Introduction B-cell non-Hodgkin lymphoma (B-NHL) is the most prevalent NHL subtype, exhibiting high heterogeneity. Chimerin 1 (CHN1), a rac guanosine triphosphatase activating protein (racGAP), is predominantly expressed in neurons, especially in the cerebral cortex, and plays an important role in axon guidance. The previous study has estimated that CHN1 was associated with B-NHL aggressiveness, showing higher expression in indolent follicular lymphoma (FL) compared to aggressive Burkitt lymphoma (BL). In silico analysis also linked high CHN1 expression with favorable outcomes in diffuse large B-cell lymphoma (DLBCL) patients, though this prognostic value requires validation. The functional role of CHN1 in B-NHL remains unclear. Therefore, we aimed to validate the prognostic value of CHN1 in DLBCL and elucidate its biological functions and signaling pathways in B-NHL cells. Methods We retrospectively collected pathological specimens from 52 DLBCL patients. CHN1 expression was assessed by immunohistochemical (IHC) staining. Kaplan-Meier analysis evaluated the correlation between CHN1 expression levels and the prognosis of DLBCL patients. Stable CHN1-overexpressing human DLBCL cell line OCI-LY3 and human Burkitt lymphoma cell line Raji were established via lentiviral transduction. Cell proliferation was measured by direct cell counting. Migration and invasion were assessed using Transwell assays. Protein expression was analyzed by Western blotting. Transcriptome sequencing of OCI-LY3^OE^ cells, followed by GO, KEGG, and GSEA enrichment analyses, identified downstream pathways. Results IHC analysis classified DLBCL patients into CHN1-high and CHN1-low groups (cut-off value: 10% positivity). The CHN1-high group exhibited significantly higher objective response (OR: 86.2% vs. 39.1%, p=0.001) and complete response (CR: 65.5% vs. 21.7%, p=0.002) rates compared to the CHN1-low group. The disease progression (PD) rate was significantly lower in the CHN1-high group (10.3% vs. 52.2%, p=0.001). Kaplan-Meier analysis demonstrated that high CHN1 expression was significantly correlated with prolonged overall survival (OS, p=0.036) and progression-free survival (PFS, p=0.002). Successful establishment of CHN1-overexpressing RajiOE and OCI-LY3OE cells was confirmed. CHN1 overexpression significantly inhibited proliferation (p<0.001) and promoted apoptosis in both cell lines (Raji: p<0.001; OCI-LY3: p=0.002). Western blot demonstrated that CHN1 downregulated the anti-apoptotic protein BCL-2 (OCI-LY3OE: p=0.029; RajiOE: p=0.036) and upregulated the pro-apoptotic protein Bax (OCI-LY3OE: p=0.047; RajiOE: p=0.029). Furthermore, CHN1 suppressed migration (OCI-LY3: p=0.004; Raji: p=0.008) and invasion (OCI-LY3: p=0.012; Raji: p=0.007). Transcriptome sequencing of CHN1-overexpressing OCI-LY3 cells identified 867 upregulated and 1,035 downregulated genes. Enrichment analyses suggested that CHN1 involvement in cell adhesion, metabolism, vesicle formation, and cell junctions, and modulate pathways including PI3K/Akt, IL6/JAK/STAT3, and IL2/STAT5 signaling. Consistently, western blot revealed that CHN1 suppressed the phosphorylation of Akt and mTOR. Treatment with the Akt activator Sc79 partially restored Akt/mTOR phosphorylation and rescued the proliferative, migratory, and invasive capacities by CHN1 overexpression. Conclusions High CHN1 expression is a favorable prognostic marker in DLBCL, associated with higher OR/CR rates, lower PD, and prolonged OS and PFS. CHN1 suppresses B-NHL progression by inhibiting proliferation, migration, and invasion in B-NHL cells. Mechanistically, the Akt/mTOR signaling pathway may be a downstream mechanism of CHN1 in B-NHL cells.

Introduction Intracerebral hemorrhage (ICH) is a rare but devastating complication of immune thrombocytopenia (ITP). Current knowledge is limited in terms of the clinical features and outcome trajectories for ICH in adults with primary ITP. We previously conducted preliminary work to predict mortality risk in patients with intracranial hemorrhage (Blood Adv, 2022), but the role of neuroimaging indicators and long-term outcomes was not evaluated. Here, we report a multicenter cohort study to explore the clinical characteristics, prognostic profiles, and recovery trajectories of adult patients with ICH. Methods Adult patients with ITP who developed ICH between January 2010 and December 2022 were retrospectively identified from 43 medical centers in China. Patients fulfilling the following criteria were included in this study: 1) a clinical diagnosis of primary ITP; 2) a diagnosis of ICH confirmed by imaging evidence; 3) ICH occurring at or after the diagnosis of ITP; 4) age over 18 years at the time of ICH diagnosis; and 5) available 30-day outcomes. Demographic information, clinical manifestations, and follow-up data were retrieved from the medical records. Neuroimaging indicators were reviewed by neurosurgery and radiology specialists at Peking University People's Hospital. Candidate predictors for 30-day mortality after ICH were included in the multivariate analysis using a forward stepwise logistic regression model. Variables remaining in the final model were determined to be independent predictors. The study protocol was approved by the central institutional review board of Peking University People's Hospital. Results One hundred sixty-six (166) patients were included in this study. Patients developed ICH at a median age of 56.5 (IQR, 39.75-67) years, and 109 of them were female. The median platelet count at ICH onset was 7×109/L (IQR, 3-22×109/L). Forty-four (44) patients had underlying diabetes and 36 patients had underlying hypertension at the time of ICH diagnosis. Twenty-eight (28) patients (16.9%) were receiving anticoagulant therapy for underlying atrial fibrillation, and these patients had significantly higher median platelet counts at ICH onset (median, 49.5×109/L vs. 6×109/L, p <0.001). Most patients had deep ICH (65.1%), followed by lobar (25.9%) and infratentorial (13.9%) ICH. A hematoma volume exceeding the previously reported location-specific cutoff for mortality risk (Stroke, 2023) was present in 32 (29.6%) patients with deep ICH, 16 (37.2%) patients with lobar ICH, and 8 (53.3%) patients with infratentorial ICH. Seventy (70) patients (42.2%) died during a median follow-up of 512 (IQR, 12-1871) days, among whom 56 patients (33.7%) died within 30 days of ICH diagnosis. In the multivariable analysis, infratentorial ICH (p =0.001), hematoma volume exceeding the location-specific cutoff for mortality risk (p <0.001), concurrent organ or life-threatening bleeding (p =0.006), and underlying diabetes (p =0.014) were identified as independent risk factors for 30-day mortality. Nineteen (19) patients developed recurrent ICH; the median time of onset was 396 (IQR, 144-1298) days after the first ICH episode. Among the patients with recurrent ICH, 7 (36.8%) were refractory to both corticosteroids and thrombopoietic receptor agonists, and 8 (42.1%) were receiving anticoagulant therapy for atrial fibrillation. Among the 30-day survivors, 6 patients were lost to follow-up and 14 patients died within 1 year of ICH diagnosis. Eighty-one (81) patients with baseline functional impairment (a 30-day modified Rankin Scale score of 3-5) had available functional data at the 1-year follow-up, and 35 (43.2%) of them achieved functional recovery (a 1-year modified Rankin Scale score of 0-2). The female sex (p =0.045) and concurrent organ or life-threatening bleeding within 30 days of ICH diagnosis (p =0.046) were associated with significantly lower probabilities of 1-year functional recovery (multivariable logistic analysis adjusted for age, ICH location, hematoma volume, hypertension, and diabetes). Conclusions In adults with ITP who developed ICH, neuroimaging indicators, bleeding diathesis, and underlying diabetes played key prognostic roles. Anticoagulant use and treatment refractoriness were associated with recurrent ICH. Among survivors of severe ICH, 43.2% achieved functional recovery at 1 year.

Introduction As a highly heterogeneous and aggressive heterogeneous lymphoid neoplasm, diffuse large B-cell lymphoma (DLBCL) exhibits various genetic alterations, leading to diverse clinical course, and varying sensitivity to treatment regimens. With a median age of 67 years at diagnosis, 19.02% of the patients were 80 years and above. Although the molecular characteristics of adult DLBCL has been well documented, the genetic alterations in patients aged ≥80 years remain poorly understood. The study aims to elucidate the genetic landscape in patients aged ≥80 years with DLBCL, and explore the possible targeted therapeutic pathways for them. Methods A total of 179 patients aged ≥80 years with DLBCL was included in the study. Sixteen patients were from Beijing Hospital, while data for 40 patients was collected from R. Schmitz et al. N Engl J Med. 2018, 51 from George W. Wright et al. Cancer Cell. 2020, 24 from Tatsuzo Mishina et al. British Journal of Haematology. 2021, 16 from Wyndham H. Wilson et al. Cancer Cell. 2021, and 32 from Rong Shen et al. Signal Transduction and Targeted Therapy. 2023. Patients were identified for different genetic subtypes by LymphoGen classifier, expect for 32 patients from Rong Shen et al. Signal Transduction and Targeted Therapy. 2023, who were defined by the LymphoPlex classifier. Results The median age of the patients was 83 years (range: 80-96), with 49.2% being male. Regarding the cell of origin (COO), 32.1% (53/165) of the patients were classified as germinal center B-cell (GCB) subtype, 58.8% (97/165) as non-GCB subtype, and 9.1% (15/165) remained unclassified. Additionally, 58.8% (97/165) of the patients were at Ann Arbor stage Ⅲ/Ⅳ, and 48.5% (80/165) of them had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥2. Among these patients, 57.5% (77/134) had elevated lactate dehydrogenase (LDH), and 31.2% (43/138) had ≥2 extranodal sites. Furthermore, 60.2% (97/161) of the patients had an International Prognostic Index (IPI) score ≥3. In terms of the therapy, 60.4% (93/154) of the patients received the R-CHOP-like regimens. The median overall survival (OS) time was 74 months, while the median progression-free survival (PFS) time was 21 months. According to the LymphoGen classifier, 18% of the patients were MCD subtype, followed by EZB (14%), BN2 (11%), ST2 (6%), A53 (5%), and N1 (2%). Notably, 9% of the patients genetically composite, and 35% were classified as others. Among the 32 patients classified by LymphoPlex classifier, 22% of them were allocated as MCD subtype, followed by TP53 (19%), EZB (13%), ST2 (9%), BN2 (3%), and 34% as NOS. There was no statistically difference between the molecular subtypes and OS or PFS (all p > 0.05). Among the 90 patients whose genetic alternations available, PIM1 (47%) was the most frequent mutation, followed by KMT2D (32%), BTG2 (26%), MYD88 (26%), CD79B (24%), and TP53 (23%). The univariate and multivariate Cox regression analyses identified BCL7A mutations (p = 0.032) and HLA-DRB1 mutations as independent prognostic biomarkers for OS of the patients. The enrichment analyses indicated that the mutant genes were primarily enriched in the lymphocyte activation and differentiation pathways, as well as JAK-STAT signaling pathway, Wnt signaling pathway, p53 signaling pathway, and NF-κB signaling pathway. Conclusions In the patients aged ≥80 years with DLBCL, the most common molecular subtype was MCD, and the most frequent mutated gene was PIM1. Mutations in BCL7A and HLA-DRB1 were identified as independent prognostic biomarkers for OS of the very old patients. The mutated genes were enriched in pathways related to the lymphocyte activation and differentiation, as well as JAK-STAT signaling pathway, Wnt signaling pathway, p53 signaling pathway, and NF-κB signaling pathway. Targeting these pathways may potentially benefit patients over 80 years old.

Objective: To retrospectively analyze the clinical characteristics and prognosis of 85 newly diagnosed patients with follicular lymphoma (FL), as well as the prognostic value of comprehensive geriatric assessment (CGA) in patients with FL aged ≥ 60 years old. Methods: The clinical data and prognosis of 85 newly diagnosed FL patients admitted from August 2011 to June 2022 were collected. The clinical features, laboratory indicators, therapeutic efficacy, survival and prognostic factors of patients were statistically analyzed, and the prognosis of patients was stratified using various geriatric assessment tools. Results: ① The patients with FL were mostly middle-aged and older, with a median age of 59 (20-87) years, including 41 patients (48.2%) aged ≥60 years. The ratio of male to female was 1∶1.36. Overall, 77.6% of the patients were diagnosed with Ann Arbor stage Ⅲ-Ⅳ, and 17 cases (20.0%) were accompanied by B symptoms. Bone marrow involvement was the most common (34.1%). ②Overall, 71 patients received immunochemotherapy. The overall response rate was 86.6%, and the complete recovery rate was 47.1% of 68 evaluated patients. Disease progression or relapse in the first 2 years was observed in 23.9% of the patient. Overall, 14.1% of the patients died during follow-up. ③Of the 56 patients receiving R-CHOP-like therapies, the 3-year and 5-year progression-free survival (PFS) rates were 85.2% and 72.8%, respectively, and the 3-year and 5-year overall survival (OS) rates were 95.9% and 88.8%, respectively. The univariate analysis showed that age ≥60 years old (HR=3.430, 95% CI 1.256-9.371, P=0.016), B symptoms (HR=5.030, 95% CI 1.903-13.294, P=0.016), Prognostic Nutritional Index (PNI) <45.25 (HR=3.478, 95% CI 1.299-9.310, P=0.013), Follicular Lymphoma International Prognostic Index (FLIPI) high-risk (HR=2.918, 95% CI 1.074-7.928, P=0.036), and PRIMA-prognostic index (PRIMA-PI) high-risk (HR=2.745, 95% CI 1.057-7.129, P=0.038) significantly predicted PFS. Moreover, age ≥60 years old and B symptoms were independent risk factors for PFS. Progression of disease within 24 months (POD24) significantly predicted OS in the univariate analysis. Conclusions: FL is more common among middle-aged and older women. Age, B symptoms, PNI score, FLIPI high-risk, PRIMA-PI high-risk, and POD24 influenced PFS and OS. The CGA can be used for treatment selection and risk prognostication in older patients with FL.

Introduction: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated thrombocytopenia due to increased platelet destruction and decreased platelet production mediated by the loss of immune tolerance. Steroids, as first-line treatments, don't provide long-term relief. Our previous clinical trials firstly confirmed the efficacy and safety of all-trans retinoic acid (ATRA) in the treatment of ITP and revealed that MSC-C5b-9 may be a stratification marker for evaluating the efficacy of ATRA (Lancet Haematol,2021; Blood,2022). This research aimed to develop a new treatment approach for resistant/recurrent ITP on the basis of the marker MSC-C5b-9. Method: We conducted a multicenter, randomized clinical trial to evaluate the efficacy and safety of ATRA combined with eltrombopag based on MSC-C5b-9 for the treatment of steroid-resistant/recurrent ITP. Following enrollment, patients were assigned randomly in a 1:1 ratio to either the eltrombopag group or the eltrombopag + ATRA group, contingent upon negative or positive results of MSC-C5b-9, respectively. The initial dose of eltrombopag was 50 mg daily, with dose adjustments based on platelet levels. For patients assigned to the ATRA group, ATRA was administered at a dose of 10 mg twice daily. Peripheral blood cell counts, bleeding, health-related quality of life and adverse events (AEs) are regularly monitored. The primary endpoint was a sustained response (SR) at 18 months after randomization, and the secondary endpoints included complete response (CR), response, relapse, early response (ER), initial response (IR) and AEs. All the statistical tests were two-sided, and we considered p values < 0.05 to be statistically significant. We performed all the statistical analyses with SPSS Statistics 27. The study has been registered at clinicaltrials.gov. NCT05438875. Results Patients were enrolled from 2022 to 2023. During this period, 96 patients were enrolled, including 29 MSC-C5b-9-positive patients. On the day of enrollment, patients were randomly assigned at a 1:1 ratio and treated with eltrombopag combined with ATRA (n=48) or eltrombopag (n=48) monotherapy. The median ages were 39.5 and 38 years, and the median durations from diagnosis were 30.5 and 15 months in the ATRA and control groups, respectively. The median baseline platelet count was 13.0 × 109/L in the ATRA group and 18.0 × 109/L in the control group. Among all the patients, SR was achieved in 64.5% of patients in the ATRA group compared with 33.3% of patients in the control group (p=0.015) at 18 months after enrollment. Among the MSC-C5b-9-negative patients, SR was achieved in 72% of patients in the ATRA group, whereas it was achieved in 23.8% of patients in the control group (p=0.003) at 18 months after enrollment. There was no significant difference in the complete response rate or response rate between the two groups (p>0.05). Notably, among the MSC-C5b-9-negative patients, the ATRA group had a significantly higher CR rate and better treatment efficacy compared with the control group (p=0.008, p=0.038). Further analysis revealed that patients who were negative for MSC-C5b-9 achieved a higher CR rate (p=0.017), and there was still a difference in the CR rate in the ATRA group (p=0.002). Stratified analysis of MSCs-C5b-9 revealed that, in the overall and ATRA groups, the efficacy of treatment in the MSC-C5b-9-negative patients was greater than that in the MSC-C5b-9-positive patients (p=0.013, p=0.006). During the follow-up period, the recurrence rate in the control group was greater (p=0.037), and the difference was more significant within MSC-C5b-9-negative patients (p=0.004). We further analyzed the time to relapse (duration of efficacy) and found that, compared with the control group, the ATRA group had a longer duration to relapse among the MSC-C5b-9-negative patients (p=0.024, p=0.004). Compared with baseline, both groups showed improvements in bleeding scores and health-related quality of life at 18 months. The severity of the AEs was grade 1-2. There was no significant difference in AEs between the groups (p>0.05). Conclusions: ATRA treatment of steroid-resistant/recurrent ITP can improve the response rate, bleeding rate and health-related quality of life and prolong the duration of treatment efficacy. Our study confirmed that MSC-C5b-9 is a biomarker for steroid-resistant/recurrent ITP and can be used to guide patient treatment.

Abstract Purpose: The purpose of this study was to investigate the remodeling of the multiple myeloma microenvironment after B-cell maturation antigen (BCMA)–targeted chimeric antigen receptor T (CAR-T) cell therapy. Experimental Design: We performed single-cell RNA sequencing on paired bone marrow specimens (n = 14) from seven patients with multiple myeloma before (i.e., baseline, “day −4”) and after (i.e., “day 28”) lymphodepleted BCMA CAR-T cell therapy. Results: Our analysis revealed heterogeneity in gene expression profiles among multiple myeloma cells, even those harboring the same cytogenetic abnormalities. The best overall responses of patients over the 15-month follow-up are positively correlated with the abundance and targeted cytotoxic activity of CD8+ effector CAR-T cells on day 28 after CAR-T cell infusion. Additionally, favorable responses are associated with attenuated immunosuppression mediated by regulatory T cells, enhanced CD8+ effector T-cell cytotoxic activity, and elevated type 1 conventional dendritic cell (DC) antigen presentation ability. DC re-clustering inferred intramedullary-originated type 3 conventional DCs with extramedullary migration. Cell–cell communication network analysis indicated that BCMA CAR-T therapy mitigates BAFF/GALECTIN/MK pathway–mediated immunosuppression and activates MIF pathway–mediated anti–multiple myeloma immunity. Conclusions: Our study sheds light on multiple myeloma microenvironment dynamics after BCMA CAR-T therapy, offering clues for predicting treatment responsivity.

Relapse is one of the major challenges in clinical treatment of acute myeloid leukemia (AML). Though minimal residual disease (MRD) monitoring plays a crucial role in quantitative assessment of the disease, molecular MRD analysis has been mainly limited to patients diagnosed with gene fusions and NPM1 mutations. Here, we report a longitudinal ultra-sensitive mutation burden (UMB) monitoring strategy for accurate MRD analysis in AML patients regardless of genetic abnormality types. Using a Quantitative Blocker Displacement Amplification (QBDA) sequencing panel with limit of detection below 0.01% variant allele frequency (VAF), a hazard ratio of 14.8 (p < 0.001) is observed in cumulative incidence of relapse analysis of 20 patients with >= 2 samples during complete remission (CR). The ROC area under curve (AUC) is 0.98 when predicting relapse within 30 weeks of CR timepoint 2 (N = 20). Furthermore, we demonstrate quantitating VAF below 0.01% is essential for accurate relapse prediction.

Background: Venetoclax (VEN) and azacitidine (AZA) are used to treat patients with newly diagnosed acute myeloid leukemia (AML) who are unfit for intensive chemotherapy or relapse/refractory AML, it is important to understand the real-world usage patterns and the outcomes after VEN-AZA therapy failure, which is crucial as it remains poorly studied. Methods: A single-center retrospective cohort study was conducted on 50 AML patients (29 newly diagnosed, 21 relapse or refractory) treated with VEN-AZA at Beijing Hospital from January 2020 to November 2023.The study was approved by the ethics committee of Beijing Hospital and adhered to the Declaration of Helsinki. The primary endpoint was overall survival, and the secondary endpoints included composite complete remission, partial remission, overall response rate, event free survival, minimal residual disease (MRD) rate, adverse event (AE) rate and the outcomes after VEN-AZA therapy failure. Results: Among newly diagnosed AML patients, the median age was 74 years. The median follow-up was 10.1 months, and the median EFS and OS were 9.87 months and 11.93 months. The ORR, CR/CRi, and MRD (<0.1%) negativity rates were 85.7%, 67.9%, and 26.3%, respectively. Twelve patients (1 refractory, 11 relapsed) received subsequent treatment following first-line VEN-AZA therapy failure. One refractory patient received VEN-AZA plus Selinexor, achieving partial remission. Two relapsed patients received VEN-AZA plus Chidamide or Gilteritinib, with one achieving CRi. One patient discontinued VEN-AZA independently for five months and relapsed, then reinitiated VEN-AZA, achieving CR after 2 cycles. The median OS after first-line VEN-AZA failure was 1.6 months (range 0-8.27 months). For relapsed/refractory AML patients, the median age was 65 years. The median follow-up was 8.53 months, and the median EFS and OS were 5.2 months and 9.1 months. The ORR, CR/CRi, and MRD (<0.1%) negativity rates were 52.4%, 42.9%, and 11.11%, respectively. Ten patients (2 refractory, 8 relapsed) received subsequent treatment. Two refractory patients received chemotherapy (CAG/HA), with one achieving CRi. Among the eight relapsed patients, two received VEN-AZA plus Enasidenib or Gilteritinib, both achieving CRi. Two patients participated in clinical trials (CAR-NK and CD33-ADC therapy) with an ORR of 50%. The median OS after second-line or more VEN-AZA failure was 0.67 months (range 0-8.63 months). Patients with six or more therapy cycles and achieving CR/CRi had longer EFS and OS. The main adverse events were hematological and infections. Conclusions: The VEN-AZA combination offers high efficacy and manageable toxicities in real-world settings. Patients with AML following failure of frontline VEN-AZA therapy often choose VEN-AZA plus targeted therapy, which offers the best efficacy. Following failure of second-line or beyond VEN-AZA therapy, patients typically choose induction chemotherapy, VEN-AZA plus targeted therapy, or clinical trials. KEYWORDS acute myeloid leukemia, hypomethylating agents, Venetoclax, relapse, refractory

Supplementary Figure S3. Cytogenetic Abnormality-associated Gene Expression and Clonal Evolution in MM Cells.

Introduction The incidence of CLL in China is estimated at 1/10 to 1/20 of its incidence in Western countries. Moreover, the geographic diversity in CLL biology was noticed. Ibrutinib, the first-in class Bruton tyrosine kinase inhibitor (BTKi) was approved in China in 2017. The long-term efficacy and safety of BTKi in Chinese CLL patients has rarely been reported. This real world study aims to analyze long-term survival and outcomes of ibrutinib in Chinese patients with CLL and explore the risk factors for PFS and OS. Methods This study (NCT06489184) included 257 CLL patients aged 18 years and older who received ibrutinib monotherapy for at least one month from Mar.18, 2014.to Apr.1, 2024. The Kaplan-Meier curves were constructed to evaluate PFS, OS, and the differences between the treatment groups were compared using the log-rank test. Cox proportional hazards model comparisons were also conducted to explore the prognostic factors of PFS and OS, and backward stepwise logistic regression method was used in the multivariate analysis to identify independent predictors. A P < 0.05 was considered statistically significant; all P values were two-sided. TP53 aberration includes either TP53 mutation or del17p. Results A total of 257 patients were enrolled in the study, with 137 treatment-naïve (TN) patients and 120 R/R CLL. The median age was 64(range: 34-92) and 180 (70.0%) were male. Regarding the biological characteristics, 59.1% (152) of the patients were at Rai stage III/IV, 34.6% (89/257) with complex karyotype (CK), 36.6% (94/257) with unmutated IGHV. TP53 mutation was detected in 27.2% (70/257) patients, del17p was 20.6%(53/257), and TP53 aberration was 34.2%(88/257). The median follow up was 40 months in the overall population, the longest follow up was till to 122 months, median estimated PFS and OS were 83 and 104 months respectively. For TN patients, the median follow-up was 38(1-122) months, and median PFS and OS was not reached. In TN group 51 patients discontinued the drug, 21(41.2%) due to PD, 17(33.3%) due to AE, 12 (23.5%) due to patient decision, and 1(2.0%) due to unknown reason. Univariate analysis identified TP53 aberration and unmutated IGHV associated with impaired PFS and OS, on the other hand, del(13q) was favorable prognostic parameter for PFS and OS. Using multivariate analysis, TP53 aberrations (HR:2.732; 95%CI:0.108-0.860; P= 0.020), del(13q) (HR:0.304; 95%CI:0.108-0.860; P=0.025) and unmutated IGHV(HR:2.777; 95%CI:1.151-6.701; P=0.023) was the independent adverse risk factors for PFS, and del(13q) (HR:0.283; 95%CI:0.087-0.917; P= 0.025) and unmutated IGHV(HR:3.389; 95%CI:1.242-9.253; P=0.017) was the independent adverse risk factors for PFS. For R/R patients, the median follow-up was 40.5 (1-119) months. Median PFS and OS were 55 and 83 months, respectively. In R/R group, 79 patients discontinued the drug. 34(43%) due to PD, 19(24.1%) due to AE, 13(16.5%) due to the patients' decision, 11(13.9%) due to death, and 2(2.5%) due to unknown reasons. Univariate analysis identified TP53 aberration, IGHV unmutated and RAI III/IV associated with impaired PFS and OS, and del(13q) was favorable factor for PFS and OS. Multivariate analysis showed that TP53 aberration (HR:1.988; 95%CI:1.043-3.789; P=0.037) and unmutated IGHV (HR:0.488; 95%CI:0.247-0.963; P=0.038) were independent adverse risk factors for PFS, and Rai stage III/IV (HR:2.541; 95%CI:1.015-6.360; P=0.046) and unmutated IGHV (HR:0.440; 95%CI:0.206-0.939; P=0.034) were independent adverse risk factors for PFS. Among the 73 dead patients, 23 were in TN group and 50 in R/R group. The causes of deaths in TN group were CLL PD (6, 26.1%), Richter Transformation (RT) (3,13%) COVID-19 and infection (6, 26.1%), other (4,17.4%), cardiovascular disease (CVD, 3,13%), and unknown (1,4.3%). However, COVID-19 and infection (13, 26%) was the most common death reason in R/R group, and CLL PD (12, 24%), RT (7,14%), unknown (7,14%), other (4,8%), cardiovascular disorders (3,6%), secondary malignancies (SM, 3,6%) and cerebral infarction (1,2%). Conclusion To our best of knowledge, this is the first multicenter real-world data in China to analysis ibrutinib monotherapy in CLL patients. Ibrutinib showed long-term effect in both TN and R/R CLL, but discontinuation due to patient decision remains a noteworthy issue in CLL treatment in China.

Introduction For previously untreated patients with diffuse large B-cell lymphoma (DLBCL) who aged over 80 years or classified as frail group by comprehensive geriatric assessment (CGA), R-miniCHOP is the standard regimen. However, due to severe comorbidities and poor physical status, about 50% of them cannot tolerate the R-miniCHOP therapy. Consequently, the median overall survival (OS) of the patients was only 1.3 years. Polatuzumab Vedotin (Pola) has been demonstrated its efficacy and safety in both newly diagnosed and relapse/refractory (R/R) DLBCL patients. In the study, Pola in combination with anti-CD20 monoclonal antibody and dexamethasone (Pola-RD) was explored its effectiveness and safety in very old/frail patients with previously untreated DLBCL. Here we present the characteristics of nine patients and preliminary results. Methods The single-center, prospective, single-arm and observational study is conducted by Beijing Hospital. Previously untreated patients with DLBCL aged ≥80 years or aged between 70 to 79 with CGA as frail were enrolled in the study. Participants received up to six 21-day cycles of Pola-RD therapy: Pola 1.8 mg/kg IV day 1, anti-CD20 monoclonal antibody (rituximab 375mg/m2 IV, or Obinutuzumab 1000mg IV day 1), and dexamethasone 15mg QD day1-5, followed up to two cycles of anti-CD20 monoclonal antibody ± dexamethasone regimens. Whole-body 18F-FDG PET/CT scan was scheduled every 3 cycles. Patients who were assessed as stable disease (SD) or progressive disease (PD) would withdraw the study. The primary endpoint is overall response rate (ORR). The secondary endpoints are 1-, and 2-year OS and progression-free survival (PFS), and safety. The treatment response was assessed by 2014 Lugano response criteria. Adverse events were graded by CTCAE 5.0. Patients' enrollment is ongoing. Results There were nine patients enrolled in the study from May, 2023 to May, 2024. Of the patients, 2/9 was male, and the median age was 80 years (77-86), with seven patients aged ≥80 years. Among them, 4/9 (44.4%) was classified as non-GCB type according to cell of origin. All of the patients were assessed as stage Ⅲ to Ⅳ by Ann Arbor staging system, and had an International Prognostic Index (IPI) score of 2 or more. Six of the patients received Next Generation Sequencing (NGS), and three of them (50.0%) had TP53 mutation. Patients presenting with gastrointestinal symptoms as their initial manifestation were not administered dexamethasone during the first cycle of treatment. With the median follow-up of 7 months (1-11), eight patients were evaluated for interim response, and five could be evaluated for the efficacy after six cycles of therapy. After two or three cycles, the complete response rate (CRR) was 37.5% (3/8), and the ORR was 87.5% (7/8). After six cycles, the CRR was 60.0% (3/5), and the ORR was 80.0% (4/5). The most common adverse events (AE) were the hematological toxicity. Neutropenia at grade 3-4 was observed in 33.3% (3/9) of the patients. No cases of anemia or thrombocytopenia of grade 3-4 were noted. Lung injury was recorded in 33.3% (3/9) of the patients, and one of them was considered as pola-related. Infection occured in 33.3% (3/9) of the patients, and two of them was grade 3. Cardiovascular events presented in 33.3% (3/9) patients, and one of them was at grade 4. Gastrointestinal events were present in 33.3% (3/9) of the patients, and none reached grade 3-4. Peripheral neuropathy was not observed among the nine patients. Among the patients, 4/9 patients complete the therapy; 2/9 are still in the process of treatment. One of them withdrew the due to pola-related lung injury after 3 cycles of therapy. One patient discontinued the therapy due to the progressive disease after 6 cycles of Pola-RD regimens. Notably, A 72-year female, with a history of coronary stent implantation, hypertension, and cerebral infarction, was enrolled in the study. Within the 2 cycles of pola-RD regimens, she experienced an acute myocardial infarction and severe heart failure, and was subsequently evaluated as stable disease. However, the patient ultimately showed no improvement and was discharged automatically. Conclusions Pola-RD may be an effective and well-tolerated therapeutic approach for very old/frail patients with DLBCL. Ongoing treatment and follow-up of the patients will be further updated. More patients are in recruitment.

Introduction Geriatric assessment can aid in optimizing treatment strategies and supportive interventions for older adults with diffuse large B-cell lymphoma (DLBCL). Recently, Fondazione Italiana Linforni developed the simplified Geriatric Assessment (sGA) and Elderly Prognostic Index (EPI) to tailor treatment and predict the prognosis of DLBCL in older adults. Herein, we validated the prognostic value of sGA and EPI, and modified the sGA to make it more effective for older DLBCL patients in China. Methods A total of 257 patients with DLBCL aged ≥65 years from Beijing Hospital and Peking University Third Hospital were included in the study. The sGA, which was modified from original geriatric assessment (oGA), incorporates age, activities of daily living (ADL), instrumental ADL, and Cumulative Illness Rating Scale for Geriatrics (CIRS-G), identifying patients into fit, unfit, and frail group. EPI integrated sGA with the IPI score and hemoglobin, identifying patients into low-, intermediate-, and high-risk group. Early mortality was defined as any death occurring within three months from the date of diagnosis. Kaplan-Meier and receiver operating characteristic (ROC) curves were used to assess survival rates and the sensitivity and specificity of the geriatric assessment tools, respectively, whereas the log-rank test was used for comparison. Univariate and multivariate Cox regression analyses were used to identify the independent biomarkers for the patients. Logistics regression analyses were used to analyze the correlation between the geriatric assessment tools and early mortality. Results In the study, both sGA and EPI were related to the progression-free survival (PFS; Figure 1A and 1B), overall survival (OS; Figure 1C and 1D), and early mortality of older patients with DLBCL in China (All p < 0.05). Although they had no ability to predict PFS ( p > 0.05; Figure 1E), ROC curves showed that sGA could predict OS ( p = 0.006; AUC: 0.602; 95%CI: 0.530-0.674; Figure 1F), and early mortality ( p = 0.002; AUC: 0.744; 95%CI: 0.634-0.853; Figure 1G) in older patients with DLBCL in China. As for EPI, it also could predict OS ( p = 0.027; AUC: 0.584; 95%CI: 0.512-0.656; Figure 1F) and early mortality ( p = 0.009; AUC: 0.703; 95%CI: 0.590-0.815; Figure 1G). To make the geriatric tools more effective for older patients with DLBCL in China, albumin, the independent prognostic biomarker for OS of the cohorts, was added into sGA to establish the modified tool sGA-A (Table 1). According to sGA-A, patients were stratified into fit (36.7%), unfit (30.9%), and frail (32.4%) group. However, 1 patient was excluded due to the deficiency of albumin. The sGA-A was associated with age ( p < 0.001), Ann Arbor stage ( p = 0.002), ECOG-PS ( p < 0.001), lactic dehydrogenase (LDH; p = 0.001), IPI score ( p < 0.001), B symptom ( p < 0.001), hemoglobin ( p < 0.001), and albumin ( p < 0.001). Besides, sGA-A was related to PFS ( p < 0.001; Figure 1H), OS (( p < 0.001; Figure 1I), and early mortality ( p = 0.010) of older patients with DLBCL in China. Furthermore, ROC curves showed that sGA-A not only could predict OS ( p < 0.001; ACU: 0.647; 95%CI: 0.577-0.717; Figure 1F), and early mortality (p = < 0.001; AUC: 0.769; 95%CI: 0.679-0.859; Figure 1G), but also could predict PFS ( p = 0.046; AUC:0.577; 95%CI: 0.502-0.652; Figure 1E). In predicting OS, sGA-A was superior to sGA ( p = 0.010), EPI ( p = 0.006). As for early mortality, sGA-A was superior to the EPI ( p = 0.033), but not sGA ( p = 0.520). Conclusions In the study, we validated that sGA and EPI could predict OS and early mortality of older patients with DLBCL in China. Based on sGA, we propose sGA-A, which combined sGA and albumin, as an effective tool for geriatric assessment in DLBCL. The sGA-A compensated for the deficits of the sGA and EPI in predicting PFS, and was superior to sGA and EPI in predicting OS and early mortality. However, further investigations on whether sGA-A could guide the treatment may assist clinicians in improve the prognosis of older patients with DLBCL.

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Maintenance therapy (MT) deepens response and prolongs progression free survival (PFS) in patients with newly diagnosed multiple myeloma (NDMM) after frontline regimens. Ixazomib, a 2nd generation oral proteasome inhibitor (PI), has been approved for MT because of its convenience and tolerability. Aims: We conducted this prospective multi-center study to compare the efficacy and safety of Ixazomib (I-MT) or Ixazomib plus Lenalidomide (IL-MT) to Lenalidomide (L-MT) as maintenance regimen in transplant-ineligible NDMM patients. Methods: This study was approved by the Institutional Review Board of Peking Union Medical College Hospital and registered (NCT04217967). NDMM patients were enrolled from 10 centers of North China MM Registry, since September 2019. Patients receiving up to 5-9 cycles of front-line regimens and reaching at least partial response (PR) started MT. If PR was not reached after 4 cycles, 2nd-line induction for 2-5 cycles was conducted till PR was reached. Ixazomib 4mg was given on day 1,8,15. Lenalidomide 25mg was given every other day on days 1–21 in a 28-day cycle. Patients in dual drug group were administrated with both Ixazomib and Lenalidomide, dose as listed above. The primary endpoint was progression free survival (PFS) from MT. Results: A total of 181 patients were enrolled, including 70 in I-MT, 63 in L-MT and 48 in IL-MT. The demographic and clinical characteristics, including gender ratio, age, paraprotein isotype, international staging system (ISS), revised-ISS (R-ISS), were comparable among different MT regimen groups (Table 1). The proportions of deletion 17p, t(4,14) and t(14,16), were slightly higher in IL-MT group. The median follow-up duration since maintenance was 23.9, 24.0 and 18.9 months in I-MT, L-MT and IL-MT, respectively. There were 74.3%, 79.4% and 81.3% of the patients reached very good PR (VGPR) or better before MT, while the rates of deep responses improved to 82.9%, 81.0% and 89.6% during follow-up. Progressive disease (PD) was recorded in 37.2% (N=26) of patients on I-MT, 19.0% (N=12) on L-MT and 29.2% (N=14) on IL-MT, respectively. The median PFS was 25.5m, not reached (NR) and 22.8m, while OS was not reached in all groups. After adjusting for age, high-risk cytogenetics, ISS, front-line induction regimens, and depth of response prior to maintenance by Cox model multivariate analysis, our data suggested that L-MT was correlated with significantly longer PFS comparing to I-MT (p=0.023, HR=0.39), while PFS in IL-MT group was similar to those of the other two groups (p=0.29, HR=0.66, Fig 1). As for safety, the prevalence of peripheral neuropathy in whole cohort was 15.7% on I-MT, 15.9% on L-MT and 18.8% on IL-MT. The incidence of gastrointestinal events was 24.3%, 1.6% and 22.9%, respectively. Hematologic toxicities developed in 5.7%, 9.5% and 10.4% of the patients. Infections were recorded in 10%, 3.2% and 2.0%. Three patients withdrew from I-MT group due to adverse events. While in L-MT and IL-MT group, 0 and 2 patients respectively switched MT regimen due to intolerability. Summary/Conclusion: We design this multi-centered prospective study to evaluate if dual drug maintenance will further strengthen response in non-transplant NDMM patients. Our preliminary data suggest that more clinicians in the real practice are inclined to prescribe IL-MT for high-risk patients. Although it is quite tolerable, whether dual-drug maintenance will provide better survival still needs to be defined.Keywords: Maintenance, Myeloma, Therapy

Summary We conducted two indirect comparisons to estimate the efficacy of zanubrutinib versus orelabrutinib in Chinese patients with relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) or R/R mantle cell lymphoma (MCL). An unanchored matching-adjusted indirect comparison (MAIC) was performed in R/R CLL/SLL patients. Individual patient data from zanubrutinib trial (BGB-3111-205) were adjusted to match the aggregated data from the orelabrutinib trial (ICP-CL-00103). A naïve comparison was performed in R/R MCL for the different response assessment methodology and efficacy analysis set between the zanubrutinib (BGB-3111-206) and orelabrutinib (ICP-CL-00102) trials. Efficacy outcomes included ORR and PFS. In R/R CLL/SLL patients, after matching, IRC-assessed ORR was comparable (86.6% vs. 92.5%; risk difference, -5.9% [95% CI: -15.8%-3.8%]); IRC-assessed PFS was similar with a favorable trend in zanubrutinib over orelabrutinib (HR, 0.74 [95% CI: 0.37-1.47]) and the 18-month PFS rate was numerically higher in zanubrutinib (82.9% vs. 78.7%). In R/R MCL patients, naïve comparison showed investigator-assessed ORR was similar (83.7% vs. 87.9%; risk difference, -4.2% [95% CI: -14.8%-6.0%]), and CR rate was significantly higher in zanubrutinib over orelabrutinib (77.9% vs. 42.9%; risk difference, 35.0% [95% CI: 14.5%, 53.7%]). Investigator-assessed PFS was similar with a favorable trend (HR, 0.77 [95% CI: 0.45-1.32]) in zanubrutinib over orelabrutinib and the 12-month PFS rate was numerically higher in zanubrutinib (77.5% vs. 70.8%). MAIC result showed zanubrutinib demonstrated favorable PFS over orelabrutinib for R/R CLL/SLL patients. The naïve comparison showed zanubrutinib had favorable PFS and higher CR rate than orelabrutinib for R/R MCL patients.

Sequence variation resulting from the evolution of IGH clones and immunophenotypic drift makes it difficult to track abnormal B cells in children with precursor B cell acute lymphoblastic leukemia (pre-B-ALL) by flow cytometry, qPCR, or next generation sequencing (NGS). The V-(D)-J regions of immunoglobulin and T cell receptor of 47 pre-B-ALL samples were sequenced using the Illumina NovaSeq platform. The IGH rod-like tracer consensus sequence was extracted based on its rod-like alphahelices structural similarity predicted by AlphaFold2. Additional data from published 203 pre-B-ALL samples were applied for validation. NGS-IGH (+) patients with pre-B-ALL had a poor prognosis. Consistent CDR3-coded protein structures in NGS-IGH (+) samples could be extracted as a potential follow-up marker for pre-B-ALL children during treatment. IGH rod-like tracer from quantitative immune repertoire sequencing may serve as a class of biomarker with significant predictive values for the dynamic monitoring of MRD in pre-B-ALL children.

Background: The outcome of patients with acute myeloid leukemia (AML) aged ⩾65 years is poor. Effective treatment options are limited for patients with AML who cannot tolerate intensive chemotherapy. Objectives: We aimed to evaluate the efficacy of low-dose decitabine in previously untreated patients with AML aged ⩾65 years who were ineligible for intensive chemotherapy based on a comprehensive geriatric assessment. Design: We performed a prospective, multicenter, open-label, and non-randomized study. Methods: Patients were enrolled at four centers in Beijing between 1 January 2017 and 31 December 2020. They were treated with decitabine at a dose of 6 mg/m 2 for 10 days. The treatment was repeated every 28 days for one cycle for a total of six cycles. The primary endpoint of our study was overall survival (OS) at the end of the first year after enrolment. The secondary endpoints included overall response rate, leukemia-free survival, relapse rate, treatment-related mortality (TRM), quality of life, safety, and transfusion dependence. Patients were continuously monitored for toxicity. Results: Overall, 47 patients (30 males and 17 females) participated in this study. The median age of the enrolled patients was 78 (range, 65−90) years. The median follow-up time was 22.2 (range, 4.6−38.8) months. Fifteen (31.9%) patients achieved complete remission (CR), 11 (23.4%) patients achieved partial remission, 3 (6.4%) patients achieved hematological improvement only, and 18 (38.3%) patients did not achieve remission. The median time to obtain CR was 2 months. The median CR was 8.5 months. Of the patients, 36 (76.6%) patients completed six cycles of treatment with low-dose decitabine, and the 1-year OS was 36.1%. According to instrumental activities of daily living scales, age, comorbidities, and albumin (IACA) scores, the median survival was 11.2 months in the unfit group and 6 months in the frail group. The 1-year OS rates in the unfit and frail groups were 49.2% and 23.4%, respectively. Grade ⩾3 non-hematological toxicity was observed in 70.2% (33/47) of the patients. TRM occurred in three patients. No early deaths occurred after treatment. Conclusion: In newly diagnosed older patients with AML whose IACA assessment was unfit or frail for standard chemotherapy, treatment with low-dose decitabine demonstrated clinical activity and good security in our study.

Rare but critical bleeding events in primary immune thrombocytopenia (ITP) present life-threatening complications in patients with ITP, which severely affect their prognosis, quality of life, and treatment decisions. Although several studies have investigated the risk factors related to critical bleeding in ITP, large sample size data, consistent definitions, large-scale multicenter findings, and prediction models for critical bleeding events in patients with ITP are unavailable. For the first time, in this study, we applied the newly proposed critical ITP bleeding criteria by the International Society on Thrombosis and Hemostasis for large sample size data and developed the first machine learning (ML)-based online application for predict critical ITP bleeding. In this research, we developed and externally tested an ML-based model for determining the risk of critical bleeding events in patients with ITP using large multicenter data across China. Retrospective data from 8 medical centers across the country were obtained for model development and prospectively tested in 39 medical centers across the country over a year. This system exhibited good predictive capabilities for training, validation, and test datasets. This convenient web-based tool based on a novel algorithm can rapidly identify the bleeding risk profile of patients with ITP and facilitate clinical decision-making and reduce the occurrence of adversities.

Objective:To investigate the predictive accuracies of four indicators based on the interim 18F-fluorodeoxyglucose (FDG) PET/CT in terms of their efficacy and prognoses in patients with extranodal diffuse large B-cell lymphoma (EN-DLBCL). Methods:Data of a total of seventy-seven newly diagnosed patients (35 males, 42 females; aged (62.7±16.2) years) with EN-DLBCL confirmed by histopathological examination or follow-up results were retrospectively analyzed from May 2011 to April 2020, including baseline PET/CT before treatment, interim PET/CT during initial chemotherapy for 3 to 4 cycles, and clinical data. Follow-up was performed through the hospital's electronic medical record system or phone call. Using the receiver operating characteristic (ROC) curve to select the optimal cutoff value for interim SUV max, patients were divided into SUV max < the cutoff value group and ≥ the cutoff group. Following the clinical practice guideline of 18F-FDG PET/CT and PET/MR in lymphoma (2021 edition), ΔSUV max=70% was chosen as the cutoff value, patients were divided into ΔSUV max%<70% group and ≥70% group. Based on the Deauville five-point scale, patients were divided into 1-3 group and 4-5 group. According to the Lugano classification criteria, patients were divided into the disease remission group and unrelieved group based on the interim response evaluation. The χ2 test, Kaplan-Meier, and Cox regression analysis were performed to analyze SUV max, Deauville five-point scale, and the Lugano classification criteria based on interim PET/CT and ΔSUV max% between baseline PET and interim PET in order to predict the efficacy of primary chemotherapy and prognosis of EN-DLBCL. Results:(1) At the end of primary chemotherapy, 51 patients (66.2%) achieved complete remission (CR). The rates of CR in SUV max<4.9 group and Deauville scores 1-3 group were 82.6% (38/46) and 85.0% (34/40), respectively, which were significantly higher than those of the other corresponding groups ( χ2=13.699, 13.108, both P<0.001). No significant difference was found between the rates of CR of patients grouped by ΔSUV max70% or the interim response evaluation based on the Lugano classification criteria ( χ2=0.018, 0.368, both P>0.05). (2) The median follow-up time was 24 (4-105) months. In addition, 19 patients (24.7%) progressed, relapsed, or died at the end of follow-up. Patients in the SUV max<4.9 group, Deauville scores 1-3 group, or remission group assessed by the Lugano classification criteria had significantly higher 2-year progression-free survival (PFS) than those in the other corresponding groups ( χ2=6.148, 4.586, and 4.765, all P<0.05). The 2-year overall survival (OS) of the remission group was significantly higher than that of the nonremission group ( χ2=7.248, P=0.007). No significant difference was found in the PFS or OS between patients grouped by ΔSUV max70% ( χ2=0.051, 3.331, both P>0.05). Furthermore, multivariate COX analysis confirmed that Lugano classification criteria and International Prognosis Index were independent predictors of PFS ( HR=12.179, 14.330, P=0.015, 0.005) and OS ( HR=8.645, 8.903, P=0.008, 0.041) in EN-DLBCL patients. Conclusion:Among the four assessment indicators of interim PET/CT in patients with EN-DLBCL, the interim SUV max<4.9 and the Deauville scores 1-3 were the better indicators for predicting CR at the end of primary chemotherapy, whereas the interim Lugano classification criteria can be considered an independent predictive factor of PFS and OS.