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.

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:Enterococcal bloodstream infection (EBSI) carries high mortality in hematologic patients, yet no prognostic model tailored to this population exists. Methods:We retrospectively analyzed 192 hematologic patients (≥14 years) with EBSI admitted between 2014 and 2024. Clinical features, microbiology, treatment, and outcomes were assessed. Candidate predictors for 30-day mortality were selected by LASSO and entered into multivariable logistic regression. A simplified risk score was derived from regression coefficients and internally validated by bootstrap resampling. Results:The median patient age was 43 years, and acute leukemia was the predominant underlying disease (72.4%). Enterococcus faecium was the leading pathogen (71.4%), with low vancomycin resistance (1.6%). Most cases (71.9%) occurred as breakthrough infections, mainly during carbapenem therapy, and 72.9% met mucosal barrier injury laboratory-confirmed bloodstream infection criteria. The 14- and 30-day all-cause mortality rates were 13.5% and 22.4%, respectively. Independent predictors of 30-day mortality included age ≥50 years (aOR=2.29, p=0.038), severe graft-versus-host disease (aOR=6.06, p=0.003), septic shock (aOR=30.01, p<0.001). The final predictive model, incorporating these three factors along with pneumonia and high-risk hematologic disease, demonstrated optimal discrimination (AUROC 0.79, 95% CI 0.705-0.867) and calibration. A derived risk score stratified patients into low- (<2 points) and high-risk (≥2 points) groups, with markedly different 30-day mortality (11.3% vs. 39.0%, P<0.001). Conclusions:In hematologic patients, EBSIs commonly arise as breakthrough infections despite broad-spectrum antibiotic coverage, most often associated with mucosal barrier injury. Our parsimonious risk score enables early identification of patients at high risk of 30-day mortality to guide timely interventions.

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.

Bacterial and fungal pulmonary infections (BFPI) are common in hematological patients and pose significant diagnostic challenges. Metagenomic next-generation sequencing (mNGS) is valuable for diagnosing BFPI. However, for hematological patients with limited access to lower respiratory tract samples (LRTS), the clinical value of blood-mNGS compared to LRTS-mNGS requires further investigation. A retrospective analysis was conducted on 160 cases with suspected pneumonia who underwent both blood-mNGS and LRTS-mNGS within one week. Diagnostic performance and impacts on antimicrobial adjustments were evaluated using clinical composite diagnosis (CCD) as the reference. Compared to CCD, LRTS-mNGS showed significantly higher positive percent agreement (PPA) than blood-mNGS [93.7

Multidrug-resistant (MDR) Acinetobacter spp. bloodstream infection (BSI) is concerning in hematologic patients, but integrated clinical and genomic analyses are scarce. We retrospectively analyzed 62 hematologic patients with Acinetobacter spp. BSI over 13 years, including 30 MDR and 32 non-MDR cases. Whole-genome sequence (WGS) was conducted on 23 MDR isolates. Checkerboard assays evaluated the in vitro activity of eravacycline combined with sulbactam, meropenem, cefoperazone–sulbactam, polymyxin B, and levofloxacin. Female (66.67

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.

VEXAS syndrome is a recently characterized hemato-inflammatory disorder caused by somatic mutations in the X-linked UBA1 gene in hematopoietic progenitor cells; however, it remains poorly characterized in Chinese populations. We retrospectively analyzed 4,512 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 30y - 74y). All 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 nonspecified hemolytic disorder. Most patients (11/16, 68.8%) exhibited constitutional symptoms and typical autoinflammation-associated multiorgan involvement, including skin lesions, ear chondritis, pulmonary infiltration, and deep vein thrombosis et al. 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 13/16 (81.3%) 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. As a relatively large cohort of VEXAS syndrome characterizing Chinese patients, this study demonstrates a higher incidence than previously suggested and challenges the prevailing notion that VEXAS syndrome is a rare disorder. VEXAS should be considered in patients with cytopenia, regardless of comorbid systemic symptoms or multiorgan involvement, necessitating UBA1 testing for early diagnosis and appropriate therapy. Increased awareness among hematologists is critical to facilitate early diagnosis through UBA1 variant testing. This can prevent unnecessary diagnostic procedures and guide timely interventions, including preemptive stem cell transplantation.

To explore the clinical characteristics and outcomes of Staphylococcus aureus bacteremia (SAB) in patients with hematological diseases and evaluate the efficacy of short-course antibiotic therapy for uncomplicated SAB in this group. We performed a retrospective study on hematological adult patients with SAB, including a high proportion of neutropenic patients. Logistic regression models fitted with inverse probability of treatment weighting were employed to evaluate the association between treatment duration and clinical outcomes in patients with uncomplicated SAB. A total of 242 patients infected with SAB were included, of whom 38 (15.7%) were caused by MRSA. The 90-day mortality and 30-day mortality rate were 11.2% (n = 27) and 4.5% (n = 11), respectively, while the 90-day recurrence rate was 5.4% (n = 13). Multivariate analysis indicated that advanced age (odds ratio [OR] = 1.063, P = 0.004), relapsed or refractory hematological diseases (OR = 14.439, P < 0.001), and polymicrobial infection (OR = 5.102, P = 0.020) were independent predictors of 90-day mortality, while MRSA bacteremia was an independent predictor of 30-day mortality (OR = 14.091, P = 0.009). Among 191 patients with uncomplicated SAB, 89 patients received short-course (median, 8.0 days; IQR, 7.0-9.0) and 102 received long-course therapy (median, 15.0 days; IQR, 12.0-19.3). In the weighted cohort, the multivariate analysis indicated that a short course of antibiotic treatment showed no significant relation with 90-day mortality (OR = 0.595, P = 0.486), 30-day mortality (OR = 0.784, P = 0.832) or 90-day recurrence (OR = 1.80, P = 0.373). For hematological adult patients infected with SAB, MRSA, and polymicrobial infection associated with poor outcomes. Short-course antibiotic therapy for uncomplicated SAB seemed to yield similar clinical outcomes as long-course one. IMPORTANCE:There is still no consensus on the optimal antibiotic course for Staphylococcus aureus bacteremia (SAB) in patients with hematological diseases. Some studies have suggested that short-course antibiotic therapy was feasible for uncomplicated SAB, but few have targeted hematological patients. Here, we described clinical characteristics and outcomes of SAB in hematological patients and highlighted advanced age, refractory or relapsed hematological diseases, and polymicrobial infection as independent predictors of 90-day mortality, while MRSA bacteremia was associated with early mortality risk. And we demonstrated that short-course antibiotic therapy (≤10 days) for uncomplicated SAB in hematological patients was non-inferior to long-course one (>10 days).

Abstract 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

Purpose:Concerns over health-related quality of life (HRQOL) in patients with aplastic anemia (AA) have been increasing worldwide. However, most researches on HRQOL in AA patients have ignored individual-level variability. Thus, our study was designed to explore practical classification of HRQOL and related variables among AA patients. Methods:A cross-sectional study was conducted from May 2022 to March 2023, utilizing convenience sampling to enroll AA patients. Data of HRQOL, sociodemographic characteristics, and clinical variables were collected. Latent profile analysis (LPA) was used to analyze the latent categories of HRQOL in AA patients, utilizing scores from eight subscales of the Medical Outcomes Study 36-Item Short Form Health Survey version 2.0. Results:A total of 229 patients completed the survey and were included in the analysis. The LPA results showed significantly individual differences and identified three subgroups of HRQOL: Group 1, poor HRQOL with role emotional limitation (n=54, 23.58%); Group 2, moderate HRQOL with role physical limitation (n=56, 24.45%), and Group 3, good HRQOL (n=119, 51.97%), respectively among AA patients. Childless, no comorbidities, transfusion independence, no AA-related symptoms, and higher annual household income were associated with Group 3, whereas higher Eastern Cooperative Oncology Group performance status (ECOG-PS) scores were associated with Group 1. Conclusion:The findings of our study revealed significant heterogeneity in HRQOL among AA patients, providing valuable information for tailoring interventions to meet individual needs, especially for those in the poor HRQOL with role emotional limitation group. To improve their quality of life, healthcare professionals should fully take into account how the HRQOL subgroups are affected by AA-related symptoms, household annual income, ECOG-PS score, children, comorbidities, and transfusion-dependence.

IFN-γ and TNF-α are two vital inflammatory factors elevated aberrantly in many diseases. Such an inflammatory microenvironment is detrimental to residual cells such as mesenchymal stem cells (MSCs), yet the precise mechanisms are not fully understood. IFN-γ and TNF-α have distinct effects on the immunoregulatory properties of MSCs, and they have been proposed as optimal priming factors to enhance the immunosuppressive capacity of engineered MSCs. Thus, the overall effects of IFN-γ and/or TNF-α exposure on MSCs needs to be elucidated. Here, it is found that IFN-γ and TNF-α synergistically induce cell death of MSCs via necroptosis. When MSCs are exposed to both IFN-γ and TNF-α, their morphological features and biological functions are impaired. Mechanistically revealed by RNA-Sequencing, the injured MSCs undergo a unique cell death process, namely necroptosis. Compared with controls, IFN-γ synergized with TNF-α to increase the expression of RIPK1, RIPK3, MLKL, and all other genes associated with necroptosis. Rescue experiments further demonstrate that this process can be reversed by RIPK3 and MLKL inhibitors but not by the RIPK1 inhibitor, suggesting a RIPK1-independent pathway. Collectively, this study discloses an inflammatory injury mechanism of MSCs, which may shed new light on revealing the MSCs deficits in many inflammatory diseases with expectations to inspire potential targeted therapies. In addition, inflammatory impairment should be taken into consideration when delivering cell therapy based on MSCs primed with IFN-γ and TNF-α.

IntroductionCarbapenem-resistant Enterobacterales (CRE) bloodstream infections (BSI) represent a frequent and grave complication among hematological patients, whose prevailing culprits are Carbapenem-Resistant Klebsiella pneumoniae (CRKP) and Escherichia coli bacteremia (EC). Nevertheless, there is a paucity of studies that have undertaken a comparative analysis of clinical outcomes in patients afflicted with CRKP and EC.MethodsThis study was conducted with the aim of identifying the microbiological and clinical characteristics of hematological patients suffering from bacteremia caused by CRKP and CREC.ResultsThe cohort included 90 patients with equal proportions of CRKP BSI and CREC BSI from 2017 to 2022. Among the tested CRE strains (n = 45) for carbapenemase (CP) genes, the KPC gene was most commonly found in CP-CRKP isolates (12/21), while the NDM gene predominated among CP-CREC strains (18/24). A comparison of drug susceptibility showed that CREC was significantly more susceptible to tigecycline than CRKP (97.73% vs. 64.86%, P = 0.018). Patients treated with tigecycline-based therapy had a higher survival rate in the CREC group (18/24,75%) compared to the CRKP group (8/14,57.1%). The CRKP group had a significantly lower rate of prior cephalosporin use within 30 days compared to the CREC group (27% vs. 49%, P = 0.03) and a higher incidence of multi-site infections before BSI (44% vs. 8.9%, P<0.001). Multivariate analysis showed that BSI caused by CRKP was an independent risk factor for survival (P = 0.029), while CAZ-AVI-based therapy emerged as an independent factor improving patient prognosis (P =0.013).ConclusionsOur results found that bacteremia instigated by CRKP was associated with a less favorable prognosis when compared to cases induced by CREC. Moreover, treatment regimens incorporating CAZ-AVI have the potential to enhance the prognosis of patients grappling with CRE BSI.

Chronic disseminated candidiasis (CDC) is an invasive fungal infection typically affecting patients with hematological diseases and severe neutropenia, associated with increased mortality. However, there is a global shortage of clinical evidence on CDC. We retrospectively analyzed clinical data from 49 CDC patients over the past decade. Clinical characteristics of primary hematological diseases, CDC diagnosis, treatment and response evaluations were included. Clinical factors associated with CDC remission and patients' survival were analyzed. The majority of patients had hematological malignancies (n = 43, 87.8%), and 27 patients (55.1%) had persistent severe neutropenia for more than 10 days prior to CDC. CT scans revealed liver lesions in 44 patients, spleen lesions in 34 patients, and kidney lesions in 9 patients. Proven, probable and possible CDC was diagnosed in 5 (10.2%), 3 (6.1%) and 41 patients (83.7%), respectively, and treatment outcomes at 3 months included 5 complete response (CR, 10.2%), 34 partial response (PR, 69.4%) and 10 treatment failure (20.4%). Caspofungin treatment showed a trend towards improving CR/PR rate, while severe neutropenia > 20 days and proven diagnosis were significantly associated with 3-month treatment failure. Kaplan-Meier curve showed achieving CR/PR within 3 months did not significantly prolong OS compared to treatment failure patients (1197.6 days vs. 564.8 days, P = 0.074). Additionally, no patient deaths were directly attributed to CDC infection. Age > 45 years old and malignancy non-remission were prognostic factors of overall survival (OS). Furthermore, a prediction model identified severe neutropenia > 20 days, proven/probable diagnosis and concomitant bacteremia as risk factors to effectively predict treatment failure. Also, patients with a risk score < 0.203 in the model exhibited more rapid treatment response. After CDC symptoms onset, lymphocyte levels remained consistently higher in treatment failure patients, while the neutrophil-to-lymphocyte ratio was persistently higher in CR/PR patients. Our findings recommend CT scans for diagnosis and caspofungin as first-line therapy while continuing scheduled chemotherapy or bone marrow transplantation. Notably, risk factors identified by the prediction model could be used to predict treatment response.

Abstract Objective: Autoimmune hemolytic anemia (AIHA) is the most prevalent form of acquired hemolytic anemia, representing a heterogeneous group of anemias. As the largest retrospective study of AIHA in Asia, this study aimed to characterize the clinical features, treatment patterns, response rates, and long-term outcomes, thereby providing benchmarks for risk stratification and the evaluation of novel therapies. Methods: This retrospective cohort study analyzed 566 AIHA patients (449 warm AIHA [wAIHA] and 117 mixed AIHA [mAIHA]) hospitalized at the Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from January 2014 to December 2023, with a median follow-up of 57 months (range: 0.03-420). We evaluated the baseline clinical and laboratory characteristics, treatment responses, and long-term outcomes, including overall survival (OS), event-free survival (EFS, composite endpoint of relapse or death), and complications (thrombosis and infections). Survival was analyzed by Kaplan-Meier and Cox regression models. Results: Analysis of the 566 AIHA patients (median onset age 48 years; 70% female) revealed distinct differences between subtypes. Compared to wAIHA, mAIHA patients exhibited an earlier onset (median 43 vs. 48 years), poorer erythropoiesis (bone marrow responsiveness index [BMRI] 125.3 vs. 173.9; reticulocyte production index [RPI] 2.5 vs. 3.6), a bimodal age distribution (peaks at 20/60 years) and cold AIHA-like features (including reduced RBC counts, elevated MCV/MCH/MCHC, and higher lymphocytes percentages) despite comparable initial hemoglobin (Hb) levels and hemolytic markers. Notably, secondary forms were significantly more prevalent in mAIHA (39.3% vs 22.5%), with systemic lupus erythematosus and CD5-CD10- small B-cell lymphoproliferative disorders (particularly marginal zone lymphoma and lymphoplasmacytic lymphoma/Waldenström macroglobulinemia) predominating among autoimmune and lymphoproliferative causes, respectively. Our cohort exhibited 1-, 3-, and 5-year OS rates of 96%, 92%, and 89% respectively. While disease progression accounted for 25.8% of mortality, while infections represented the leading cause of non-AIHA deaths (31.8%). Multivariable Cox regression established five independent risk factors including age ≥60 (HR=3.04), glucocorticoid (GC) non-response (HR=2.45), opportunistic infections (HR=2.13), Hb <6 g/dL (HR=1.98), and BMRI <121 (HR=1.73). Serologically, IgM- (HR=3.18) and IgM+IgA-mediated (HR=6.56) subtypes had worse OS than IgG+C3 controls in wAIHA patients. The median EFS was 17 months (1-/3-/5-year EFS: 54.5%/37.5%/29.9%), with relapses occurring primarily during treatment tapering (71.8%) or with infections (27.1%, primarily respiratory). Thrombosis occurred in 10.2% (wAIHA) and 7.7% (mAIHA), mostly during active hemolysis (84.8%/66.7%), with 43.6% of thrombosis occurred within 1-month post-diagnosis. Among opportunistic infections, fungal infections predominated (80.6%; Aspergillus, Candida, Pneumocystis). First-line GCs were used in 98.9% of patients, with response rates of 92.3% in wAIHA and 97.3% in mAIHA, demonstrating non-inferior efficacy in mAIHA. Second-line therapies (64.5%) comprised rituximab (54.5%, with comparable efficacy between standard-dose and low-dose), cyclosporine (17.5%), androgens (13.2%), cyclophosphamide (4.7%), mycophenolate mofetil (3.0%), splenectomy (2.5%) and others. Refractory AIHA was observed in 3.2% (wAIHA) and 3.5% (mAIHA) cases, demonstrating resistance to ≥3 lines of therapies including splenectomy/immunosuppressants. Conclusion: This study revealed that mAIHA presents with an earlier onset, more secondary forms, cold agglutination-like features and poorer bone marrow compensation compared to wAIHA. Independent risk factors for mortality were identified as age ≥60 (HR=3.04), GCs resistance (HR=2.45), opportunistic infections (HR=2.13), Hb <6 g/dL (HR=1.98), and impaired erythropoiesis (BMRI <121, HR=1.73). Serologically, IgM-mediated wAIHA or with concurrent IgA involvement (IgM+IgA-mediated) showed worse OS. Notably, cold agglutinin titers showed limited predictive value for OS or treatment response. A nomogram model was developed to facilitate risk stratification. Documentation of treatment patterns and responses illustrates the therapeutic landscape of AIHA in Asian populations and establish a crucial baseline for evaluating emerging therapies.