cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) and T cell receptor (TCR) profiling in T-LGLL patients. A CD8+ terminal effector subset is identified, marked by reduced KLRG1 expression. Remarkably, high fidelity of leukemic clonality was specially limited in KLRG1- large granular lymphocytes (LGLs), not seen in KLRG1+ LGLs in T-LGLL patients or in KLRG1- LGLs in healthy controls. KLRG1- leukemic LGLs show upregulated PI3K signaling with enhanced cytotoxicity and exhaustion, persisting after conventional treatment. In a pilot trial of linperlisib (a PI3Kδ inhibitor) for refractory cases, 7 of 8 participants quickly respond with satisfactory safety. This study is registered at ClinicalTrials.gov (NCT05676710).

While Azacitidine combined with HAG (HHT, low-dose cytarabine, G-CSF) regimen has shown promise in treating older and unfit patients with acute myeloid leukemia (AML), its efficacy in younger patients remains understudied. This study evaluates the effectiveness and safety of Azacitidine combined with the HAG regimen in a broader patient cohort, including newly diagnosed and relapsed/refractory AML patients. This single-center, prospective cohort included patients with acute myeloid leukemia admitted to our center from June 2019 to Oct 2022 for induction chemotherapy with the HAGA regimen (Azacitidine combined with HAG). We focused on patients' remission rate, MRD (minimal residual disease) conversion and safety. 71 patients with newly diagnosed or R/R AML were enrolled in this study, with a median follow-up time of 20.5 months. After two cycles of HAGA, patients received 3 cycles intermediate-dose Cytarabine and 1 cycle HAGA regimen as consolidation therapies. The CRc (composite complete remission) rate of HAGA regimen as induction chemotherapy for the overall cohort was 85.9% (61/71), which included 71.8% (51/71) CR and 14.1% (10/71) CRi. The CRc with MRD-negative rate was 76.1%. Median OS (overall survival) and DFS (disease free survival) were not yet reached, and the estimated 24-month OS rate was 65.4% (95%CI: 48.4-78.0%), the estimated 24-month DFS rate 66.0% (95%CI: 48.1-79.0%). Only one patient died in induction. The HAGA regimen can be a new option in addition to intense chemotherapy for newly diagnosed or R/R AML, and with high safety.

BACKGROUND:Immunosuppressive treatments induce and maintain remissions in a majority of patients with acquired pure red cell aplasia (aPRCA); however, salvage therapy for non-responders remains unsatisfactory. METHODS:In this prospective, open-label, clinical trial (NCT04423367), patients with refractory/relapsed aPRCA were recruited and received subcutaneous bortezomib at 1.3 mg/m2 in combination with dexamethasone 40 mg weekly(BD regimen) for 12 weeks. The primary endpoint was the overall response rate at 12 weeks. RESULTS:In total, 18 patients were enrolled, including 10 (55.6%) with primary aPRCA and 8 (44.4%) with plasma cell dyscrasia-associated aPRCA. The overall response rate and complete response rate were 61.1% and 55.6%, respectively. Intensive short-term BD regimen led to rapid response, with a median time to response of 40 days (range 21-77 days). Extended maintenance was unnecessary after the 12-week treatment. At a median follow-up of 16.5 (6-51) months, the median treatment-free survival (TFS) was 7 (2-48) months. There was no significant difference in the overall hematological response rate between primary and secondary aPRCA (60% vs. 62.5%, p = 0.914). Adverse events were recorded in 5 patients, including infection, deep venous thrombosis, hyperglycemia, constipation, and liver injury. CONCLUSION:The BD regimen may serve as an effective second-line therapy for refractory/recurrent/intolerant aPRCA patients, with manageable adverse events and possibly longer TFS.

This study aimed to assess the prevalence of somatic mutations (SMs) in severe/very severe aplastic anemia (V/SAA) and transfusion-dependent nonsevere aplastic anemia (TD-NSAA) prior to immunosuppressive therapy (IST) and their impact on treatment efficacy. Next-generation sequencing was used to analyze 114 hematopoiesis-related genes at disease onset in 312 patients. SMs were detected in 17.9% of cases, involving 25 genes, most commonly DNMT3A (14, 20.9%) and BCOR (9, 13.4%). SMs were more frequent in patients over 40 years old, predominantly with a single mutation of low variant allele frequency (< 20%). Patients with SM were older and had lower lymphocyte counts. SMs did not significantly influence hematologic responses at 3, 6, or 12 months, relapse, progression, death, survival, or failure-free survival (p > 0.05). Grouping patients by mutated genes revealed no significant differences in IST efficacy, though Group I (PIGA or BCOR/BCORL1) showed higher hematologic response rates in patients over 40 years of age. The cumulative incidence of clonal evolution was higher in Group II (DNMT3A, TET2, ASXL1, FAT1, or RUNX1), though not statistically significant. SMs in V/SAA and TD-NSAA were infrequent and did not affect IST outcomes or treatment decisions. However, the higher clonal evolution incidence in certain mutations warrants further research.

Background: Thrombopoietin receptor agonists combined with ALG/ATG and cyclosporine are the standard immunosuppressive therapy for severe aplastic anemia (SAA). However, early response rates remain suboptimal. Cyclophosphamide has shown efficacy in relapsed/ refractory AA. Therefore, we designed a clinical trial to evaluate cyclophosphamide combined with the standard immunosuppressive therapy as a first-line treatment for SAA and very severe aplastic anemia (VSAA) to improve early response rates. Methods: This study was a single-arm, prospective, phase II clinical trial using a Simon two-stage design. The primary endpoint was the overall response rate (ORR) at 3 months. Newly diagnosed SAA/VSAA patients received a combination treatment as follows: porcine ALG at 25 mg/kg/day from days 1 to 5, cyclosporine at 3-5 mg/kg/day continuously, herombopag at 15 mg/day starting from day 1 and continued for 6 months, cyclophosphamide at 20 mg/kg/day on days 29-30 and days 43-44. Results: Among the 36 patients evaluable for the primary endpoint, the 3-month ORR was 66.7% (24/36), with a complete response (CR) rate of 8.3% (3/36) and a superior remission rate of 22.2% (8/36). 28 patients were evaluable for the 6-month efficacy, the ORR at 6 months was 75% (21/28), with a CR rate of 28.6% (8/28) and a superior remission rate of 64.3% (18/28). The most common adverse events after cyclophosphamide were grade 1-2 gastrointestinal reactions (100%) and grade 3-4 neutropenia (66.7%), with a median duration of 6 days (range: 4-33 days). The infection rate within 3 months was 58.3% (21/36). The mortality rate within 3 months was 0%. Conclusion: Cyclophosphamide in combination with standard immunosuppressive therapy as first-line treatment shows good safety and efficacy, with two-thirds of patients achieving a response and becoming transfusion-independent within 3 months.

Myelofibrosis is a rare and often fatal hematological neoplasm, and the treatment of myelofibrosis-associated anemia remains suboptimal, with no improved therapies. Luspatercept was shown to display some efficacy in a phase 2 clinical trial for Myelofibrosis with anemia, yet relevant research are limited. Threrfore, data from patients diagnosed with refractory anemic primary or post-essential thrombocythemia/polycythemia vera myelofibrosis, who were treated with luspatercept for at least 9 weeks, were retrospectively collected. Eighteen patients with myelofibrosis treated with luspatercept were enrolled. Median age was 68 years (range, 44–80 years), and 27.8

Introduction Platelet transfusion refractoriness (PTR) represents a significant clinical challenge, markedly elevating the risk of hemorrhagic mortality in some patients with transfusion-dependent aplastic anemia. There is an urgent need for effective therapeutic strategies to enhance platelet transfusion responsiveness, beyond the administration of repeated platelet transfusions. Methods We conducted a single-arm, single-center, prospective pilot study involving patients with aplastic anemia who exhibited platelet transfusion refractoriness, as evidenced by a decrease in the corrected count increment (CCI) on at least two occasions (1-hour CCI < 7500 or 24-hour CCI < 4500 post-transfusion). Daratumumab was administered intravenously at a dose of 8 mg per kilogram of body weight once weekly for four consecutive weeks. The primary endpoints were adverse events and overall response rate (ORR), defined as the percentage of patients achieving at least two effective platelet transfusions, followed by a 12-week follow-up. Results A total of 10 patients were recruited with 8 reaching the 12-week primary endpoint. Within this subset, one patient was administered daratumumab monotherapy, six received a combination therapy with cyclosporine, and one was treated with a regimen including tacrolimus and danazol. The median baseline platelet count was 2.5×109 per liter (range, 1 to 13). The ORR at 12 weeks was 87.5% (7 out of 8 patients), with a median time to response of 3 weeks (range, 1 to 6). The most frequently observed adverse events were grade 1-2 electrolyte imbalances (75%) and grade 1 general symptoms (62.5%), such as fatigue, headache, and insomnia. Throughout the study, a total of 38 transfusions were administered, with transfusion reactions occurring in 4 cases (10.5%). The infection rate during the 12-week follow-up period was 50% (4 out of 8 participants), with infections classified as severity grade 2-3. Importantly, no fatalities were reported during the study period. Conclusion Anti-CD38 targeted therapy demonstrates promising preliminary efficacy in addressing platelet transfusion refractoriness, while exhibiting mild and tolerable adverse reactions in patients with aplastic anemia. (Funded by the National Clinical Research Center for Blood Diseases Fund for Clinical Research; ClinicalTrial.gov ID: NCT05832216). Keywords: Aplastic anemia, Platelet transfusion refractoriness, CD38 monoclonal antibodies

Background: Hepatitis-associated aplastic anemia (HAAA) is a rare variant of severe aplastic anemia (SAA) characterized with a syndrome of bone marrow failure that traditionally occurs within 6 months of an acute attack of hepatitis. HAAA is potentially lethal if left untreated. Management includes immunosuppression with antithymocyte globulin and cyclosporine and allogeneic hematopoietic stem cell transplantation. Addition of thrombopoietin receptor agonist (TPO-RA) improves both the overall response rate and complete response rate of SAA patients. Here, we tried to investigate the effect and adverse events of TPO-RA added to standard immunosuppressive therapy for HAAA. Methods: A total of 17 HAAA patients who received ATG, cyclosporine and TPO-RA as first-line treatment between April 2019 and January 2024 were enrolled. 6 patients were SAA and 11 patients were very severe aplastic anemia (VSAA) according to the criteria of the International Aplastic Anemia Study Group. All TPO-RAs were added within 1 months after ATG initiation at dose of their standard administration respectively. Results: Of all the patients, 8 received avatrombopag (2 with SAA and 6 with VSAA), 5 received eltrombopag (1 with SAA and 4 with VSAA), and 4 received hatrombopag (3 with SAA and 1 with VSAA). The median neutrophil count was 0.23 (range 0.01-0.78) ×109/L, median reticulocyte count was 11 (range 1-40) ×109/L, and median platelet count was 5 (range 1-12) ×109/L. All patients achieved the end-point of 3 months and 16 patients achieved the end-point of 6 months. The rate of complete response was 11.8% and rate of overall response was 52.9% at 3 months. The rate of complete response at 6 months was 41.2% and rate of overall response was 70.6%. The overall response rate of patients treated with avatrombopag, eltrombopag and hatrombopag were 37.5% vs 40% vs 100%, and 62.5% vs 60% vs 100% at 3, 6 months after IST, respectively. The overall response rate at 3 months and 6 months were both higher than historical results of standard IST (ATG and cyclosporine, 34.1% at 3 months and 56.1% at 6 months). All TPO-RAs were safe, and there was no drug-related liver dysfunction. No patient discontinued TPO-RA due to adverse events. Conclusions: In conclusion, the addition of TPO-RA to IST was safe and associated with higher overall response rate among patients with HAAA.