BACKGROUND:Therapeutic strategies for myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPNs) remain suboptimal. Selinexor, an oral selective inhibitor of exportin 1, represents a mechanism-based therapeutic approach. Preclinical and clinical evidence indicated synergistic antileukemic effects when selinexor was combined with hypomethylating agents or janus kinase inhibitors. METHODS:A prospective, single-arm trial was conducted to evaluate selinexor plus either azacitidine (for MDS-dominant features) or ruxolitinib (for MPN-dominant features) in patients with MDS/MPN. The primary end point was the overall response rate at 6 months, which was assessed according to 2015 International Working Group criteria. Secondary end points included safety, progression, and survival. RESULTS:Twenty patients were enrolled (four with MDS-dominant features, 16 with MPN-dominant features). The median age was 66 years in the MDS group and 62.5 years in the MPN group. The overall response rate was 60% (12 of 20 patients; 95% confidence interval [CI], 36.1%-80.5%) overall, 75% (three of four patients; 95% CI, 31.1%-95.4%) in the MDS group, and 56.3% (nine of 16 patients; 95% CI, 33.2%-76.9%) in the MPN group. In the MDS group, clinical benefits included improvements in the total symptom score, erythroid response, platelet response, and spleen response (one in each of four patients; 25% for each response). In the MPN group, partial responses occurred in two of 16 patients (12.5%), and partial bone marrow responses occurred in three of 16 (18.8%), with additional benefits including spleen response (five of 16; 31.3%), total symptom score improvement (two of 16; 12.5%), erythroid response (two of 16; 12.5%), and platelet response (one of 16; 6.3%). Adverse events occurred in 14 patients (70%). Three patients experienced grade 3 or greater events, including two disease-related fatalities. After a median follow-up of 6 months (range, 2-15 months), one patient's disease transformed to acute myeloid leukemia. CONCLUSIONS:Selinexor combined with azacitidine or ruxolitinib showed encouraging efficacy with a manageable safety profile in patients with MDS/MPN.

To evaluate the real-world efficacy and safety of iptacopan in complement inhibitor-naïve patients with paroxysmal nocturnal hemoglobinuria (PNH) in China. This retrospective study included data collected from patients who commenced iptacopan treatment for PNH. Changes in clinical and laboratory indicators were examined after 1, 3, and 6 months and during the subsequent follow-up. A total of 54 patients were enrolled, including 17 (31.5

Effective therapeutic options remain limited for adults with relapsed or refractory (R/R) warm autoimmune hemolytic anemia (wAIHA) and Evans syndrome (ES). We conducted a prospective, single-center, open-label clinical trial to evaluate the efficacy and safety of sirolimus. Adult patients with R/R wAIHA or ES and hemoglobin levels <100 g/L received oral sirolimus (1-3 mg/day; target trough concentration, 4-15 ng/mL) for ≥ 6 months. The co-primary endpoints were overall response rate (ORR) and complete response rate (CRR) at 6 months; secondary endpoints included 12-month efficacy, safety, and relapse rates. Seventy-eight consecutive patients were enrolled (median age, 52 years [IQR, 38-65]), including 63 (80.8%) with wAIHA and 15 (19.2%) with ES. With a median follow-up of 13.9 months (IQR, 12.7-17.0), sirolimus achieved a 6-month ORR of 80.7% (81.0% for wAIHA, 80.0% for ES) and CRR of 51.3% (52.4% for wAIHA, 46.7% for ES). Median times to overall and complete response were 2.4 months (IQR, 1.8-5.0) and 3.6 months (IQR, 2.3-7.0), respectively. Responses were sustained at 12 months (ORR, 78.2%; CRR, 50.0%). Treatment-emergent adverse events occurred in 28.2% of patients and were predominantly mild and reversible. Relapse and mortality rates were 12.7% and 2.8%, respectively. No baseline clinical characteristics were independently associated with response at 6 months. Sirolimus demonstrated clinically meaningful efficacy, durable responses, and a favorable safety profile, supporting its role as a steroid-sparing option for steroid-dependent patients and a potential treatment alternative for steroid-refractory R/R wAIHA and ES. NCT05925023.

Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-rare condition, characterised by complement-mediated red blood cell breakdown, resulting in haemolytic anaemia. Associated symptoms, such as fatigue, impact on patient quality of life. Little is known about the comparative perceptions of symptom burden and treatment preferences among patients and physicians. This study analysed secondary data from the Adelphi Real World PNH Disease Specific Programme™, a cross-sectional survey of physicians and patients with PNH in France, Germany, Italy, Spain, China, and Japan conducted January–November 2022. Haematologists and haematologist–oncologists reported demographic and clinical data for ≤10 consecutive consulting adult patients with PNH. Only patients with both physician-reported and patient-reported data were included in the study. Patients and physicians reported on clinical signs and symptom burden, treatment satisfaction, and preferred route of administration. Bivariate analyses were used to compare physician and patient responses. Forty-two physicians reported data for 225 patients. Median (interquartile range) patient age was 44.0 (35.0–56.0), 56.9

Key points Explanation of novelty Paroxysmal nocturnal hemoglobinuria is characterized by red blood cell (RBC) destruction and a prothrombotic state.[v][1] Treatments exist such as complement 5 inhibitors but these carry the risk for iatrogenic extravascular hemolysis and anemia.[vi][2] As reported here, the novel, oral complement factor B inhibitor MY008211A yielded increases in hemoglobin and RBC levels, while adverse events over 44 weeks were largely mild to moderate in severity, and infections generally consisted of respiratory infections.[vii][3] Paroxysmal nocturnal hemoglobinuria (PNH) is a life-threatening disease characterized by red blood cell (RBC) destruction, blood clots, and impaired bone marrow function.[viii][4] We evaluated the efficacy and safety of 3 dosages of MY008211A, a novel complement factor B inhibitor,[ix][5] for treating PNH.[x][6] This was a multicenter, open-label, phase 2, dose-finding study of MY008211A among Chinese men and women with complement inhibitor–naive PNH and signs of active hemolysis.[xi][7] Patients with hemoglobin <100 g/L were assigned to oral MY008211A 400 mg twice daily (BID), 600 mg BID, or 800 mg once daily (QD) for 12 weeks and could then continue treatment with 400 mg BID during a 32-week extension.[xii][8] The primary endpoint was the proportion of patients achieving an increase in hemoglobin concentration of ≥20 g/L vs baseline on day (D)84, without RBC transfusions after 4 weeks of dosing.[xiii][9] Safety assessments included adverse events (AEs).[xiv][10] Fifteen, 9, and 10 patients were assigned to MY008211A 400 mg BID, 600 mg BID, and 800 mg QD, respectively.[xv][11] All patients completed the study and its 32-week extension.[xvi][12] On D84, all 34 patients achieved increases in hemoglobin concentration of ≥20 g/L from baseline;[xvii][13] all patients maintained this increase at D308.[xviii][14] Through D308, grade ≥3 AEs occurred in 5 (33%), 5 (56%), and 4 (40%) patients in the 400-, 600-, and 800-mg groups, respectively.[xix][15] There were no deaths.[xx][16] In this multicenter, open-label study of 3 dosages of MY008211A for PNH, all patients achieved and maintained increases in hemoglobin of ≥20 g/L from baseline without RBC transfusions. ### Competing Interest Statement Y.C., R.X., C.T., L.L., X.G., Y.Z., X.L., R.K., W.C.W., and G.R., are employees of Createrna. F.Z., B. H., H.T. have received research grants from Createrna. C. X. is a scientific advisor of Createrna. C.D.C. declares relationships with Alexion, Apellis, Genentech, InnaRx, Novartis, Omeros, and Regeneron. All other authors declare no competing interests. ### Clinical Trial NCT06050226 ### Funding Statement This study was funded by Wuhan Createrna Science and Technology Co., Ltd. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as [ClinicalTrials.gov][17]. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors [1]: #fn-8 [2]: #fn-9 [3]: #fn-10 [4]: #fn-11 [5]: #fn-12 [6]: #fn-13 [7]: #fn-14 [8]: #fn-15 [9]: #fn-16 [10]: #fn-17 [11]: #fn-18 [12]: #fn-19 [13]: #fn-20 [14]: #fn-21 [15]: #fn-22 [16]: #fn-23 [17]: https://ClinicalTrials.gov

Background/Objectives: Eliglustat is an oral therapy for Gaucher disease type 1 (GD1) that may reduce infusion-related logistical burden, particularly in resource-constrained settings. Post-approval evidence from routine clinical practice in China remains limited. This study evaluated its real-world effectiveness and safety in Chinese adults with GD1. Methods: This retrospective, multicenter study included adults with GD1 receiving eliglustat monotherapy for ≥6 months. Outcomes included plasma glucosylsphingosine (lyso-Gb1), hemoglobin (HGB), platelet count (PLT), liver and spleen volumes, and adverse events (AEs). Depending on distribution, paired changes were analyzed using paired t tests or Wilcoxon signed-rank tests. p < 0.05 was considered statistically significant. Results: Nineteen patients were included in the effectiveness analysis, with a median follow-up of 7 months (range, 6-9). Lyso-Gb1 decreased from 468 to 210 ng/mL (p < 0.0001). HGB increased from 123 to 131 g/L (p = 0.147); among six patients with baseline anemia, 83.3% improved and 33.3% normalized. PLT increased from 109 to 132 × 109/L (p = 0.019); among 12 patients with baseline thrombocytopenia, 58.3% improved. Liver volume decreased from 1808 to 1747 mL (p = 0.016) (1.22 to 1.01 multiples of normal; p < 0.001). Spleen volume decreased from 473 to 452 mL (p = 0.016) (4.69 to 5.17 multiples of normal; p = 0.015). Lyso-Gb1 reduction was greater in patients without prior enzyme replacement therapy (ERT) exposure than in those with prior ERT exposure (-55.1% vs. -43.1%; p = 0.049). In the safety analysis group (n = 90), suspected drug-related AEs occurred in 27.8% of patients, mainly gastrointestinal or skin-related, and were limited to grade I/II. No serious AE or treatment discontinuation occurred. Conclusions: In routine clinical practice in China, eliglustat was associated with rapid substantial reductions in plasma lyso-Gb1, early improvements in hematologic and visceral parameters, and favorable short-term tolerability in adults with GD1.

Splenic angiosarcoma is a rare aggressive tumor originating from vascular endothelial cells of the spleen,typically presenting with splenomegaly,fatigue,and weight loss.Patients accompanied by anemia,thrombocytopenia,and bone marrow biopsy showing fibrosis are prone to be misdiagnosed with primary myelofibrosis.This article retrospectively analyzes the clinical characteristics of two cases initially diagnosed as primary myelofibrosis but negative for common driver gene mutations (JAK2,CALR,and MPL).One case was confirmed through splenectomy due to progressive splenomegaly,while the other was identified via bone marrow biopsy indicating angiosarcoma invasion.Both cases were ultimately pathologically confirmed as primary splenic angiosarcoma after splenectomy.Through literature review,we aim to enhance awareness of this rare disease,emphasizing that primary splenic tumors secondary to myelofibrosis should be differentially diagnosed in the cases of driver gene mutation-negative myelofibrosis.

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare life-threatening hematologic disorder with high thromboembolic mortality. In the context of large patient population and limited use of complement inhibitors, the clinical characteristics and disease progression of patients in China have not been well studied. Objectives The China PNH Registry was initiated to advance understanding of the disease by collecting data and describing PNH disease burden, progression, and clinical outcomes with different medical interventions. Design This is a multi-center, prospective observational study in patients with PNH regardless of treatment for PNH. Methods This real-world study enrolled 716 PNH patients irrespective of treatment, collecting baseline demographics, clinical/laboratory data, and treatment patterns (including eculizumab dosing and safety) for descriptive analyses across PNH subtypes. Results 52.0% of the enrolled patients had classic PNH, 47.2% had bone marrow failure (BMF/PNH), and 0.8% had subclinical PNH. Classic PNH patients had a higher proportion of PNH red blood cells (RBCs) (39.0% vs. 18.0%), PNH neutrophils (86.1% vs. 52.4%), and PNH monocytes (90.2% vs. 47.7%) than BMF/PNH patients. 343/496 patients had LDH > 1.5 ULN, with a higher proportion in classic PNH than BMF/PNH (74.7% vs. 63.1%). 582 patients had at least one of the PNH-related symptoms, the most common being fatigue (63.7%), red/dark urine (46.6%). Although eculizumab has become a reimbursable complement inhibitor in China, only 28.5% of the patients received eculizumab treatment during the study period. The other main treatment methods were supportive care (46.6%), corticosteroids (28.1%), and RBC transfusion (7.5%). Conclusion Current data revealed a gap between real-world practice and guideline recommendations, indicating that standard treatment — particularly complement inhibitors — remains underutilized despite being essential for improving long-term patient outcomes. Trial registry name The China Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry. Registration number NCT06154512.

The clinical need for treating anemia in aplastic anemia (AA) patients remains unmet. Luspatercept has been shown to be effective in myelodysplastic neoplasms (MDS). Patients who were newly diagnosed with non-transfusion-dependent non-severe AA (NTD-NSAA) were randomly assigned to receive either cyclosporine (CsA) combined with luspatercept or CsA monotherapy at a 1:1 ratio. This study (ClinicalTrials.gov NCT05399732) aimed to compare their treatment responses, safety, disease progression, and outcomes. In total, 58 patients participated in the final analysis, with 29 receiving CsA+luspatercept and 29 receiving CsA monotherapy. With a median follow-up of 12 months (range: 6–25) and 12 months (range: 7–25), respectively, the overall response rates (ORRs) were 69.0

Romiplostim N01 (QL0911) is a novel thrombopoietin receptor agonist (TPO-RA) ; however, clinical data regarding its efficacy and safety in patients with refractory aplastic anemia (AA) who have failed multiple prior lines of therapy are limited. This retrospective single center study analyzed the clinical outcomes of 32 patients with refractory AA who received romiplostim N01 at Peking Union Medical College Hospital between May 2024 and December 2024. All patients had previously failed to respond to full dose cyclosporine and at least two oral TPO-RA administered for adequate treatment durations and had been treated with romiplostim N01 for ≥3 months and followed for ≥6 months. The median age of the cohort was 62 years (range, 24-79 years) , and 11 patients (34.4% ) were male. Thirty patients had transfusion-dependent non-severe AA (TD-NSAA) , and 2 had severe AA (SAA) . The median duration of romiplostim N01 treatment was 5 months (range, 3-10 months) , and the median follow-up time was 6 months (range, 6-10 months) . The overall response rates (ORR) at 3 months, 6 months, and the last follow-up were 71.9% , 75.0% , and 75.0% , respectively, and the complete response rates (CRR) were 28.1% , 28.1% , and 31.2% , respectively. The median time to hematologic response was 1 month (range, 1-4 months) , and the median time to complete response was 3 months (range, 1-4 months) , indicating a rapid onset of action even in this refractory population. A total of 14 patients (43.8% ) experienced adverse events, all of which were grade 1 and improved with symptomatic management; no dose reductions or treatment discontinuations were required, and no treatment related liver dysfunction, thrombotic events, or deaths were observed. During follow-up, relapse occurred in 3 patients who had previously responded (3/26, 11.5% ) , and newly detected myelodysplastic syndrome (MDS) -related gene mutations were identified in 2 patients (6.3% ) . No new or expanding paroxysmal nocturnal hemoglobinuria (PNH) clones were detected. These findings suggest that romiplostim N01 can induce rapid and high hematologic response rates with a favorable safety profile in patients with refractory AA who have failed full-dose cyclosporine A and multiple oral TPO-RA; no obvious short-term signals of clonal evolution were observed.

Eculizumab, a humanized monoclonal antibody targeting complement C5, is the first approved drug for complement-mediated diseases and indicated to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, myasthenia gravis, and neuromyelitis optica spectrum disorder. The introduction of eculizumab has improved the prognosis of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome to near-normal life expectancy and quality of life. Administration of eculizumab resulted in a rapid and sustained reduction in hemolytic activity and a consequent risk of thrombosis in paroxysmal nocturnal hemoglobinuria, and thrombotic microangiopathy in atypical hemolytic uremic syndrome, respectively. Nevertheless, many patients still have difficulty accessing eculizumab treatment because of its high costs. Biosimilars to reference eculizumab may increase patient access to treatment by creating market competition and eventually decreasing treatment costs. Clinical use of biosimilars in Europe in the last 15 years has demonstrated that they are as safe and effective as their reference products, and can also drive cost reductions and increase patients' access to treatment. This review aims to increase awareness about the importance of biosimilars of reference eculizumab and their entry for use in patients with paroxysmal nocturnal hemoglobinuria or atypical hemolytic uremic syndrome based on the accumulated experience of other previously approved biosimilars, and to provide an overview of the stringent biosimilar development pathway in general and the concept of extrapolation in particular.

Iptacopan, a first-in-class, oral, selective complement factor B inhibitor, demonstrated efficacy and safety as monotherapy in C5 inhibitor (C5i)-experienced (APPLY-PNH [NCT04558918]) and C5i-naive (APPOINT-PNH [NCT04820530]) patients with paroxysmal nocturnal hemoglobinuria (PNH). In APPLY-PNH and APPOINT-PNH, changes in fatigue (FACIT-Fatigue) and health-related quality of life (HRQOL; EORTC QLQ-C30) from baseline to Day 168 were evaluated. The proportion of patients achieving meaningful within-patient change (MWPC) on the FACIT-Fatigue and 4 EORTC QLQ-C30 subscales (physical functioning, role functioning, fatigue, dyspnea) was evaluated using anchor-based thresholds. Correlations between FACIT-Fatigue scores, lactate dehydrogenase (LDH), and hemoglobin (Hb) levels were also assessed. In APPLY-PNH (iptacopan, n=62; C5i, n=33), more patients in the iptacopan group reached the MWPC threshold for FACIT-Fatigue than in the C5i group (51% vs 11%). More patients achieved MWPC on domains of the EORTC QLQ-C30 in the iptacopan group (39%-49%) than the C5i group (9%-20%). In APPOINT-PNH (N=40), 56% achieved MWPC on the FACIT-Fatigue, and the proportion of patients who achieved MWPC on the EORTC QLQ-C30 ranged from 41% to 55%. In C5i-experienced patients, increased Hb levels correlated with improvement in FACIT-Fatigue scores (R=0.48, P<0.001). In C5i-naive patients treated with iptacopan, increased Hb (R=0.42, P<0.001) and decreased LDH (R=−0.53, P<0.001) correlated with improved FACIT-Fatigue scores. C5i-experienced and -naive patients receiving iptacopan exhibited meaningful improvement in fatigue, HRQOL, and disease-related symptoms, which correlated with clinical improvement in hematologic markers of disease control. These trials are registered at www.ClinicalTrials.gov as NCT04558918 (APPLY-PNH) and NCT04820530 (APPOINT-PNH).

Abstract Introduction: Patients with paroxysmal nocturnal hemoglobinuria (PNH) often develop iron deficiency (ID) due to chronic intravascular hemolysis (IVH), which can lead to iron loss in the urine and, consequently, require iron supplementation. Conversely, when IVH is controlled by terminal complement component 5 (C5) inhibitors e.g. eculizumab, some patients remain anemic due to extravascular hemolysis (EVH), and they may accumulate iron from frequent blood transfusions and/or increased intestinal iron absorption, which may lead to iron overload (IO). Serum ferritin (SF) is a well-established indicator of ID (when low) and IO (when high). Several studies demonstrated increased levels of SF during anti-C5 therapy due to emerging EVH and ongoing blood transfusions (Röth. IJH. 2011, Risitano. BJH. 2012, Schaap. Hemasphere. 2023, Waheed & Kuter. AJH. 2021). Here, we report SF changes in patients with PNH treated with the factor B inhibitor iptacopan for 48 weeks in the Phase 3 APPLY-PNH (anti-C5 pretreated patients) and APPOINT-PNH (anti-C5 naïve patients) trials. Methods: Iptacopan-treated patients with available SF values at baseline (Day 1) and at the end of treatment (Week 48) were included in the analysis and divided by baseline SF into three categories: low SF (below the lower limit of normal), normal SF, and high SF (above the upper limit of normal). Median (interquartile range [IQR]) SF was calculated for anti-C5-naïve patients and anti-C5-pretreated patients separately. The categorical distribution of patients at baseline and at Week 48 was assessed to evaluate how many patients moved to another SF category. The same SF analysis was repeated in patients with a hematological response, defined as a 2 g/dL hemoglobin (Hb) increase at Week 48 versus baseline in the absence of blood transfusion from Day 14 to Week 48. To minimize the confounding effect of factors known to impact SF levels, patients who were either iron-supplemented, iron-depleted, or with a C-reactive protein level >10 mg/L at the time of SF measurement were excluded from the analysis. Results: Thirty anti-C5-naïve and 36 anti-C5-pretreated patients were included in the analysis. In anti-C5 naïve patients, median (IQR) SF was 21 (12–44) ng/mL at baseline; 40.0% of patients had low SF and 10.0% of patients had high SF. In anti-C5-pretreated patients, median (IQR) SF was 460 (204–788) ng/mL at baseline; none of the patients had low SF, whereas 61.1% of patients had high SF. In 12 anti-C5-naïve patients with low SF at baseline, median (IQR) SF increased from 11 (10–15) ng/mL at baseline to 29 (13–63) ng/mL at Week 48; 7/12 (58.3%) patients achieved normal SF. In 3 anti-C5-naïve patients with high SF at baseline, median (IQR) SF decreased from 539 (399–2464) ng/mL at baseline to 294 (161–1693) ng/mL at Week 48; 2/3 (66.7%) achieved normal SF. In 15 anti-C5-naïve patients with normal SF at baseline, median (IQR) SF was 33 (22–54) ng/mL at baseline and 36 (21–73) ng/mL at Week 48; 12/15 (80.0%) patients maintained normal SF at Week 48, whereas 2/15 (13.3%) had low SF and 1/15 (6.7%) had high SF at Week 48. There were no anti-C5-pretreated patients with low SF at baseline. In 22 anti-C5-pretreated patients with high SF at baseline, median (IQR) SF was 748 (508–866) ng/mL at baseline and 731 (352–956) ng/mL at Week 48; 4/22 (18.2%) achieved normal SF at Week 48. In 14 anti-C5-pretreated patients with normal SF at baseline, median (IQR) SF was 179 (106–260) ng/mL at baseline and 66 (48–164) ng/mL at Week 48; 13/14 (92.9%) of patients maintained normal SF, whereas 1 patient had low SF at Week 48. The SF changes in patients who gained at least 2g/dL of Hb were consistent with those seen in the overall population. However, in 18 anti-C5-pretreated patients with high SF at baseline, the median SF showed a decreasing trend from 653 (490–822) ng/mL to 554 (338–891) ng/mL at Week 48. Conclusions: Treatment with iptacopan normalizes SF in anti-C5-naïve PNH patients with low SF by blocking IVH. In contrast to anti-C5 therapies, SF does not increase during iptacopan treatment in anti-C5-pretreated PNH patients, indicating that these patients no longer demonstrate EVH-related, persistent anemia, or require blood transfusions. Thus, by targeting IVH and EVH, iptacopan restores iron homeostasis to a more physiological state, possibly preventing ID and IO in patients with PNH.

BACKGROUND:Romiplostim (ROM), a second-generation thrombopoietin receptor agonist (TPO-RA), has shown promising results in patients with refractory aplastic anemia (AA); however, its optimal dosage, efficacy, and safety in patients with refractory AA who experienced treatment failure with immunosuppressive therapy (IST) and other types of TPO-RAs remain unclear. In the present study, we aimed to retrospectively assess the efficacy and safety of high-dose ROM in these patients. PATIENTS AND METHODS:Patients who received ROM consecutively for at least 3 months between 8 April 2023 and 23 October 2023, and were followed up for at least 6 months after therapy were analyzed. All enrolled patients had failed to respond and stopped the previous treatments for at least 3 months before receiving ROM. RESULTS:Eleven patients were followed up for at least 6 months; all experienced treatment failure with IST and at least two types of other TPO-RAs. They had a median age of 54 years (range: 27-77 years), and eight (72.7%) were women. The patients' initial and maximal ROM dose was 20 μg/kg per week. At a median follow-up of 8 months (range, 6-8 months), 72.7% (8/11) of the patients reached the response criteria at a median of 1 month (range: 1-3 months). Of these patients, 54.5% (6/11) met the criteria for a complete response at a median of 2.5 months (range: 1-3 months), and 27.3% (3/11) achieved a trilineage response. No severe ROM-related adverse events that led to treatment discontinuation or dosage reduction were observed. Notably, 12.5% (1/8) of the responders relapsed at 5 months after stopping ROM for 2 months. CONCLUSION:High-dose ROM with an initial dosage of 20 μg/kg per week is effective and safe for patients with refractory AA who experienced treatment failure with IST and multiple oral TPO-RAs, exerting a rapid response.

Abstract Introduction: wAIHA is a rare type of anemia caused by destruction of red blood cells (RBCs) mostly due to IgG (warm antibody) binding to RBC antigens. Treatment goals include raising hemoglobin (Hb) to stable levels, symptom resolution, transfusion independence, and reducing risk of thrombosis. Rilzabrutinib, an oral, covalent, reversible, and highly selective BTK inhibitor that acts through multi-immune modulation, may treat wAIHA by reducing pathogenic autoantibodies directed against RBC, FcγR-mediated phagocytosis, chronic inflammation, and complement activation. In the phase 2B LUMINA2 part A study (NCT05002777), patients (pts) with wAIHA (N=22) receiving rilzabrutinib for 24 weeks (wks) showed robust overall and durable Hb response, reduced fatigue, decreased hemolytic markers and markers of inflammation, and favorable safety (Cooper, ASH 2024). Long-term follow-up in the core part B (Wk 50 assessment) showed sustained efficacy with durable Hb response and stable Hb levels, decreased hemolytic and inflammatory biomarkers, reduced fatigue, and well-tolerated safety profile (Fattizzo, EHA 2025; Cooper, EHA 2025). Here, we examine the efficacy and safety of rilzabrutinib in the continued follow-up of the core part B of the LUMINA2 study, with assessment at 74 wks. Methods: Adult pts with relapsed/refractory or corticosteroid (CS)-dependent primary wAIHA, ECOG PS of 0-2, Hb levels <10 g/dL, ≥1 abnormal marker of hemolysis, positive direct antiglobulin test, and unsustained response to CS were eligible for Part A. To progress to core part B, part A pts had to complete the 24-wk course of oral rilzabrutinib (400 mg bid) and demonstrate overall Hb response by Wk 24. Core part B period lasted until the last pt completed 52 wks in part B. Stable doses of concomitant CS (or dose reduction) and rescue therapy were permitted. Hb levels, hemolytic markers, frequency of blood transfusions, change from baseline in FACIT-Fatigue scores, and safety were evaluated at the 74-wk follow-up. Results: As of 21May2025, 15 of 22 (68%) pts from part A (14 primary wAIHA, 1 erroneously enrolled with cold agglutinin disease) had entered part B and 9 of 15 (60%) have completed core Part B (≥74 wks); 11 (73%) pts received rilzabrutinib for ≥52 wks in part B. At baseline, 15 pts who entered part B had a median age of 68 y (range, 33-87; 27% ≥75 y) and 40% were female. For 14 primary wAIHA pts, median time since diagnosis was 7.1 y (maximum 47 y; 60% ≥3 y). Nine (60%) pts received ≥3 prior medications; 6 (40%) pts received rilzabrutinib monotherapy and 9 (60%) received concomitant CS. Median baseline Hb level was 8.2 g/dL (range: 5.8-11.4) and at Wk 74 was 11.7 g/dL (range: 6.6 to 14.7). Increased Hb levels were associated with reduced hemolytic markers. At Wk 74, median LDH levels decreased by 37%, reticulocytes by 63%, and total bilirubin by 62%. Six (40%) pts received blood transfusions by end of core part B. Clinically meaningful increase in FACIT-Fatigue scale scores was observed with median change from baseline of 5.0 (IQR: 2-11) at Wk 74 (median: 44.4). Two pts (male, 87 y; female, 61 y) opted to discontinue rilzabrutinib due to maintaining durable response at Wks 50 and 58 of part B; both achieved drug-free remission (Hb 14.1 g/dL at Wk 50 and 13.6 g/dL after 5 mo in Pt 1; Hb 11.8 g/dL at Wk 58 and 12.0 g/dL after 4 mo in Pt 2) through Wk 74 (remission for 24 and 16 wks, respectively, after treatment discontinuation) and decreased hemolytic markers. At data cutoff, rilzabrutinib was given for a median duration of 62 wks (range, 26-134) in core part B. Twelve (80%) pts had adverse events (AEs) due to any cause, 5 (33%) with treatment-related AEs. The most common any-cause AEs were diarrhea (33%), upper respiratory tract infection (27%), back pain (20%), and headache (20%). Six pts (40%) had any-cause serious AEs (none were treatment related). There was one treatment-emergent AE that led to treatment discontinuation in a pt with relapsed wAIHA, per investigator judgement. There were no AEs of special interest or deaths. Conclusion: Extended follow-up of pts treated with rilzabrutinib showed continued efficacy with sustained Hb response, with some pts achieving drug-free remission; decreased hemolytic markers; clinically meaningful improvement in fatigue score; and a favorable safety profile in pts with wAIHA. Efficacy and safety of rilzabrutinib will be further evaluated in a phase 3, randomized, placebo-controlled study (LUMINA3).

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening hematologic disorder characterized by complement dysregulation on affected blood cells, leading to both intravascular (IVH) and extravascular hemolysis (EVH). KP104 is a novel bifunctional recombinant protein drug composed of a humanized anti-C5 monoclonal antibody fused to the regulatory domain of complement factor H, with dual inhibitory activity of both terminal and proximal complement pathways. Aims: Final analysis of efficacy and safety outcomes from a 2-year Phase 2 trial (NCT05476887) of KP104 in complement inhibitor–naïve PNH patients, including data from an 8-week safety follow-up after end of treatment (EoT). Methods: Eighteen complement inhibitor–naïve patients were enrolled across three dose-escalation cohorts (n=6 per cohort). Following 12–13 weeks of initial dosing, all patients transitioned to a weight-based optimal biologic dose (OBD) given SC Q2W as reported previously (ASH 2023 & 2024). All patients received ≥2 years of treatment, including 64–105 weeks at OBD, except for one patient with coexisting myeloproliferative neoplasms (MPN) who withdrew consent at week 90. Twelve of the seventeen remaining patients elected to participate in an 8-week post-EoT follow-up to evaluate the durability of clinical response and for safety monitoring. Results: Substantial clinical improvements observed at one year were sustained through the 2-year treatment period. At the completion of 2-year treatment, 100% of patients maintained a hemoglobin (Hgb) increase of ≥2 g/dL from baseline, with a mean (SD) Hgb level of 13.7 (±1.5) g/dL and an average increase of 6.7 (±2.0) g/dL from baseline. Hgb normalization (≥12 g/dL) was achieved in 82.4% (14/17) of patients. All patients maintained LDH levels ≤1.5× the upper limit of normal (ULN), with values remaining in the normal or near-normal range. No patients required red blood cell transfusions during the study. KP104 was well tolerated over the 2-year treatment period. There were no serious adverse events (SAEs) or patient discontinuation due to treatment-emergent adverse events (TEAEs). The most frequently reported TEAEs included COVID-19 (38.9%), injection site induration (27.8%), hyperuricemia (16.7%), nasopharyngitis (16.7%), hyperlipidemia (11.1%), headache (11.1%), influenza (11.1%), and influenza-like illness (11.1%). Two BTH events were recorded during the 2-year treatment period: one occurred early in the lowest-dose cohort prior to OBD transition and was associated with gastroenteritis; the second occurred in a patient with coexisting MPN while on OBD. No major vascular events and no new safety signals beyond those previously reported (ASH 2024) were observed. A total of 12 patients participated in a follow-up study spanning 4-8 weeks post–EoT, including one patient with concurrent aplastic anemia. At EoT, 83.3% (10/12) of patients achieved Hgb normalization (≥12 g/dL), with a mean Hgb of 13.9 ± 1.7 g/dL, and all patients (100%, 12/12) had LDH levels ≤1.5× ULN. Following KP104 discontinuation, Hgb normalization was maintained in 83.3% (10/12) at week 4 (mean Hgb: 13.7 ± 2.4 g/dL), 77.8% (7/9) at week 6 (mean Hgb: 12.7 ± 2.6 g/dL), and 80.0% (4/5) at week 8 (mean Hgb: 11.2 ± 3.3 g/dL). LDH levels ≤1.5× ULN were observed in 66.7% (8/12) at week 4, 37.5% (3/8) at week 6, and 20.0% (1/5) at week 8. No new safety signals emerged during the post–EoT follow-up. Conclusion: KP104 demonstrated robust and durable efficacy, with a favorable safety profile, over the entire 2-year treatment period in complement inhibitor–naïve PNH patients. All patients achieved transfusion independence, with sustained improvements in hemoglobin and LDH levels throughout the treatment period. Importantly, a substantial proportion of patients maintained clinical benefit during the 4-8 weeks safety follow-up post-EoT, suggesting a significant efficacy cushion beyond active dosing of the drug. These findings demonstrate the potential of KP104 as an attractive monotherapy for PNH with desired efficacy and safety.

BACKGROUND:The factor B inhibitor iptacopan improved 24-week outcomes in adult patients with paroxysmal nocturnal haemoglobinuria in the phase 3 APPLY-PNH and APPOINT-PNH trials; the trial extension periods assessed clinical activity and safety up to 48 weeks. Here, we report the final 48-week data from APPLY-PNH and APPOINT-PNH. METHODS:In both APPLY-PNH and APPOINT-PNH trials, patients were aged 18 years or older, with paroxysmal nocturnal haemoglobinuria (red and white blood cell population sizes ≥10%) and without laboratory evidence of bone marrow failure. In APPLY-PNH (an open-label, randomised, phase 3 trial conducted in 39 centres [38 hospitals, one outpatient research clinic] from 12 countries or regions), patients with haemoglobin concentration lower than 10 g/dL on anti-C5 treatment (stable eculizumab or ravulizumab regimen for ≥6 months) were randomly assigned (8:5) via interactive response technology to either receive oral iptacopan 200 mg twice daily (iptacopan group) or to continue their individual intravenous eculizumab or ravulizumab regimen for 24 weeks (anti-C5 group). Randomisation was stratified by type of anti-C5 and receipt of red blood cell (RBC) transfusions in the preceding 6 months. In APPOINT-PNH (an open-label, single-arm, phase 3 trial conducted in 12 hospitals from eight countries), complement inhibitor-naive patients with paroxysmal nocturnal haemoglobinuria and with haemoglobin concentration lower than 10 g/dL and lactate dehydrogenase (LDH) concentration higher than 1·5 times the upper limit of normal received iptacopan 200 mg twice daily for 24 weeks. Both trials had 24-week extension periods in which all patients received iptacopan monotherapy. Primary endpoints were the proportion of patients with an increase from baseline in haemoglobin concentration of 2 g/dL or higher (APPLY-PNH and APPOINT-PNH) and haemoglobin concentration 12 g/dL or higher (APPLY-PNH) between weeks 18 and 24, all in the absence of RBC transfusions between weeks 2 and 24; results for these primary endpoints have been reported previously. We report final activity and safety data at the completion of both trials (week 48). Prespecified endpoints at week 48 included percentage of patients with a haemoglobin increase from baseline of 2 g/dL or higher or haemoglobin 12 g/dL or higher (including post-transfusion data). Efficacy data were analysed per the intention-to-treat principle, and safety was analysed according to the treatment that patients received. APPLY-PNH and APPOINT-PNH are registered with ClinicalTrials.gov, NCT04558918 and NCT04820530, respectively. FINDINGS:In APPLY-PNH, between Jan 25, 2021, and April 8, 2022, 62 patients (43 [69%] female, 19 [31%] male; 48 [77%] White, 12 [19%] Asian, two [3%] Black) were randomly assigned to the iptacopan group and 35 patients (24 [69%] female, 11 [31%] male; 26 [74%] White, seven [20%] Asian, two [6%] Black) to the anti-C5 group; 61 (98%) and 34 (97%), respectively, entered the extension period. At trial completion (March 6, 2023), the median duration of iptacopan treatment was 337 days (IQR 168-338). In APPOINT-PNH, 40 patients were enrolled between July 19, 2021, and May 17, 2022, and received iptacopan (17 [43%] female, 23 [58%] male; 12 [30%] White, 27 [68%] Asian, one [3%] Black); all entered the extension period. At trial completion (April 18, 2023), the median duration of iptacopan treatment was 337 days (IQR 337-344). At week 48, irrespective of RBC transfusions, the number of patients who had an increase in haemoglobin concentration of 2 g/dL or higher was 51 (86%) of 59 in the APPLY-PNH iptacopan group, 21 (72%) of 29 in the APPLY-PNH anti-C5-to-iptacopan group, and 38 (97%) of 39 in APPOINT-PNH. The number of patients who had haemoglobin concentration of 12 g/dL or higher at week 48 was 40 (68%) of 59 in the APPLY-PNH iptacopan group, 17 (59%) of 29 in the APPLY-PNH anti-C5-to-iptacopan group, and 31 (79%) of 39 in APPOINT-PNH. There were no treatment discontinuations because of treatment-emergent adverse events or deaths. Across the 48-week trials, clinical breakthrough haemolysis occurred in seven (7%) of 96 iptacopan-treated patients in APPLY-PNH (including both groups) and two (5%) of 40 in APPOINT-PNH, but it was generally mild or moderate with no iptacopan discontinuation. Three major adverse vascular events occurred in APPLY-PNH by trial completion; all were considered unrelated to iptacopan. The most common treatment-emergent adverse event was COVID-19 in APPLY-PNH (iptacopan: 18/62 patients [29%]; anti-C5-to-iptacopan: 8/34 [24%]) and headache in APPOINT-PNH (12/40 [30%]). Severe and serious treatment-emergent adverse events were experienced by six (10%) and nine (15%) of 62 patients in the APPLY-PNH iptacopan group, respectively; in APPOINT-PNH, these were experienced by four (10%) and eight (20%) of 40 patients, respectively. The most common serious treatment-emergent adverse event was COVID-19, occurring in one (2%) of 62 patients in the APPLY-PNH iptacopan group and two (5%) of 40 patients in APPOINT-PNH. No severe treatment-emergent adverse events occurred in more than one patient. INTERPRETATION:Long-term data indicate durable haemolysis control with iptacopan in paroxysmal nocturnal haemoglobinuria, maintained normal or near-normal haemoglobin, and no new safety concerns. We believe that these data support iptacopan as a potential therapy option, suggesting that we are in a new treatment era for paroxysmal nocturnal haemoglobinuria. FUNDING:Novartis.

Abstract Background There are unmet needs for patients with warm antibody autoimmune haemolytic anaemia (wAIHA) and Evans syndrome (ES) who are refractory/relapsed to steroids or other second or third line therapies. Mammalian target of rapamycin(mTOR) inhibitor sirolimus has been demonstrated effective in some retrospective studies. This study aimed to assess the efficacy and safety of sirolimus for refractory/relapsed wAIHA and ES prospectively. Methods This single centre prospective study was conducted at Peking Union Medical College Hospital (PUMCH). Patients diagnosed with primary or secondary wAIHA and ES who were refractory/relapsed to at least full dose and duration of glucocorticoid were enrolled. After signing the consent forms, participants received sirolimus at a dosage of 1-3 mg/day and maintained the tough concentration of 4-12ng/ml. Patients had to be treated for at least 6 months and continued the treatment till the end of follow-up if responded. Regular follow-up assessments were performed for a minimum duration of 12 months. The primary endpoints of the study were the overall response rate (ORR) and the complete response rate (CRR) at 6-month. Secondary endpoints included ORR and CRR at 12-month, safety and recurrence rates. This study was registered at clinical trials.gov (NCT05925023). Results Between June 2023 and October 2024, 78 patients (28 males, 50 females) were finally enrolled. 63 (80.8%) patients were diagnosed as wAIHA and 15 (19.2%) patients as ES. The median age was 52 (interquartile range [IQR] 38–65) year-old, with 10.3%(8/78) transfusion dependent (TD). The overall response rate was 76.9%(60/78), 80.7%(63/78), 78.9%(56/71) at 3, 6 and 12-month, the complete response rate was 39.7%(31/78), 51.3%(40/78), 52.1%(37/71) respectively. The time to achieve OR and CR were 26 days (IQR 25–93), 76 days (IQR 30–180), respectively. In a median of 13.9 months(IQR 12.7–17.0) follow-up time, 28.2%(22/78) patients reported treatment-emergent adverse events(TEAEs). The most common TEAEs were mucositis (15.4%), infections (7.7%) and gastrointestinal disorder(6.4%). All were mild and reversable under systemic treatments. Relapse happened in 12.7%(9/71) of patients. 2.8% (2/71) died at the end of follow-up. In both univariate and multivariate regression analysis, no factors were found to predict significantly OR, CR at 6-month(p>0.05). Conclusion Sirolimus was effective for patients with primary refractory/relapsed wAIHA and ES, with mild side effects and low relapse rate.

Background: Patients with lower-risk myelodysplastic syndromes (MDS) may experience anemia and a high transfusion burden, alongside a risk of progression to acute myeloid leukemia. Luspatercept, a recombinant fusion protein that acts as an erythroid maturation agent, was FDA/EMA-approved in 2020 based on the phase III MEDALIST trial. There remains an unmet need for anemia treatment in Asian patients for whom red blood cell (RBC) transfusion is a standard of care, and in whom rates/severity of anemia and serum erythropoietin levels are often higher versus Western patients. Objectives: The objective of this study was to assess the efficacy, safety, and tolerability of luspatercept in Asian patients with anemia due to transfusion-dependent lower-risk MDS with ring sideroblasts. Design: This was a phase II, single-arm, interventional bridging study (NCT04477850). Methods: Patients from China and Japan with very low-, low-, or intermediate-risk MDS with ring sideroblasts who were RBC transfusion-dependent received subcutaneous luspatercept starting at 1.0 mg/kg every 3 weeks. The primary endpoint was RBC transfusion independence (TI) ⩾8 weeks (weeks 1–24). Results: There was a statistically significant, clinically meaningful improvement of anemia in Asian patients; 60% ( n = 18, p < 0.0001) achieved RBC-TI for ⩾8 weeks and 43% ( n = 13) for ⩾12 weeks (weeks 1–24). Safety was consistent with the known profile of luspatercept in MDS. Conclusion: These results support luspatercept as a well-tolerated, efficacious alternative to transfusions for Asian patients with lower-risk MDS, who tend to have more severe anemia. Trial registration : clinicaltrials.gov, NCT04477850.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, life-threatening disorder characterized by complement-mediated haemolysis, leading to anaemia and thrombosis. HRS-5965 is a novel, oral, selective complement factor B inhibitor targeting the alternative pathway, potentially reducing both intra- and extravascular haemolysis. In this randomized, open-label phase II study, we evaluated the efficacy and safety of HRS-5965 monotherapy in complement inhibitor-naïve adult PNH patients. Twenty-six patients were randomized 1:1 to receive HRS-5965 50 mg orally twice daily (BID) (with potential up-titration to 100 mg BID) or 75 mg BID for 12 weeks. The primary end-point was the change in haemoglobin (Hb) from baseline to Week 12. Both groups showed marked Hb increases, with least squares mean increases of 37.6 and 37.7 g/L for the 50 and 75 mg BID groups respectively. Lactate dehydrogenase levels declined by 87% and 85% from baseline. The most common treatment-related adverse events were mild lab abnormalities, including increased alkaline phosphatase and alanine aminotransferase. In conclusion, HRS-5965 monotherapy at either 50 or 75 mg BID resulted in substantial Hb improvements and reduced haemolysis with an acceptable safety profile, suggesting its potential as a promising oral therapy for complement inhibitor-naïve PNH patients.