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

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

Abstract Introduction: Suboptimal response to therapy, early disease relapse, and limited long-term survival remain critical challenges in a substantial number of patients with multiple myeloma (MM). While cross-sectional imaging studies are commonly obtained in clinical practice, only limited information is currently incorporated into risk stratification efforts and clinical decision making. Here, we investigate the use of novel image-based biomarkers to identify patients at high risk for adverse outcomes. Methods: We obtained the pretreatment 18F-FDG PET/CT scans of patients with newly diagnosed MM with available clinical and laboratory data seen at Mayo Clinic between 2006 and 2022. In this analysis, we included 637 patients with detectable metabolic tumor volume on their pretreatment scan. The native DICOM images were pre-processed and subjected to automated image segmentation using nnU-Net (nnU-Net v1.0, inference using a pre-trained hematologic malignancies model). Limitations of this automated segmentation approach include heterogeneity introduced by varying image quality, technical variability in PET reconstruction, and potential inclusion of non-neoplastic FDG-avid lesions in segmented regions. PyRadiomics was used to extract quantitative radiomics features for clinical prediction modeling. We evaluated the predictive power of tumor size-, shape-, and texture-related radiomics features for identifying high-risk disease (advanced ISS stage at diagnosis, the presence of high-risk FISH abnormalities, failure to achieve a stringent complete response [sCR] to first-line therapy by IWMG criteria, and early mortality). All radiomics features were quantile-normalized for downstream modeling. Forward and backward feature selection as well as testing for multicollinearity were used to remove redundant features. Results: Median age at diagnosis of the 637 myeloma patients was 64 years (range 22–90), and 387 patients (61%) were male. After a median follow-up of 4.4 years (95% CI 0.2–11.7), median overall survival (OS) was 7.3 years (95% CI 6.3–8.3). Increased total tumor volume (upper tertile vs lower tertiles), measured by the total tumor surface area, was associated with advanced ISS stage (III vs I+II; OR 1.73, 95% CI 1.24–2.42, p=0.001, n=637). Increased tumor density (dichotomized at the median), measured by the median gray level intensity (OR 1.93, 95% CI 1.94–3.12, p=0.007, n=303), and decreased tumor heterogeneity (lower tertile vs upper tertiles), measured by the variability of gray-level intensities (OR 1.88, 95% CI 1.49–3.12, p=0.012, n=303), were associated with the presence of high-risk cytogenetics. Both increased total tumor volume (4.9% increase per tertile, 95% CI 2.2–7.6, p<0.001, n=600) and tumor density (8.9% increase per tertile, 95% CI 4.5–13.3, p<0.001, n=600) were independently associated with more extensive bone marrow involvement at diagnosis. Increased tumor heterogeneity (upper tertiles vs lower tertile), as measured by rapid changes of gray level intensities, was associated with failure to achieve a stringent complete response to first-line therapy (OR 0.50, 95% CI 0.30–0.82, p=0.006, n=351). Increased tumor volume was associated with shorter OS (HR 1.35 per tertile, 95% CI 1.11–1.63, p=0.002, n=301), independent of age, sex, ISS stage, and the presence of high-risk cytogenetics. A simple additive score consisting of tertiles of total tumor volume, ISS stage, and plasma cell labeling index ≥2% identified patients at risk of mortality within 3 years of diagnosis (OR 2.00, 95% CI 1.40–2.85, p<0.001, n=126), with moderate discrimination (AUC=0.71). Sensitivity analysis demonstrated total tumor volume and texture as most predictive of overall survival in a random forest survival model (C-index 0.712, 95% CI 0.649–0.775) and tumor texture as most predictive of response to therapy in a random forest classification model (C-index 0.693, 95% CI 0.607–0.779). Conclusions: Automated image segmentation and radiomics feature extraction from 18F-FDG PET/CT scans produces biomarkers that capture disease stage, burden, and risk in newly diagnosed MM. Total tumor volume and heterogeneity are strongly associated with important disease characteristics and can be used to identify patients at high risk for therapeutic resistance, early mortality, and inferior long-term outcomes.

Abstract Despite a characteristic indolent course, a substantial subset of follicular lymphoma (FL) patients has an early relapse with a poor outcome. Thus far, efforts to identify factors that predict survival have been unsuccessful. However, we and others have demonstrated the prognostic relevance of CD4+ T cells in the tumor microenvironment (TME) of FL and developed a bio-clinical risk model (called BioFLIPI) that offers improved risk stratification (Mondello et al, BCJ 2021). However, the mechanisms defining different BioFLIPI scores remain to be fully understood. To identify the programs associated with the BioFLIPI scores, we first interrogated the RNA-seq of purified B cells from 67 newly diagnosed FL1-3A (BioFLIPI 1 n=21; BioFLIPI 2-3 n=36; BioFLIPI 4 n=10). We found 1,156 upregulated genes and downregulation of 930 genes in BioFLIPI 4 vs 1, including well-known immune molecules such as CD70, IL10RA, CD69, and CCR6 (FDR<0.05). Gene set enrichment analysis (GSEA) using the MSigDB confirmed a negative enrichment in multiple immune response and interferon gamma signatures and revealed striking positive enrichment for cell proliferation and antigen presentation pathways in BioFLIPI 4 compared to BioFLIPI 1 tumors. The same pathways were dysregulated in BioFLIPI 2-3 but a lower magnitude. To investigate the somatic mutations associated with different BioFLIPI scores, we performed WES of the same 67 FLs and further expanded this cohort for a total of 90 patients (BioFLIPI 1 n=26; BioFLIPI 2-3 n=51; BioFLIPI 4 n=13). We found enrichment for mutations in several regulators of the germinal center in BioFLIPI 4 and 2-3, such as MEF2B (p=0.029), FOXO1 (p=0.038) and IRF8 (p=0.035), suggesting the cooperation of multiple oncogenic events promoting lymphomagenesis. In contrast, BioFLIPI 1 tumors harbored a higher rate of mutations in TNFRSF14 gene, known to enhance anti-lymphoma immune response. To investigate whether BioFLIPI modulates immune signatures of the microenvironment, we performed TME deconvolution by applying CIBERSORTx to bulk RNA-seq of these 67 FLs. We found that FLs with BioFLIPI 4 and 2-3 were enriched for CD4+ Tcm exh (p=0.02), Tem exh (p=0.04), Tfhexh (p=0.07) and NK cells (p=0.01) compared to BioFLIPI 1. In line with this data, CyTOF performed on a subset of these patients (BioFLIPI 1 n=12; BioFLIPI 2-3 n=25; BioFLIPI 4 n=6) confirmed progressive increase of CD4+ Tcm exh (p=0.006), Tem exh (p=0.009) and Tfh exh (p=0.025) cells from BioFLIPI 1 to BioFLIPI 4. Single cell RNA/BCR-seq of 21 FLs (BioFLIPI 1 n=6; BioFLIPI 2-3 n=12; BioFLIPI 4 n=3) corroborated a higher abundance of Tem exh, cytotoxic (CTL) Tem exh, Tfhexh and NK cells in BioFLIPI 4 and 2-3. Conversely, CD8+ naïve T cells were prevalent in BioFLIPI 1 tumors. Differential gene expression in T cell clusters from BioFLIPI 4 vs BioFLIPI 1 FL revealed a marked upregulation of multiple immune genes involved in antigen presentation (e.g., HLA-DRB, HLA-DQA, HLA-DPA/B) and immune response (e.g., ETS1, TNFSF8, IL7R). GSEA showed a positive enrichment for antigen presentation signatures and negative enrichment for TNFα signaling and Oxphos metabolism. Similar findings were observed in BioFLIPI 2-3 FLs. Using CellChat analysis, we found a stronger interaction between malignant B cells and Tem exh and CTL Tem exh cells in BioFLIPI 4 and 2-3 vs BioFLIPI 1 tumors. This was linked to an increased strenght of MHCI-CD8 interaction and concordant decrease of MHCII-CD4. Notably, the suppressive BTLA-TNFRSF14 signaling axis was present in BioFLIPI 4 and 2-3 but not in BioFLIPI 1 FLs. This was accompanied by a decreased signaling through TNF/LTA-TNFRSF1B, CD80/CD86-CD28/CTLA4. Linking the BioFLIPI-specific immunogenicity to lymphomagenesis, we found that FL patients with BioFLIPI 4 had two-three folds higher risk of transformation to an aggressive lymphoma (12% vs 7%) or death (21% vs 3%) than those with BioFLIPI 1, suggesting that this immune dysfunction favors the expansion of a dominant tumor clone and promotes a more aggressive form of FL. Collectively, our findings demonstrate that BioFLIPI scores in FL reflect distinct patterns of tumor immunogenicity that shape the TME. Notably, high BioFLIPI scores are paradoxically associated with enhanced antigen presentation alongside a suppressed immune response. This suggests a sustained antigen-specific T cell response that may drive immune exhaustion, promote tumor progression, and ultimately lead to histologic transformation

Abstract Background: Follicular lymphoma (FL) is a germinal center–derived B cell malignancy characterized by the clonal expansion of a dominant malignant B cell population. While prior studies have identified transcriptional subtypes across patients, most analyses have treated B cells within individual tumors as a transcriptionally uniform population. However, this assumption has not been systematically tested using high-resolution, clonotype-resolved transcriptomic data. The broader landscape of intratumoral B cells—including those not belonging to the dominant clone—remains poorly defined, and their roles in disease biology are not well understood. These unexpanded, intratumoral B (ITB) cells may include residual non-malignant populations, early-stage malignant cells, or immune-modulating cells with distinct roles in the tumor microenvironment. It is also unknown whether their presence varies across patients or correlates with clinical features or immune microenvironmental interactions. Methods: We performed integrated single-cell 5′ RNA sequencing and B cell receptor (BCR) repertoire sequencing on 7 newly diagnosed FL 1-3A fresh-frozen lymph node biopsies (Dasari et al., Blood Cancer Discov 2025). Using a high-confidence approach that incorporates heavy and light chain pairing, V and J gene usage, and CDR3 nucleotide junction identity, we classified B cells into two groups: (1) cells belonging to the dominant expanded clone (FL B cells) and (2) all other B cells with detectable and non-expanded BCRs (ITB). These clonal identities were then integrated with single-cell transcriptomic profiles using Seurat and Immcantation pipelines. Differential expression analysis was conducted using edgeR to compare FL B cells to ITB cells across all FL biopsies. Results: After quality filtering, a total of 44,637 single cells were retained across all 7 samples (minimum per sample: 3,847 cells), including malignant and non-malignant B cells as well as diverse tumor microenvironment populations. The proportion of B cells assigned to the dominant FL clone varied substantially across tumors, ranging from 22% to 89%, indicating that some tumors contain a substantial population of ITB cells. In one tumor, we identified two expanded malignant B cell clones comprising 40.6% and 34.4% of all cells. These clones exhibited non-overlapping V and J gene usage (IGHV3-11/IGHJ5 vs. IGHV3-72/IGHJ3), distinct CDR3 junctions, and different immunoglobulin isotypes (IGHG1 vs. IGM). BCL2 was expressed in most cells within both clones (Clone 1: 87.8%, Clone 2: 67.0%), with mean log-normalized expression levels of 1.79 and 0.95, respectively. Both clones formed distinct UMAP clusters and showed transcriptional divergence from ITBs, with 453 differentially expressed genes (DEGs) identified for Clone 1 and 98 for Clone 2 (adjusted p<0.01, |log₂FC|>1, min.pct≥0.25). Additionally, 748 DEGs were identified between the two clones. This evidence of clonal divergence within a single FL tumor reinforces the need to reconsider intratumoral homogeneity in FL and suggests that multiple malignant clones may sometimes coexist. When comparing FL clones to ITB cells across tumors we found that FL clones exhibited a transcriptional program enriched for proliferation and cell cycle regulators, including MKI67 (p<0.005), E2F1 (p<0.0001), CDKN2A (p<0.0001), and CDKN2B (p<0.01), as well as elevated expression of AICDA (p<0.01), EZH2 (p<0.0001), and PD-L1 (p<0.05). As expected, the malignant cells also had higher expression of BCL2 (p<0.01) and CD10/MME (p<0.0001). In contrast, ITB cells demonstrated relatively higher expression of SELL (p<0.0001) and TNFRSF14 (p<0.05), which were significantly downregulated in the FL clone. Conclusions: Together, these findings challenge the prevailing notion that FL tumors are defined by a single homogeneous malignant B cell population. Instead, our data support a model in which multiple transcriptionally and functionally distinct B cell populations coexist within tumors, including dominant clones and a diverse population of ITB cells. This is, to our knowledge, the first study to comprehensively characterize these populations using integrated, lineage-aware single-cell multiomic profiling across FL patients. These insights may ultimately inform new strategies for understanding tumor evolution, immune evasion, and therapeutic targeting in follicular lymphoma.

Abstract Introduction: cBTKi have made a substantial impact in pts w/ MCL, but pts who develop PD while on treatment w/ cBTKi have historically had poor responses to subsequent lines of therapy (LOT). Brexucel, lisocel, and the non-covalent BTKi pirto have been approved in this population. While two RW studies have substantiated the benefit of brexucel, similar data for pirto are lacking. Accordingly, we aimed to evaluate the outcomes of pts treated w/ pirto in the RW setting. Methods: We performed a multi-center retrospective cohort study of adult pts w/ a diagnosis of MCL who experienced PD after any approved cBTKi and subsequently received pirto. Pts who received pirto w/ bridging intent and those who switched to pirto due to intolerance of cBTKi were excluded. The 95% exact binomial confidence intervals (CI) were calculated for overall response rate (ORR) and complete response rate (CRR). Progression-free survival (PFS) and overall survival (OS) were defined as the time from pirto start to PD or death, whichever occurred first, and the time from pirto start to death, respectively, and calculated w/ the Kaplan-Meier method. The log-rank test was used to compare survival curves. A multivariate (MV) Cox proportional hazard model was built to calculate adjusted hazard ratio (aHR). Analyses were performed w/ SAS, version 9.4. Results: Data on 111 pts w/ MCL treated across 21 institutions were collected. Median (mdn) age was 72 (range 33 – 93) years. Twenty-seven pts (24%) were female, 3 (3%) were Asian, 5 (5%) Black, 9 (8%) Hispanic, 86 (77%) White. Among the 53 (48%) pts w/ available MIPI-c at diagnosis, 28 (53%) pts were high-risk. Ki67 at diagnosis was available in 84 (76%) pts: of those, 58 (69%) had a Ki67 ≥30%, and 41 (49%) ≥50%. TP53 mutational status was available in 70 (63%) pts: 33 (47%) had documented TP53 mutation and 10/52 (19%) pts had a disease w/ complex karyotype. Pts had a mdn of 3 (range 1 – 9) prior LOT (n=106). Ninety-one pts (86%) received chemo-immunotherapy (CIT), 16 (15%) autologous stem cell transplant, 19 (18%) venetoclax (ven), 29 (27%) chimeric antigen receptor T-cell, 4 (4%) allogeneic stem cell transplant. For cBTKi, 39 (35%) pts received ibrutinib, 56 (50%) pts acalabrutinib, 33 (30%) pts zanubrutinib, and 17 (15%) pts received more than one cBTKi. The mdn time from the last dose of cBTKi to pirto start was 55 (range 0 – 2587) days, w/ 51 (46%) pts who switched from a cBTKi directly to pirto. Thirty (27%) pts had no response (stable disease or PD as best response) to cBTKi, and 40 (36%) pts had no response to the last LOT. Two (2%) pts received pirto in combination w/ CIT, 8 (7%) w/ an anti-CD20 monoclonal antibody (mAb), 11 (10%) w/ ven ± a mAb, while 86 (77%) pts as single agent. In 104 (94%) pts, pirto was given at full dose, 10 (9%) pts had a subsequent dose reduction. A total of 35 serious (grade ≥3) adverse events (AE) were documented in 27 (24%) pts: 4 (4%) pts had a serious bleeding AE, 5 (5%) pts a serious cardiac AE, 10 (9%) a serious GI AE, and 16 (14%) a serious infectious AE. Ninety-eight (88%) pts were evaluable for response. The ORR was 40% (95% CI 30% – 50%) w/ a CRR of 29% (95% CI 20%– 39%). At the last follow-up, 29 (26%) pts remained on pirto w/ a mdn treatment duration of 15.1 months (range 0.4 – 26). Fifty-eight (52%) pts died, 35 (78%) because of PD. At a mdn follow-up of 15.8 (range 0.4 – 26) months among survivors, the mdn PFS was 4.7 months (95% CI 3.3 – 8.2) and the mdn OS was 13 months (95% CI 9.2 – not available). Using the log-rank test, age (quartile groups), number of LOT (1-2 vs. 3-4 vs. 5+), time from cBTKi to pirto (quartile groups), Ki67≥30%, and high MIPI-C did not result in a statistically significant difference in PFS (p>0.05). Presence of TP53 mutation was associated w/ a non-statistically significant adverse trend in PFS (p=0.0585). No response to cBTKi and Ki67≥50% were associated w/ a statistically significant inferior PFS in log-rank test (p=<0.05), which persisted in a MV Cox regression model (aHR 2.4, 95% CI 1.4-4.2, and aHR 2.6, 95% CI 1.6-4.4, respectively). Conclusions: This is the first RW report on pirto in MCL pts. In this high-risk population, ORR to pirto was comparable to the BRUIN trial, while PFS was significantly worse, especially in pts w/ no response to cBTKi and w/ a high Ki67. However, prolonged remissions were seen in a subset of pts, suggesting that a better characterization of this population w/ durable benefit from pirto is needed.

Abstract Background: Prognostication for patients with non-transformed relapsed/refractory (R/R) follicular lymphoma (FL) is not well defined. Progression of disease within 24 months (POD24) and number of lines of prior therapy are commonly used to benchmark outcomes and for trial eligibility in this space. However, a comprehensive model for risk prediction in R/R FL is lacking. Here we utilize patients from the LEO Consortium for Real World Evidence (CReWE) and Iowa/Mayo Clinic Lymphoma SPORE MER to develop a clinical prediction model for R/R FL. Methods: Patients with grade 1-3A FL were prospectively enrolled at diagnosis in the MER and/or initiated second line or later therapy (2L+) for non-transformed FL at one of the 8 LEO Centers from a previous LEO CReWE study (Casulo et al, Lancet Haem 2022). All available lines of therapy were abstracted; lines of therapy after histologic transformation were not used in the analyses. A management plan of observation was considered as a type of therapy in the 1L setting but not in the 2L+ setting. Clinical variables and outcomes were abstracted at each line of therapy. Variables considered for modeling included demographics, clinical labs, treatment history, and pertinent clinical variables (including FLIPI and FLIPI24 components). Multiple imputation was used to address missing data in modeling; beta-2 microglobulin (B2M) was unable to be imputed due to the amount of missing data. Index therapy was defined as the date of initiation of a line of therapy (2L, 3L or 4L) for non-transformed FL. The primary endpoint for model development was the time from index therapy until the histologic transformation or lymphoma-related death (HT/LD). Cox proportional hazards models were used for model development. Modeling was first performed separately for each line of therapy and then evaluated across lines. Bootstrapping on imputed datasets was used to assess optimism in model performance. Results: N=1001 patients initiated 2L+ therapy and were utilized for modeling. Of these patients, N=654 initiated 3L and N=344 initiated 4L therapy. Median age at index therapy was (60, 61, and 62) for lines 2-4, respectively. Median follow-up by line of therapy was 8.2, 6.1, and 6,1 years and number of HT/LD events for modeling was 272, 154, and 88, respectively. Observed outcomes decreased modestly as the line therapy increased: median event-free (1.6, 1.5, and 1.2 years) and overall survival (17.6 years, 14.5 years, and 12.3 years), for lines 2-4, respectively. 5-year estimates of HT/LD by line of therapy were 21.6% (95% CI: 18.9-24.3), 23.7% (95% CI: 19.9-27.4) and 29.3% (95% CI: 23.3-34.7), respectively. A clinical prediction model was independently developed for each line of therapy; the final model for each line consisted of the same variables: increasing age, male sex, higher LDH, lower hemoglobin, higher white blood cell count, prior immunochemotherapy exposure, and shorter time since initial diagnosis. The parameter estimates for these variables were broadly similar across the different lines of therapy. The model output is an individual patient's risk of HT/LD. Patients with high-risk FLP-R, as defined using the upper quartile of FLP-R risk scores for each line, had observed 5 year HT/LD rates of 43%, 44% and 51% in lines 2-4, respectively. In contrast, patients with the lower quartile of FLP-R risk scores had observed 5 year HT/LD rates of 10%, 6% and 8% in lines 2-4, respectively. The optimism-corrected c-statistic for the FLP-R model across all lines of therapy was 0.685. This added significant information beyond FLIPI diagnosis (c=0.533) FLIPI at index line (c=0.563), the line of therapy (c=0.525), POD24 status (c=0.578), or all 4 variables combined (c=0.614). Conclusions: The FLP-R model identifies a group of patients with non-transformed FL in the R/R setting who are at very high risk of transformation and/or lymphoma-related death across lines of therapy. FLP-R features 4 of the 5 components of the 1L FLIPI24 prediction model (B2M was unavailable for modeling) with the addition of sex, treatment history and time since initial diagnosis. The number of prior therapies is not sufficient to identify high-risk populations for clinical trial enrichment in the R/R FL setting and model discrimination for FLP-R was greatly improved over FLIPI and/or POD24 across lines of therapy. A Shiny app will be provided for model implementation; external validation is planned.

Abstract Introduction: Axi-cel, an autologous anti-CD19 CAR T-cell therapy has shown high and durable response rates and a manageable safety profile among R/R FL pts in the ZUMA-5 trial (Jacobson et al. 2022; Neelapu et al. 2024). Evidence from real-world data showed favorable early outcomes in a broader population using CIBMTR data, with comparable outcomes by ZUMA-5 eligibility, age, lines of therapy (LOT), and prior bendamustine (benda) use (Jacobson et al. 2023). This study investigated long-term outcomes and the association between age, performance status, comorbidities, and therapies given prior to infusion among R/R FL pts treated with axi-cel. Methods: Pts with R/R FL who received commercial axi-cel between 03/2021–10/2023 in the US were identified from the CIBMTR® registry; pts without consent, with prior non-transplant cellular therapy, and FL grade 3B or 3A/3B unspecified or unknown were excluded. Descriptive analyses were done among all pts and by age at infusion (<65 vs ≥65 y), Karnofsky performance score (KPS), presence of hepatic, cardiovascular (CV), or moderate to severe pulmonary comorbidities, prior treatments (benda pre-leukapheresis, autologous hematopoietic stem cell transplant [autoHSCT]), and lymphodepletion (LD) therapy. Multivariable (MV) Cox and logistic regression were used to adjust for confounders. Results: In total, 238 pts from 68 centers were included (data cut-off October 2024). Median age at infusion was 61 yr (range, 29-83; ≥65 yr, 38%), and 79% were non-Hispanic White. KPS of pts was ≤70% (11%), 80% (35%), or 90-100% (54%); 2% had ECOG ≥2. Most (75%) had ≥1 clinically significant comorbidity (hepatic, 6%; CV, 15%; pulmonary, 18%). Median (min, max) prior LOT was 4 (1,13); 74% received benda pre-leukapheresis, and 6% had benda LD therapy. At a median follow-up of 24.1 months, objective response rate (ORR) was 96% (complete response [CR] rate, 91%). The 2-yr (95% CI) DOR, PFS, and OS were 70% (63-77), 64% (57-71), and 84% (78-89) respectively. Grade ≥3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 4% and 18% of pts (any grade, 74% and 42%), respectively. Prolonged cytopenias by day 30 occurred in 14% of pts (neutropenia [10%] and thrombocytopenia [8%]) while 29% had clinically significant infections at 6 months. Second primary malignancies occurred in 16 pts (7%), with 7 (2%) being therapy-related myeloid neoplasm. The leading primary causes of death (n=34) were relapse/progression (10; 29%), organ failure (7; 21%), and infection 5 (15%). Cumulative incidence of non-relapse mortality at 2-yr was 9%. Outcomes were generally comparable among age, autoHSCT, and comorbidity subgroups. However, effectiveness outcomes differed by prior benda use (Yes vs No): ORR (95% vs 98%); CR (88% vs 98%); DOR (65% vs 89%), PFS (58% vs 84%), and OS (82% vs 91%) at 2 years. By LD therapy (single agent benda vs cyclophosphamide + fludarabine [Cy + Flu]): the ORR was 93% vs 96%; CR rate was 57% vs 93%. On MV analysis, prior benda use was associated with (OR/HR [95% CI]): worse CR (0.02 [<0.01-0.43]), DOR (3.69 [1.51-9.02], and PFS (2.21 [1.12-4.38]). Pts given benda LD therapy had (OR/HR [95% CI]): worse CR rate (0.02 [<0.01-0.16]), DOR (7.59 [2.33-24.72]), and PFS (4.89 [1.79-13.39]) compared to those who received Cy + Flu. CRS and ICANS were lower among those with prior benda use (Yes vs No): any-grade CRS (70% vs 87%); Grade ≥3 CRS (3% vs 8%); any-grade ICANS (36% vs 61%); and grade ≥3 ICANS (17% vs 25%). By LD therapy (single agent benda vs Cy + Flu): the Grade ≥3 CRS and ≥3 ICANS were 0% vs 5% and 7% vs 19% respectively. Any-grade ICANS was higher among those aged ≥ 65 yr vs <65 yr (53% vs 35%). On MV analysis, pts who had prior benda use were less likely to have any-grade CRS (0.30 [0.12-0.75]), and any-grade ICANS (0.23 [0.11-0.50]. Pts ≥ 65 yr had higher any-grade ICANS (2.31 [1.18 – 4.50]). Summary/Conclusion: This long-term follow up of axi-cel in R/R FL shows durable responses and manageable safety similar to ZUMA-5. Outcomes among the elderly and those with comorbidities were generally comparable to the overall R/R FL population. Although benda use pre-leukapheresis was associated with less durable responses, we were unable to determine whether this association is limited to use close to axi-cel infusion, as data on timing of use was unavailable. The associations for benda LD should be interpreted with caution given the small sample size.

Abstract Background Adult xanthogranuloma (AXG) is a rare clonal histiocytic neoplasm (HN) with a poorly defined mutational landscape. Clinically and immunophenotypically, AXG can resemble other HNs such as Erdheim-Chester Disease (ECD) which frequently harbor MAPK pathway alterations and carry BRAF V600E mutations in close to 50% of cases. However, due to the rarity of AXG, the prevalence of the BRAF V600E mutation and the broader mutational landscape is not well known. In this study, we characterize the mutational profile of AXG. Methods We conducted a retrospective analysis of patients diagnosed with AXG at our institution between January 1, 2016, and July 15, 2025. The study was approved by the institutional review board. To ensure inclusion of true AXG cases, only patients with a confirmed histopathologic diagnosis and without multisystemic involvement or characteristic imaging findings of ECD, such as symmetric long bone osteosclerosis, were included. BRAF alterations were identified by immunohistochemistry (IHC) and/or next-generation sequencing (NGS). We also performed an extensive literature review of mutational studies in AXG and included cases that underwent comprehensive NGS. Results Seventeen patients with AXG were identified. The median age at diagnosis was 40 years (range: 18–75 years). Out of the 17 patients, 11 (65%) reported the face as the primary site of disease, and 11 (65%) had solitary lesions. Of the 17 patients, 13 (76%) underwent BRAF V600E IHC staining, and none tested positive. Twelve (71%) patients had tissue samples analyzed via NGS, and none exhibited the BRAF V600E mutation. Eight of the 12 (67%) patients with NGS testing harbored other alterations involving the MAPK pathway. These included BRAF fusions (n=3), KRAS mutations (n=2), and individual cases with TRAF7 mutation, ALK1 fusion and FGFR1 fusion. One patient was found to have a mutation in WRN, which is not previously reported in AXG. Three patients had no identifiable pathogenic alterations on NGS. Ten patients were monitored without treatment, 2 underwent surgical resections and 3 received chemotherapy (1 had a complete response [CR], 2 achieved a partial response). One patient with FGFR1 fusion was treated with pemigatinib and achieved a CR for over 3 years. One patient with TRAF mutation obtained a CR after treatment with rituximab. We also identified 51 cases of AXG with adequate mutational testing reported in the literature, which reported findings similar to ours. In a retrospective study from France involving 29 patients, MAPK alterations were observed in 55% of cases: however, only 10% harbored BRAF V600E mutations (1). Another analysis of 270 patients with various HN subtypes included 13 individuals with AXG, none had BRAF mutations. MAP2K1 mutations were seen in 31% of patients (2). Taken together, across a combined cohort of 68 AXG patients, the most common alterations were: KRAS mutations (16%), fusions (14%), MAP2K1 mutations (7%) and BRAF V600E (6%). Among fusions, the most involved gene was BRAF (50%), and GAB2 was the most common fusion partner (n=2). In total, 59% of patients had MAPK alterations. These findings collectively underscore the diverse mutational landscape of AXG and highlight the rarity of BRAF V600E mutations relative to closely related HNs. Conclusion We present a series of AXG cases with mutational profiling, from our institution and the published literature. We demonstrate that MAPK alterations are frequently observed in AXG and are driven by heterogeneous mutations. In contrast to other HNs where BRAF V600E mutations are common, we identified no such mutations in our cohort and found only rare cases in the literature. Our institutional data, along with findings from the existing literature, suggest that AXG may have a distinct molecular profile compared to other HNs. A deeper understanding of its mutational landscape may offer insights into disease biology and identify therapeutic targets. ReferencesAnnabi E, Mahévas T, Chasset et al. Clinical, Histopathologic, and Molecular Features and Treatment of Multiple Xanthogranuloma in Adults. JAMA Dermatol. 2025;161(7):765-768. doi:10.1001/jamadermatol.2025.0886.Durham BH, Lopez Rodrigo E, Picarsic J, et al. Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms. Nat Med. 2019;25(12):1839-1842. doi:10.1038/s41591-019-0653-6

Abstract Introduction: Iron deficiency (ID) is a global epidemic with discrepant definitions of both ID and anemia in pregnancy. Iron requirements increase during pregnancy and deficiencies should be corrected to avoid adverse maternal-fetal outcomes. Current guidelines recommend only screening for ID during pregnancy in the presence of anemia despite the global epidemic of ID in reproductive-age females and availability of ferritin as a high-value biomarker. To address this unmet need and gap in care, we implemented a standardized approach to screening and treating ID in pregnancy. Methods: In March 2024 at the ASH Quality Improvement Training Institute, our multidisciplinary team with representatives from hematology, obstetrics, anesthesiology, and patient blood management developed a quality improvement (QI) initiative to standardize an approach to screening and treating ID in pregnancy. After local dissemination and education of the standardized care pathway via patient/provider handouts and divisional presentations, obstetric providers paired ferritin testing with two standard hemoglobin assessments in early (8-12 weeks gestation) and late (24-28 weeks gestation) pregnancy to minimize lab draws and optimize logistics. The process was facilitated by modifying prenatal order sets in the electronic medical record. ID was defined as a ferritin <50 mcg/L and anemia was defined as a hemoglobin <11 g/dL. If ID was present in early pregnancy, oral iron supplementation was offered; if ID was present in late pregnancy, an IV iron infusion (low molecular weight iron dextran, 1 gram) was offered regardless of anemia status. Results: Obstetric data were captured pre-intervention from January 2023 – February 2024 (n=2097 pregnancies) and post-intervention from March 2024 – June 2025 (n=2429 pregnancies). Ferritin screening rates improved from 10% (205/2097) to 63% (1534/2429). Of those ferritin tests, 66% demonstrated ID in the pre-intervention cohort and 69% demonstrated ID in the post-intervention cohort. Anemia rates by measured hemoglobin during pregnancy were 25% in both the pre-intervention and post-intervention cohorts despite 92% having documentation of prenatal vitamins containing iron (PNV). Iron dextran infusion rates improved from 0.9% (18/2097) to 21% (507/2429). Of those receiving IV iron dextran, 39% had documentation of both PNV as well as additional oral iron supplementation. Overall, the median hemoglobin improved from 10.7 to 11.8 g/dL in those receiving IV iron dextran. This included increases from 12.0 to 12.8 g/dL in those without anemia and from 11.2 to 12.1 g/dL in those with ferritin 30-50 mcg/L after IV iron. Prior to initiation of this QI project, 3.1% of pregnancies (65/2097) required a blood transfusion during admission for delivery. After initiation of this project, 2.7% of pregnancies (65/2429) required a blood transfusion, of which 46 did not receive IV iron and 33 did not have a ferritin checked. Conclusions: ID in pregnancy is underrecognized and undertreated. Through a multidisciplinary QI initiative, screening for ID improved from 10% to over 60% of pregnancies within one year of project initiation. Over the same period, there was a 20-fold increase in the number of IV iron dextran infusions resulting in an increase in median hemoglobin by over 1 g/dL and a signal for decreased transfusion requirements. This occurred despite almost universal supplementation with a PNV. This standardized approach to screening and treating ID was performed by the obstetrics teams and could be implemented within varied practice models. Given the potential implications for reevaluation of appropriate reference ranges and equitable prenatal care globally, additional studies are warranted to better characterize ID in pregnancy as well as clinical sequelae for both mothers and infants. Simultaneously, discussions are needed around current guidelines and recommendations for both screening and treating ID in pregnancy.