Cusatuzumab is a monoclonal antibody that binds with high affinity to CD70, a cell surface protein overexpressed on CD34+ acute myeloid leukemia (AML) progenitors and leukemia stem cells. This phase Ib study assessed the safety, tolerability and efficacy of adding cusatuzumab to standard-of-care azacitidine and venetoclax (CVA) or a cusatuzumab and venetoclax (CV) doublet regimen in patients newly diagnosed with AML who were ineligible for intensive chemotherapy. Cusatuzumab 20 mg/kg was administered intravenously on days 3 and 17 of 28-day cycles combined with standard dosing of venetoclax ± azacitidine. Overall, 44 patients were treated with CVA. Common hematologic treatment-emergent adverse events (TEAEs) were neutropenia (77.3%), thrombocytopenia (77.3%) and anemia (45.5%); non-hematologic TEAEs included nausea (45.5%), diarrhea (43.2%), constipation (40.9%), fatigue (36.4%) and vomiting (31.8%). Grade ≥3 infectious complications included febrile neutropenia (38.6%), sepsis (36.4%) and pneumonia (9.1%). The overall composite response rate (complete remission [CR] + CR with partial hematologic recovery [CRh] + CR with incomplete hematologic recovery [CRi]) was 77.3% (CR, 47.7%; CRh, 20.5%; CRi, 9.1%). Among CR/CRi responders, 53% achieved negative measurable residual disease by multiparameter flow cytometry. Median overall survival was 12.0 months (95% confidence interval: 8.7-NE) months. Sixteen patients were treated with CV and had similar safety but less favorable responses and survival than those treated with CVA. These results support further development of CVA for the treatment of AML (clinicaltrials.gov identifier: NCT04150887).
Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subtype of B-cell ALL associated with poor response to induction chemotherapy, suboptimal measurable residual disease (MRD) clearance, and inferior survival outcomes compared to non-Phlike subtypes. We retrospectively analyzed 140 consecutive adult patients with Ph-like ALL treated at our institution. The median age was 33.5 years, and the majority harbored CRLF2 rearrangements (85%). IKZF1plus deletion and JAK mutations were identified in 26% and 37% of patients, respectively. The majority (75%) received pediatric-inspired regimens (PIR), which were associated with higher complete remission (CR) rates (p=0.034), reduced risk of relapse (p.
The phase 3, open-label LACEWING study evaluated efficacy and safety of the FMS-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib (GIL) plus azacitidine (AZA) in newly diagnosed (ND) FLT3-mutated (FLT3mut+) acute myeloid leukemia (AML) ineligible for intensive induction chemotherapy (IIC). Patients were enrolled into a safety cohort (n=15) or randomized (n=168) to GIL+AZA, GIL, or AZA. We present final (6.5-year) outcomes and additional data on mutational subgroups, measurable residual disease (MRD), and pharmacokinetics. Median overall survival (OS) was 9.82 versus 9.23 months (GIL+AZA vs AZA, p=0.182) and 5.24 months (GIL). Corresponding two-year OS rates were 18.8%, 12.9%, and 4.5%. Overall response rates were 70.2% versus 36.8% (GIL+AZA vs AZA, nominal p.
Endothelial dysfunction in patients after severe injury with hemorrhagic shock is associated with excessive release of ultralarge von Willebrand factor (VWF) without a corresponding increase in ADAMTS13 (A disintegrin and metalloprotease thrombospondin type 1 motifs, member 13), resulting in acquired ADAMTS13 deficiency and VWF hyperadhesive activity. We hypothesized that the VWF to ADAMTS13 imbalance is exacerbated by increased VWF oxidation, rendering it resistant to cleavage by ADAMTS13. Plasma indices of endotheliopathy and coagulopathy in 100 hemorrhagic shock patients were obtained, ADAMTS13-to-VWF ratio was calculated and correlated with indices of adverse outcomes using Classification and Regression Tree modeling. A novel mass spectrometry method was used to quantify the rate of VWF cleavage in individual patients. In a mouse model of polytrauma and hemorrhagic shock, a single dose of human recombinant ADAMTS13 was administered and VWF cleavage, VWF activity, and parameters of lung dysfunction examined. We detected a reduced rate of cleavage and increased oxidation rate of selective methionine residues of VWF in these patients. In mice, recombinant ADAMTS13 decreased the adhesive activity and enhanced cleavage of plasma VWF, and improved parameters of lung dysfunction. The present study supports the conclusion that an imbalance between VWF and ADAMTS13 drives, at least in part, the endotheliopathy of trauma and the associated adverse outcomes and suggests a potential therapeutic target for severely injured patients with hemorrhagic shock.
KMT2A partial tandem duplication (KMT2A-PTD) is a recurrent genetic alteration in acute myeloid leukemia (AML), but its role as a measurable residual disease (MRD) marker before allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unclear. We retrospectively analyzed 180 KMT2A-PTD AML patients undergoing allo-HSCT at Peking University People's Hospital between 2015 and 2025. Pre-transplant KMT2A-PTD MRD was quantified by real-time quantitative PCR, with positivity defined as ≥1500 copies/10⁵ ABL1. Among 158 patients transplanted in complete remission (CR), 144 had pre-transplant MRD assessment, and 34 (24%) were MRDpositive. Compared with MRD-negative patients, MRD-positive patients had significantly inferior 3- year overall survival (OS, 49% vs. 80%; p.
Belantamab mafodotin is approved globally for relapsed/refractory multiple myeloma (RRMM) based on the phase 3 DREAMM-7 (belantamab mafodotin, bortezomib, dexamethasone [BVd]) and DREAMM-8 (belantamab mafodotin, pomalidomide, dexamethasone) studies. Ocular events in these studies were common, transient, and associated with high rates of resolution. Exposure-response analyses using Cycle 1 exposures (data from the DREAMM-6, DREAMM-7, and DREAMM-8 trials) and BVd dosing regimen simulation (using a previously-developed and validated framework) were performed to support benefit-risk analysis of belantamab mafodotin dosing strategies to improve outcomes. Higher Cycle 1 belantamab mafodotin exposure was significantly associated with higher probabilities of overall response, very good partial response or better (≥VGPR), and shorter time to response, as well as ocular events including grade ≥2/≥3 ophthalmic exam findings (OEFs), and best-corrected visual acuity worsening to 20/50 or worse in both eyes. However, multivariate models predicted that the benefit of increased probability of ≥VGPR with a 2.5 mg/kg vs 1.9 mg/kg starting dose (70.4% vs 54.3%) outweighed the risk for modest increases in clinically meaningful ocular events. Simulated regimens with a 2.5 mg/kg first dose demonstrated high efficacy, with regimens that stepped down to 1.9 mg/kg and utilized schedule extensions (planned or in response to ocular events) showing improved tolerability. Altogether, a belantamab mafodotin starting dose of 2.5 mg/kg in RRMM is important to achieve deeper response and outweighs modest improvements in tolerability from a 1.9 mg/kg starting dose. Subsequent step-down to 1.9 mg/kg along with schedule extensions can be used to manage tolerability while still achieving meaningful efficacy.
Multiple myeloma represents a systemic disease of the bone marrow (BM) niche, in which immune and skeletal pathways are tightly interconnected. However, the independent prognostic significance of bone and immune-related markers in newly diagnosed multiple myeloma (NDMM) remains incompletely understood. Semaphorin (Sema) 4D, activin-A, and periostin ELISA, LEGENDplex™ Human Bone Metabolism Panel and proteomic analysis for novel biomarker identification were conducted in 71 consecutive samples from NDMM patients. In 25 patients, genomic analysis was performed on sorted clonal plasma cells. NDMM patients had a median age at diagnosis of 65 years and a median follow-up of 2.5 years. Interleukin (IL)-1β and Sema4D levels predicted progression-free survival (PFS), highlighting their role in disease relapse. Proteomic profiling revealed a systemic signature associated with worse prognosis, enriched in complement activation components. Complement C5 significantly affected PFS and time to progression (TTP). IL-1β and C5 predicted PFS independently of the second revision of the International Staging System (R2-ISS) stage, and a similar trend was noted for Sema4D. Myeloma bone disease (MBD) did not significantly affect overall survival, PFS, or TTP, suggesting that contemporary treatments mitigate its impact. Genomic analyses identified variants associated with inferior PFS, including HLA-DRB5 (c.300_306delinsCGGG) and HLA-DQB1 (c.317_319delinsCGG). Sema4D and the IL-1β-complement cascade emerged as key drivers of disease progression, independent of R2-ISS stage, representing potential prognostic and therapeutic targets in NDMM.
Disease burden at the time of BCMA-directed chimeric antigen receptor (CAR) T-cell infusion is a key determinant of outcome in relapsed or refractory multiple myeloma (RRMM). Bridging therapy is frequently administered between leukapheresis and infusion to prevent disease progression, yet its clinical impact remains unclear. We conducted a multicenter real-world cohort study of 399 patients with RRMM treated with BCMA-directed CAR T-cell therapy, including 348 (87%) who received bridging therapy. Bridging therapy recipients had more advanced and biologically adverse disease, including higher rates of high-risk cytogenetics and penta-class refractoriness. Bridging efficacy varied substantially by regimen (P.
Minimal residual disease (MRD) assessment has emerged as a key prognostic marker in multiple myeloma (MM), with MRD negativity (undetectable MRD, uMRD) correlating with improved progression-free and overall survival. The International Myeloma Working Group recommends standardized protocols for MRD detection, including the EuroFlow-based next-generation flow cytometry (NGF), although its implementation in routine care remains challenging. We evaluated the feasibility and clinical utility of two CE-IVD-approved EuroFlow tubes for MRD detection in a real-world clinical setting, and investigated the relationship between bone marrow (BM) immune profiles and disease outcomes. Between December 2021 and February 2024, 74 MM patients (58 of them classified as transplant-eligible) underwent 97 MRD evaluations after achieving at least a very good partial response (VGPR). Using ≥2 million events/sample, a median sensitivity of 10⁻⁵ was achieved; 45% of cases were uMRD. After a median follow-up of 19 months, one relapse occurred in the uMRD group, whereas 15 relapses and 3 deaths were observed among persistent MRD (pMRD) patients. Immunophenotypic profiling revealed a higher granulocyte-to-lymphocyte ratio and a lower proportion of CD56dim NK cells, possibly reflecting immune rebalancing after bone marrow recovery. Our findings confirm the feasibility and prognostic relevance of NGF-based MRD detection using standardized commercial panels, and highlight the potential of immune profiling to provide additional biological insights into MRD dynamics in multiple myeloma.
