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Abstract Introduction: Multiple myeloma (MM) accounts for nearly 20% of all hematologic cancers in the US and remains a substantial clinical burden, with patients (pts) requiring multiple lines of therapy (LOT). While advances such as BCMA-directed CAR T-cell therapy have improved outcomes, challenges persist, including disease relapse, treatment toxicities (CRS, ICANS, and non-ICANS neurotoxicities), and access. AZD0120 (formerly GC012F) is a first-in-class autologous BCMA/CD19 dual-targeting CAR T-cell therapy using the FasTCAR rapid manufacturing platform that preserves the naive and central memory T-cell phenotypes with marked in vivo proliferative capacity. Phase 1 investigator-initiated trials in China demonstrated deep, durable responses and a favorable safety profile following single-infusion AZD0120 in newly diagnosed and relapsed/refractory MM (RRMM) (Du J, et al. EHA 2024 and ASCO 2023). Here, we report for the first time preliminary phase 1b results from DURGA-1, an ongoing phase 1b/2 clinical trial evaluating the safety and efficacy of AZD0120 in pts with RRMM. Methods: This open-label, single-arm, US-based, multicenter study (NCT05850234) evaluated the safety/tolerability of 2 dose levels (DL) of AZD0120 in pts with RRMM along with preliminary efficacy. Eligible ptswere aged ≥18 y with RRMM (3+ prior LOT [pLOT] including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody), ECOG PS 0–1, and documented evidence of progressive disease. Exposure to BCMA-directed therapy ≥6 mo with best response of PR or better was permitted. Pts underwent lymphodepletion followed by a single infusion of AZD0120. Pts in DL1 received 1x105 cells/kg; DL2 received 3x105 cells/kg. Dose escalation and recommended phase 2 dose (RP2D) were determined by a safety review committee. Phase 1b primary objectives included safety/tolerability and RP2D determination; secondary objectives included efficacy, cellular kinetics (CK), and pharmacodynamics. Results: As of data cutoff (DCO) on 18 July 2025, a total of 25 pts received infusion of AZD0120 (n=12 DL1; n=13 DL2). The median age was 64 y (range 44–78), median pLOT was 4 (range 3–7), 72% were triple-class refractory, 20% had prior BCMA CAR T-cell therapy, 4% had prior teclistamab, 28% had high-risk cytogenetic features [del(13q), del(17p13), t(4;14), t(14;16), amp(1q)], and 8% had extramedullary plasmacytomas. The median time from apheresis to release was 14 d (range 10–30). Median time from apheresis to infusion was 28 d (range 19–44) with 5 pts receiving bridging therapy. Median follow-up was 1.4 mo (range 0–19.3). No dose-limiting toxicities were reported for either dose. The most common treatment-emergent AEs (TEAEs, any grade) were CRS (64%), neutrophil count decreased (56%), and anemia (32%). The most common grade ≥3 TEAEs were neutrophil count decreased (52%), lymphocyte count decreased (32%), and white blood cell count decreased (32%). CRS was reported in 75% of pts at DL1 (all grade 1) and 54% at DL2 (46% grade 1; 8% grade 2), with no cases of grade ≥3 CRS. Median time to CRS onset (DL1/DL2) was 9 d (range 2–11), with a median duration of 2 d (range 1–4); 12 pts (48%) received tocilizumab for CRS management and 12% received dexamethasone. No cases of ICANS, related non-ICANS neurotoxicity, IEC-colitis, or secondary primary malignancies have been reported. There have been no deaths. For efficacy-evaluable patients (n=15), ORR was 100% (33% sCR, 47% VGPR, 20% PR). CR rates in evaluable pts were 30% in DL1 (n=10) and 40% in DL2 (n=5); median time to response was 0.9 mo for both DLs (range 0.9–1.9 DL1; 0.6–1.8 DL2). All MRD-evaluable pts (n=5 DL1; n=3 DL2; DCO 01 July 2025) were MRD-negative by NGS at a sensitivity of 10-5. Three pts in DL1 with ≥12 mo follow-up maintained MRD negativity. Consistent with robust in vivo expansion, CK analysis from 16 evaluable pts (DCO 12 June 2025) demonstrated a median Tmax of 13 d post-infusion with a median Cmax of 85,266 copies/mg gDNA. Median persistence was 42 d (range 13–273). Updated clinical data with additional follow-up will be presented. Conclusion: Preliminary phase 1b results demonstrated AZD0120 was well tolerated, with a low incidence of serious AEs, no grade ≥3 CRS, and no ICANS. FasTCAR-manufactured AZD0120 had expectedin vivo expansion, which may have resulted in the predictable CRS profile. A single infusion of AZD0120 achieved early, deep responses with 100% MRD negativity from 4L+ triple-class‒exposed pts with RRMM.

Abstract Introduction: Axatilimab is an anti–colony-stimulating factor 1 receptor (CSF-1R) monoclonal antibody that targets monocytes and macrophages, key mediators of inflammation and fibrosis in chronic graft-versus-host disease (cGVHD). Axatilimab is approved by the US Food and Drug Administration at a dose of 0.3 mg/kg (up to a maximum dose of 35 mg) every 2 weeks (Q2W) for patients with cGVHD after ≥2 prior lines of therapy, based on results from the pivotal phase 2 AGAVE-201 clinical trial (NCT04710576). Patients treated with the 0.3 mg/kg Q2W dose in the AGAVE-201 study were able to transition to 0.6 mg/kg every 4 weeks (Q4W) dosing based on the investigator's discretion and per study protocol criteria. Aims: To describe the safety and feasibility of transition from axatilimab 0.3 mg/kg Q2W to 0.6 mg/kg Q4W dosing using data from AGAVE-201. Methods: Patients treated with axatilimab 0.3 mg/kg Q2W in AGAVE-201 who had their Cycle 7 assessment and achieved a partial or complete response (PR/CR) per National Institutes of Health criteria that was sustained for ≥20 weeks or had not progressed were able to change their dosing schedule to 0.6 mg/kg Q4W (without dose capping) per the study protocol and investigator discretion. Safety and treatment duration were assessed in this post hoc analysis; patients who received additional systemic therapies were excluded. The data cutoff was March 30, 2025. Results: In the first 6 treatment cycles, 59 of the 80 patients (73.8%) randomized to axatilimab 0.3 mg/kg Q2W had a response to treatment (primary endpoint). Of these 59 patients, 19 (32.2%) transitioned to 0.6 mg/kg Q4W dosing. Among these 19 patients, demographics (median [range] age, 50.0 [20–73] y; male, 63.2%) and baseline clinical characteristics (median [range] number of organs involved at baseline, 3.0 [2–8]; severe disease, 73.7%; prior use of ibrutinib, ruxolitinib, or belumosudil, 89.5%) were comparable to the full cohort initially randomized to 0.3 mg/kg Q2W. Overall response rate in the first 6 treatment cycles among the 19 patients who switched to 0.6 mg/kg Q4W was 94.7% (95% CI, 74.0%–99.9%; CR, 5.3%; PR, 89.5%); 1 patient had stable disease and thus was eligible to switch, per investigator discretion. Patients were on treatment for a median (range) of 20.9 (2–32) months after switching doses; 16 of 19 patients (84.2%) maintained the 0.6 mg/kg Q4W dose after dose switching. The safety profile for axatilimab was generally similar before and after the dosing change. After switching to 0.6 mg/kg Q4W, 10 patients (52.6%) had grade ≥3 treatment-emergent adverse events (TEAEs); pneumonia was the only grade ≥3 TEAE reported in >1 patient (n=2). TEAEs led to treatment interruptions in 4 patients (21.1%) and discontinuations in 3 patients (15.8%) after switching. The most common TEAEs after switching to 0.6 mg/kg Q4W were fatigue (n=5 [26.3%]), upper respiratory tract infection (n=5 [26.3%]), and headache (n=4 [21.1%]); 1 patient (5.3%) had an infusion-related reaction (n=1 [rash]). Incidences of on-target TEAEs were generally similar before and after the switch, including elevations in alanine aminotransferase (n=3 before switching and n=1 after) and amylase (n=0 and n=1).Conclusion: Transition to 0.6 mg/kg Q4W (without dose capping) is feasible and well tolerated in patients treated with axatilimab 0.3 mg/kg Q2W on the AGAVE-201 study. The Q4W dosing strategy at the 0.6 mg/kg dose identified no new safety signals. Patients had a prolonged duration of therapy, with a median of 20.9 months (1.7 y), and 84% of patients continued treatment, suggesting ongoing clinical benefit. These data provide evidence of the safety and feasibility of a 0.6 mg/kg Q4W dosing strategy in alignment with the AGAVE-201 protocol.

Abstract Introduction: HMA monotherapy (HMAm) continues to be the standard of care for HR-MDS. While the addition of VEN to azacitidine (AZA) improved overall survival (OS) and complete remission (CR) rates among older pts with acute myeloid leukemia (AML) over AZA monotherapy, the recently completed phase III VERONA trial of AZA+/-VEN in HR-MDS failed to show an OS benefit for AZA/VEN over AZA monotherapy. Using the icMDS VALIDATE database, we compared outcomes of pts with HR-MDS treated with HMA or HMA/VEN as frontline therapy. Methods: The icMDS VALIDATE database includes over 4000 adult MDS pts who received HMA-based therapy from 32 international centers in 9 countries. For this analysis, we included pts with HR-MDS defined by International Prognostic Scoring System [IPSS] ≥1.5 or IPSS-revised [IPSS-R] ≥4 (at diagnosis or HMA initiation) and treated with HMAm or HMA/VEN as frontline therapy for HR-MDS. We assessed responses based on IWG 2023 criteria (Zeidan A et al, Blood 2023). Composite complete remission (cCR) was defined as CR+CRbi+CRuni+CRh+CRequivalent. We calculated OS from time of HMA initiation to date of death from any cause. Pts lost to follow-up were censored at the date they were last known to be alive. We used Kaplan-Meier methods to calculate OS and compared OS between different groups using the log-rank test. We used Cox and logistic regression models to adjust for baseline prognostic variables as appropriate. The study was funded by an independent grant from Abbvie. Results: A total of 1907 pts met eligibility and were included (1552 AZA, 221 decitabine, 134 HMA+VEN). 479 pts subsequently underwent allogeneic stem cell transplant (allo-SCT; 430 after HMAm [32.6%]; 49 after HMA/VEN [37.1%]). Our cohort was enriched for pts with adverse disease characteristics including complex karyotype (33.6%) and TP53 mutations (28.7%). Compared to pts treated with HMA/VEN, pts treated with HMAm were more likely to be male (p=0.012), have lower baseline platelet counts (p=0.037), peripheral blood (PB) blasts (p=0.004), or bone marrow blasts (p<0.001), and were less likely to have very high risk IPSS-M (p<0.001), TP53 mutations (p<0.001), or complex karyotype (p=0.020). In unadjusted analyses, the rate of cCR was significantly lower in HMAm treated pts compared to HMA/VEN treated pts (27.7% vs. 48.8%, p<0.001). However, CR rate was not significantly different (11.7% vs. 17.1% for HMAm and HMA/VEN, respectively, p=0.22). After adjusting for age, sex, and IPSS-M, pts treated with HMA/VEN were more likely to achieve cCR compared to HMAm with an odds ratio (OR) of 2.49 (95% CI: 1.56-3.96, p<0.001). When separated by TP53 mutation status, the OR for cCR for HMA/VEN vs HMAm was 4.17 (95%CI: 2.14-8.31; p<0.001) and 1.27 (95%CI: 0.54-2.86; p=0.57) for TP53 wild-type and TP53-mutant pts, respectively. In unadjusted analyses, median OS was 17.4 months for HMAm and 19.6 months for HMA+VEN, and OS did not differ significantly by treatment type (p=0.33). For HMAm treated pts, the OS rates at year 1, 2, 3 were 0.65 (95%CI: 0.63-0.67), 0.38 (95%CI: 0.36-0.40), and 0.27 (95%CI: 0.25-0.29), respectively. For HMA/VEN treated pts, the OS rates at year 1, 2, 3 were 0.64 (95%CI: 0.56-0.73), 0.45 (95%CI: 0.36-0.56), and 0.37 (95%CI: 0.27-0.51), respectively. In a multivariate analysis adjusting for age, sex, PB blast, IPSS-M and allo-SCT as a time-varying covariate, treatment with HMA/VEN vs HMAm did not significantly influence OS (hazard ratio (HR) of OS for HMA/VEN vs HMAm: 0.89, 95%CI: 0.69-1.13, p=0.33). When stratified by TP53 mutation status, HR of HMA/VEN vs. HMAm was favorable for TP53 wild-type (HR: 0.47; 95%CI: 0.29-0.74) but not TP53-mutant pts (HR=0.96; 95%CI: 0.66-1.41). Adjusting for other variables in the model, HR for pts who underwent vs. those who did not undergo allo-SCT were 0.65 (95% CI: 0.49-0.85) and 0.36 (95%CI: 0.24-0.53) in TP53 wild-type and mutant patients, respectively. Conclusion: In this large, international retrospective analysis from the icMDS VALIDATE database, HMA/VEN was associated with higher cCR rates—but not CR rates—compared to HMAm among pts with HR-MDS, though we observed no significant differences in OS. In our analysis, clinical benefit from the addition of VEN was most clear in TP53 wild-type pts, and allo-SCT was associated with improved OS regardless of baseline TP53 status. Our analysis was limited by the relatively small number of HMA/VEN-treated pts and heterogeneous real-world treatment patterns.

Abstract Background B-cell maturation antigen (BCMA)-targeting immunotherapies represent a promising class of treatment for the management of immunoglobulin light chain (AL) amyloidosis, a disease that is related to clonal plasma cells. Etentamig is a 2nd generation, off-the-shelf, fully human BMCA X CD3 bispecific antibody with bivalent BCMA domain and low CD3 affinity that targets both BCMA-expressing plasma cells and CD3-expressing T cells. Etentamig monotherapy is being studied in multiple myeloma (MM) in an ongoing phase 3 study (NCT06158841). Here, we report the first safety and efficacy results from M24-209, an open-label phase 1/2 study evaluating etentamig monotherapy in patients (pts) with relapsed/refractory (RR) AL amyloidosis from dose level 1 (DL1). Methods The phase 1 dose escalation (ESC) portion of the study (NCT06158854) with etentamig enrolled pts with RR AL amyloidosis with ≥1 prior lines of therapy (LOT), including a proteasome inhibitor and an anti-CD38 monoclonal antibody with no prior BCMA exposure. Eligible pts were required to have a difference in involved and uninvolved serum free light chain (dFLC) of ≥50 mg/L, and pts with Mayo Clinic 2004 cardiac risk stage IIIb with NT-proBNP ≥8500 pg/ml were excluded. Three dose groups were explored in dose ESC (etentamig dose levels [DL] 1, 2, and 3). In all cohorts, pts will receive up to 24 cycles of treatment and will be followed until disease progression. In dose ESC, the primary objectives are to determine safety/tolerability, pharmacokinetic/pharmacodynamic, and recommended phase 2 dose. The secondary objectives include evaluation of efficacy as measured by hematologic response and organ response. Responses are investigator assessed per consensus guidelines (Comenzo, et al. Leukemia. 2012. 26[11]:2317-25; Palladini G, et al. Amyloid. 2021 [Epub];28[1]:1-2). Results As of 17 July 2025, all DLs in dose ESC have been fully enrolled, and 12 pts have been treated with etentamig at DL1. Due to short follow-up, this initial report only includes data from DL1, with further follow-up data from ESC to be included at the time of presentation. Median duration of follow up in DL1 was 9.4 months (8.3–13.8) with 83% of pts continuing treatment. Median age for pts was 72 years (range, 56–85 years). Median number of prior LOT was 2 (range, 1–6), and median time from initial diagnosis was 3.6 years. Thirty-three percent have received a prior stem cell transplant and 50% previously received the regimen of daratumumab with cyclophosphamide, bortezomib, and dexamethasone in combination. Median dFLC at study baseline was 110. 5 mg/L (range, 56.6–617.5). At baseline, 83% of pts had cardiac involvement, 25% had renal involvement, and 8% had hepatic involvement. Eighty-three percent of pts had lambda AL amyloidosis. Treatment-emergent adverse events were reported in 100% (42% Grade ≥3) of pts at DL1. Cytokine release syndrome (CRS) occurred in 2 pts (17%, all Grade 1), with no instances of any grade immune effector cell-associated neurotoxicity syndrome (ICANS). CRS occurring after the first dose had median time to onset of 6.8 hours (range, 6.7–6.9). Grade ≥3 infections occurred in 1 pt (8%, all Grade 3). Grade ≥3 neutropenia also occurred in 1 pt (8%, all Grade 3), and no Grade ≥3 events of thrombocytopenia or anemia occurred. No Grade 5 events have occurred. Within the dose ESC DL1 cohort, the overall hematologic response rate was 100%, with all pts achieving ≥VGPR and 83% of pts achieving complete response (CR). The median time to CR was 0.9 months (0.3–9.3). The median duration of response has not yet been reached and 100% of pts remain in their best overall response by investigator assessment. To date, no pts have experienced hematologic progression on study. Cardiac response was observed in 30% of evaluable pts. Renal response was seen in 67% of evaluable pts. Conclusions In the DL1 cohort, etentamig showed a manageable safety profile in AL amyloidosis with low incidence and severity of CRS, no ICANS, and limited Grade ≥3 cytopenia events. Deep and rapid hematologic responses were observed with 100% ≥VGPR rate and 83% hematologic CR rate. Additional dose-level data will be presented at the time of the meeting. All pts remain in ongoing follow-up and evaluation, and the study will begin the dose expansion (EXP) portion after dose selection.

Abstract Introduction: Primary myelofibrosis (PMF), a myeloproliferative neoplasm (MPN), features bone marrow fibrosis, splenomegaly, and abnormal blood cell production. Aberrant JAK/STAT signaling, elevated cytokines or hyperactive NFκB are implicated in MPN pathogenesis; however, their interplay remains unclear. JAK inhibitors (JAKi) alleviate PMF symptoms, but they don't fully address disease progression or mitigate cytokine storms. NFκB inhibitors have shown promise in MPN models but are associated with off-target effects and toxicities. This study aims to elucidate the mechanisms of JAKi resistance and develop novel therapeutic strategies targeting hyperactive NFκB in vitro and in vivo, offering potential benefits beyond current JAKi therapies. Methods: To investigate JAKi resistance in PMF, ruxolitinib-resistant HEL cells were generated and NFκB/JAK2/STAT signaling was examined by Western blot. Biomarkers associated with JAKi response were identified in PMF patients treated with BMS-9115437 (Gangat et al, Blood Cancer J, 2023) via Western blot. Molecular mechanisms of MPN pathogenesis were further elucidated using Affymetrix HG-U133Plus2 assay on RNA from treatment-naïve PMF, essential thrombocythemia (ET), polycythemia vera (PV) patients and healthy donors, followed by KEGG and gene set enrichment (GSE) analysis. In vitro, NFκB was inactivated by shRNA, Ixazomib or emetine followed by Western blot for NFκB/JAK2/STAT phosphorylation as well as flow cytometry and clonogenic assays for cell growth. NFκB DNA binding activity was determined by electrophoretic mobility-shift assays (EMSA). The therapeutic and preventive effects of Ixazomib and emetine were evaluated in HEL-engrafted nude mice by assessing tumor formation, development, and underlying mechanisms using Western blot, H&E and IHC staining. Results: Short-term JAKi (BMS-911543, ruxolitinib) exposure altered JAK2 phosphorylation, increasing Tyr1008 phosphorylation and decreasing Tyr221, Tyr570, and STAT5 phosphorylation. Notably, JAK2, STAT3 and STAT5 were phosphorylated in ruxolitinib-resistant HEL cells or after treatment cessation, implying sustained signaling activity. Western blot analysis and clinical data in PMF patients (n=3) receiving BMS-911543 showed no hyperphosphorylation of JAK2 Tyr1008 with diverse responses independent of JAK2V617F status. A lack of correlation between JAK2 and STAT5 expression/phosphorylation suggests that other factors contribute to hyperactive STAT5 in PMF. Symptomatic improvement in a JAK2V617F-positive patient correlated with decreased STAT5 protein expression and phosphorylation, potentially serving as a predictor for JAKi response. Transcriptomic analysis in MPN patients (PMF (n=11), ET (n=6), PV (n=4), HD (n=5)) pinpointed the transcriptomic dissimilarities between PMF and PV or ET, and highlighted the higher NFκB activity in PMF compared to PV or ET. The importance of NFκB in PMF was further evidenced by the network analysis for the overproduction of circulating cytokines in PMF patients (Tefferi et al, JCO, 2011). In vitro studies revealed that NFκB overexpression promotes cell proliferation and inhibits apoptosis through enhanced IL-6/IL-6R expression and JAK2/STAT5 phosphorylation. Inactivating NFκB using shRNA, emetine, or ixazomib reversed these effects. Further, IL-6 treatment increased JAK2 phosphorylation. In vivo studies showed that Ixazomib significantly reduces tumor volume (734 ±133 to 98 ±14 mm3; P <0.001) and weight (582 ±156 to 87 ±22 mg; P =0.0005) compared to controls. Emetine similarly suppressed tumor growth dose-dependently without affecting spleen weight and even prevented tumor formation when administered prior to cell engraftment. Mechanistically, both Ixazomib and emetine inhibited NFκB and JAK2 phosphorylation while increasing cleaved caspase-3 in tumors. Conclusions: We discovered that STAT inactivation independently predicts improved outcomes in PMF and that NFκB hyperactivity holds particular significance for PMF compared to other MPN subtypes. We identified a NFκB-IL-6-JAK2-STAT axis in regulating PMF growth regardless of JAK2V617F status. Targeting NFκB with novel inhibitors Ixazomib and emetine disrupts the NFκB-IL-6-JAK2-STAT axis, suppressing PMF growth and offering potential therapeutic alternatives to overcome current JAKi limitations.

Abstract Introduction Diffuse large B-cell lymphoma (DLBCL) is a heterogenous disease with varied expressions of CD30. Brentuximab vedotin (BV) is a CD30-directed antibody-drug conjugate approved for treatment of patients with relapsed or refractory DLBCL in combination with lenalidomide (Len) and rituximab (R). In the phase 3 ECHELON-3 study (NCT04404283), BV + Len + R showed significant overall survival (OS) benefit compared with placebo + Len + R in patients with relapsed or refractory DLBCL. Subgroup analysis from this study showed that BV + Len + R provided clinical benefit regardless of CD30 expression level. We hypothesized that even sub-threshold levels of CD30 expression, below the detection limits of immunohistochemistry (IHC), may be sufficient to elicit the antitumor activity of BV. Here, we further investigated whether trace amounts of CD30 staining are required for patients to benefit from BV + Len + R. Methods In the ECHELON-3 study, patients with relapsed or refractory DLBCL were randomized 1:1 to receive BV + Len + R or placebo + Len + R. The primary endpoint was OS, with progression-free survival (PFS) and objective response rate (ORR), per Lugano 2014, as key secondary endpoints. CD30 expression was assessed by IHC by central and/or local testing. CD30 positivity was scored as the percentage of CD30 positive cells out of neoplastic cells or out of total lymphocytes, when neoplastic cells could not be distinguished. In this updated analysis, patients with CD30 <1% staining by central laboratory IHC were further grouped into CD30 <1% with trace staining and CD30 <1% with no staining. Results Overall, 60 patients in the BV + Len + R group had CD30 <1% expression; of these, 34 had CD30 <1% with trace staining and 26 had CD30 <1% with no staining. In the placebo + Len + R group, 63 patients had CD30 <1% expression; of these, 36 had CD30 <1% with trace staining and 27 had CD30 <1% with no staining. In the overall CD30 <1% groups, numerically greater OS and PFS benefits were observed with BV + Len + R vs placebo + Len + R (HR for OS, 0.57; 95% CI, 0.36-0.89 and HR for PFS, 0.53; 95% CI, 0.34-0.82). In patients with CD30 <1% with trace staining, BV + Len + R showed a numerically higher OS compared with placebo + Len + R, with HR of 0.48 (95% CI, 0.26-0.90); median OS was 15.6 vs 5.2 months. In patients with CD30 <1% with no staining, there was a trend toward higher OS with BV + Len + R vs placebo + Len + R, with HR of 0.66 (95% CI, 0.34-1.28); median OS was 14.8 vs 11.8 months. Similarly, in patients with CD30 <1% with trace staining, BV + Len + R showed a trend toward longer PFS compared with placebo + Len + R, with HR of 0.60 (95% CI, 0.33-1.11); median PFS was 2.8 vs 1.5 months. In patients with CD30 <1% with no staining, a numerically longer PFS benefit was observed with BV + Len + R vs placebo + Len + R, with HR of 0.41 (95% CI, 0.21-0.79); median PFS was 4.2 vs 2.7 months. In the overall groups, ORR was 60.0% with BV + Len + R and 34.9% with placebo + Len + R. Higher ORR was observed with BV + Len + R compared with placebo + Len + R in both CD30 <1% with trace staining (55.9% vs 25.0%) and CD30 <1% with no staining (65.4% vs 48.1%) groups. Conclusions Results from this updated analysis indicate that visible CD30 detection by IHC is not required for response to BV + Len + R in patients with relapsed or refractory DLBCL. Treatment with BV + Len + R showed efficacy benefit compared with placebo + Len + R regardless of CD30 expression level, including in patients with no visible CD30 IHC staining. These results are consistent with those from the overall ECHELON-3 study population, in which significant improvement in OS was demonstrated with BV + Len + R compared with placebo + Len + R.

Abstract Background: Sickle cell disease (SCD) is marked by wide variability in clinical phenotypes and severity due to environmental, clinical, and genetic factors. Variants in iron-regulatory genes are well described modifiers of clinical presentation in different diseases, but their role in modulating SCD phenotype has been sparsely studied in African populations. In this cross-sectional study, we investigated the role of single nucleotide polymorphisms (SNPs) in iron-regulatory genes in SCD severity and lifetime transfusion(Tx) requirement. Methods: The study was approved by the institutional review board of Lagos University Teaching Hospital, Lagos, Nigeria. Clinical data were abstracted from medical records and patient interviews using a structured questionnaire. Participants were recruited in steady state and were stratified according to the severity score previously described by Shah et al. (Clinicoecon Outcomes Res. 2020;12:625). Biochemical analyses included serum transferrin and serum iron; transferrin saturation (TS) was calculated. Genotyping was performed using the Axiom Precision Medicine Research Array (PMRA; Thermo Fisher Scientific). Seventy-one single nucleotide polymorphisms (SNPs) in genes implicated in iron metabolism were analyzed, including SLC40A1 (ferroportin), HFE (homeostatic iron regulator), HJV (hemojuvelin), HAMP (hepcidin), and TFR2 (transferrin receptor 2). SNPs whose variants were not represented in this cohort, including HFE C282Y and H63D, were excluded. Ensembl and NCBI databases were used to describe the wild-type (WT)/variant alleles and gene consequences. Univariate and multivariate logistic regression were used to analyze binary outcomes, and age-adjusted linear regression for Tx burden. Odds ratios (OR) and regression coefficients (β) were estimated using the WT as the reference. Multiple-testing correction was performed as necessary. Statistical analyses were conducted in R version 4.4.1, with p<0.05 considered significant. Results: We included 60 genotyped, confirmed HbSS patients; median age was 22 years (range: 18–43), 22 (37.3%) were female, 42 (70.0%) were classified as mild severity (Class I), 5 (8.0%) as Class II, and 13 (22.0%) as severe (Class III). Twenty-seven (45.0%) had never received a blood Tx, while 33 (55.0%) had received Tx, median of 2units (range: 1-10). On univariate analysis (UVA), five SNPs (rs10218795, rs10188230, rs114250626, rs4287798, and rs634349) were significantly associated with severe phenotype; three of these remained significant on multivariable analysis (MVA). Two were associated with higher odds of severe phenotype: rs10177654 (OR = 28.9, 95% CI: 3.0–100.0, p = 0.03) and rs10218795 (OR = 15.0, 95% CI: 2.4–327.0, p<0.01), while rs10188230 was associated with lower odds (OR = 0.03, 95% CI: 0.008–0.28, p<0.01). Results remained consistent after adjusting for age. For lifetime transfusion burden, both UVA and MVA identified two significant SNPs: rs4667289, associated with higher transfusion burden (β = 2.6, 95% CI: 0.04–5.2, p = 0.047) and rs11568344, associated with lower transfusion burden (β = –1.8, 95% CI: –3.5 to –0.36, p = 0.02). Genotype distributions for the five significant SNPs were as follows: rs10177654 (SLC40A1, transcription factor binding site), TT(WT) 12 (20.3%), TC 30 (50.8%), CC 17 (28.8%); rs10188230 (SLC40A1, intron variant), TT (WT) 32 (54.2%), TC 22 (37.3%), CC 5 (8.5%); rs10218795 (HJV, intron variant), CC (WT) 22 (37.3%), TC 29 (49.2%), TT 8 (13.6%); rs4667289 (SLC40A1 proximal intergenic), GG (WT) 46 (78.0%), AG 10 (16.9%), AA 3 (5.1%); rs11568344 (SLC40A1 splice region variant), GG (WT) 47 (79.7%), AG 9 (15.3%), AA 3 (5.1%). Compared with the homozygous WT, patients with rs10188230 had a lower median TS (21.65% vs. 43.3%, p = 0.04), while those with rs4667289 had a higher median TS (83% vs. 31%, p<0.01). When adjusted for age and lifetime Tx, rs4667289 remained significant (β = 47.8, 95% CI 3.6-82.8, p = 0.03). No other SNPs showed association with TS. Conclusion: We present novel genetic data on iron-regulatory variants in African patients with sickle cell disease, identifying SNPs in SLC40A1 and HJV associated with disease severity. Most of these are yet to be fully described in the literature, and their intronic locations suggest possible regulatory roles. We hope to further validate these findings in larger cohorts and through functional studies to clarify their impact on iron metabolism and clinical significance.

Abstract Background: Graft-versus-host disease (GVHD) remains the leading cause of non-relapse morbidity and mortality in allogeneic hematopoietic-stem-cell transplantation (allo-HSCT) recipients. Clinical scoring systems (e.g., EBMT, HCT-CI, DRI, etc.) can stratify risk but show modest predictive performance (C-statistics 0.49–0.67) when it comes to GVHD. To address this gap, we developed GVHD-Intel 1.0, a real-time, scalable, and interpretable machine learning (ML) framework from an international study to predict both acute (aGVHD) and chronic GVHD (cGVHD), providing individual and bulk predictions using common input variables and HLA alleles. Methods: This retrospective global study, approved by respective institutional review boards, included electronic health records from three tertiary care centers in Abu Dhabi, UAE, and King Hussein Cancer Center (KHCC), Jordan, from 2009 to 2023. The model was developed in phases. The UAE399 cohort (399 HSCT recipients) served as the baseline dataset. To enhance model generalizability, 55 adult allo-HSCT recipients from KHCC were added to the training set. Two distinct test cohorts were used: UAE46 (46 allogeneic HSCT recipients from UAE) and KHCC150 (150 adult allogeneic HSCT recipients from KHCC), collected later and independently of training data. Variables included donor type, sex mismatch, disease status, time from diagnosis to transplant, and agents used in conditioning and GVHD prophylaxis (e.g., TBI, ATG, alemtuzumab use etc.). HLA alleles (A, B, C, DQ, DR) were symbolically encoded and transformed via one-hot encoding. GVHD events were classified as aGVHD (<100 days) or cGVHD (≥100 days). Missing values were excluded, and class imbalance was handled via class weighting. GVHD-Intel 1.0, co-developed with MBZ University of Artificial Intelligence, features modular ensemble architecture, drug-level feature engineering, novel HLA encoding for low-resolution compatibility scoring, and built-in interpretability using SHAP and LIME. The framework is cloud-deployable for both real-time and batch predictions. Results: The GVHD-Intel 1.0 was externally tested on two independent, temporally and institutionally distinct cohorts (UAE46 and KHCC150), demonstrating strong and consistent predictive performance for both acute and chronic GVHD. For cGVHD prediction, the model achieved an AUC (area under the curve or C-statistic for binary outcomes) of 0.832, F1 score of 0.896, accuracy of 82.7%, PPV of 0.930, sensitivity of 0.864, Brier score of 0.178, and log loss of 0.543. For aGVHD, performance metrics included an AUC of 0.802, F1 score of 0.860, accuracy of 77.6%, PPV of 0.930, sensitivity of 0.799, Brier score of 0.196, and log loss of 0.581. Model calibration remained strong across both tasks, with Brier scores <0.20. Conclusions: GVHD-Intel 1.0 is a robust, interpretable machine learning framework developed from real-world, multicenter data. By integrating widely available clinical variables and HLA allele data, it outperforms conventional clinical risk scores in predicting both acute and chronic GVHD in allo-HSCT recipients. Slightly reduced performance in aGVHD prediction is likely due to the lack of relevant variables. Next steps include prospective validation across multiple transplant centers globally and continued refinement through expanded data integration. GVHD-Intel 1.0 holds strong potential as a clinically valuable, scalable decision-support tool that can be enacted widely and easily by practicing transplant physicians worldwide in all types of settings.

Abstract Introduction Although chemo-free regimens are increasingly used in elderly patients with large B-cell lymphoma (LBCL), most still receive conventional chemoimmunotherapy. Patients up to 75–80 years old are usually treated with full-dose R-CHOP, while 80+ patients receive the attenuated R-miniCHOP regimen as standard of care. Prior studies have shown that in patients aged 65+ years, R-CHOP was associated with improved survival based on propensity score matching (PSM) analysis (Al-Sarayfi, Am J Hematol, 2023), though this did not include comorbidity data. Furthermore, no formal studies have focused specifically on 80+ patients. We aimed to perform a PSM comparison of R-CHOP versus R-miniCHOP to better inform treatment decisions in this population. Methods We harmonized and pooled data from 237 LBCL patients receiving chemotherapy with rituximab (out of all 263 80+ patients) from the prospective LEO cohort (USA, n=147; 2015–2020) and NiHiL registry (Czech Republic, single center, n=116; 2010–2023). Of them, 205 (86%) receiving anthracycline(A)-based regimens were included. Baseline characteristics, comorbidities, treatments, and outcomes were collected. PSM (1:1, caliper 0.2) was performed to compare R-CHOP and R-miniCHOP using age, ECOG performance status (PS), clinical stage, lactate dehydrogenase (LDH), and major comorbidities (heart disease, history of stroke, and other recent cancer) as matching variables. The endpoints were overall survival (OS), event-free survival (EFS), and lymphoma-specific survival (LSS, defined as death attributed to lymphoma progression). Results Among 205 A-treated patients, median age was 83 years (range 80–99); 30% had ECOG PS 2–4, 67% clinical stage III–IV, 34% ≥2 involved extranodal sites, 59% elevated LDH, and 58% had International Prognostic Index (IPI) scores 3–5. Median follow-up was 5.5 years; median OS and EFS were 4.1 and 3.4 years, resp. A-based regimens comprised full-dose R-CHOP-like (n=79; 39%; R-CHOP n=74, DA-EPOCH-R n=5) and R-miniCHOP (n=126; 61%). Patients receiving R-CHOP-like regimens had more favorable baseline characteristics (median age 82 vs 83 years, P=0.04; ECOG PS 2–4: 16% vs 39%, P<0.01; IPI 3–5: 46% vs 66%, P=0.03) and a lower, though not statistically significant, comorbidity burden (mean 1.14 vs 1.39; heart disease 35% vs 45%, P=0.22; history of stroke 4% vs 6%, P=0.64; other cancer 6% vs 5%, P=0.87). R-CHOP-like regimens vs R-miniCHOP had superior OS (median 6.3 vs 3.4 years; HR=0.61, 95% CI 0.42–0.90; P=0.01) and EFS (median 5.3 vs 2.1 years; HR=0.58, 95% CI 0.40–0.83; P<0.01), with no significant difference in LSS (2-year 89% vs 82%, HR=0.77, 95% CI 0.39–1.54, P=0.46). To mitigate selection bias, we performed PSM on patients with available baseline characteristics treated with R-CHOP (n=69) and R-miniCHOP (n=121), resulting in 63 matched pairs. Matched cohorts were well-balanced on age (median 82 years in both cohorts; P=0.68), ECOG PS 2–4 (17% vs 19%; P=0.82), IPI 3–5 (52% vs. 59%; P=0.41), and comorbidity burden (mean 1.10 vs. 1.29; P=0.30). The presence of heart disease (40% in both cohorts), history of stroke (5% vs 6%), and cancer (5% vs 6%) were similar. Survival modestly favored R-CHOP, but differences were not significant: median OS 5.3 vs 3.5 years (HR=0.73; 95% CI 0.46–1.15; P=0.17), median EFS 3.8 vs 2.8 years (HR=0.76; 95% CI 0.49–1.18; P=0.23), and 2-year LSS 88% vs 84% (HR=1.09; 95% CI 0.45–2.63; P=0.85). Treatment-related mortality was similar in both cohorts (16%). Among R-miniCHOP patients, survival outcomes did not differ between matched (n=63) and unmatched (n=63) groups (OS P=0.72; EFS P=0.23; LSS P=0.27). Unmatched (n=16) R-CHOP patients had a trend toward improved survival compared to matched (n=63) individuals (OS P=0.10; EFS P=0.049; LSS P=0.24). Conclusion This is the first PSM-based analysis comparing R-CHOP and R-miniCHOP in LBCL patients 80+ years old. Despite inherent limitations of a non-randomized design and limited number of matched patients, our findings – derived from two prospective cohorts – suggest that R-miniCHOP may offer outcomes comparable to R-CHOP, particularly with respect to LSS. While these results support R-miniCHOP as an appropriate frontline option, treatment decisions remain highly individualized. These data may help inform clinical decision-making and provide a basis for designing future trials targeting this population, where R-miniCHOP could serve as a comparator arm. Funding: NU21-03-00411, U01 CA195568.

Abstract Introduction: Liso-cel, an autologous, CD19-directed CAR T cell product, has demonstrated consistent efficacy in a broad population of pts with B-cell malignancies, including R/R LBCL. Its well-established safety profile has made OP delivery commonplace. This, combined with recent changes to postinfusion monitoring requirements, offers pts the potential for greater access to care. Here, we describe real-world safety and effectiveness outcomes for pts with R/R LBCL who received liso-cel as standard of care (SOC) therapy in the inpatient (IP) or OP setting. Methods: This was an observational study of pts in the US with R/R LBCL who received commercial liso-cel as second-line (2L) or later treatment (tx) in the IP or OP setting between 02/2021 and 02/2025 and had ≥1 postinfusion assessment reported in the Center for International Blood & Marrow Transplant Research (CIBMTR). Safety outcomes included rates of AEs of special interest and nonrelapse mortality (NRM). Postinfusion hospitalizations in the OP group were also assessed. Effectiveness outcomes included ORR, CR rate, duration of response (DOR), PFS, and OS. All results are reported descriptively. Results: Of 1116 eligible pts, 34% (n=375) were intended for OP tx, as reported to the CIBMTR, including 82 of 195 (42%) pts who received liso-cel as 2L tx. Among pts treated in the IP vs OP setting, median (range) age was 71.5 y (21.5–91.2) and 69.8 y (25.0–86.1), respectively, and most pts were male (59% and 61%). Proportions of pts with high-grade B-cell lymphoma (16% and 12%), ≥2 extranodal involvement sites (26% and 26%), and secondary CNS involvement (5% and 4%) were similar for the IP and OP groups, respectively. In contrast, 48% vs 37% of pts in the IP vs OP groups, respectively, had elevated LDH before infusion and 10% vs 3% had ECOG PS ≥2. One or more comorbidities were reported for 72% and 65% (including cardiac, 36% and 32%; pulmonary, 30% and 26%; active infections requiring ongoing tx, 6% and 3%) of pts in the IP and OP groups, respectively. Median (range) number of prior lines of therapy was 3 (1–13) in the IP group and 3 (1–16) in the OP group. Use of bridging therapy was reported in 65% of the IP group and 62% of the OP group. Median (95% CI) follow-up for this study was 12.7 mo (12.5–13) in the IP group and 12.6 mo (12.4–12.8) in the OP group. Safety was similar in both settings; any-grade CRS was reported in 52% of IP vs 49% of OP setting pts, with low rates of grade 2 CRS (15% vs 11%) and grade ≥3 CRS (3% vs 2%) in both groups. Any-grade immune effector cell–associated neurotoxicity syndrome (ICANS) rates were also similar in pts in the IP vs OP setting (28% vs 23%), with low rates of grade 2 ICANS (5% vs 4%) and grade ≥3 ICANS (10% vs 8%). Prolonged cytopenia (grade 4 thrombocytopenia and/or neutropenia at 30 d after infusion) was reported in 12% and 14% in the IP and OP groups; clinically significant infections at any time after infusion occurred in 48% of IP and 42% of OP setting pts. In the IP and OP groups, 37% and 30% of pts died, most commonly due to PD (25% and 21%) and the NRM rates at 12 mo were 7.1 (95% CI, 5.2–9.4) and 4.1 (95% CI, 2.2–6.8). Among OP setting pts, 46% were not hospitalized after infusion; of those hospitalized after OP infusion, median (IQR) time to hospitalization was 5 d (3-8) and duration of stay was 5 d (3-9). Response rates were high in both the IP (ORR, 80% [95% CI, 77–83]; CR rate, 70% [95% CI, 66–73]) and OP setting (ORR, 83% [95% CI, 79–87]; CR rate, 74% [95% CI, 69–79]). At ~12 mo follow-up, median (95% CI) DOR was not reached (NR; NR–NR) in either group with 12-mo DOR rates of 59% (95% CI, 54–63) and 63% (95% CI, 56–69), respectively. Median (95% CI) PFS was 11.8 mo (8.8–NR) in the IP group vs NR (NR–NR) in the OP group, with 12-mo PFS rates of 49% (95% CI, 45–53) and 56% (95% CI, 50–61), respectively. Median (95% CI) OS was NR (NR–NR) in both groups with 12-mo OS rates of 65% (95% CI, 61–68) in the IP group and 74% (95% CI, 68–78) in the OP group. Conclusions: These results continue to demonstrate that one-time tx with liso-cel results in deep, clinically meaningful efficacy in the SOC setting across a broad population of pts with R/R LBCL. Despite the few differences reported in baseline characteristics, outcomes were consistent among pts treated in the IP and OP care settings. The well-established safety profile of liso-cel is conducive to OP tx, allowing ~50% of pts to remain out of the hospital postinfusion.