Supplementary Figure 6. Effects of CAR-T cell therapy on target expression and body weight in xenograft models.

Orelabrutinib is a potent, irreversible, and highly-selective BTK inhibitor that has been approved for the treatment of relapsed/refractory chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). This randomized, phase 3 study (ClinicalTrials.gov identifier: NCT04578613) compared orelabrutinib with chemoimmunotherapy in patients with treatment-naïve CLL/SLL. From February 20, 2021, to July 8, 2024, 192 eligible patients were randomly assigned (1:1) to receive either orelabrutinib (91 patients) or chlorambucil plus rituximab (101 patients), comprising the intention-to-treat population. At a median follow-up of 21.4 months (data cutoff, May 17, 2024), the primary endpoint of progression-free survival (PFS) per independent review committee (IRC) was not reached (NR; 95% CI, not estimable [NE]-NE) with orelabrutinib versus 19.4 months (95% CI, 16.6-NE) with chlorambucil plus rituximab (hazard ratio [HR], 0.32; 95% CI, 0.18-0.58; p < 0.0001; crossing the efficacy boundary). The IRC-assessed overall response rate (90.1% vs 79.2%; p = 0.041) and duration of response (HR, 0.30; 95% CI, 0.15-0.60; p = 0.0003) also favored orelabrutinib over chlorambucil plus rituximab. In the safety population, treatment-related adverse events occurred in 82 of 91 patients (90.1%) receiving orelabrutinib and 89 of 98 patients (90.8%) receiving chlorambucil plus rituximab, with 32 (35.2%) and 59 (60.2%) at grade 3 or worse, respectively. Orelabrutinib maintained or improved patient-reported outcomes compared with chemoimmunotherapy. In summary, orelabrutinib significantly improved PFS and response versus chemoimmunotherapy in patients with treatment-naïve CLL/SLL, with a manageable safety profile, supporting it as an effective alternative first-line option.

Supplementary Figure 4. Binding profiles of LL-PR002 evaluated by alanine scanning on T2 cells.

Renal involvement in chronic lymphocytic leukemia (CLL) is uncommon but can lead to significant morbidity. Membranoproliferative glomerulonephritis (MPGN) is among the most frequently reported glomerular lesions associated with CLL and may presents with nephrotic syndrome. Early recognition of the association between renal lesions and CLL is crucial for guiding treatment and improving both renal and hematologic outcomes. We report two biopsy-proven cases of CLL-associated MPGN successfully treated with next-generation Bruton’s tyrosine kinase inhibitors (BTKis). Both patients presented with nephrotic-range proteinuria. In Case 1, the patient exhibited monoclonal IgG-κ gammopathy and isolated low serum C3, suggestive of complement-mediated injury without direct immunoglobulin deposition. He achieved sustained hematologic and renal remission with orelabrutinib following early discontinuation of rituximab–chlorambucil due to infection. In Case 2, renal biopsy showed interstitial infiltration by CLL cells and immune complex deposition, supporting a leukemic infiltration and immune-complex mediated mechanism. Zanubrutinib led to clinical improvement, and rituximab was later added to further reduce proteinuria. These cases underscore the critical role of kidney biopsy in clarifying diagnosis and underlying mechanisms. In this case series, the treatment regimen centered on next-generation BTKis enabled patients to achieve concurrent favorable renal and hematologic remission with good tolerability.

Multiple myeloma (MM) develops with the acquisition of genetic abnormalities in plasmacytes and changes in microenvironment cells (MECs). Despite the progress in understanding MM disease mechanism through omics studies, the genomic/transcriptomic profiling remains limited in Chinese MM patients. Here, we collected 277 newly diagnosed MM (NDMM) patients in the Shanghai MM Omics (SMMO) project. Analysis of 267 cases with whole-genome/whole-exome sequencing and RNA sequencing (RNA-seq) identified three genetic groups (MY, HRD, and MS/CD). Using single-cell RNA sequencing (scRNA-seq), we investigated 59 NDMM subjects from SMMO, 20 relapsed cases from public database and 30 normal controls. Eight subpopulations of plasmacytes from NDMM (mSP1-mSP8) were defined, each showing unique signatures while forming a differentiation trajectory. The mSP2 is worth noting due to its high proliferative property. Regarding MECs, we found T cell subsets including T-helpers, Tregs, and cytotoxic T cells all in dysfunctional status and increased myeloid-derived suppressor cells such as macrophages mainly in M2 polarization, both constituting a milieu in favor of MM cell growth and immune escape. Furthermore, we scrutinized the crosstalk between MM cells and MECs and that among distinct MECs. A dynamic, comprehensive MM pathogenesis network was revealed, with a number of ligand-receptor pairs. Importantly, the mSP2 signature can be projected to the MM cell RNA-seq data of 235 patients to generate a Score100 with prognostic value in SMMO. Via multivariate analysis of the International Staging System, Consensus Genomic Staging, and Score100, we propose a practical MM stratification model for evaluating aggressive myeloma.

PURPOSE:Chimeric antigen receptor (CAR) T-cell immunotherapy in acute myeloid leukemia (AML) remains challenging because of the lack of specific cell surface antigens that are highly expressed on leukemic blasts but largely absent in hematopoietic stem/progenitor cells (HSPC) and healthy tissues. Targeting intracellular antigen via T-cell receptor (TCR)-like CAR T cells offers a promising alternative. This study aimed to develop nanobodies targeting the intracellular antigen preferentially expressed antigen in melanoma (PRAME) and develop a novel nanobody-based TCR-like CAR T-cell therapy. EXPERIMENTAL DESIGN:We investigated the PRAME expression level by analyzing the RNA sequencing data from 1,007 patients with AML and healthy donor samples. We explored the relationships between PRAME expression and the prognosis of AML. Novel nanobodies targeting PRAME425-433/human leukocyte antigen A2 (HLA-A2) were generated via alpaca immunization and yeast surface display and then used to construct TCR-like CAR T cells. The antileukemia potency of the PRAME-targeted TCR-like CAR T cells and their on-target/off-tumor toxicity against normal HSPCs were evaluated. RESULTS:PRAME was highly expressed in AML cells but largely absent in normal hematopoietic cells and healthy tissues and was correlated with poor clinical outcomes in AML. The CAR T cells based on the nanobody targeting PRAME425-433/HLA-A2 exhibited specific and potent antileukemic cytotoxicity against PRAME+HLA-A2+ AML cells in vitro and in vivo, whereas they showed negligible effects on the viability and function of normal HSPCs. CONCLUSIONS:This study demonstrates that PRAME is a promising target for the immunotherapy of AML, and nanobody-based TCR-like CAR T cells targeting PRAME425-433/HLA-A2 exhibit potent antileukemic activity with a favorable off-target safety profile.

ABSTRACT:GPRC5D has emerged as a promising therapeutic target in relapsed/refractory multiple myeloma (R/R MM), particularly following progression after B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell (CAR-T) therapies. RD118 is a novel CAR-T therapy incorporating a fully human single-domain antibody fragment targeting GPRC5D. In this phase 1 study, 18 R/R patients (17 with MM and 1 with a history of primary plasma cell leukemia) received a single infusion of RD118 at 1.0 × 106, 2.0 × 106, or 3.0 × 106 CAR+ T cells per kg. At a median follow-up of 17.0 months, the overall response rate (ORR) was 94.4%, including 72.2% complete or stringent complete responses. Among the 7 patients previously exposed to BCMA-directed CAR-T therapy, ORR reached 85.7%. Median progression-free survival (PFS) was 18.2 months (95% confidence interval, 14.4 to not estimable), with 12-month PFS and overall survival rates of 82.1% and 93.3%, respectively. Cytokine release syndrome occurred in 88.9% of the patients, primarily grade 1 to 2. One patient developed grade 3 immune effector cell-associated neurotoxicity, which resolved within 72 hours. No cerebellar toxicities or treatment-related deaths were reported. These findings support that RD118 is a highly effective and safe therapeutic option for heavily pretreated R/R MM. This trial was registered at www.clinicaltrials.gov as #NCT05759793 and #NCT05219721.

OBJECTIVE:To retrospectively analyze the characteristics and influencing factors of COVID-19 infection in patients with multiple myeloma (MM) who underwent autologous hematopoietic stem cell transplantation (AHSCT). METHODS:The clinical data of MM patients who underwent AHSCT in Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine from May 26, 2021 to December 26, 2022 were collected. The onset of COVID-19 infection, corresponding symptoms and laboratory tests were followed up in outpatient or by the means of telephone contact and online questionnaires. Related analysis was then performed. RESULTS:This study included 96 patients, and 72 cases among them were infected with COVID-19 while 24 cases were uninfected. Logistic regression analysis showed that vaccination did not significantly reduce the risk of COVID-19 infection, but patients who received two doses of the vaccine had a lower risk of developing moderate and severe disease than those who did not receive or received one dose (OR =0.06, P =0.029). Patients who received daratumumab before had a higher risk of COVID-19 infection (OR =5.78, P =0.039), while those with a history of immunomodulatory drugs (IMiDs) had the opposite effect (OR =0.31, P =0.028). The use of both drugs did not affect the severity of COVID-19 infection. CONCLUSION:For MM patients undergoing AHSCT as first-line chemotherapy, COVID-19 vaccination does not significantly reduce the infection rate, but it plays a role in preventing moderate and severe cases. The application of antineoplastic drugs with different mechanisms has a certain impact on the susceptibility to the COVID-19, which should be considered comprehensively when creating treatment plans.

T-cell acute lymphoblastic leukemia (T-ALL) is a relatively rare hematological malignancy, characterized by the uncontrolled proliferation of immature T lymphoblasts and associated with a generally unfavorable prognosis. Our previous research has demonstrated that decreased mitochondrial activity is associated with the aggressiveness of T-ALL tumors. However, the mechanisms underlying this phenomenon and its contribution to treatment resistance remain largely elusive. We have built up the largest known T-ALL tumor bank, with a median follow-up of 32 months, including our transcriptomic data from 79 newly sequenced tumors that adds to the 54 publicly accessible samples. Computational analyses and a series of functional assays were performed to investigate the molecular links between altered mitochondrial activity and drug resistance. The transcriptomic analysis revealed that down-regulation of mitochondrial activity is a potent driver of ABCB1 activation, a gene strongly associated with multidrug resistance. In tumors with low mitochondrial activity, the impaired fatty acids β-oxidation leads to intracellular lipid accumulation, which is directly involved in ABCB1 activation. Indeed, our data show that lipid neo-synthesis and accumulation promotes the activation of lipogenic transcription factors, liver X receptors (LXRs), which act as drivers of ABCB1 expression. Tumor data analyses confirmed that high ABCB1 expression in tumour samples is indeed associated with reduced mitochondrial gene expression, lipid droplet enrichment, increased tumour aggressiveness, and significantly shorter patient survival. Our study demonstrates that reduced mitochondrial activity drives multidrug resistance in adult T-ALL via lipid-mediated activation of ABCB1. These findings enhance our understanding of the biology of aggressive T-ALL and provide insight into mechanisms of resistance to conventional chemotherapy. Consequently, we propose that targeting de novo lipogenesis and restricting dietary fats, such as caprylic acid, may help overcome treatment resistance in patients with T-ALL exhibiting low mitochondrial activity. The clinical trial was registered under the identifiers ChiCTR-ONRC-14004968 and ChiCTR2000031553 at ClinicalTrials.gov.

Multiple myeloma (MM) relapse still occurs after a durable response to anti-B cell maturation antigen (BCMA) chimeric antigen receptor-engineered T (CAR-T) cell therapy with less-defined factors. Herein, we investigated a CAR-T-exposed MM patient who relapsed after 12 months of remission by single-cell transcriptome sequencing. The bone marrow CAR-T population at relapse exhibited exhaustion and proliferation attenuation. The recurrent myeloma cells were deficient in or weakly expressed TNFRSF17 (BCMA) but possessed an identical immunoglobulin clonality to the baseline tumor. Interestingly, combined with the transcriptome profile of the myeloma strains, MM cells with BCMA negativity featured high ANXA1 expression that was identified as an inferior prognostic indicator for MM patients. At a single-cell resolution, BCMA-negative myeloma could be present in the MM patients without CAR-T cell exposure and displayed an increased level of intrinsic ANXA1 transcripts. In vitro assays unveiled that Annexin A1 (ANXA1) elevation conferred growth capacity to BCMA-negative myeloma cells via AMPKα signaling activation and disturbed CAR-T cell fitness. Blockade of Annexin A1 reduced BCMA-negative myeloma cell proliferation. Murine models further demonstrated that Annexin A1 inhibition could effectively diminish BCMA-negative myeloma that escaped from CAR-T’s attack. Together, our data identified ANXA1 as a potential target for BCMA-negative myeloma clearance. The ANXA1-targeting strategy might be helpful for CAR-T treatment optimization.

The existing risk models for multiple myeloma (MM) are suboptimal for the stratification of patients with primary plasma cell leukemia (pPCL), a rare and peculiar MM. In this study, we aimed to develop a staging system for pPCL defined as the presence of ≥ 5

Background Combining IKZF1plus genotyping and minimal residual disease status at three months of treatment helps refining risk stratification for adult BCR::ABL1–positive acute lymphoblastic leukemia (BCR::ABL1+ ALL) in our previous study. (Wang C, et al. Blood Cancer J. 2024 Apr 24;14(1):71). In parallel, ABL1 kinase domain mutations persist as a major therapeutic challenge. In spite of prognostic significance of the two factors individually, studies on the association of IKZF1plus genotype and ABL1 mutations remain limited. Aim To establish the prognostic profile and investigate underlying biological features of concomitant IKZF1plus genotype and ABL1 mutations in adult BCR::ABL1+ ALL. Methods Fron June 2014 to December 2024, newly diagnosed adult BCR::ABL1+ ALL patients (aged ≥18) treated in our institute were included. The patients received a TKI-based [imatinib or flumatinib (a second-generation TKI)] standardized VIP regimen (Vincristine/Idarubicin/Prednisone), and eligible patients were recommended to undergo allo-HSCT. At diagnosis, fresh bone marrow or blood samples were collected from patients with written informed consent. Multiplex ligation-dependent probe amplification (MLPA) was used for IKZF1plus genotyping at diagnosis, polymerase chain reaction was employed to routinely monitor MRD and ABL1 mutation status, and bulk RNA sequencing was utilized to characterize biological features. (Clinical Trial Registration Number: ChiCTRONRC-14004968, ChiCTR2100042248 and ChiCRT2100044308). Results According to MLPA results, 246 newly diagnosed BCR::ABL1+ ALL patients were classified into IKZF1plus (n = 98), and non-IKZF1plus genotype (n = 148), respectively. And based on ABL1 mutation analysis, the patients were categorized into three groups: T315I mutation (n = 62), mutations other than T315I (non-T315I, n = 34), and no mutation (n = 150), respectively. Compared to no mutation group, T315I mutation group exhibited a notably higher proportion of IKZF1plus genotype (P = 0.02), adults aged older than 65 years (P = 0.01), higher white blood cell counts (P = 0.02), MRD positivity at 3 months of treatment (P < 0.001), relapse (P < 0.001) and death (P < 0.001). Similarly, relative to non-T315I mutation group, T315I mutation group also demonstrated a significantly greater frequency of IKZF1plus genotype (P = 0.01) and relapse (P = 0.004). Till July 31, 2025, the overall median follow-up period was 31.8 months (range, 6.4-122.4). The 3-year overall survival (OS) of T315I mutation group was the worst [34.4% (95% CI: 19.8%-49.1%)], lower than non-T315I mutations group [61.7% (95% CI: 41.8%-81.7%), P = 0.07] or no mutation group [91.2% (95% CI: 85.8%-96.5%), P < 0.001]. Then focusing on IKZF1plus genotype, patients were stratified into three subgroups based on ABL1 mutation analysis:IKZF1plus/T315I (n = 34), IKZF1plus/non-T315I (n = 9), and IKZF1plus/no mutation (n = 55). IKZF1plus/T315I subgroup exhibited the lowest 3-year OS rate [21.2% (95% CI: 3.0%-39.4%)], and allo-HSCT markedly improved their 3-year OS [allo-HSCT: 47.6% (95% CI: 18.8%-100.0%) vs non-HSCT: 8.4% (95% CI: 1.3%-53.7%), P = 0.001]. In comparison, IKZF1plus/non-T315I subgroup showed a moderately better 3-year OS rate [42.9% (95% CI: 6.2%-79.5%), P = 0.17], with allo-HSCT associated with a trend toward improved prognosis. Lastly, IKZF1plus/no mutation subgroup demonstrated the highest 3-year OS rate [88.3% (95% CI: 78.5%-98.1%), P < 0.001], whose outcomes were similar in patients undergoing allo-HSCT or not. Additionally, transcriptomic profiling via RNA sequencing revealed that compared to IKZF1plus/no mutation subgroup,IKZF1plus/T315I subgroup was characterized by significant down-regulation of p53 signaling pathways (P = 0.03), indicating a potential molecular basis for their poor prognosis. Conclusion Integrating IKZF1plus genotyping and ABL1 mutation status, our findings firstly refine risk stratification and delineate distinct prognostic subgroups in high-risk adult BCR::ABL1+ ALL with IKZF1plusgenotype. Notably, IKZF1plus patients harboring T315I mutation constitute a subgroup with dismal survival, likely associated with the down-regulation of p53 pathways, and they would benefit from allo-HSCT. Conversely, IKZF1plus cases without ABL1 mutations exhibit a markedly favorable prognosis.

Birelentinib (DZD8586) is a LYN/BTK dual inhibitor designed to block both BTK-dependent and BTK-independent BCR signalling. In TAI-SHAN5 (NCT05824585) and TAI-SHAN8 (NCT06539182, CTR20240120) studies, patients who failed front line BTKi and/or BCL2i showed an overall response rate (ORR) of 84.2%. Similar responses were observed in patients with prior treatment of covalent BTKi, non-covalent BTKi as well as BTK degraders, with BTK C481X or “kinase-impaired” mutations (ASCO 2025). Here we report follow-up results of these studies. The data from TAI-SHAN5 and TAI-SHAN8 studies were pooled for the efficacy and safety analysis. Tumor response was assessed by investigators per iwCLL 2018 or Lugano 2014 criteria, as appropriate. All enrolled patients were included in safety analysis, and those patients enrolled by January 2025 were included in efficacy analysis to assess efficacy with long-term follow-up. As of July 7, 2025, a total of 65 patients with r/r CLL/SLL have been enrolled and received DZD8586 at doses ranging from 25 mg to 100 mg once daily (QD). At the recommended phase 3 dose (RP3D), 50 mg QD, 44 patients were enrolled. The median age was 62.5 years, 68% were male, and 64% had ECOG score of 1 or 2. The median number of prior therapies was 2 (range 1-5). Del(17p) and/or TP53 mutation was detected in 37% of the patients. Prior therapies included BTK inhibitor (71%, including 7% treated with non-covalent BTK inhibitor and 5% treated with BTK degrader), BCL-2 inhibitor (23%), and chemoimmunotherapy (41%). BTK mutations were detected in 55% of patients, including kinase proficient BTK mutation (55%) and kinase impaired BTK mutation (32%). In the efficacy analysis set at RP3D (N=19), 16 out of 19 patients achieved tumor response, with overall response rate (ORR) of 84.2%. Tumor response was observed in patients who received prior treatment with BTK inhibitors (ORR 82.4%, including non-covalent BTK inhibitors [2/2, ORR 100%]), Bcl-2 inhibitor (5/6, ORR 83%), and BTK degrader (1/2, ORR 50%). With median follow-up of 8.3 months, the estimated 12-month PFS rate was 61.9%. As of data cut-off date, the longest responder was on therapy for 12.1 months. DZD8586 was well tolerated across the doses investigated. No new safety signals were identified. At the RP3D, the most common ≥grade 3 drug-related TEAEs were neutropenia (22.7%). No febrile neutropenia was reported. No major bleeding or atrial fibrillation was reported. Nine percent of the patients had drug-related TEAEs leading to dose reduction. Only one patient discontinued treatment due to drug-related TEAE (cough). No drug-related TEAE related death was reported. DZD8586 showed encouraging anti-tumor activity with well tolerated and manageable safety profile in heavily pre-treated CLL/SLL patients, including patients with prior covalent BTKi, non-covalent BTKi, BTK degrader, and Bcl-2 inhibitor treatment. Durable tumor response was observed. The updated data will be presented at the meeting.

Chimeric antigen receptor T-cell (CAR-T) therapy has been successfully applied in clinical treatment, especially for hematologic malignancies such as multiple myeloma (MM), but its broad application is limited by cytokine release syndrome (CRS), a potentially life-threatening complication. Although metabolic alterations are known to accompany CRS, predictive biomarkers for its onset, severity, and associated metabolic remodeling remain unknown, hindering proactive clinical management. Here, we analyzed longitudinal serum metabolic profiles from 19 patients with relapsed/refractory MM receiving CAR-T therapy, with validation in an independent cohort of 23 patients. We observed dysregulated arginine metabolism that progressed alongside clinical CRS. At pre-lymphodepletion (Day-5), over half of differentially abundant metabolites were enriched in unsaturated fatty acid (UFA) synthesis pathways, which were exclusively upregulated in patients who later developed severe CRS. Furthermore, two lysophosphatidylcholines, namely, lysoPC(16:0) and lysoPC(15:0), were significantly associated with delayed CRS onset, with elevated concentrations correlated with a prolonged time to onset; this association was independently validated. These findings revealed that arginine metabolism was a pathological axis in CRS, UFAs were severity predictors, and specific lysoPCs were modulators of onset time. Collectively, they provide proactive CRS management, addressing critical gaps in predictive biomarkers to advance the safe, broad CAR-T application in MM.

Introduction: BCL2 inhibition is an established CLL/SLL therapeutic strategy, and combination with Bruton tyrosine kinase inhibition (BTKi) achieves therapeutic synergy. Mesutoclax (ICP-248) is highly selective and potent BCL2 inhibitor with improved pharmokinetical profile and metabolic stability. Orelabrutinib is a marketed second-generation BTKi with best kinase selectivity and good efficacy and safety in CLL/SLL. Herein, we present updated results of two ongoing studies of mesutoclax alone or combined with orelabrutinib in patients with treatment-naive (TN) or relapsed/refractory (R/R) CLL/SLL (NCT06378138; NCT05728658). Methods: Patients with TN CLL/SLL were randomized 1:1 with stratification, by age and TP53/del (17p) status, to receive mesutoclax (100 mg or 125mg once daily [cycles 3-14]) after two cycles orelabrutinib (150mg once daily [cycles 1-17]) lead in. Patients with R/R CLL/SLL received mesutoclax monotherapy until disease progression or unacceptable toxicity. Mesutoclax was administrated with a 5-week ramp-up schedule to the target dose to mitigate risk of tumor lysis syndrome (TLS). TN CLL/SLL can be continuously treated with orelabrutinib if stopping rules (undetectable MRD [uMRD; ≤10-4] at cycle 17) are not reached. Results: Between Apr 2023 and Sep 2024, 66 patients were enrolled: 42 patients were TN (mesutoclax 100 mg, n=21; 125 mg, n=21) and 24 patients were R/R. The median age for TN and R/R CLL/SLL were 59.5 y and 61.7 y, respectively. At baseline, 76.2% (32/42) of TN CLL/SLL patients had moderate or high TLS risk, while 70.8% of R/R CLL/SLL patients were refractory disease, among which 41.7% of patients were previously treated with BTKi. The median prior therapeutic line was 2 (range 1-7). Mesutoclax is well tolerated with good safety profile. No dose-limiting toxicities (DLTs) observed up to 150 mg QD, and maximum tolerated dose (MTD) not reached. As of Jul 21, 2025, all patients were still on treatment. Most treatment emergent adverse events (TEAEs) were grade 1-2, with no TEAEs leading to drug discontinuation or death reported. The most common grade ≥3 TEAEs include neutrophil count decreased, white blood cell count decreased and platelet count decreased. After 2 cycles of orelabrutinib lead in, 100% TN patients with high TLS risk were effectively debulked to moderate or low risk, and no clinical or laboratory TLS occurred. In TN CLL/SLL, the overall response rate (ORR) was 100% and the complete remission rate (CRR) was 28.6% at 125 mg. At week 36 of the combination therapy, the peripheral blood (PB) uMRD rate was 65% (13/20) at 125 mg. The median time to CR was 7.1 mo (range, 3.5-9.4 mo), the median time to uMRD was 5.8 mo (range, 5.5-11.3 mo). The ORR was 100% and CRR was 27.8% in R/R CLL/SLL patients at 125 mg. In 10 R/R CLL/SLL patients who failed prior BTKi treatment, the ORR was 100% and CRR was 30.0%, PB uMRD rate was 20.0%. 12-mo progression-free survival (PFS) rate was 100%. Conclusions: Mesutoclax monotherapy or in combination with orelabrutinib demonstrated a tolerable safety profile across all dose levels tested. Substantial efficacy and deep remission were observed in both TN CLL/SLL patients receiving mesutoclax 125mg combined with orelabrutinib and R/R CLL/SLL treated with mesutoclax alone.

Introduction: Since the introduction of first-generation Bruton tyrosine kinase inhibitors (BTKis) nearly a decade ago, BTKis have become foundational agents in both first- and second-line therapies for CLL/SLL. Continuous BTKi treatment is often complicated by dose reductions or treatment interruptions due to various factors, which clinical and real-world studies have linked to patient prognosis, potentially affecting progression-free survival (PFS) and overall survival (OS). However, comprehensive real-world analyses addressing the characteristics, clinical outcomes, and long-term efficacy and safety implications of varied dose modification and interruption scenarios remain scarce. To address challenges such as the low incidence of CLL/SLL in Asian populations and incomplete electronic medical records, we established a standardized outpatient treatment management system for CLL/SLL. This system aims to standardize therapeutic protocols, enhance treatment adherence, and ensure comprehensive and accurate clinical data collection, thereby providing robust real-world evidence. Within this framework, dose reductions and interruptions during BTKi therapy are meticulously documented, and their impact on clinical outcomes is systematically evaluated. Methods: This retrospective study included CLL patients aged 18 years and older who received care at the CLL/SLL specialized clinics affiliated with Shanghai Jiao Tong University School of Medicine between January 2018 and April 2025. Eligible patients had undergone at least one month of covalent BTKi therapy, including ibrutinib, zanubrutinib, or orelabrutinib. Patients enrolled in clinical trials were excluded. All patients were included irrespective of their treatment status at enrollment. Results: A total of 324 patients under specialized outpatient observation were enrolled; among BTKi-treated patients, the median age was 65 years (range, 25–91), with a male-to-female ratio of 2.6:1. Treatment-naïve (TN) patients numbered 225 (69.44%), and relapsed/refractory (R/R) patients numbered 99 (30.56%). The proportion of TN patients receiving BTKi increased from 22.7% in 2018 to 100% in 2024. Patients younger than 65 years accounted for 40.74% (132/324), and 43.5% (87/200) exhibited del(17p)/TP53 aberrations, reflecting the evolution of BTKi-based regimens in clinical practice in China.With a median follow-up of 42 months, the median OS was not reached, and the 42-month PFS rate was 70.22%. Among all patients, 88 received full-dose BTKi, 231 were in the dose reduction/interruption group, and 5 were lost to follow-up.A total of 352 dose reduction or temporary interruption events were recorded, attributed to non-hematologic adverse events (AEs) in 68.8%, hematologic AEs in 4.5%, concomitant hematologic and non-hematologic AEs in 10.5%, social factors in 5.4%, and physician judgement in 10.8%. The proportion of AE-related dose modifications or interruptions by year were: 83.33% (20/24) in 2019, 86.08% (68/79) in 2020, 87.23% (82/94) in 2021, 76.40% (68/89) in 2022, 51.85% (42/81) in 2023, and 38.46% (15/39) in 2024. COVID-19-related events accounted for 38.6% (136/352) of all events.Among 295 adverse event (AE)-related dose reduction or interruption events, 82 involved switching between covalent BTK inhibitors (defined as switching events; 76 single switches, 3 involving 2 switches), while 213 did not involve switching (non-switching events). Statistical comparison of duration categories of dose modification/interruption (≤7 days, 7–14 days, >14 days) revealed that the duration in the switching group was significantly shorter than that in the non-switching group (χ² = 50.8, df = 2, p = 9.31×10⁻¹²).Early (0 to 3 months) dose reduction/interruption events were significantly associated with worse OS (hazard ratio [HR] = 3.29, p = 0.014) and PFS (HR = 3.93, p = 0.008). Additionally, comparison between non-switching (n = 124) and switching (n = 51) groups demonstrated significant impact on PFS (HR = 0.36, p = 0.022) and OS (HR = 0.34, p = 0.018), favoring the switching group. This study underscores the critical role of standardized management and comprehensive real-world monitoring in elucidating and mitigating the impact of dose modifications and treatment interruptions during BTKi therapy for CLL/SLL.

7010 Background: New therapies are needed for patients with relapsed or refractory (r/r) CLL/SLL following covalent and/or non-covalent BTK inhibitors. While early clinical data showed encouraging anti-tumor activities from BTK degraders in these patients, resistance mutations to both BTK inhibitors and degraders have already been reported. In addition, concerns with emerging clinical safety signals from these degraders may limit their longer-term clinical use. DZD8586 is a rationally designed LYN/BTK dual inhibitor with high selectivity against other TEC family members. Here we report results from ongoing phase 1/2 clinical studies of DZD8586 in r/r CLL/SLL patients with prior treatment of covalent and/or non-covalent BTK inhibitors as well as BTK degraders. Methods: The data from two clinical studies, TAI-SHAN5 (NCT05824585) and TAI-SHAN8 (NCT06539182, CTR20240120), were pooled for the safety and efficacy analysis in patients with CLL/SLL. Modulation of PD biomarkers was evaluated at doses tested. Tumor response was assessed by investigators per iwCLL 2018 or Lugano 2014 criteria as appropriate. Results: As of January 3, 2025, a total of 40 patients with r/r CLL/SLL have been enrolled and received DZD8586 at doses ranging from 25 mg to 100 mg once daily (QD). The median age was 64.5 years, 62.5% were male, and 60% had ECOG score of 1 or 2. A total of 30 patients were evaluable for efficacy analysis. The median number of prior therapies was 2 (range 1-8). Most common prior CLL/SLL therapies included BTK inhibitor (76.7%), and Bcl-2 inhibitor (43.3%). Patients previously treated by non-covalent BTK inhibitor (13.3%) and BTK degrader (13.3%) were also reported. Across all dose levels, 15 out of 30 patients achieved tumor response, with objective response rate (ORR) of 50%. At the recommended phase 2 dose (RP2D) of 50 mg QD, 9 out of 14 patients achieved tumor response, with ORR of 64.3%. Efficacy was observed in patients with prior BTK inhibitor treatment (ORR 52.2%), and Bcl-2 inhibitor treatment (ORR 46.2%). Seventy five percent patients who received prior BTK degrader treatment achieved partial response. As of the data cut-off date, the longest responder was on therapy for 12.1 months. Deepening response was observed with longer treatment time. DZD8586 was well tolerated across the doses investigated. At the RP2D, the most common ≥grade 3 TEAEs were neutropenia (15%) and pneumonia (10%). No major bleeding or atrial fibrillation was reported. No grade 4/5 AEs reported. Conclusions: DZD8586 showed encouraging anti-tumor activity with a well tolerated and manageable safety profile in heavily pre-treated CLL/SLL patients, including patients with prior covalent BTKi, non-covalent BTKi, BTK degrader and Bcl-2 inhibitor treatment. PK/PD results confirmed dose/exposure-dependent pathway inhibition by DZD8586. The updated data will be presented at the meeting. Clinical trial information: NCT06539182 , NCT05824585 .

BACKGROUND:Acute leukaemia represents a crucial health challenge. However, nationwide data delineating the incidence of acute leukaemia subtypes, as well as mortality and survival outcomes, remain scarce in China. We aimed to provide a comprehensive assessment of the epidemiology of acute leukaemia subtypes across China. METHODS:We conducted a population-based cancer registry analysis and cohort study in China, by integrating data from five national databases through unique national identification numbers. The main outcomes were age-standardised rates (ASRs) for incidence and mortality and overall survival for acute leukaemia subtypes. Acute leukaemia incidence and mortality data in 2019 were extracted from National Cancer Centre (NCC) registries linked to the Hospital Quality Monitoring System (HQMS), stratified by age, sex, and region. ASRs were calculated with Segi's world standard population with 95% CIs across the general population. For the survival analysis, we established a cohort from the Chinese Childhood Leukaemia Registry (33 530 children aged 0-14 years) and National Adult Acute Leukaemia Registry of China (71 477 adults aged ≥15 years) for 2016-20, integrated with the Cause of Death Reporting System and HQMS. Patients were stratified by subtype, age, sex, region, molecular characteristics, treatment modalities, and diagnosis period (2016-18 vs 2019-20). Overall survival and cause-specific survival were assessed with the Kaplan-Meier method at multiple timepoints (1 month, and year 1 to year 5) in our cohort. Multivariate Cox regression analysis was performed to identify prognostic factors. FINDINGS:Based on NCC registries covering a population of 628·4 million, we estimated 43 275 new acute leukaemia cases and 27 049 deaths in 2019 in China, with an ASR for incidence 2·83 (95% CI 2·78-2·88) per 100 000 population and an ASR for mortality of 1·51 (1·48-1·54) per 100 000 population. The ASR for the incidence of non-acute promyelocytic leukaemia-acute myeloid leukaemia was 1·24 (95% CI 1·21-1·26) per 100 000 population, that of acute lymphoblastic leukaemia was 0·92 (0·89-0·95) per 100 000 population, and that of acute promyelocytic leukaemia was 0·22 (0·21-0·23) per 100 000 population. The incidence of acute leukaemia spiked in children aged 1-4 years (4·54 per 100 000), then declined, and then rose markedly after age 60 years, peaking at 9·33 per 100 000 in people aged 75-79 years, before declining, while overall mortality remained relatively low across younger age groups (0-44 years), then increased progressively with advancing age, from 1·23 per 100 000 in adults aged 45-49 years to 8·77 per 100 000 in those aged 80-84 years. In children, 5-year overall survival was 66·5% (95% CI 65·3-67·9) for non-acute promyelocytic leukaemia acute myeloid leukaemia, 91·1% (89·6-92·6) for acute promyelocytic leukaemia, and 85·4% (84·9-85·8) for acute lymphoblastic leukaemia; in adults, 5-year overall survival was 23·9% (23·4-24·3) for non-acute promyelocytic leukaemia acute myeloid leukaemia, 82·5% (81·7-83·4) for acute promyelocytic leukaemia, and 30·1% (29·2-30·9) for acute lymphoblastic leukaemia. Survival improved in the more recent period (2019-20 vs 2016-18: hazard ratio 0·97 [95% CI 0·95-0·99]; p=0·0014), particularly among younger adults with non-acute promyelocytic leukaemia acute myeloid leukaemia (aged <60 years) and acute lymphoblastic leukaemia (aged <40 years), with improvements primarily attributable to expanded application of allogeneic haematopoietic stem-cell transplantation. However, prognosis remained poor in patients with acute leukaemia aged 60 years and older (5-year overall survival 14·9% [95% CI 14·3-15·5] in patients aged 60-74 years, and 4·8% [4·2-5·4] in patients aged ≥75 years). INTERPRETATION:This comprehensive nationwide study of acute leukaemia incidence, mortality and survival outcomes across China establishes age-specific epidemiological benchmarks, enabling ongoing risk factor monitoring, while supporting expanded transplantation access for eligible patients and highlighting the urgent need for novel, less toxic therapies for older patients who bear a disproportionately higher disease burden. FUNDING:State Key Laboratory of Medical Genomics, Double First-Class Project, Overseas Expertise Introduction Project for Discipline Innovation, National Natural Science Foundation of China, Innovative Research Team of High-level Local Universities in Shanghai, Shanghai Guangci Translational Medical Research Development Foundation, and CAMS Innovation Fund for Medical Sciences. TRANSLATIONS:For the Chinese translation of the abstract see Supplementary Materials section.