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Abstract Background: KMT2A-rearranged acute myeloid leukemia (KMT2Ar AML) is characterized by chromosomal translocation involving KMT2A gene at 11q23, resulting in fusion with variety of partner genes. It is usually associated with poor outcomes, high risk of relapses and suboptimal responses to conventional therapies. While NPM1-mutated (mt) AML is considered favorable risk, they are equally dismal in relapse refractory (RR) setting. Menin inhibitors have emerged as a promising therapeutic strategy, particularly in RR AML patients (pts) with KMT2Ar and NPM1-mt genotypes. While revumenib, a menin inhibitor approved for managing RR KMT2Ar acute leukemia, no menin inhibitor is currently approved for NPM1-mt AML. In this study, we evaluated clinical outcomes of adults with KMT2Ar AML and performed a comparative analysis of pts with RR KMT2Ar and NPM1-mt AML using data from the Mayo Clinic. Methods: After screening 102 AML pts with reported KMT2A abnormalities, we identified 33 adults with confirmed KMT2Ar diagnosed between 2012 and 2024 for retrospective analysis. Clinical and molecular/cytogenetics data, induction type (intensive chemotherapy [IC] vs non-intensive chemotherapy [NIC]), response, transplant use, and survival outcomes were reviewed. A separate analysis was performed comparing 20 RR KMT2Ar AML pts with 20 propensity score matched RR NPM1-mt AML pts from a pool of 125 NPM1-mt RR pts. Results: The median age was 50 years (yrs) (range [R], 19.0-75.0), and 60.6% were < 60 yrs. Most cases were de novo AML (64%), and the most frequent translocation was t(6;11)(q27;q23)/MLLT4 (27%), followed by t(10;11)(p12;q23)/MLLT10 (21%), t(9;11)(p21.3;q23.3)/MLLT3 (15%), and t(11;19)(q23;p13.1)/ELL (12%). Other KMT2A fusion partners were rare and collectively accounted for the remaining cases. The median follow-up was 57 months (mo) (R, 7.0-109.0). The overall response rate (ORR) was 91%, and composite complete remission (CRc, , including CR, CRi, and CRh) was 73%. The CRc rates were comparable between IC and NIC (80% vs 62%, p=0.24). CRc were not significantly different by disease type (de novo [71.4%] vs secondary [sAML] [75%], p= 0.82) or KMT2A fusion partner gene (60% for t[9;11]/MLLT3 vs. 57.1% for t[10;11]/MLLT10 vs 55.6% for t[6;11]/MLLT4, p=0.069). Seventeen (52%) pts received an allogeneic stem cell transplantation (allo-HCT). The median overall survival (mOS ) for the entire cohort was 16 mo (R, 11.0-34.0). In subset analysis, IC compared to NIC was associated with significantly longer mOS (30 vs 11 mo, p=0.014). The mOS was also superior in pts <60 vs ≥60 yrs (32 vs 8 mo, p=0.005). Similarly, de novo cases had better mOS than sAML (22.0 vs 9.5 mo, p=0.052). Among KMT2Ar subtypes, t(6;11)/MLLT4 showed the longest mOS (54 mo [R, 30.0-not reached (NR)]), while t(9;11)/MLLT3 had the shortest (11.0 mo, [R 9-NR]), but differences were not statistically significant (p=0.32). The mOS was significantly longer among allo-HCT pts (30 vs 11 mo, p=0.005). Among 29 pts who experienced RR disease, the median relapse free survival (RFS) was 3 mo (R, 2.0-10.0). First salvage therapy yielded a CRc of 43.8% in 16 evaluable pts. When compared to a propensity matched cohort of 20 RR NPM1-mt AML pts, the CRc rates was 57.9% vs 50% in RR NPM1-mt and KMT2Ar AML (p= 0.68). The mRFS was not significantly different between RR KMT2Ar and NPM1-mt AML, (3 vs 4 mo, p=0.9). However, KMT2Ar pts had inferior mOS compared to NPM-mt AML (12 vs 65 mo, p=0.004). We further compared survival between NPM1-mt and KMT2Ar pts stratified by allo-HCT status. Among those who underwent allo-HCT, NPM1-mt pts had longer mOS (NR vs 22 mo, p=0.037). Among non-allo-HCT pts, mOS was numerically higher in NPM1-mt vs KMT2Ar (19 vs 8 mo, p=0.11). Conclusions: This single institusion cohort of adult AML with KMT2Ar underscores the biological and clinical heterogeneity of this high-risk group. IC was associated with a survival benefit, particularly among younger and fit patients. However, the outcomes following relapse remained poor, highlighting the urgent need for improved post-remission and salvage therapies. Comparative analysis with matched RR NPM1-mt AML pts revealed similarly dismal survival outcomes. Emerging data from single-arm studies of menin inhibitors in both frontline and RR settings among pts with NPM1-mt and KMT2Ar AML are encouraging and may represent a paradigm shift in treatment.

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 CAR T cell treatment is the standard of care for patients (pts) with primary refractory and relapsed large B-cell lymphoma (LBCL) within the first 12 months of chemoimmunotherapy, or for those unfit for autologous stem cell transplant (ASCT) regardless of timing of relapse. Consequently, the role of ASCT is limited to pts with late relapse (>12 months) who achieve a complete or partial response (CR or PR) to salvage therapy and are deemed eligible for ASCT based on comorbidities and performance status. In this report, we evaluated post-ASCT outcomes in this population of pts. Methods We conducted a retrospective cohort study using publicly available data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Adult pts (age ≥18 years) with DLBCL, NOS, and high-grade large B-cell lymphomas (HGBL) who relapsed after having responded to initial treatment and who remained on response for at least 12 months since diagnosis were selected. We considered for this analysis only pts who achieved a CR or PR after salvage treatment at the time of relapse, documented on pre-ASCT CT or PET scan (per the 2014 Lugano definition). CIBMTR databases used for this study included pts who received ASCT from 2013 to 2021. We compared baseline characteristics between ASCT in CR vs PR using the Wilcoxon rank sum test for continuous variables and the Pearson's χ2 test for categorical variables after ignoring missing data. Primary endpoints included Progression-free survival (PFS) and overall survival (OS). Non-relapse mortality (NRM) and relapse rate were among the secondary endpoints. Results 182 were included in the analysis: 100 were in CR and 82 in PR before ASCT. The median age at ASCT was 60 years (range, 26-79). Race distribution was similar across CR and PR pts. Advanced-stage disease at diagnosis (stage III–IV) was seen in 61% of CR pts and 55% of PR pts. High-grade B-cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements was similar in the CR and PR groups (7% vs 4%). The median number of lines of treatment before ASCT were identical in CR and PR pts (N=2). BEAM was the most frequently used transplant conditioning regimen in both groups (80%). Median follow-up after ASCT was 34 months (range, 1–95): it was 37 months (range 1-95) in the CR group and 26 months (range 1-79) in the PR group For the entire cohort, OS at 3 years was 67.6% and PFS was 50.6%. NRM was 1.7% at 100 days and 3.4% at 1 year. Cumulative incidence of relapse at 3 years was 43.9%. The NRM analysis showed no statistically significant difference between pts in CR and PR. The 3-year OS for CR pts was 73.9%% compared to 59.4% for PR pts (95% CI, 0.334-0.99; p=.044). The 3-year PFS for CR pts was 59.8%, compared to 38.6% for PR pts (95% CI, 0.321-0.784; p=.001). The median PFS for CR pts was 52.01 months, compared to 14.05 months for PR pts. The cumulative incidence of relapse at 3 years in CR and PR pts was 35.2% vs 55.7%, respectively (95% CI, 0.311-0.811; p=.003.). Higher age (HR 1.03; p=.026) and number of previous lines of treatment (HR 1.43; p=.002) were associated with inferior OS. For PFS, no variables showed any significant impact in univariable analysis. The stepwise multivariable analysis showed that only the number of previous treatments had a significant impact on the OS (p=.009), while undergoing ASCT on a PR was the only factor significantly associated with shorter PFS (HR 1.41; 95% CI, 1.09-1.82; p=.029). Conclusion This dataset supports that ASCT provides high efficacy in pts experiencing late relapses (after 12 months) achieving CR following pre-transplant savage and validates the value of achieving CR. Outcomes for PR are inferior, and this analysis provides a benchmark for future investigations. At this time, until convincing on other non-transplant treatment show superior outcomes in this setting, ASCT remains a standard of care for fit pts with chemo-sensitive late relapsed DLBCL. In this group of patients, who have a better prognosis compared to patients who relapse within a year the major hurdle is achieving a remission pre-ASCT.

Abstract Background: Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative option for myelofibrosis (MF) but carries significant non-relapse mortality (NRM). Splenomegaly in MF patients undergoing allo-HCT is linked to delayed engraftment, poor graft function, and worse overall survival (OS). Strategies to reduce spleen size pre-HCT have been explored. Splenic irradiation (SI) offers a non-invasive approach for rapid spleen size reduction, though data on transplant outcomes are limited. Retrospective studies suggest SI just before HCT may reduce relapse and effectively shrink spleens with acceptable toxicity. Methods: We conducted a single-center observational study on MF patients with splenomegaly undergoing allo-HCT between 2022–2024. SI (100 cGy in 5 fractions) was delivered within 6 weeks pre-HCT. Primary endpoints: engraftment kinetics (including primary engraftment failure), time to neutrophil/platelet engraftment, and transfusion independence. Secondary endpoints: OS, progression-free survival (PFS), relapse, NRM, and rates of acute/chronic GVHD. Kaplan–Meier methods were used for OS/PFS; cumulative incidence functions with competing risks were used for relapse/NRM. Results: Thirteen patients were analyzed. Median age was 63 (range 40–74) years, and 54% were male. Eight (62%) patients had primary MF, 3 (23%) post-essential thrombocytosis, and 2 (17%) post-polycythemia vera. Eleven (94.6%) patients had prior Ruxolitinib therapy, and 10 (76.9%) harbored a JAK2 mutation with a median variant allele frequency of 51% (range 34%–94%). DIPSS risk at transplant was low in 1 (7.7%), intermediate-1 in 8 (61.5%), and intermediate-2 in 4 (30.8%) patients. Median pretransplant spleen size was 22.4 (range 14.5–28) cm. Two patients had a history of thrombosis, including 1 with portal vein thrombosis. The median interval between SI and stem cell infusion was 14 (range 10–43) days. The median HCT-CI score was 2 (range 0–6), and the median KPS was 80% (range 80–100%). Most patients (76.9%) received a HLA-matched unrelated donor transplantation, while 3 (23.1%) received haploidentical donor grafts. All grafts used peripheral blood stem cells. Reduced-intensity conditioning (RIC) was used in 11 (84.6%) patients, while 2 (15.4%) received myeloablative conditioning (MAC). Five (38.5%) patients received total body irradiation (TBI) as part of conditioning, with all receiving a TBI dose of 200 cGy. All patients received post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis. With a median follow-up of 17.1 months, median neutrophil engraftment occurred at 18 (range 14–45) days, platelet engraftment at 30 (range 15–434) days, red blood cell transfusion independence at 35 (range 11–341) days, and platelet transfusion independence at 24 (range 10–312) days. Median hospital stay was 26 (range 14–86) days. Primary engraftment failure occurred in 1 (8.3%) patient. One (7.7%) patient developed veno-occlusive disease. Four (33.3%) patients experienced CMV reactivation, and 3 developed CMV disease requiring systemic therapy. Median post-transplant spleen size was 16.6 (range 12.2–25.2) cm, and 30% of patients achieved >50% spleen size reduction, with a median time of 114 (range 45–212) days, with none having a normal spleen at day 30 post-transplant but 2 (15%) patients having a normal spleen at day 100 post-transplant. At 1 year, OS was 73.3% (95%CI, 51.5–100%), and PFS was 66% (95%CI, 44%–100%). The 1-year cumulative incidence of relapse was 7.6%, while 1-year NRM was 25.7%. Seven (53%) patients developed acute GVHD, with 1 patient experiencing grade III acute GVHD that progressed to sepsis and death at day 248 post-transplant. Two additional deaths occurred (graft failure=1, multiorgan failure=1). Two (15%) patients developed moderate chronic GVHD Conclusion: In this single-center cohort, SI pre-allo-HCT was feasible, tolerated, and associated with promising OS and PFS. Engraftment occurred in >90%, with one case of primary engraftment failure and most achieving transfusion independence within reasonable time frames. SI reduced spleen size in >30%, though acute GVHD was frequent. It remains uncertain whether the incidence and severity of GVHD may be influenced using TBI as part of the conditioning regimen (albeit reduced in intensity) in addition to splenic irradiation. Larger prospective studies are needed to clarify SI's impact on engraftment, transfusion dependence, GVHD, and outcomes in MF patients.

Abstract Background Chimeric-antigen-receptor (CAR) T-cell therapy has transformed outcomes for relapsed or refractory hematologic malignancies, yet early identification of patients at highest risk for death remains elusive. A prognostic model that leverages only the information routinely available at the time of CAR-T evaluationcould guide pre-infusion counseling, intensity of follow-up, and resource allocation. Methods We analyzed a prospectively maintained cohort of CAR-T recipients treated at Mayo Clinic to develop and test our model. For each patient, data (vital signs, lab results, cardiac assessments [ECG and echocardiography], and PET/CT images) from initial CAR-T evaluation (up to 60 days prior to CAR-T infusion) was considered. Vital signs and labs were left un-imputed, while ECG, echocardiographic parameters, and PET/CT features were forward-filled from the preceding 60 days. Each patient-day was labeled as “outcome present” or “no outcome,” enabling supervised training of gradient-boosting models to predict overall survival (OS) at 6 months post CAR-T infusion. Model performance was evaluated using the area under the ROC curve (AUC) with 10,000-fold bootstrapping with data shuffling between each iteration to derive confidence intervals for stability. To enhance interpretability, we also developed a simplified model using the top 19 features (determined by Shapley value-based importance), aiming to preserve predictive accuracy with a smaller feature set. Results A total of 570 CAR-T cell treated patients were included in this study (476 patients in the training cohort and 94 patients in the validation cohort). The median age was 64 years and 61% males. The primary diagnoses were B-cell lymphoma (324 patients) and multiple myeloma (246 patients). A total of 4,851 individual vital-sign readings, 11,781 laboratory measurements were included. PET/CT images were available in 318 patients. The ML model demonstrated high discriminative ability for predicting OS at 6 months post CAR-T infusion. Vital signs alone produced a mean AUC of 0.63; radiomics features alone produced a mean AUC of 0.71, while laboratory tests alone produced a mean AUC of 0.84. The features most contributory to each single-modality model were then combined into a simplified multimodal model with a total of 19 features, which produced a mean AUC of 0.87, with a 95% CI of 0.73 - 0.97. The 19 features included in the simplified model were: LDH, ferritin, uric acid, eosinophils, fibrinogen, D-dimer, heart rate, mean arterial blood pressure, QTc, QT interval, and the radiomics features of sphericity, first-order Kurtosis, first-order mean, first-order energy, first-order total energy, shape maximum2D diameter (sagittal plane), SUV CoV, SUVp90, shape flatness. This multimodal predictive model was then applied to the validation cohort (uninvolved with model training or testing), which produced an AUC of 0.93, with a 95% CI of 0.84 - 0.98. Conclusions Our ML-driven approach successfully predicts overall survival 6 months post CAR-T infusion, highlighting those individuals at most risk of poor outcomes at the time of CAR-T evaluation. The strong performance of the multimodal version of the model suggests that each data domain contributes complementary resolving power, and by including novel data types, such as PET CT radiomics features, the most accurate predictions could be realized. By providing accurate, near-real-time risk stratification for poor outcomes within 6 months of CAR-T infusion, the model could facilitate proactive patient management. Prospective studies of the integration of this ML model into CAR-T treatment workflows will be crucial to confirm its clinical benefits and to facilitate its adoption in practice.

Abstract Introduction Odronextamab, a CD20×CD3 bispecific antibody, demonstrated compelling efficacy with a generally manageable safety profile in heavily pretreated patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) in the Phase 2 ELM-2 study (NCT03888105; Kim TM, et al. Ann Oncol 2024). Pts in ELM-2 received odronextamab monotherapy until disease progression or unacceptable toxicity, with dosing frequency reduced to every 4 weeks (Q4W) in those with sustained complete response (CR) for at least 9 months. Here, we report longer term outcomes in the global FL population of ELM-2, including efficacy and safety in pts who switched to Q4W dosing. Methods Details of the ELM-2 study for the R/R FL cohort have been reported previously. Odronextamab monotherapy was administered intravenously, with step-up dosing in Cycle (C) 1 to help mitigate the risk of cytokine release syndrome (CRS), followed by 80 mg in C2–4, then 160 mg every 2 weeks (Q2W) maintenance. Pts with a CR for ≥9 months switched from 160 mg Q2W to Q4W. Pts with the opportunity for response assessment at 12 weeks were included in this analysis. Primary endpoint was objective response rate (ORR) per Lugano criteria by independent central review (ICR). Key secondary endpoints included CR rate, duration of response (DOR), and progression-free survival (PFS) by ICR, overall survival (OS), and safety. Results As of May 5, 2025 data cutoff, 128 pts with R/R FL Grade (Gr) 1–3a were evaluable for efficacy and safety analysis (overall global population). Median duration of odronextamab exposure was 42.9 weeks (range 0.4–264.0) and median follow-up was 34.1 months (95% CI 33.8–37.9). Eligible pts (n=48) switched to Q4W dosing, with median duration of follow-up from time of switching to Q4W dosing of 19.7 months (95% CI 16.2–31.9). Baseline characteristics were generally similar between the overall population and the subgroup of pts who switched to Q4W dosing. The ORR by ICR in the overall population was 80.5% and CR rate was 74.2%, with a median DOR of 26.0 months and median duration of CR of 32.2 months. In pts with sustained CR for ≥9 months who transitioned to Q4W maintenance, the median DOR from time of switching was 31.5 months. In the overall population, the median PFS was 24.1 months and median OS was not reached (estimated 24- and 36-month OS rates: 70.1% and 64.3%, respectively). In pts with CR, median PFS was 38.0 months and median OS was not reached (24- and 36-month OS rates: 80.1% and 75.2%). All 128 pts had treatment-emergent adverse events (TEAEs), with Gr ≥3 TEAEs reported in 112 pts (87.5%). Discontinuation due to TEAEs occurred in 29 pts (22.7%), and 5 pts died due to treatment-related TEAEs. With the 0.7/4/20 mg step-up regimen, CRS was reported in 55.0% (33/60; Gr 3 in 1 pt) of pts, with no new CRS events observed after switching to Q4W. Infections occurred in 81.3% (Gr ≥3, 46.1%) of pts, with COVID-19 (any Gr, 39.8%) the most frequent. After switching to Q4W dosing, the rate of any grade infection was 81.3% (Gr ≥3, 39.6%). Opportunistic infections (narrow SMQ defined) were reported in 18% (Gr ≥3, 8.6%) of pts in the overall population, with 22.9% (Gr ≥3, 8.3%) of pts having an opportunistic infection after switching to Q4W. Conclusions In the ELM-2 study with ~3-year follow-up in heavily pretreated pts with R/R FL, odronextamab continued to demonstrate deep and durable responses, as well as encouraging PFS and OS, particularly in the majority of pts who achieved CR. Responses remain durable in those who switched to Q4W dosing, lasting for a median additional 31.5 months from the time of switching, demonstrating the long-term, continued therapeutic benefit of odronextamab in pts with R/R FL. The safety profile remained generally manageable, with no new safety signals observed, and no evidence of increased infection risk in pts who switched to Q4W maintenance. Updated data will be presented.

Abstract Background In advanced-stage classical Hodgkin lymphoma (cHL), achieving a negative interim PET (iPET) after two cycles of ABVD is generally considered a favorable prognostic marker. Most patients with early metabolic response proceed to complete therapy without residual disease. However, a subset of patients experience discordant end-of-treatment (EOT) findings, with evidence of the disease despite an initial complete response. This study aimed to identify baseline clinical features that might help predict this unexpected outcome.Methods A retrospective review was conducted of 122 patients with stage III or IV cHL treated at our institution between 2016 and 2024. All patients achieved complete metabolic response (Deauville score ≤3) on iPET following two cycles of ABVD. Clinical and laboratory data, including IPS score, bone marrow, and extranodal involvement, were collected. The primary outcome was residual disease identified at EOT-PET. Logistic regression was used to identify predictive factors. Disease-free survival (DFS) was estimated using Kaplan-Meier analysis.Results Of the 122 patients with negative iPET scans, 21 (17.2%) were found to have residual uptake on EOT-PET. The median age was 28 years; 63% were male, and 70.5% had nodular sclerosis subtype. Most patients (69.7%) had stage IV disease. In univariate analysis, no baseline variable- including IPS score, bone marrow involvement, extranodal disease, or B symptoms- was significantly associated with residual PET positivity. However, in multivariate analysis, stage IV disease emerged as an independent predictor, with a statistically significant association with residual disease at EOT (OR 3.32; 95% CI, 0.97–11.37; p = 0.041). The median follow-up was 28.8 months. The median DFS was not reached, and the estimated two-year DFS was 83%.Conclusions While early metabolic remission on interim PET is reassuring, a notable proportion of patients still demonstrate residual disease by the end of therapy. Stage IV disease was independently associated with this outcome when adjusted for other variables. No significant associations were identified with IPS score, bone marrow, or extranodal involvement. These findings suggest that relying solely on interim PET may overlook residual risk in a subset of patients, particularly those with extensive disease burden at baseline.

Abstract Background: Atypical Hemolytic Uremic Syndrome (aHUS) remains a diagnostic challenge as it shares overlapping features of Thrombotic Thrombocytopenic Purpura (TTP) and Shiga-toxin mediated HUS (STM-HUS). It is caused by complement activation in the alternative pathway and is mostly related to genetic defects in complement-related factors or acquired autoantibodies. Early recognition and treatment have excellent outcomes. Case Presentation: A 74-year-old female with Hypertension presented with a 3-week history of non-bloody diarrhea and was found to have acute kidney injury (AKI) with creatinine 5.27 mg/dL (baseline 0.5), anemia (7.5 g/dL), and thrombocytopenia (123×10⁹/L) and normal liver function. CT imaging of the abdomen revealed uncomplicated sigmoid diverticulitis and mesenteric lymphadenopathy. She was treated with intravenous fluids and started on antibiotics with ceftriaxone and metronidazole for diverticulitis. Despite fluid resuscitation, renal function deteriorated, necessitating initiation of intermittent hemodialysis. Due to anemia, thrombocytopenia and AKI further workup with peripheral smear pursued showed schistocytes, helmet cells, and keratocytes. Hemolysis labs showed LDH 1433 U/L, undetectable haptoglobin, and a negative direct Coombs test. Methylmalonic acid level was normal. Homecystine level was elevated. These findings were consistent with microangiopathic hemolytic anemia. Coagulation profile was normal. Given concern for TTP, ADAMTS13 was obtained but returned at 68%, ruling out TTP. Shiga toxin PCR was negative, ruling out STM-HUS. Complement level checked showed low C3 and C4, suggesting complement activation and consumption. Total complement, Factor 8, factor B, monoclonal protein were within normal. A renal biopsy was initially postponed due to uncontrolled hypertension. Eculizumab was started. Renal biopsy later done confirmed aHUS. Following initiation of eculizumab, the patient's renal function progressively improved, and she was able to discontinue hemodialysis. Laboratory markers of hemolysis stabilized, with normalization of LDH, haptoglobin, homocystine and complement. She completed the induction phase of eculizumab and entered a long-term monitoring phase, with labs every 2 weeks for 6 months, then monthly for 36 months. No relapses were noted to date and is off dialysis. Conclusion: Differentiating aHUS from TTP and STM-HUS is critical, as management strategies differ significantly. Prompt initiation of eculizumab can reverse renal injury and prevent further organ damage.

Abstract Background In patients with myelofibrosis (MF) undergoing allogeneic hematopoietic cell transplantation (allo-HCT), graft-versus-host disease (GVHD) prophylaxis has traditionally included a calcineurin inhibitor (CNI) plus methotrexate (MTX). We conducted a retrospective study comparing the safety and efficacy of post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis to CNI-based regimens. Methods This study was approved by the Mayo Clinic IRB. Patients with myelofibrosis who underwent allo-HCT after 2016 at Mayo Clinic in Arizona and Florida were included. Categorical variables were compared using Chi-square or Fisher's exact tests. Overall survival (OS) was defined from transplant to death, and progression-free survival (PFS) from transplant to relapse or death. OS and PFS were estimated using Kaplan-Meier methods; univariate differences were assessed with log-rank tests. The cumulative incidence of acute and chronic GVHD and time to neutrophil and platelet engraftment were analyzed using competing risk models, with death as a competing event; differences were tested using Gray's test. Cox proportional hazards models were used to estimate adjusted hazard ratios (HRs). Results A total of 110 patients were included. 53 patients received PTCy-based prophylaxis (43 PTCy/Tac/MMF, 1 PTCy/CSA/MMF, 9 PTCy/Siro/MMF), while 57 received non-PTCy regimens (54 Tac/MTX +/- 39 T-cell depletion, 2 CSA/MMF, 1 Tac/MMF). Median age at transplant was 63 (range: PTCy 40-76; others 38-74) years in both groups; 59 were male (58.5% PTCy vs 49.1% others). Median Karnofsky Performance Status (KPS) and HCT–Comorbidity Index (HCT-CI) in patients receiving PTCy vs non-PTCy were 90 vs 80 and 1 vs 3, respectively. Conditioning intensity was similar: 22.6% myeloablative vs 21.7%, and 77.4% reduced-intensity vs 76.7% in PTCy and non-PTCy, respectively (p=1.000). Stem cell source was peripheral blood in all patients except one in the non-PTCy group who received bone marrow. 58 patients had primary MF (54.7% PTCy vs 50.9% others), and 52 had secondary MF (45.3% PTCy vs 49.1% others), including essential thrombocythemia (28.3% PTCy vs 31.6% others), polycythemia vera (17.0% vs 15.8%), and MPN-NOS (0% vs 1.8%). Median follow-up was 26.2 months (95% CI: 20.7-52.7) in the PTCy and 60.6 months (95% CI: 53.1-70.6) in the non-PTCy cohort. CD3 and CD33 donor chimerism ≥95% at day +100 was 66.7% and 86.7% in PTCy vs 63.6% and 92.7% in others, respectively (p=0.50); day +100 driver molecular mutations were present in 32.1% of PTCy and 32.0% of others (p>0.99). Rates of acute GVHD grades ≥2 and ≥3 were not statistically significant, in the PTCy group (37.7% vs 49.1% p=0.229 and 17.0% vs 22.8% p=0.445, respectively). Chronic GVHD (any grade) occurred in 42.3% of PTCy vs 38.2% of others (p=0.664), while moderate-to-severe cGVHD was lower with PTCy (21.2% vs 27.3% p=0.461). Platelet engraftment was significantly delayed in the PTCy group (median 33 vs 21 days, p=0.030). Median time to neutrophil engraftment was also delayed in the PTCy group (20 vs 17 days, adjusted p=0.025). Age-adjusted HR for time to platelet engraftment was 0.60 (95% CI: 0.41–0.90; p=0.014), and for neutrophil engraftment 0.65 (95% CI: 0.44–0.95; p=0.025), indicating significantly delayed hematopoietic recovery with PTCy. Graft failure occurred in 9.4% vs 5.3% (p = 0.48); primary 7.5% vs 3.5%, secondary 1.9% vs 1.8% in PTCy vs non-PTCy groups, respectively. Relapse or progression occurred in 11.3% of PTCy vs 17.5% of others (p=0.355); four patients in the non-PTCy group progressed to AML post-transplant, versus none in the PTCy group (p=0.119). 1-year TRM was 22.6% in the PTCy group and 14.0% in the non-PTCy group, p = 0.324. Median OS was 72.8 months in the PTCy group (95% CI: 49.9 months, upper limit not estimable [NE]) and 93.4 months in the non-PTCy group (95% CI: 48.5 months, upper limit NE), although the difference was not statistically significant (p=0.739). After adjusting for age and HCT-CI, there were no significant differences in PFS (adjusted HR 1.37; 95% CI: 0.73–2.56; p=0.331) or OS (adjusted HR 1.27; 95% CI: 0.64–2.51; p=0.498). Conclusions In myelofibrosis patients undergoing allo-HCT, PTCy-based GVHD prophylaxis showed similar rates of grade ≥2 acute and moderate-severe chronic GVHD compared to non-PTCy regimens. Engraftment was significantly delayed, while OS and PFS were comparable. PTCy appears to be a safe and viable alternative to CNI-based prophylaxis.