Citations

Abstract The current European Leukemia Net guidelines (ELN22) classify AML patients with intermediate-risk cytogenetics and MDS-associated mutations (MDSm, mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse-risk but do not use MDSm+ to alter the risk stratification of patients who otherwise classify as favorable-risk. NPM1 mutations (NPM1+) are one of the most common alterations in AML and remain a favorable-risk biomarker for patients without co-occurring FLT3-ITD mutations or adverse-risk cytogenetics (NPM1+/ITD-/ARcyto-). However, prior studies have shown that older patients (≥65 years) with favorable-risk AML, including NPM1+/ITD-/ARcyto- genotype, have significantly higher relapse rates and decreased survival despite receiving comparable intensive chemotherapy regimens to their younger counterparts. Given that MDSm frequency increases with age in patients with NPM1+ AML, it raises the question as to whether MDSm contribute to poorer outcomes in older patients. To date, there have been differing results in retrospective studies examining the effect of MDSm on NPM1+ AML. Some cohorts demonstrate worse outcomes in those that have NPM1+/MDSm+ AML (Chan et al., Blood Adv. 2024), whereas others do not show a significant difference in NPM1+ AML with or without MDSm (Eckardt et al., Leukemia 2023; Othman et al., Blood 2024; Ruhnke et al., Blood Adv. 2025). We examined the mutational landscape in a large group of pre-treatment, diagnostic specimens from 271 patients, which included 119 patients enrolled in SWOG clinical trials (SWOG-9031, SWOG-9333, S0106, and S0112), 96 patients from the UW/FHCC Hematopoietic Repository, and 56 patients from the BeatAML cohort. All patients were treated with curative intent as per standard practice or on clinical trials and had adequate cytogenetic information and long-term follow-up data. Event-free and overall survival (EFS, OS) were estimated using the Kaplan-Meier method and compared using Cox regression models stratified by cohort. MDSm+ occurred in 17% of patients, with the most common mutations being in SRSF2 (7%) and SF3B1 (3%). To assess the impact of MDSm on outcomes of favorable-risk NPM1+ AML, we performed univariate analyses comparing OS and EFS for NPM1+ AML grouped by ELN22 favorable risk/MDSm-, ELN22 favorable/MDSm+, and ELN22 intermediate/adverse risk. Compared to NPM1+/MDSm- (n=116), favorable-risk NPM1+/MDSm+ (n=33) had worse OS with HR 2.0 [95% CI (1.1, 3.3), p=0.008] and had similar OS to those that are classified as ELN22 intermediate/adverse risk (n=122). There was no significant difference in EFS or complete remission rates between NPM1+ favorable risk with and without MDSm (p=0.36 and p=0.6, respectively). When we grouped the ELN22 favorable risk patients by age (<65 years vs. 65+ years), MDSm+ in younger patients did not show a difference for OS (HR 0.99, p=0.98). Older ELN22 favorable-risk patients (≥65) had poor OS regardless of presence of MDSm compared to younger MDSm- patients: older MDSm- (n=91) with HR 2.4, 95% CI (1.3, 4.6), p=0.005 and older MDSm+ (n=25) with HR 3.5, 95% CI (1.9, 6.3), p<0.0001. There was a trend toward worse OS in MDSm+ compared to MDSm- older patients, but this was not statistically significant (HR 1.42, p=0.33). Since most MDSm are in splicing factor genes (SF3B1, SRSF2, U2AF1, ZRSR2), we examined the effect of splicing factor mutations vs. other MDSm+ in ELN22 favorable risk and did not find a significant difference in OS (HR=1.01, p=0.97). Those with non-splicing MDSm+ had worse EFS compared to MDSm- and splicing MDSm+ (HR 4.12, p=0.0037), although no difference in OS. In this study, MDSm+ in the context of favorable-risk NPM1+ AML are associated with worse OS in a univariate analysis. However, this difference is likely due to the increased prevalence of MDSm with increasing age and overall worse outcomes of NPM1+ AML in older patients. When stratified by age, older NPM1+ AML patients had worse OS than younger NPM1+ patients overall, although presence of MDSm trended toward even worse OS in older patients. In younger patients, MDSm+ are not associated with a significant difference in OS, which is a similar finding compared to prior studies. Our findings suggest that NPM1+ AML is not necessarily “favorable-risk” in older patients, particularly with concurrent MDSm. Therefore, further understanding of the underlying biology of age in the context of NPM1+ AML is needed to improve outcomes for older patients.

Abstract Background: Dissemination and implementation science (D+I) efforts often begin after clinical trial (CT) efficacy data are available. However, delaying this work limits opportunities to identify barriers and facilitators that can enhance adoption of evidence-based practices. Integrating D+I during trial development, activation, and conduct supports more timely, effective, and scalable implementation. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) includes >125 centers, conducting transplant and cellular therapy (TCT) trials with practice-changing potential, with >17,000 patients enrolled since 2001. Data from Center for International Blood and Marrow Transplant Research (CIBMTR) provides a way to measure real-world adoption. With this comprehensive structure in place, the BMT CTN launched a D+I Committee that established a D+I process to better understand uptake of CT findings and to leverage that information to promote adoption. Methods: Informed by established D+I frameworks, a structured, cyclical process to integrate implementation considerations spanning the CT lifecycle was developed. A multidisciplinary team including experts in D+I, clinicians, and investigators iteratively refined the proposed D+I algorithm. The process begins upstream when a trial concept is approved to move forward, it is shared with the D+I Committee for initial assessment. This includes a landscape review for studies in development using CIBMTR data, literature, and expert experience. The Committee then reviews the developing protocol with the BMT CTN protocol team to proactively identify implementation barriers and facilitators to implementation in real-world settings and outline plans for dissemination. The Committee also provides recommendations for integrating relevant implementation data collection and analyses within the protocol. After study completion, both clinical efficacy and implementation outcomes are analyzed, followed by active dissemination. Additional assessment using surveys, qualitative methods, and CIBMTR data occurs after dissemination to understand adoption. Insights gathered also inform further refinement of the process. Tools and templates are in development to build capacity and ensure consistency for Committee members. Results: To date, the Committee has published three peer-reviewed articles addressing implementation implications of three BMT CTN trials (PMC7735536, PMC8578257, PMC9364468) and a fourth is in press. Using the designed D+I process flow, a current effort used a survey sent to US CIBMTR centers, to evaluate factors influencing the implementation of results of the BMT CTN 1703 trial of post-transplant cyclophosphamide as graft-versus-host disease (GvHD) prophylaxis and assessed dissemination and adoption considerations for the upcoming BMT CTN 2203 CT of ruxolitinib as GvHD prophylaxis. CIBMTR data is being analyzed to demonstrate practice patterns before, during, and after BMT CTN 1703 study completion. This effort has allowed for further refinement of the BMT CTN D+I process flow and has highlighted critical opportunities for incorporating dissemination and implementation objectives and endpoints into BMT CTN protocols. We also used the process to guide a review of severe aplastic anemia treatment gaps and ongoing studies. This review underscored how proactive transplant and non-transplant stakeholder engagement and early implementation planning, core elements of this process, can bridge evidence to practice and advance access to care. A complementary survey on current practice patterns in severe aplastic anemia is ongoing. Conclusions: With the existing structure of the BMT CTN and associated practice registry of the CIBMTR, the BMT CTN D+I Committee developed a systematic process to build D+I considerations into trial workflows to increase real-world impact. This process aims to ensure that barriers to uptake of trial results can be identified and addressed appropriately, improving care quality for patients undergoing TCT.

Abstract BACKGROUND Ivosidenib is an oral inhibitor of mutant isocitrate dehydrogenase type I (IDH1) currently approved for the treatment of IDH1 mutated acute myeloid leukemia and myelodysplastic syndrome (MDS). Hematopoietic stem and progenitor cells carrying preleukemic mutations, referred to as clonal hematopoiesis (CH), are the origin of myeloid neoplasms (MN). Individuals who have cytopenias and CH, but do not meet diagnostic criteria for a hematologic malignancy, are classified as having Clonal Cytopenias of Undetermined Significance (CCUS), a condition associated with a high risk of progression to MN. While CCUS patients (pts) can have multiple mutations, they show lower mutational burden on average compared to MN. Thus, we hypothesized that treatment with ivosidenib would improve cytopenias in IDH1-mutant CCUS. METHODS; We performed a decentralized phase II single-arm study to characterize the safety and efficacy of ivosidenib in IDH1-mutant CCUS (NCT0503044). Drug was shipped to pts with local oncologists performing standard-of-care clinical exams supplemented by study team lead interviews for adverse event monitoring. Research labs were drawn by local providers or through Quest. QT corrected interval (QTc) was monitored through a mobile electrocardiogram device (AliveCor). Eligible patients were aged ≥ 18 years and had confirmed IDH1-mutant CCUS with at least 6 months of unexplained cytopenias (hemoglobin<10 g/dL, platelets<100 x109/L or absolute neutrophil count <1.8 x109/L). The primary endpoint was hematologic response of at least 8 weeks in duration based on the IWG 2006 criteria for MDS. RESULTS 20 pts with IDH1-mutant CCUS have been enrolled. Most were male (70%) with a median age of 66 (range 41-79). Overall, 74% had a self-reported race of non-Hispanic white, 11% of Hispanic white, 5% of Asian and 11% of black or African American. Most pts presented with neutropenia (95%) including some with co-occurring thrombocytopenia (21%). One pt presented with anemia and thrombocytopenia without neutropenia. Prior to treatment, the average number of co-mutations beyond IDH1 was 2 (range 0-3), with most pts (74%) harboring a co-occurring spliceosome gene mutation. The IDH1 variant allele fraction (VAF) was lower in the blood (mean=19%, range 3-35%) than in the bone marrow (mean=31%, range 18-43%) in most (93%) patients. Out of the 20 enrolled pts, 17 received at least 8 weeks of therapy at the time of our data cutoff (7/29/2025) and were included in the efficacy analysis. Grade ≥3 adverse events (AEs) occurred in five patients (26%) including two with grade ≥3 treatment-related adverse events (pancytopenia and sepsis in the first pt, rash in the second pt). The most common all-grade treatment-related adverse events were nausea (n=5, 26%), prolonged QTc (n=3, 16%), anemia (n=3, 16%), and diarrhea (n=3, 16%). There were no instances of reported differentiation syndrome. Overall, 82% of pts achieved a hematologic response (14/17) including improvement in neutropenia (88%) and thrombocytopenia (75%). With a median follow-up of 16 months (range 0.6-24 months), the median duration of hematologic response was not reached. Among responders, 86% had a continued response at one year. Two pts progressed to MDS after 4 and 17 months of treatment characterized by recurrence of cytopenias and the emergence of new clones. A surveillance bone marrow biopsy was performed at 18 cycles for the 8 pts who remained on treatment with none showing disease progression. Most pts (90%, N=9/10) treated for at least 12 months had a decrease in IDH1-mutant CH VAF over time and 40% (N=4/10) showed IDH1 mutation clearance (VAF <2%) with a median time to clearance of 9 months. Among those with decreasing IDH1 clonal burden, all had a corresponding decrease in other co-occurring mutations present at baseline with one responder showing emergence of a newly detectable CHEK2 mutation without disease progression. CONCLUSIONS Decentralized trials represent a feasible solution for the conduct of clinical trials in rare hematologic neoplasms and precursor conditions. Ivosidenib was well-tolerated and induced durable hematologic remissions in IDH1-mutant CCUS. Most pts showed a reduction in clonal burden with mutation clearance commonly seen with long-term treatment demonstrating that ivosidenib modifies the natural history of IDH1-mutant CCUS.

Abstract Introduction Elevated levels of fetal hemoglobin (HbF) ameliorate sickle cell disease (SCD) manifestations. BEAM-101 is an investigational cell therapy comprising ex vivo base-edited autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) that directly target the HBG1/2 promoters to disrupt BCL11A binding, switching production from sickle (HbS) to majority anti-sickling HbF. We present ongoing data from the BEACON study (NCT05456880), a Phase 1/2, single-arm, open-label study evaluating a single dose of BEAM-101 in individuals with SCD and severe vaso-occlusive crises (sVOCs). Methods Eligible patients were aged 12–35 years with SCD and ≥4 sVOCs in the 2-year period prior to informed consent. After mobilization with weight-based or tiered fixed-dose plerixafor, autologous CD34+ HSPCs were collected by leukapheresis and genetically modified with an adenine base editor. Following conditioning with pharmacokinetically adjusted myeloablative busulfan (target cumulative AUC 80 hr*mg/L), patients received a single dose of BEAM-101 (≥3.0×106 viable CD34+ cells/kg). Patients were then monitored for neutrophil and platelet engraftment, adverse events (AEs), total Hb, Hb fractions, % F-cells, hemolysis markers, sVOCs, and additional protocol endpoints for up to 24 months. Results As of June 16, 2025, enrollment has been completed and 46 patients have initiated mobilization. Of the 26 patients who have received BEAM-101, mean duration of follow-up was 6.2 (range 1.0–18.7) months. Baseline demographics were: age 18–34 years, 24 βS/βS genotype, 21 self-reported Black/African American, and 11 female. One patient, who successfully engrafted and obtained stable HbF levels >60%, withdrew consent 5 months post-infusion. For the 26 treated patients, the median number of stem cell collection cycles was 1 (range 1–4); 18 (69.2%) required a single cycle, 4 required 2 cycles, and 4 required >2 cycles. Target cell dose was achieved with a median of 3 (1–12) collection days. Patients received a mean BEAM-101 dose of 8.4 (range 3.2–23.4) ×106 viable CD34+ cells/kg. By the data cut, patients achieved neutrophil (n=26) and platelet (n=24) engraftment at a median of 18 (12–30) days and 19 (11–50) days, respectively, with a median duration of 7 (4–17) days of neutropenia. Of the 24 evaluable patients, 9 (37.5%) achieved platelet engraftment without requiring platelet transfusion through the transplant process. No patients had ≥Grade 3 AEs or serious AEs related to BEAM-101. One patient died due to respiratory failure, assessed as likely related to busulfan conditioning, 4 months post-infusion as previously reported. Mean total Hb increased to 12.1 (range 9.0–14.7) g/dL by Month (M) 1 (n=24), 15.6 (11.9–18.6) g/dL by M6 (n=11), and was sustained through follow-up. Four patients had total Hb levels above the normal range beyond M6 without any associated clinical manifestations or need for therapeutic intervention. Erythropoietin levels trended towards normal in all patients, including those with elevated total Hb. Mean endogenous HbF (HbF/[HbF+HbS]) was >60% and HbS was <40% by M1, which was sustained through last follow-up. At M6, mean % F-cells were 99.2% (97.0–99.9; n=10) and mean HbF/F-cell was 20.8 (18.0–23.9; n=9) pg, exceeding the protective threshold of 10 pg against sickling. Peripheral blood editing was at a mean of 68.5% by M3 (n=16), 69.6% by M6 (n=10), and 72.8% by M12 (n=5). Hemolysis markers and sickling parameters normalized or improved for all patients. No patients experienced any investigator-reported sVOCs post-engraftment. Conclusions The BEAM-101 treatment process is characterized by a low number of mobilization and collection cycles and high editing efficiency, resulting in rapid neutrophil and platelet engraftment and robust pancellular HbF expression, with durability observed up to 18 months. Additionally, there is a corresponding reduction in HbS levels to <40%, and improvements or resolution of hemolysis parameters and anemia, along with resolution of investigator-reported sVOCs post-engraftment. The safety profile of the BEAM-101 treatment regimen is consistent with busulfan conditioning, autologous HSCT, and underlying SCD. These results demonstrate the potential for base editing of the HBG1/2 promoters as a safe and effective therapeutic modality for the treatment of SCD that also has the potential to minimize hospitalization and treatment process burden for patients, families, and sites.

Abstract Introduction Nadir bone marrow biopsies (BM Bx) are routinely performed around day 14 to assess early response to AML intensive induction therapy. The presence of residual disease prompts initiation of reinduction therapy, often with another cycle of intensive chemotherapy. Whether there are characteristics of nadir BM Bx that predict for response to intensive reinduction is unknown. To evaluate this, we analyzed data from ECOG-ACRIN clinical trials in AML of intensive induction chemotherapy with nadir biopsy information available to determine predictors of outcomes after reinduction. Methods We included patients from ECOG-ACRIN E1900 (Fernandez NEJM 2009) and arm A of E2906 (Foran ASH 2015) who received induction therapy with daunorubicin and cytarabine (7+3), had residual disease (blasts ≥5% or cellularity ≥20%) at nadir BM Bx and received reinduction chemotherapy. Nadir BM Bx characteristics that were evaluated included blast percentage and cellularity as well as both absolute and relative (percentage change, e.g. 20% to 10% = -50%) differences calculated between diagnosis and nadir for each parameter. Complete remission (CR) after reinduction therapy, disease free survival (DFS) and overall survival (OS) were outcomes for all analyses. Logistic regression models were used to evaluate associations with CR, and Cox proportional hazards models were used for DFS and OS. For models evaluating changes in blast percentage or cellularity as predictors, baseline blast percentage or cellularity was included as a covariate, respectively. Results Of 1013 patients identified, 750 (74%) had a nadir biopsy, 233 (23%) had evidence of residual disease, received reinduction therapy, and were included in the primary analysis. The median age was 58 and 42% were female. Cytogenetic risk category (by ELN2017) was adverse in 31%, intermediate in 66% and favorable in 3%. The median nadir BM Bx blast was 30% (range 0 to +97%) and cellularity was 20% (0 to +100%). The median absolute difference in blast percentage between baseline and nadir BM Bx was -15% (-95% to +66%) with a median relative difference of -36% (-100% to +400%). After reinduction, 118 patients (52%) achieved a CR. Neither absolute difference in blast percentage (OR 0.99, 95%CI 0.98-1.00, p=0.20) nor relative difference (OR 1.00, 95%CI 0.99-1.00, p=0.33) predicted CR. There was similarly no association with DFS (HR = 1.00, 95%CI: 0.99-1.01, p=0.65) or OS (HR = 1.00, 95%CI 0.99-1.01, p=0.76). Blast reduction ≥50% similarly did not predict these outcomes. We also evaluated the impact of any reduction in blast percentage (responders) from baseline to nadir and again found no association with CR (OR 1.65, 95%CI 0.90-3.03, p=0.11). Similarly, there was no association with DFS (HR 0.74, 95%CI 0.51-1.09, p=0.13) or OS (HR 0.81, 95%CI 0.58-1.13, p=0.21) in responders vs nonresponders. No association with CR, DFS or OS were identified when performing the same analysis in intermediate and adverse cytogenetic subgroups. We found no association with CR when nadir cellularity was assessed as a continuous variable (OR 0.99, 95%CI 0.98-1.00, p=0.10) or by relative difference (OR 0.99, 95%CI 0.99-1.00, p=0.10). There was a trend towards association with absolute reduction in cellularity from baseline to nadir and CR (OR 0.99, 95%CI 0.98-1.00, p=0.06). No association was identified between relative difference in cellularity and DFS and OS, nor was there an association among cytogenetic risk subgroups with any outcome. Discussion In intensively treated patients with residual disease at nadir BM Bx (i.e. day 14) who received intensive reinduction, the likelihood of achieving a CR was not influenced by the magnitude of disease reduction nor the extent of disease at the time of nadir biopsy. Similarly, there were no nadir biopsy features that predicted DFS or OS after intensive reinduction therapy. Given alternative reinduction therapies such as hypomethylating agents and venetoclax are available, these results suggest that the decision to attempt a second intensive induction cycle following the unequivocal presence of residual disease should not be influenced by characteristics of the nadir BM Bx. Although patient-specific factors such as patient fitness may favor a switch to less intensive options, these results support consideration of intensive reinduction therapy in patients with residual disease at nadir biopsy, even without changes in blasts or cellularity.

Abstract Introduction: NAVD has become a standard-of-care for frontline (1L) treatment (tx) of advanced stage cHL, based on the results of the S1826 study. S1826 demonstrated a 1-year progression free survival (PFS) of 94% for NAVD compared to 86% for brentuximab vedotin-AVD, which remained durable at 2 years (Herrera et al, NEJM 2024). Adverse events (AEs) and efficacy have not been reported in patients (pts) treated with NAVD outside of a clinical trial. Hence, we sought to evaluate safety profile and efficacy outcomes of pts with cHL treated with 1L NAVD in a real-world setting (RWS). Methods: In this multicenter retrospective cohort study, we included pts ≥18 years with cHL treated with 1L standard of care NAVD between 2023 and 2025 at 20 US academic sites. The safety evaluable cohort received at least 1 cycle of NAVD and included pts who have not completed tx. The efficacy evaluable cohort had completed 6 cycles of tx including end of treatment (EOT) PET-CT and included pts who intended to complete tx but died or discontinued due to progressive disease or AEs. The primary endpoint was EOT overall response rate (ORR). Secondary endpoints included EOT complete response rate (CRR), PFS and overall survival (OS). PFS and OS were calculated from the start date of tx and analyzed using the Kaplan Meier method. Results: A total of 311 pts with cHL were treated with NAVD with 26% of pts with tx ongoing (n=83) and 73% with tx completed (n=228). Baseline demographics included 55% male pts, 60% with stage IV disease (stage IIB, n=4) and 84% with nodular sclerosis subtype. Median age was 37 years (range 18-88), 29% had bulky disease (>7.5 cm), 28% were EBV positive (n=74/268), 8% had history of an autoimmune disease, and 31% had an IPS 4-7. G-CSF was given in 64% of pts. All patients were safety evaluable. Tx was interrupted (any length) in 24%, reduced in 12%, and discontinued in 14%. The most common reason for dose reduction was neuropathy in 4%. Nivolumab was discontinued in 10% and all therapy in 3.7% due to toxicity. Any AE and any grade 3 or higher AE (>G3) were observed in 92% and 62%, respectively. Neutropenia of any grade occurred in 68% (48% >G3), infection in 25% (10% >G3), and neuropathy in 30% (2.8% >G3). Hospitalization for an AE occurred in 20% (4.5% febrile neutropenia). Among pts with complete data (n=305), any immune related AE (irAE) occurred in 78 pts (25.6%) with any >G3 irAE in 23 pts (7.5%). The most common irAEs included hypothyroidism (7.9%, all grade 1-2), hepatotoxicity (1.6% G1/G2, 3.3% >G3), inflammatory arthritis (3% G1/G2, 0.6% >G3), rash (2.6%, all grade 1-2), and colitis (1% G1/G2, 1% >G3). Other notable >G3 irAEs included adrenal insufficiency (n=2), AKI/ATN (n=1), myocarditis (n=1), diabetes (n=1) and pancreatitis (n=1). Of 84 irAE events, 47 (56%) have had complete resolution. Among all pts, 14.4% (n=45) required systemic steroids at any time (intravenous in 4.1%), 3.2% (n=10) require ongoing steroids/immunosuppression and 8.3% other therapy for an irAE (n=23 levothyroxine, n=1 hemodialysis, n=1 heart failure tx, n=1 insulin). Among all pts, 265 (85%) had an interim PET-CT after 2-4 cycles. The ORR and CRR at interim PET-CT were 97% and 78%, respectively. In the efficacy evaluable population (n=228), the EOT ORR and CRR were 96% and 90%. The median follow up was 10.2 mo (range 0.27-28.52). The 1-year PFS and OS estimates were 93.8% (95% CI: 90.8-98.4%) and 99.1% (95% CI: 97.9-100%), respectively. In multivariable analysis (MVA), only IPS score (OR 0.6, 95%CI: 0.59-0.60) was associated with lower CRR. In Cox univariable analysis, EBV+ status (HR=14.8, 95% CI: 3.2-69.2), IPS score (HR=1.5, 95% CI: 1.0-2.2), and ESR (HR=1.02, 95% CI: 1.00-1.04) were associated with worse PFS. Among the 11 pts with progression/relapse, 9 were primary refractory. 10 pts were started on second line (2L) therapy, and all pts are alive (1 pt pending 2L tx initiation). There were 2 deaths: one related to infectious complications and other unknown and both occurred after the first cycle of therapy. Conclusions: Pts treated with NAVD in a large RWS showed comparable response rates and 1-year survival outcomes to those in the pivotal S1826 trial. Most AEs were similar and grade 1-2, but close monitoring of irAEs is necessary given the potential long-term toxicity of checkpoint inhibitors and potential for ≥G3 irAEs (7.5%) in this young patient population. Our data supports the use of NAVD for 1L advanced stage cHL.

Abstract Background: Although progression-free survival (PFS) in early-stage (ES) classic Hodgkin Lymphoma (cHL) is high, there remains a subset of patients (pts) at higher risk of worse outcomes, particularly in those with unfavorable risk disease. Leveraging pt-level data from within the HoLISTIC (Hodgkin Lymphoma International STudy for Individual Care) Consortium, the E-HIPI was developed in clinical trial pts and validated in real-world registry pts to predict 2-year (y) PFS (Rodday. NEJM Evidence 2025). Continuous, objective, and readily measurable pre-treatment variables were considered, with sex, maximum tumor diameter, albumin, and hemoglobin included as significant predictors. Using the E-HIPI, interactive calculators for pt risk, comparison, and stratification were created (https://rtools.mayo.edu/holistic_ehipi/). Although the E-HIPI was developed and validated in both unfavorable and favorable ES cHL pts, the clinical predictors are primarily markers of unfavorable disease. In the development and initial validation cohorts, 2y PFS was 93.7% and 90.3%, respectively, the C-statistic was 0.63 in both cohorts, calibration was strong with slight underprediction of events in the validation cohort, and the E-HIPI outperformed the historic binary classification of patients as favorable or unfavorable using EORTC criteria. However, since pts in the original E-HIPI development and validation were primarily treated with ABVD chemotherapy protocols, additional validation is needed, particularly among pts with unfavorable ES cHL who were treated initially with more intensive chemotherapeutic platforms (e.g., BEACOPP-based). Thus, we conducted an external validation of the E-HIPI in pts treated on recent unfavorable ES cHL GHSG trials. Methods: The validation cohort included 2367 adults (ages 18 to 60y) with newly-diagnosed unfavorable cHL from randomized phase 3 trials conducted by the GHSG (HD14 von Tresckow. JCO 2012; and HD17 Borchmann. Lancet 2021). We calculated the predicted probability of 2y PFS events based on the E-HIPI model equation (scale 1-100%). Model performance was assessed using discrimination and calibration. Discrimination, which is the model's ability to separate high and low risk pts, was assessed using Harrell's C-statistic. Calibration, which is the model's ability to accurately predict absolute risk, was assessed by comparing observed and predicted probabilities of 2y PFS events within quintiles of predicted probabilities and estimating calibration-in-the-large (predicted minus observed event rate) and the calibration slope. Results: For pts treated on unfavorable GHSG trials, mean age was 33y, 95% had stage II disease, mean baseline E-HIPI score (i.e., predicted 2y PFS event rate) was 6.0% (SD=2.3%), and the observed 2y PFS rate was 96.2% (95%CI: 95.4-97.0%). The C-statistic was 0.65 (95% CI: 0.59-0.70), calibration-in-the-large was 0.02, and the calibration slope was 1.08 (95% CI: 0.52, 1.64). Within the lowest risk E-HIPI quintile, the observed 2y PFS event rate was 1.6%, compared with 6.1% in the highest risk quintile. Conclusions: In external validation of the recently published E-HIPI in pts with cHL treated on unfavorable GHSG trials using more intensive BEACOPP-based protocols, discrimination was similar to the original development and validation cohorts. Collectively, the E-HIPI is a treatment-agnostic prediction tool across varied treatment regimens for unfavorable ES cHL pts. Better 2y PFS in the GHSG trials than in the E-HIPI development and initial validation cohorts may have contributed to mild misclassification, likely reflecting differences in treatment regimens. This may be resolved with recalibration or incorporating granular treatment variables into future models. Additional research is needed to understand E-HIPI performance in pts with favorable disease who have even lower event rates as well as to more fully predict individualized pt outcomes across varied chemotherapy platforms and radiation received for all ES cHL pts.

Abstract Background: Philadelphia chromosome–negative (Ph–) ALL is a genetically heterogeneous entity defined by recurrent cytogenetic and molecular aberrations that shape its clinical trajectory and prognosis. Historically poor outcomes in adults prompted significant changes in therapeutic approaches over the past decade, resulting in improved survival. Currently, blinatumomab is a bispecific T-cell engager targeting CD19 in leukemic cells and CD3 on T Lymphocytes. It has shown significant results in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL). However, its role in the frontline treatment of Philadelphia chromosome–negative (Ph–) B-ALL, particularly in combination with chemotherapy, is continuously being explored. Objective: Our purpose is to evaluate the efficacy of blinatumomab-based frontline regimens in adolescents and adults with newly diagnosed Ph– B-ALL through a systematic review and meta-analysis of proportions. Methods: We systematically searched PubMed, Embase, and Cochrane from inception through May 2025. Eligible studies included adolescents or adults with a cut off age of 15 years old, with newly diagnosed Ph– B-ALL where blinatumomab was used in the induction phase, consolidation phase, or both. Primary outcomes were complete remission (CR), measurable residual disease (MRD) negativity, and 3-year overall survival (OS). Random-effects proportional meta-analyses were conducted using logit or Freeman–Tukey transformations. Risk of bias was assessed using RoB 2 for Randomized Controlled Trials and ROBINS-I for prospective trials. Subgroup analysis was performed, dividing subgroups by phase of Blinatumomab utilization; either induction, consolidation or both. To tackle heterogeneity in the MRD pooled results, we conducted a Meta-regression to evaluate the link between different treatment phases and sample sizes. Results: Thirteen studies (n = 878 patients) met the inclusion criteria. The pooled CR rate after induction-phase blinatumomab was 78% (95% CI: 71–85%; I² = 21.2%). The pooled MRD negativity rate was highest in the induction-only group, at 90% (95% CI: 83%–95%), with no significant heterogeneity (I² = 0%). The consolidation group showed a pooled MRD negativity rate of 88% (95% CI: 75%–96%), though heterogeneity was substantial (I² = 74.2%, p = 0.0087). For patients treated during both induction and consolidation, the pooled MRD negativity rate was 89% (95% CI: 82%–94%), also with no observed heterogeneity (I² = 0%). The overall pooled MRD negativity rate across all ten studies was 89% (95% CI: 84%–93%), using a random-effects model with Freeman–Tukey double arcsine transformation. A meta-analysis of four studies reporting 3-year overall survival (OS) following frontline blinatumomab-based therapy was performed, stratified by treatment phase. In the consolidation subgroup, the pooled 3-year OS was 83% (95% CI: 76%–88%), with no heterogeneity (I² = 0%, p = 0.4032). In contrast, for patients treated during both induction and consolidation, the pooled 3-year OS was 52% (95% CI: 22%–81%), with substantial heterogeneity (I² = 88.6%, p < 0.0001). Conclusions: Blinatumomab-based regimens in the frontline setting are associated with high MRD clearance and complete remission rates, particularly when used during induction or consolidation. However, the predominance of non-randomized studies, small sample sizes, and heterogeneity in MRD assessment limit definitive conclusions. Prospective randomized trials are needed to clarify the optimal integration of blinatumomab in frontline Ph– B-ALL therapy.

Abstract Introduction Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) for which the only approved therapies are JAK inhibitors which improve splenomegaly and disease-related symptoms. Inflammatory pathways beyond JAK-STAT are critical in the pathobiology of MF and contribute to patients' clinical manifestations. IL-1β is a master regulator of inflammation which is overexpressed in MPNs, preferentially supports the MPN mutant stem cell, and interacts with key cytokines that are implicated in fibrogenesis, inflammatory symptoms, and disease progression. Knockout of IL-1β in MPN mouse models led to an abrogated clinical phenotype, while pharmacologic inhibition of IL-1β resulted in reduction of reticulin fibrosis and osteosclerosis. Canakinumab is a fully human monoclonal antibody that binds to and neutralizes IL-1β. It is approved for rare inflammatory disorders with a safety profile that has been extensively studied in the CANTOS trial that assessed cardiovascular outcomes in high-risk patients (pts). Based upon these data, we designed a phase 2 study of canakinumab in pts with MF. Methods NCT05467800 is a Myeloproliferative Neoplasm Research Consortium (MPN-RC) ongoing open-label, 2-part, phase 2 study of canakinumab in pts with MF. Part 1 enrolled pts with MF previously treated with or ineligible to receive a JAK inhibitor. Canakinumab was given subcutaneously at a dose of 200mg on day 1 of 21-day cycles. Primary response assessment occurred at week 24 following cycle 8. Responding pts could continue to receive canakinumab. Eligible pts had platelets >25 x109/L and a need for MF-directed therapy defined as ≥ 1 of the following: hemoglobin <10 g/dL, transfusion dependency, splenomegaly palpated ≥ 5cm below left costal margin, and/or MPN-SAF version 4.0 TSS ≥ 10. The primary endpoint was overall response rate (ORR) including CR, PR, or CI after 8 cycles (24 weeks). A Bayesian optimal phase 2 (BOP2) design was used with an interim analysis performed after 10 pts. Results In part 1, 14 pts were enrolled and 13 were treated. One pt discontinued prior to starting treatment due to rapidly progressive disease. Enrollment onto part 1 has closed with 2 pts remaining on treatment. Median age was 70 y (range: 55-83). Eleven (84.6%) pts had received prior ruxolitinib. Median hemoglobin was 8.2 g/dL (range: 5.7-13.2), median platelet count was 114 x 109/L (range: 21-484), and median WBC was 9.7 x 109/L (range: 2.4-71.4). Five (38.5%) pts were transfusion dependent. Median MF-SAF TSS at baseline was 15 (range: 4-46). Median spleen volume at baseline was 1522 cm3 (range: 362cm3-2997cm3). Pts received a median of 9 cycles (range: 2-19). Three (23%) pts responded at week 24, achieving a CI-symptom response (TSS50). Six (46%) pts experienced progression of disease due to spleen volume increase. Median hemoglobin was 8.2 g/dL at baseline, 7.9 g/dL at week 12, and 9.0 g/dL at week 24. Median platelet count was 114 x 109/L at baseline, 98 x 109/L at week 12, and 183 x 109/L at week 24. Median MF-SAF TSS declined from 15 at baseline to 10 at week 12 and 9 at week 24. Eleven (85%) pts exhibited symptom improvement during treatment (MF-SAF TSS percent change from baseline range -20% to -85%). In pts with baseline hsCRP ≥ 1.0 (n = 8), canakinumab led to a reduction at week 24 (or EOT if prior to week 24) in 5/8 (62.5%) with a median decrease in CRP of 37%. The most common adverse events (AEs) were anemia and thrombocytopenia and often attributed to underlying disease. Non-hematologic grade ≥ 3 AEs occurred in 3 pts and were deemed unrelated to canakinumab, except for one grade 3 increase in bilirubin that was possibly related per the treating physician. Conclusion The IL-1β inhibitor, canakinumab, resulted in consistent symptom improvement and exhibited beneficial impact on cytopenias in pts with R/R MF while demonstrating a manageable toxicity profile. Consistent with pre-clinical data, inhibition of IL-1β had little impact on splenomegaly, an observation that was likely enhanced by frequent JAK inhibitor discontinuation prior to study start. Given the encouraging impact on MF symptoms, blood counts and reassuring safety profile, the study was amended to enroll pts on a stable dose of a JAK inhibitor (ruxolitinib, fedratinib, momelotinib, or pacritinib) who have the potential to benefit from additional therapy. Part 2 is currently enrolling at multiple sites and updated clinical and correlative data will be presented at the meeting.

Abstract Introduction: CD19-directed CAR T-cell (CAR-T) therapy has substantially improved clinical outcomes for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, notable toxicities are associated with CAR-T, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Variable practice patterns have emerged regarding the use of CRS/ICANS prophylaxis (ppx) via corticosteroids and/or other pharmacologic agents, but the utility of these approaches on reducing CRS or ICANS following CAR-T in B-ALL remains unknown. Thus, we utilized the Real-World Outcomes Collaborative for CAR T in ALL (ROCCA) database to evaluate associations between ppx and the development and severity of CRS or ICANS following brexucabtagene autoleucel (brexu-cel) for B-ALL. Methods: Adult patients (pts) who received standard-of-care brexu-cel for relapsed/refractory B-ALL across 40+ US centers were included. Primary endpoints were the incidence of CRS and ICANS within 28 days of CAR-T infusion. Secondary endpoints included timing of CRS and ICANS onset, progression-free survival (PFS) and overall survival (OS). Univariable and multivariable logistic regression evaluated associations between ppx and incidence of CRS/ICANS; KM and log-rank methods were used for survival analyses. Results: A total of 378 pts were included: 53 pts (14.0%) received CRS/ICANS ppx and 325 (86.0%) received no ppx. Ppx agents included steroids only (26.4%), steroid and anakinra (52.8%), anakinra only (15.1%), and steroid and tocilizumab (5.7%). Pts in the ppx group had a higher proportion of Hispanic pts (64% vs 34%), Ph-like (36% vs 19%) and a lower proportion had 0-5% bone marrow blasts at apheresis (38% vs 53%). The ppx and no ppx groups were similar in age, prior therapies, CAR-T indication, and marrow blasts >50%. Cumulative incidence of any grade (gr) CRS was 94% with ppx and 86% with no ppx (p=0.025), of any gr ICANS was 53% with ppx and 51% with no ppx (0= 0.85). Cumulative incidence of gr 3-4 CRS was 9% in the ppx group and 10% in the no ppx group (p=1.00), of gr 3-4 ICANS was 26% in the ppx group and 29% in the no ppx group (p=0.71). Median time to onset for any gr CRS or any gr ICANS was identical in the ppx and no ppx cohorts (CRS: 5 days, range ppx 1-9 days, no ppx 0-14 days; ICANS: 7 days, ppx 1-20 days, no ppx 0-16 days). Univariate logistic regression analyses showed no significant association between ppx and the incidence of gr 2-4 CRS (OR 1.34, 95% CI: 0.75-2.40, p=0.326) or gr 3-4 ICANS (OR 0.88, 95% CI: 0.46-1.70, p=0.708). Multivariate analysis adjusting for ethnicity, leukemia genetic sub-type, and pre-apheresis disease burden similarly found no significant associations between ppx and gr 2-4 CRS (adjusted OR 1.06, 95% CI: 0.55-2.01, p=0.870) or gr 3-4 ICANS (OR 1.23, 95% CI: 0.59-2.55, p=0.584). When comparing steroid-only ppx (N=14) to steroid combinations or other drug ppx (N=39), there was no significant differences in gr 2-4 CRS (57% vs 44%, p=0.345) or gr 3-4 ICANS (43% vs 21%, p=0.115). Comparing cumulative incidence of dexamethasone (dex) exposure, pts in the ppx group had numerically greater dex exposure than pts in the no ppx group, with median (range) dosing of 182 mg (10-1386mg) and 100mg (1-4000mg), respectively. Finally, we found no significant differences in PFS or OS based on ppx. Median PFS was 9.6 months in the ppx group vs 13.3 months in the no ppx group (p=0.646) and median OS was 17.2 months in the ppx group vs 34.4 months in the no ppx group (p=0.170). Conclusions: In this large cohort of adult patients with R/R ALL receiving brexu-cel CAR-T therapy, prophylaxis intended to prevent CRS/ICANS was ineffective at reducing CRS/ICANS incidence, time to onset, or overall steroid exposure. Furthermore, PFS and OS were comparable between patients who received prophylaxis and those who did not. In the absence of prospective trials in B-ALL, these data suggest that current strategies of CRS/ICANS prophylaxis has limited benefit.