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Abstract Background Mosaic chromosomal alterations (mCAs) are large-scale somatic gains, losses, or copy-neutral loss of heterozygosity (CNLOH) detectable by genotyping of peripheral blood DNA. They represent a form of clonal hematopoiesis and are observed in 0.5-5% of cancer-free individuals. The presence of any autosomal mCA has been associated with >3-fold risk of hematological malignancies. In particular, mCAs occurring in regions related to lymphoid malignancies have an 11-fold increased risk of lymphoid malignancies and a 68.6-fold risk for chronic lymphocytic leukemia (CLL). Monoclonal B-cell lymphocytosis (MBL), the precursor state to CLL, is defined by <5×10⁹/L clonal B cells in otherwise healthy individuals and is classified as low-count (<0.5x109/L) or high-count (0.5-5x10⁹/L) based on clonal B-cell count. MBL is also associated with increased risk of lymphoid malignancy (beyond CLL), with 4.3-fold and 74-fold risk in individuals with low- and high-count MBL, respectively. We previously reported a significant enrichment of autosomal mCAs in MBL, demonstrating a 1.7-fold association in those with low-count MBL and a 50.5-fold association in those with high-count MBL. Whether mCAs independently predict lymphoid malignancy risk after accounting for MBL status is unknown. Here, we evaluated the impact of mCAs on risk of incident lymphoid malignancies in individuals with MBL and in individuals screened negative for MBL. Methods CLL-type MBL (CD5 positive) was identified using flow cytometry assay on peripheral blood. Participants were age ≥40, had no prior hematologic malignancy, and were enrolled through the Mayo Clinic Biobank or the Division of Hematology at Mayo Clinic, Rochester. Participants were followed for incident lymphoid malignancy, including CLL, with diagnoses confirmed by medical record review. mCAs with cell fraction >1% were detected from array-based genotyping of whole blood DNA. Cox proportional hazards models, adjusted for age and sex, estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of developing an incident lymphoid malignancy in individuals with autosomal mCA versus those without an autosomal mCA. Results In 4,331 participants with available MBL and mCA status, the median age was 67 years, and 45% were male. Flow cytometry identified 3,231 individuals who screened negative for MBL, 754 individuals with low-count MBL, and 346 individuals with high-count MBL. Autosomal mCAs were present in 6.5% of individuals without MBL, 7.6% with low-count MBL, and 71.1% with high-count MBL. Over a median follow-up of 6.9 years, 237 individuals developed an incident lymphoid malignancy. The most common types were CLL, multiple myeloma, and diffuse large B-cell lymphoma. Ignoring MBL status, the presence of an autosomal mCA was associated with increased risk of lymphoid malignancy (HR = 2.65; 95% CI: 1.45–4.86; P = 0.002), replicating previous results. However, after excluding individuals with MBL, this association attenuated; those with mCA alone did not have a significantly elevated risk (HR = 1.60; 95% CI: 0.57-4.52; P = 0.38) compared to individuals without MBL or mCA. We next examined the effect of mCAs among individuals with MBL. In those with low-count MBL, the most frequent mCA events were 13q loss (2.1%), 12 gain (1.9%), and 4q CNLOH (1.2%), and individuals with an mCA had a borderline significant risk of developing a lymphoid malignancy (HR = 2.78; 95% CI: 1.01–7.67; P = 0.049) compared to those without an mCA. Similarly, in those with high-count MBL, the most frequent mCA events were 13q loss/CNLOH (31.2%), 12 gain (13.0%), and 11q loss (4.9%), and the presence of an mCA conferred an increased risk compared to those without mCA (HR = 1.51; 95% CI: 1.09-2.08; P = 0.012). Conclusions Autosomal mCAs were more frequent in individuals with high-count MBL compared to those with low-count or no MBL. mCAs showed limited predictive value for lymphoid malignancy among individuals without MBL. In contrast, in individuals with low-count MBL, autosomal mCAs emerged as a potential biomarker for identifying those at risk of developing a lymphoid malignancy. In high-count MBL, mCAs were also a biomarker, but were driven by known chromosomal abnormalities identified through clinical testing. These findings suggest that the utility of mCAs as a predictive marker for lymphoid malignancy is contingent on the presence of MBL and may inform risk stratification and surveillance strategies in this population.

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.

Abstract Background: Multiple myeloma (MM) remains incurable, though key advances such as chimeric antigen receptor T-cells (CAR-T) and immunomodulatory agents, now evolving toward cereblon E3 ligase modulatory drugs (CELMoDs), have substantially improved the longevity and quality of life for patients (pts). Idecabtagene vicleucel (ide-cel) is a CAR-T targeting B-cell maturation antigen (BCMA), now US FDA-approved for pts who have received ≥2 prior lines of therapy including a proteasome inhibitor, immunomodulatory agent, and CD38 monoclonal antibody. Ide-cel was initially FDA-approved for ≥4 prior lines of therapy based on the KarMMa-1 study, which demonstrated a median progression-free survival (PFS) of 8.8 months across all cell doses and median overall survival (OS) of 19.4 months (Munshi et al., New Eng J Med 2021). Although promising, the fact that virtually all pts relapse post-ide-cel indicates that further progress is needed. To that end, iberdomide is an investigational CELMoD that in combination with dexamethasone has demonstrated a 30% response rate in early phase studies of triple class-refractory MM (Lonial et al., Lancet Haem 2022). Additionally, in laboratory-based correlative studies, iberdomide, at doses of ≤1 mg (well below the recommended phase 2 dose of 1.6 mg) was shown to augment immune function, including enhanced T-cell activation and cytotoxicity, and modulation of the cytokine milieu (Amatangelo et al., Cell Rep Med 2024). Iberdomide's combined properties of direct MM cytotoxicity and T-cell potentiation have clear, potential relevance to CAR-T clinically, providing the conceptual basis for the CADMIUM study (NCT06179888), exploring the effects of iberdomide as post-ide-cel maintenance therapy in MM. Study Design and Methods: This is a randomized phase II trial with a safety run-in to evaluate if treatment with iberdomide maintenance post-ide-cel can significantly improve PFS vs. standard of care (SOC) observation without therapy, in pts with relapsed/refractory MM with ≥4 prior lines of therapy, who have received ide-cel within 3 months of registration, and no evidence of MM progression or additional MM therapy since ide-cel. Pre-ide-cel iberdomide exposure is permissible but refractoriness is not. The safety run-in will confirm tolerability of the iberdomide dose to be carried forward, where doses to be tested include: iberdomide 1 mg orally on days 1-21 of a 28-day cycle (dose level 1; DL1) and iberdomide 0.7 mg on days 1-21 of a 28-day cycle (DL2). Dose-limiting toxicities (DLTs) include any of the following during the DLT period of a pt's first three months on iberdomide: prolonged Grade 3 non-hematologic toxicities, Grade 4 non-hematologic toxicities, prolonged Grade 4 neutropenia or thrombocytopenia, or any adverse event requiring iberdomide interruption for >4 weeks. Six pts will be enrolled onto DL1; if at most 1 of these pts has a DLT, DL1 will be carried forward to the randomized part of the study. Otherwise, 6 pts will be enrolled onto DL2. The randomized part of the trial will randomize 60 pts 1:1 to either iberdomide or SOC observation without therapy. A 1-sided log-rank test with α=0.15 has 81% power to detect a true hazard ratio (iberdomide/SOC) of 0.55 or less, corresponding to an improvement in median PFS to 16 vs. 8.8 months with SOC. One interim analysis for futility is planned. Secondary outcomes include OS, best response by International Myeloma Working Group (IMWG) criteria, and deepening of response, particularly conversion to complete response with a bone marrow minimal disease-negative state by Adaptive clonoSEQ (sensitivity 1e-6). Robust correlative studies will include CAR-T persistence, assays of T- and other immune cell function, and pathological analyses of whether BCMA expression on MM cells (prior to enrollment or at relapse) or other markers predict clinical outcomes. Study status: To date, 12 pts have been screened, with 7 pts enrolled on study as part of the safety run-in (1 patient replaced). Enrollment data will be updated at presentation. Notably, an amendment is forthcoming which will enhance correlative studies and broaden eligibility criteria to include patients who have received ≥2 prior lines of therapy, conforming with ide-cel's current FDA label. Study COI: BMS is supporting correlative studies. Study Support: U10CA180821, U10CA180882; BMS; U10CA180868 (NRG Oncology); http://acknowledgements.alliancefound.org

Abstract Background: Polycythemia vera (PV) is characterized by excessive erythrocytosis and elevated hematocrit (Hct), which is associated with increased risk of thrombotic events. Controlling Hct levels (<45%) is a key therapeutic goal to reduce thrombotic events. Sapablursen (ISIS 702843) is a liver-directed, ligand-conjugated antisense oligonucleotide that suppresses transmembrane serine protease 6 (TMPRSS6) to enhance hepcidin production thereby restricting iron availability and reduced erythrocytosis. We are reporting the topline results of the IMPRSSION study (NCT05143957), an ongoing global, open-label phase 2 trial evaluating the safety and efficacy of sapablursen for Hct control and reducing phlebotomy rate in patients with PV. Methods: Eligible patients met 2016 WHO diagnostic criteria for PV, were required to have >3 phlebotomies within six months prior to screening, including >1 phlebotomy in the last 12 weeks. There were no exclusions for HCT prior to randomization. Patients received monthly subcutaneous doses of sapablursen in Cohort A (high dose) or Cohort B (low dose), during a 37-week treatment period. The primary efficacy endpoint was the reduction in the frequency of phlebotomy during the last 20 weeks of the treatment period (Week 17-37) compared to baseline (defined as the mean weekly phlebotomy rate during the six months prior to screening through the first dose of sapablursen). Phlebotomy was performed when Hct levels were ≥45% or at the investigator's discretion, confirmation of Hct was not required for phlebotomy. Serial assessments of serum hepcidin, TSAT and ferritin were conducted. The 10-item Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS) assessed the change in symptoms from baseline to Week 37. Results: Forty-nine (49) patients received at least one dose of sapablursen (full analysis set) in either Cohort A (n=32) or Cohort B (n=17). The median age was 61 years, 40 (82%) were male, and 29 (59%) classified as high risk. The primary endpoint was met at both dose levels. The weekly phlebotomy rate (mean±SD) decreased from baseline of 0.15±0.07 (~7.8/yr) to 0.05±0.09 (~2.6/yr) during the primary endpoint window (Week 17-37) in Cohort A (n=32, p<0.0001; 95%CI, -0.13, -0.07), and from 0.17±0.07 (~8.9/yr) to 0.07±0.07 (~3.6/yr) in Cohort B (n=17, p=0.0001; 95%CI, -0.14, -0.06). The mean MPN-SAF-TSS was reduced at Week 37 by 32% in Cohort A (change from baseline LSM -6.2, p=0.005) and 11% in Cohort B (change from baseline LSM -2.7, p=0.344). The proportion of patients with Hct control (<45%) without phlebotomy from week 17 to 37 in Cohort A and B was 53% (17/32) and 35% (6/17), respectively. Serum hepcidin was increased from baseline values of 0.25±0.6 to 5.05±4.7 nM at Week 13 in Cohort A (p<0.0001) and from 0.68±1.7 to 2.06±3.6 nM in Cohort B (p=0.0142). A sustained low TSAT was observed between Weeks 17-37 (6.0±2.1% and 5.5±2.0% in Cohort A and 8.9±5.0% and 7.0±3.4% in Cohort B). Serum ferritin increased over time from 18±22 ng/mL and 28±58 ng/mL at baseline in Cohort A and B, respectively, to 44±47 ng/mL and 41±85 ng/mL at Week 37, respectively. Sapablursen was generally safe and well-tolerated. The incidence of injection site reactions was 12.2% (6/49). Injection site reactions did not recur following multiple injections, were not progressive and resolved spontaneously. There was one death on study due to transformation to AML which was deemed as not related to the study drug. Conclusions: Treatment of PV patients with sapablursen increased serum hepcidin, controlled Hct, reduced phlebotomy need and improved quality of life in a dose-dependent manner. These findings highlight the potential of sapablursen as a therapeutic approach in PV and support further development.

Abstract SWOG 1318 evaluated the feasibility of combining the tyrosine kinase inhibitor (TKI) dasatinib with prednisone and blinatumomab in older patients (pts) with Philadelphia chromosome positive (Ph+) B-acute lymphoblastic leukemia (ALL). Here, we present longer follow up (median follow up 5.6 years) with outcomes, predictors of response, and translational medicine studies. Methods: This trial was activated through the NCTN in January 2014 and closed to accrual in April 2021. Pt eligibility included: age > 65 years, Ph+ ALL, no evidence of central nervous system (CNS) disease, and adequate organ function. Treatment has been previously described (Blood Adv 2023; 7(7): 1279-85). Statistics: Categorical and quantitative endpoints comparisons used Fisher's exact and Wilcoxon tests. Survival endpoints used the Kaplan-Meier method and Cox regression models and were landmarked for post-baseline events as needed (i.e., number of cycles). Translational medicine studies: Single cell ATAC seq (10x genomics) was performed on 9 archived cryopreserved diagnostic samples from patients with > 500,000 cells. All samples successfully completed library preparation, sequencing, and demonstrated adequate blast clusters for analysis. Briefly, cryopreserved cells were thawed, and transposases were introduced into nuclei in single cell suspension and used to generate GEM beads. ATAC seq libraries were prepared per manufacture instructions. Libraries were then sequenced on a 25B flow cell on Novaseq X plus (Illumina). The data were analyzed with cloupe (version 9.0.0). Results: Twenty-four eligible patients were enrolled. The median age was 73 years (range 65-87). All pts had newly diagnosed Ph+ ALL. Seventy-nine percent of pts had additional cytogenetic abnormalities. Twenty-two pts (92%) achieved a complete remission (CR) during dasatinib and prednisone induction therapy. Most sites also monitored patient's blood or bone marrow with real-time quantitative PCR to quantify the BCR-ABL1 transcript for molecular response. Of 19 patients analyzed 17 (89%) were in a major or complete molecular remission at some point after treatment, with at least 12 of these patients achieving complete molecular remission. Three patients remain on maintenance. The median follow up for patients who are alive is 5.6 years (range 4.4-8.3). Five- year OS and DFS estimates are 63% (95% CI: 40-78%) and 64% (95% CI: 40-80%). Two patients relapsed in the CNS. One pt proceeded to allogeneic hematopoietic stem cell transplant (HSCT) and 1 to autologous HSCT. Increased age was associated with a decreased chance of achieving CR as best response (median age in responder group 73.2 years [range 65-82.9]; median age in non-responder group 85.5 [range 83.8-87.3]; p=0.02). Patients with extramedullary disease had shorter DFS (HR 0.22, 95% CI 0.04-1.15, p=0.07). Increased number of cycles of blinatumomab received was associated with a trend towards improved OS (HR 0.66, 95% CI 0.41-1.08, p=0.10). Translational medicine studies for chromatin accessibility in the blast clusters demonstrated improved OS in patients with homogeneous blast clusters (HR 0.42, 95% CI 0.06-3.04, p=0.39), high DUX4 differential accessibility (HR 0.26, 95% CI 0.03-2.55, p=0.25), and ATAC seq data corresponding to decreased chromatin accessibility in HOXA2 (HR 0.09, 95% CI 0.01-1.05. p=0.06). Conclusions: Despite an elderly population, this trial demonstrated impressive outcomes with longer follow-up for patients with Ph+ ALL. The number of cycles of blinatumomab and the presence of extramedullary disease may be important factors in outcome. Translational studies suggest additional markers may be predictors of overall survival, and these will need to be studied on larger scale studies. Decreased chromatin accessibility to HOXA2 was associated with a trend towards improved OS. Additional translational medicine will also be presented at the meeting.

Abstract Introduction: Brexu-cel is a highly effective treatment for R/R B-ALL, with complete responses achieved in 71% of patients (pts) treated in the pivotal ZUMA-3 trial. Patients with B-ALL with high-risk (HR) genetics are known to have inferior outcomes with chemotherapy, but little is known about the influence of HR ALL genetics on responses to chimeric antigen receptor (CAR)-T in adults. In this study, we assessed the impact of HR ALL genetics on outcomes in a large cohort of adult patients treated with brexu-cel for R/R Philadelphia chromosome (Ph)-negative B-ALL. Methods: Patient characteristics and outcomes were obtained from the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) database which includes data from 40 U.S. centers. NCCN guidelines (NCCN Guidelines in Oncology, ALL v2.2025) were used to define HR B-ALL genetics; lack of HR genetics was defined as standard-risk (SR). The primary outcome was event-free survival (EFS), defined as lack of response, disease progression, or death from any cause. Secondary outcomes were overall survival (OS), relapse free survival (RFS) and response rates including complete response (CR), CR incomplete count recovery (CRi), measurable residual disease negative CR (MRD-) by flow or NGS and progressive disease (PD). Multivariable models were adjusted for age, pre-infusion blast percentage, prior allo-HCT, and post CAR-T allo-HCT (modeled as a time-varying covariate). Results: The cohort included 286 pts: 169 with HR and 117 with SR B-ALL. The HR cohort included TP53m (n=24, 14%), KMT2Ar (n=16, 9%), CRLF2r (n=65, 39%) and other HR genetics such as JAK2 and other Ph-like, IKZF1, complex cytogenetics (n=64, 38%). Relative to SR pts, HR pts were more commonly Hispanic (50% vs 28%). HR and SR pts had similar disease burden pre-apheresis (>5% blasts: 58% vs 53%), prior blinatumomab (60% vs 58%), prior inotuzumab (42% vs 46%), and prior allo HCT (27% vs 37%). The presence of CNS disease (11% HR vs 12% SR) and extramedullary disease (EMD, 22% HR vs 29% SR) at apheresis was also similar. CR/CRi was achieved in 90.5% of evaluable HR pts (n=147) and 90.2% of evaluable SR pts (n=102); MRD- rates were also similar between HR and SR pts at 78.9% and 78.2% respectively. In unadjusted analyses, EFS did not significantly differ between HR pts (median 9.6 mos; 1-yr: 46%, 95% CI 38%-54%) and SR pts (median 11.6 mos; 1-yr: 48%, 95% CI 38%- 58%). Median RFS (HR: 12.2 mos, SR: 13.3 mos) and median OS (HR: 22.4 mos, SR: 21.0 mos) were also similar. Multivariable models demonstrated no significant associations between HR B-ALL and EFS (HR 1.09, 95% CI 0.73-1.63), RFS (HR 1.13, 95% CI 0.71-1.80), or OS (HR 0.96, 95% CI 0.62- 1.48) relative to SR ALL. 28% of HR patients and 21% of SR patients underwent consolidative allo-HCT. Among the HR subgroup, CR/CRi rate was lowest in KMT2Ar (71%) relative to TP53m (95%), CRLF2r (95%), and other HR genetics (89%). The median EFS was lowest in KMT2Ar (4.1 mos), followed by TP53m (6.9 mos), CRLF2r (11.6 mos), and other HR (11.1 mos). Median OS was also lowest in KMT2Ar (6.8 mos) vs 22.4 mos in TP53m and not reached in CRLF2r or other HR. PD was highest in KMT2Ar pts (29%), as compared to 11% HR other, 10% SR, and 5% TP53 and CRLF2r. The rate of relapse among those that achieved CR across the groups was similar and ranged between 28% -40%. Rates of CD19 negative relapse were similar between all subgroups (13%-15%), however 21% of KMT2A pts underwent myeloid transformation as compared 0% for TP53 and CRLF2 pts, and 2% among other HR and SR pts. 25% of KMT2Ar patients underwent consolidative allo-HCT as compared to 32% CRLF2 pts, 29% TP53 pts, 25% other HR pts and 21% SR pts. Multivariable models evaluating the different genomic subgroups demonstrated that relative to SR B-ALL, only KMT2Ar was associated with inferior OS (HR 3.17, 95% CI 1.53-6.58, p=0020). No associations were seen between HR subgroups and EFS. Conclusion: To our knowledge, this analysis represents the largest examination of adult B-ALL recipients of CAR-T assessed by genomic risk group. We found that response rates and survival outcomes following brexu-cel were similar among HR and SR B-ALL pts, including pts with TP53m and CRLF2r. However, pts with KMT2Ar had lower response rates and dismal EFS and OS, with higher rates of PD and myeloid transformation at relapse, suggesting that alternative strategies are necessary to improve outcomes for patients with R/R KMT2Ar B-ALL.

Abstract Background: Four bispecific antibodies (bsAbs), teclistamab, elranatamab, talquetamab, and linvoseltamab have been approved for use in the U.S. in patients (pts) with relapsed/refractory (R/R) multiple myeloma (MM). The objective of this analysis was to describe healthcare resources utilization (HCRU) in Medicare pts initiating treatment (≥1 medical claim) with teclistamab for R/R MM, and to explore how HCRU differs for pts who initiate in the inpatient (IP) vs outpatient (OP) setting. We focused only on teclistamab due to insufficient follow-up for robust analyses of other bsAbs. Methods: The study used data from a 100% sample of fee-for-service Medicare enrollment and medical (Parts A and B) claims data during the “study period” spanning from 12 months prior to the approval of teclistamab to the end of availability of claims data (Oct 25, 2021–Sep 30, 2024). The study population included all pts in the database with ≥1 diagnosis of MM and ≥1 claim for teclistamab ≥30 days prior to the end of the study period. Patients were required to be continuously enrolled for Medicare medical benefits for the 12 months up to and including the 1st claim for teclistamab (the “index date”). Other main eligibility criteria included: 1) index date on/after availability of both IP and OP procedure codes for teclistamab; 2) no claims for MM treatment other than teclistamab or a corticosteroid within 0–30 days post index date; 3) if 1st administration of teclistamab was in the OP setting, dosage was consistent with first step up dose (SUD) and 4) ≥65 years of age as of index date. For each patient, the follow-up period was defined as the period from the index date to first occurrence of death, end of continuous enrollment, or end of study period. Setting of initiation of treatment was defined based on the setting of the first claim for teclistamab (IP or OP). For pts who initiated teclistamab in the IP setting, completion of SUD was defined as ≥1 OP administration with a full treatment dose of teclistamab (i.e., not an SUD) that occurred ≥10 days post index date. For those who initiated teclistamab in an OP setting, completion of SUD was defined as ≥2 OP administrations of teclistamab at a full treatment dose. The number of hospitalizations and physicians' office and hospital OP visits during teclistamab treatment were calculated on a per patient per month (PPPM) basis. Results: A total of 2,185 pts had ≥1 claim for teclistamab during the study period. Of these, 1,373 met all eligibility criteria. Mean (median) age at index date was 75 (74) years and 49% were female. Mean (median [range]) follow-up was 8.2 (7 [0.2–22.7]) months. Overall, 87% of pts initiated teclistamab in an IP setting, with a mean length of stay (LOS) for the index hospitalization of 9.3 days. Among those initiating teclistamab in an OP setting, 41% were hospitalized within 1 month of treatment initiation. Among all pts (IP or OP initiation of treatment), the Kaplan–Meier estimated median duration of teclistamab treatment was 6.1 months; 87% of pts completed SUD. Patients had a mean (median) of 0.72 (0.32) hospitalizations PPPM and 6.4 (5.8) hospital outpatient or physician's office visits PPPM during teclistamab treatment. Conclusions:Most pts with MM receiving teclistamab initiate treatment in an IP setting, with hospital LOS consistent with dosing guidance from the prescribing information. A substantial proportion of those who initiate teclistamab in an OP setting are hospitalized within 30 days. Treatment duration and percentage of pts completing SUD were consistent with values in other real-world studies of teclistamab. Patients receiving teclistamab have a high hospitalization burden during treatment initiation and frequent hospitalizations and OP visits over the course of treatment. These results highlight the need for novel treatments, administration models, and/or implementation of standardized supportive care guidelines to reduce the hospital burden and increase time on treatment for pts receiving bsAbs in real world settings.

Intravascular lipomas are rare benign tumors composed of adipose tissue that originate from the walls of blood vessels. They most commonly arise from veins, are typically asymptomatic, and rarely occur in the lower extremities. When large, these tumors can cause symptoms related to venous obstruction, such as swelling and pain. We report a case of a 75-year-old man with an intravascular lipoma in the right common femoral vein, identified during evaluation of lower extremity swelling and poorly healing ulcers. Surgical resection was ultimately required. This case contributes to the few published reports of pathologically proven symptomatic intravascular lipomas involving the lower extremity veins. Comprehensive preoperative imaging played a critical role in characterizing the lesion. The case facilitates a discussion of key differential diagnoses, such as atypical lipomatous tumors/well-differentiated liposarcoma and leiomyosarcoma.