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Abstract Background: Despite advances in LBCL treatment, 35–45% of patients relapse or have refractory disease highlighting an unmet clinical need. Clinical trials are essential to advancing lymphoma treatment, yet participation remains low – especially among certain populations. We hypothesized that participation in clinical trials as part of first-line therapy is associated with improved survival outcomes and conducted this retrospective study in a multi-center cohort. Methods: The LEO cohort prospectively enrolled newly diagnosed patients with LBCL between 2015 and 2020 at 8 academic medical centers in the United States. LBCL histology's included T-cell/histiocyte rich LBCL, Primary mediastinal LBCL, high grade B-cell lymphoma and DLBCL NOS. Pathology was reviewed and classified by a LEO pathologist. Clinical and treatment data (including trial participation) were abstracted from medical records. The primary outcome endpoint is overall survival (OS) defines as the time from diagnosis to death from any cause or last follow up. Univariable and multivariable Cox proportional hazards models were used to evaluate the association between OS and therapeutic trial participation. Univariable models assessed each baseline covariate, with and without interaction with trial participation. The multivariable model adjusted for age, sex, race/ethnicity, diagnosis to treatment interval [DTI], and IPI, including an interaction between IPI and trial participation which was justified per minimal Akaike information criteria. All models clustered on institution. Results: Among the 2636 patients with LBCL, the median age was 63 (range 18 – 99), 57% were male, 75% non-Hispanic white (NHW), 12% Hispanic (H) and 7.3% African American (AA), 62% had Stage III/IV disease, and 214 (8.0%) participated in a clinical trial as part of first line therapy. Overall, between ages 18 – 80, clinical trial participation increased with age (55 % in ages 18-30 vs 11% in ages 71-80) but dropped significantly for patients > 80 (3.4%). There were no significant differences in the rate of trial participation by sex (male 8.6 % vs female 7.5%; p=0.35), race/ethnicity (NHW 8.9% vs H 5.5% vs AA 6.3%; p=0.061), body mass index (underweight [<18.5] 4.5% vs normal [18.5-24.9] 7.7% vs overweight [25-29] 8.3% vs obese (>30) 8.5; p = 0.75) or Rural-Urban Continuum Codes (Metro[1-3] 8.5% vs non-metro Urban [4-6] 7.6% vs non-metro Rural [7-9] 5.4 %; p=0.49). Patients with advanced disease more commonly participated in a trial. Most patients received systemic treatment (98%), with 94% of patients receiving an anti-CD20 antibody and 91% of patients receiving anthracycline-based therapy. Importantly, there was no difference in anthracycline use in trial participants vs nonparticipants (92 vs 91%; p=0.53). Patients with high IPI scores [3-5] were more likely to participate on trials compared to those with low scores [1-2] (8% vs 5.9% respectively, p= 0.012). Patients who participated in clinical trials had significantly longer median DTI (26 days vs 21 days; p <0.0001) and had a significantly lower number of comorbidities compared to non-participants (mean 0.55 vs. 0.69; p=0.032). Among patients with low IPI (0–2), 5-year OS was 89% trial participants (CTP) compared to 82% for non-participants (CTNP). Among patients with high IPI (3–5), 5-year OS was 78% for CTP vs 60%for CTNP. The multivariable Cox model demonstrated a significant interaction between trial participation and IPI, with trial participation with low IPI having a non-significant hazard ratio (HR) of 0.87 with 95% CI (0.57,1.32), while trial participation with high IPI had a significant HR of 0.57 (0.44, 0.74). Additionally, increased age, male sex, black race, and lower DTI were associated with increased hazard. Conclusion: Patients at high risk of poor outcomes such as those with advanced age (80+), higher comorbidities burden, and those needing more urgent therapy (shorter DTI) were less likely to participate in clinical trials. In this multi-institutional cohort of patients with LBCL treated at academic centers, frontline trial participants had outcomes that were equivalent or better than those receiving standard care. These finding underscore the value of clinical trial participation even in the frontline setting and support trial designs that expand inclusion- allowing participation of patients who are older, medically complex or in need urgent therapy.

Abstract Introduction: THRLBCL is a rare disease accounting for less than 10% of all diffuse large B-cell lymphoma (DLBCL) subtypes. THRLBCL was associated with poor outcomes in the pre-rituximab era, with limited contemporaneous data. Optimal frontline treatment remains unclear with some studies advocating for intensive regimens. The goal of this international study is to analyze the survival and treatment-related outcomes in patients with newly diagnosed THRLBCL treated with rituximab-containing chemotherapy and to compare with a DLBCL, not otherwise specified (NOS) cohort. Methods: THRLBCL and DLBCL patients prospectively enrolled in the Lymphoma Epidemiology of Outcomes (LEO) (NCT02736357) (7/2015 to 5/2020), Molecular Epidemiology Resource (1/2010 to 6/2015), and Czech Lymphoma Study Group project (NiHiL) (NCT03199066) (2/2010 to 11/2023) were analyzed. Diagnosis was made in dedicated hematopathology centers in both registries. We excluded patients with prior nodular lymphocyte-predominant Hodgkin lymphoma, central nervous system involvement, and not treated with rituximab-containing therapy. Event-free survival (EFS) and overall survival (OS) were estimated by Kaplan-Meier.Univariate associations were derived via Cox model and multivariate models were constructed by forward selection of significant variables with P≤0.05. Propensity score matching (1:5, caliper 0.2) between THRLBCL and DLBCL NOS patients was performed using IPI score components and treatment as covariates. Results: We identified 158 patients (LEO: 67 and NiHiL: 91) with THRLBCL. Among them, 140 patients received rituximab-containing regimens and were included in this analysis. Median age was 58 years (range, 19-89) with 57% aged ≤60 years. Most patients were male (n= 88; 63%) and had ECOG performance status (PS) of 0-1 (n= 111; 79%), stage III-IV (n= 111; 79%), elevated LDH (n= 92; 66%), and B symptoms (n= 84; 60%). Fifty (36%) patients had ≥2 extranodal (EN) sites, mostly liver (n= 39; 28%) and lung (n= 16; 11%), bone marrow (BM) involvement was observed in 26% (n= 37). Bulky disease (≥7.5cm) was present in 50 (36%) and IPI score ≥3 in 68 (48%) patients. The median diagnosis-to-treatment interval was 23 days (IQ range, 13-38.5). Frequent regimens were R-CHOP (n= 106; 75.7%), followed by intensive regimens such as R-MegaCHOP/ESHAP, R-HyperCVAD/MA, and R-CODOX-M/IVAC (n= 15; 10.7%), and R-CHOEP/EPOCH-R (n= 10; 7.14%). With a median follow-up of 3.92 years, the 4-year EFS & OS were 71% and 80%, respectively. Lymphoma was the main cause of death (n= 15; 11%) among 30 events. No difference in 4-year EFS (70% vs. 76%; P= 0.55) & OS (80% vs 82%; P= 0.96) were observed between R-CHOP and intensive regimens. Factors associated with shorter EFS and OS in univariate analysis for THRLBCL were ECOG PS 2-4: (HR= 3.3; P<.001 & HR= 5.97, P<.001, respectively); ≥2 EN sites (HR= 1.85, P= 0.043 & HR= 2.54, P= 0.014, respectively); B symptoms (HR= 2.35, P= 0.014 & HR= 2.84, P= 0.023) and IPI score (HR= 1.5, P= 0.002 & HR= 2.16, P<.001). Stage III-IV and BM involvement were associated with shorter OS only (HR= 7.36, P= 0.05 & HR= 2.18, P= 0.036, respectively). Among them, only ECOG PS 2-4 (OS: HR= 3.6, P= 0.003) and B symptoms (EFS: HR= 2.3, P= 0.046) were independent predictors of survival in multivariate analysis. Finally, we compared baseline characteristics and survival between THRLBCL (n= 140) and DLBCL NOS (n= 6099; LEO/MER: 2069 & NiHiL: 4030) treated with rituximab-containing regimens. Patients with THRLBCL were younger (≤60 years: 57% vs. 38%; P<.001), more frequently had ECOG PS 0-1 (79% vs 76%; P= 0.012), stage III-IV (79% vs 63%; P<.001), B symptoms (60% vs 38%; P<.001), and liver involvement (28% vs 7%; P<.001), compared to DLBCL NOS. Subtype was not associated with survival (OS HR= 0.79, P= 0.262 & EFS HR= 0.93, P= 0.662) when adjusted for IPI score. With a median follow-up of 4.89 years in the DLBCL NOS cohort, we observed similar 4-year EFS (71% vs 67%; P= 0.197) & OS between histologies (80% vs 77%; P= 0.125). These results were confirmed in propensity matching for EFS (HR= 0.98, P= 0.897) and OS (HR= 1.07, P= 0.732). Conclusions: In this large international analysis of patients with newly diagnosed THRLBCL contemporaneously treated, we observed similar survival rates compared to DLBCL NOS treated with R-CHOP and intensive regimens. ECOG PS and the presence of B symptoms were independent factors associated with survival.

Abstract Introduction: The Duffy null variant (genotype or phenotype) is associated with lower circulating absolute neutrophil counts (ANC) without increased risk for infection. It is found in ~66% of people identifying as Black or African American vs <1% of people of Asian or European ancestry. Many ANC reference intervals (RI) are not representative of the Duffy null population. There are no adult Duffy null WBC RI and no pediatric Duffy null ANC or WBC RI. Thus, we aimed to assess Duffy null ANC and WBC distributions as well as develop WBC and ANC RI for adults and pediatrics. Methods: Twenty-three sites across the United States collected samples with all sites excluding participants with conditions or medications that could impact ANC or WBC. Only Duffy null participants were included. Sex, race, ethnicity, age, sample collection type, practice setting, Duffy testing method, ANC, and WBC were recorded. The non-parametric method for determining lower limit of normal (LLN), upper limit of normal (ULN), and 90% confidence intervals (CI) around the limits was performed according to the Clinical and Laboratory Standards Institute guidelines. Specific ULN and LLN are not reported as these are preliminary data. The Mann-Whitney U test was used to compare sex and prior data; differences by age groups were assessed with Kruskal-Wallis test. Results: 316 participants 18+ years-old (y/o) were assessed of whom 62.3% (n=197) are female, 97.5% (n=308) identified as Black or African American, and 94.9% (n=300) identified as non-Hispanic. Median age was 47 y/o (IQR: 32-60.5). Median ANC was 2600/uL (IQR: 1860-3530; range: 400-7400); 28.6% (n=90) of participants had ANC <2000/uL, 13.6% (n=43) had ANC <1500/uL, and 2.5% (n=8) had <1000/uL. The 90% CI around the LLN was 810-1070/uL and 5570-7130/uL around the ULN. Consistent with prior data, there was a difference in median ANC by sex (male: 2400/uL; female: 2710/uL; p=0.02). There was no significant difference between this ANC data and previously published Duffy null ANC data (p=0.28). Median WBC was 5.4x109/L (IQR: 4.4-6.5; range: 2.10-11.64) with 4.1% (n=13) of participants with WBC <3.0x109/L. The 90% CI around the LLN is 3.68-4.30x109/L and 11.02-12.97x109/L around the ULN. 515 participants between 0-17 y/o were assessed with 51.8% (n=267) females, 94.8% (n=488) identified as Black or African American, and 94.0% (n=484) identified as non-Hispanic. Among pediatric participants, 56.8% (n=291) had ANC <2000/uL, 38.7% (n=198) had ANC <1500/uL, and 14.4% (n=74) had ANC <1000/uL. For those <1 y/o (n=29), median ANC was 950/uL (IQR: 840-1360; range: 111-3910). There are currently too few samples to predict ULN and LLN. Median WBC was 8.85x109/L (IQR: 7.03-10.16; range: 4.17-13.53). For those 1-5 y/o (n=143), median ANC was 1735/uL (IQR: 1100-2550; range: 207-5810) with a 90% CI around the LLN of 207-820/uL and 4020-5810/uL around the ULN. Median WBC was 6.72x109/L (IQR: 5.64-8.25; range: 3.68-12.97). For those 6-11 y/o (n=128), median ANC was 1590/uL (IQR: 1090-2470; range: 420-5490) with a 90% CI around the LLN of 420-910/uL and 4340-5490/uL around the ULN. Median WBC was 5.42x109/L (IQR: 4.45-6.70; range: 2.80-10.50). For those 12-17 y/o (n=215), median ANC was 2190/uL (IQR: 1460-2930; range: 204-5850) with a 90% CI around the LLN of 540-930/uL and 4350-5510/uL around the ULN. Median WBC was 5.06x109/L (IQR: 4.26-6.20; range of 2.04-9.91). There is a significant difference in ANC by age category (p<0.0001). Conclusion: This is the first report of healthy pediatric Duffy null ANC and WBC data and the first large-scale verification of adult Duffy null ANC and WBC data. Final RI are expected in September 2025. Among adults with the Duffy null phenotype, ANC LLN are likely between 810-1070/uL. Pediatric ANC LLN are likely as low as 207-820/uL (1-5 y/o), 420-910/uL (6-11 y/o), and 540-930/uL (12-17 y/o). These findings redefine “normal” as a significant proportion of healthy participants have ANC or WBC below current RI or below thresholds typically defined as disease. Limitations include heterogeneous sample populations and collection methods. Future analyses will assess differences between collection sites or methods. Ultimately, this work lays the foundation for a more scientifically sound and equitable approach to medical care by ensuring that RI accurately reflects health for the entire community. Healthcare systems are strongly encouraged to adopt Duffy null-specific ANC and WBC RI.

Abstract Introduction: The prognosis of patients (pts) with histological transformation (HT) of Waldenström macroglobulinemia (WM) remains dismal with standard chemoimmunotherapy. CD19-targeted chimeric antigen receptor T-cell therapies (CAR-T) can lead to durable responses in relapsed/refractory (R/R) large B-cell lymphoma (LBCL) and are approved in the second or third line settings. Pts with HT-WM were largely excluded from CAR-T trials. We previously reported high response rates in a series of 23 pts. The aim of the present study was to evaluate a larger cohort of pts with R/R HT-WM treated with CAR-T with a longer follow-up. Methods: We performed a multicenter retrospective study of pts with biopsy-proven transformed WM/lymphoplasmacytic lymphoma treated with CAR-T in the French DESCAR-T registry (NCT04328298), 4 centers from ECWM and 4 US centers. This study includes updated data from previously published cases (Durot et al, Blood, 2024). Responses were assessed according to the Lugano 2014 criteria. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to the ASTCT 2019 consensus criteria. Hematological toxicity and infections were graded according to the NCI CTCAE (version 5.0). Progression-free survival (PFS) and overall survival (OS) were calculated from the date of CAR-T infusion and estimated using the Kaplan-Meier method. Results: 50 pts were included (39 from DESCAR-T centers, 7 from US centers and 4 from ECWM centers). Median age was 60 (range: 32-72) and 68 (range: 42-82) years at WM diagnosis and CAR-T infusion, respectively. MYD88L265P and CXCR4 mutations were present in 79% (23/29) and 15% (2/13) of patients with available data, respectively. The median time from WM to HT diagnosis was 5.3 years (range: 0-32). Median prior lines of therapy was 1 (range: 0-9) for WM and 2 for HT (range: 0-4). Twenty (40%) pts previously received a BTK inhibitor for WM or HT, 12 (24%) underwent prior autologous SCT and 1 pt allogeneic SCT. 40% of pts presented primary refractory disease and 44% were refractory to last treatment before CAR-T. 40 pts (80%) received bridging therapy, of whom 17 (44%) responded (7 complete responses (CR)). 35 (70%), 10 (20%), and 5 (10%) pts received axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), and lisocabtagene maraleucel (liso-cel), respectively. The best overall response rate (ORR) was 94%, with 44 (88%) pts reaching CR. With a median follow-up of 25.7 months (range: 1-69) from CAR-T infusion, the median PFS was 1.2 years (95% CI: 0.5-4.5) and median OS was 4.2 years (95% CI: 1.2-not reached). Median duration of response was 1.5 years (95% CI: 0.4-4.4), with a median of 4 years (95% CI: 1.5-NR) for pts still in CR at 6 months after CAR-T. 22 pts experienced relapse/progression after CAR-T, 19 related to LBCL and 3 to WM. Median survival after relapse was 7.9 months (95% CI: 3.8-25.3). At LBCL relapse after CAR-T, salvage therapy consisted of CD20xCD3 bispecific antibodies for 9 pts, lenalidomide +/- anti-CD20 or anti-CD19 antibody for 6 pts, and BTKi for 3 pts. Among 19 pts who died, 14 (74%) were due to progressive disease and 5 (26%) from infections. 37 (76%) pts experienced CRS, including 2 (4%) grade 3 events, and 22 (45%) had ICANS, with 2 (4%) ≥ grade 3 events. 17 (35%) pts presented infections, including 12 ≥ grade 3. 21 (43%) pts developed ≥ grade 3 prolonged cytopenias (ie, not resolved within 30 days post infusion). CNS involvement due to LBCL was present in 11 pts (22%) at the time of CAR-T. 6 of them had ICANS, with 1 grade 4. The best ORR was 91% (best CR 91%). Only 1 patient did not obtain a response, with stable disease at 1 month and progression at 3 months. The median PFS was 1.2 year (95% CI: 0.2-NR) and median OS was NR (95% CI: 0.5-NR). On univariate analysis, only elevated LDH was correlated with worse PFS (HR 2.5, p=0.04) and OS (HR 3.3, p=0.04). Other variables, including number of prior lines of therapy, MYD88 mutation status, primary refractory disease, refractory to last treatment, CNS involvement before CAR-T, response after bridging therapy and type of CAR-T received, were not associated with inferior PFS or OS. Conclusion: This cohort represents the largest series of pts with transformed WM treated with anti-CD19 CAR-T. We confirm the high efficacy previously reported with an acceptable safety profile, including for pts with CNS involvement due to LBCL at CAR-T infusion.

Abstract Background: Despite recent therapeutic advances in AS cHL, PET-adaptive chemotherapy-based regimens remain a first-line treatment option, especially for patients (pts) without access to novel agents. Most PET-adaptive regiments start with either 2 cycles of escBEACOPP (escBEACOPP2) or ABVD (ABVD2) prior to interim PET assessment (iPET), followed by treatment de-escalation or intensification by iPET result. There have been no direct comparisons of escBEACOPP2 vs ABVD2 PET-adaptive regimens. Additionally, the AS-Hodgkin Lymphoma International Prognostication Index (A-HIPI) score (Rodday JCO 2023) has not been fully explored in escBEACOPP2 regimens. Therefore, we utilized multiple analytic approaches to compare outcomes of PET-adaptive escBEACOPP2 and ABVD2 regimens, while adjusting for and assessing the effect of the baseline A-HIPI score. Methods: Through the global HoLISTIC Consortium (www.hodgkinconsortium.com), we obtained individual patient data from 4 AS clinical trials of newly diagnosed cHL pts treated with PET-adaptive escBEACOPP2 (AHL2011) or ABVD2 (SWOG0816, RATHL, HD0607) regimens. Pts were restricted to age 18 to 65 years (y), stage IIB-IV, and PET-adapted treatment arms. Positive iPET was based on Deauville score >3. Treatment effects of escBEACOPP2 vs ABVD2 (reference) on 5y progression-free survival (PFS) and overall survival (OS) were first evaluated using Cox models. Importantly, baseline disease risk was adjusted for using the 5y PFS or OS A-HIPI score (including stage, sex, age, bulk, lymphocyte count, albumin, white blood cell count), where higher scores indicate higher predicted risk (scale 1-100). The A-HIPI was modeled per 1 standard deviation (SD) increase. Our multistate model (MSM) comprised 4 health states: diagnosis, sustained remission at 1yr, treatment failure, and death from any cause. Pts all started in the diagnosis state and transitioned to other states without return to prior states. We assessed the impact of treatment on transitions (except binary sustained remission at 1y) that involved ≥5 pts per treatment group, adjusting for A-HIPI for all transitions. All effects are reported as adjusted hazard ratios (aHRs) with 95% confidence intervals (CI). Results: 2,381 AS cHL pts were included (n=372 for escBEACOPP2, n=2009 for ABVD2). For escBEACOPP2 and ABVD2 groups (median follow-up 60 and 56 months), respectively, the mean baseline A-HIPI scores (i.e., predicted 5y PFS event rate) were 25.1 (SD=6.3) and 22.9 (SD=6.5), the rates of positive iPET were 11.3% and 17.0%, 5y PFS was 87.0% and 79.5%, and 5y OS was 96.3% and 94.6%. In Cox models, escBEACOPP2 was associated with significantly improved PFS compared to ABVD2 (aHR=0.54, 95% CI=0.39-0.73); the aHR for OS was 0.67 (95% CI=0.37-1.19). Notably, higher risk A-HIPI score was associated with significantly worse PFS (aHR=1.42, 95% CI=1.31-1.54) and OS (aHR=1.60, 95% CI=1.47-1.76), independent of treatment. In the MSM, the effect of escBEACOPP2 compared to ABVD2 regimens was modeled in 3 transitions with adjustment for A-HIPI score: those treated with escBEACOPP2 had lower likelihood of treatment failure with (aHR=0.38, 95% CI=0.22-0.66) or without (aHR=0.61, 95% CI=0.40-0.92) sustained remission at 1y; the aHR for treatment failure to death was 0.55 (95% CI=0.25-1.22). Higher risk baseline A-HIPI score was associated with higher likelihood of treatment failure and death without sustained remission at 1y (aHR=1.43, 95% CI=1.28-1.61 and aHR=2.50, 95% CI=1.80-3.49, respectively). Furthermore, higher risk baseline A-HIPI score was associated with higher likelihood of treatment failure after achieving sustained remission at 1y (aHR=1.29, 95% CI=1.12-1.48) as well as death after treatment failure (aHR=1.54, 95% CI=1.27-1.86). Conclusions: Comparing newly diagnosed adult AS cHL PET-adaptive regimens with adjustment for baseline A-HIPI score, we found pts treated with escBEACOPP2 on AHL2011 had improved PFS versus pooled pt data from 3 ABVD2 trials. Using MSM, we further demonstrated that escBEACOPP2 was associated with a lower likelihood of treatment failure with or without achieving sustained remission at 1yr. In addition, baseline A-HIPI score was associated with PFS and OS, which was independent of treatment. Finally, higher baseline A-HIPI scores maintained prognostic impact throughout the disease course, including increased risk of treatment failure for pts in remission at 1yr and death after treatment failure.

Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel) is a highly effective BCMA-redirected CAR T-cell therapy for RRMM. While the pivotal CARTITUDE-1 trial established a target dose of 0.75 x 10^6 CAR+ viable T-cells/kg, the approved cell dose is 0.5-1.0 x 10^6 and the optimal dosing strategy to balance efficacy and toxicity remains unclear. This question is of interest given that a dose-response association has been demonstrated for idecabtagene vicleucel (a related BCMA-directed CAR T product). It has also been hypothesized that lower doses of cilta-cel may be associated with reduced toxicity. This study aims to evaluate the association between cilta-cel dose and key efficacy and toxicity outcomes using a large, real-world dataset from the US Multiple Myeloma Immunotherapy Consortium. Methods: We conducted a multicenter, retrospective analysis of 751 RRMM patients treated with commercial cilta-cel across 15 US academic centers. The administered cilta-cel dose (million cells/kg) was categorized into four groups: low (<0.5), standard-low (0.5 to <0.6), standard (0.6 to <0.8), and standard-high (0.8 to 1.0). We compared incidence rates of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), delayed neurotoxicity (DNT), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) across these dose categories using logistic regression. Best response rates and progression-free survival (PFS), estimated using the Kaplan-Meier method, were also compared, with differences assessed using the log-rank test for the latter. Results presented are derived from multivariable models adjusting for extramedullary disease, ECOG status, penta-refractory disease and receipt of bridging therapy. Results: Among 751 infused patients, the dose distribution was: <0.5 (n=33), 0.5 to <0.6 (n=131), 0.6 to <0.8 (n=550), and 0.8 to 1.0 (n=37). The four dose groups were well-balanced in terms of baseline patient and disease characteristics, including age, high-risk cytogenetics, and extramedullary disease, with the exception of t(14;16), which was more common in the standard-low and standard dose groups (p=0.006). There were no statistically significant differences in the rates of any grade CRS (p=0.11), any grade ICANS (p=0.84), grade ≥3 ICANS (p=0.36), duration of CRS (p=0.18) or ICANS (p=0.64), or IEC-HS (p=0.16) across the four dose categories. Time to onset of CRS was shorter for the standard-high dose compared to the low dose (6 days vs. 8 days; p=0.08). Importantly, there was no significant difference in the rate of DNT (3.0%, 9.2%, 8.8%, 5.4%; p=0.24). Similarly, there was no significant difference in overall response rates (97%, 96%, 96%, 88%; p=0.50) or complete response rates (75%, 65%, 75%, 66%; p=0.10) by dose. The median follow-up was 12.3 months (IQR: 6.9, 20.5). For patients who received a standard-low dose (0.5, 0.6), the median PFS was 17.5 (IQR: 13.5, NR) months. For the standard dose range of (0.6, 0.8), the median PFS was 28.7 (95% CI: 19.8, NR) months, while the median PFS for the standard-high dose (0.8, 1.0) was not reached. For the low dose range of <0.5, the median follow up was only 8.7 months, which did not allow reliable estimation of the median PFS. While the overall difference in PFS among the groups did not reach statistical significance by the log rank test, there was a clear trend toward improved PFS with higher cell doses in the multivariable model, with outcomes clearly ordered in the same direction as the cell dose categories. A similar trend was also evident in the rates of 12-month PFS which showed an improvement with increasing dose (62% ,67%, 73%, 80%). Conclusions: In this large, real-world cohort of RRMM patients treated with cilta-cel, a lower cell dose was not associated with reduced incidence or severity of CRS, ICANS, DNT, or IEC-HS. Conversely, a dose-response correlation with PFS was observed, with higher doses trending toward longer median and 12-month PFS. It remains unknown if a lower cell dose in the commercial setting reflects poor T cell quality, yet these findings suggest that dose reduction of cilta-cel may not be an effective strategy to mitigate toxicities and might be associated with a trend toward lower efficacy. Therefore, the standard target dose should be utilized to maximize patient outcomes and further prospective dose exploration is warranted.

Abstract Introduction: The GPRC5D-directed bispecific antibody (BsAb) Talquetamab (Talq) has shown promising results for patients (pts) with relapsed/refractory multiple myeloma (RRMM) in the MonumenTAL-1 clinical trial (Chari et al. NEJM 2022). However, there are limited data on the use of Talq in the real-world setting. Methods: All pts with RRMM who started Talq between 8/2023-3/2025 across 15 US academic centers were included. High-risk cytogenetic abnormalities (HRCA) were defined as del(17p), t(4;14), t(14;16) and/or gain/amplification 1q21. Time-to-event analyses were estimated using the Kaplan-Meier method. Toxicities including CRS and ICANS were graded using CTCAE v5.0 or ASTCT criteria. Results: A total of 484 pts were included, with a median age of 65 years (range 35-89), and 83 pts (17%) were aged ≥75 years. 20% of pts were black. 21% had baseline CrCl<40, 65% had HRCA and 29% had >1 HRCA (i.e Ultra high-risk MM). The median number of prior lines of therapy was 6 (IQR 4, 8). 50% were penta-refractory, 69% received at least one prior BCMA-directed therapy (46% CART; 32% BsAb). Prior to initiation of Talq, 11 pts (2%) had CNS MM, 29 (6%) had PCL and 126 (26%) had true extramedullary disease (EMD). 70% would have been ineligible for the MonumenTAL-1 trial. For most pts (n=405; 84%) the dosing strategy from Cycle 2 was 0.8 mg/kg every 2 weeks. and the 0.4 mg/Kg weekly dosing was used in 28 patients (6%). In 6% of pts, an additional drug was added to Talq, mostly pomalidomide (n=20) or daratumumab (n=10). 101 pts (21%) received Talq as bridging for CART. Median duration of Talq treatment was 102 days. 62% developed CRS (Grade ≥3, 2%; including one Grade 5 event). 15% developed ICANS (Grades 3-4, 4%). Steroids were used in 213 patients (44%), tocilizumab in 145 (30%) and anakinra in 9 (2%). 22 patients (5%) required ICU stay during the first cycle, for a median of 6 days (range 1-31). A total of 200 pts (41%) had infections (median 1 infection each, range 1-6), including 99 (20%) with bacterial infections, 113 (23%) viral infections and 21 (4%) fungal infections. IVIG was used in 261 pts (54%). 79% of patients (n=384) developed Talq-related oral toxicity, 55% (n=269) skin toxicity and 199 (41%) nail toxicity. 157 patients died after a median follow up of 11.5 months (mos), and the leading causes of death were MM progression (n=120) and infection (n=10). 8 pts (1.7%) developed invasive second primary malignancies. The ORR was 73%, including 46% ≥VGPR. The median PFS (mPFS) for the entire cohort was 7.8 mos (95% CI 6.9-9.4) and the 12 months PFS rate was 39%. The median OS had not been reached and the 12 months OS rate was 63%. For pts who would have been eligible for MonumenTAL-1, the mPFS was 12.2 mos (95% CI 9.7 – not reached (NR); for trial-ineligible pts, the mPFS was 6.9 mos (5.8 – 8.0; p=0.003). For BCMA-naive pts, the mPFS was 15.7 mos (11.8-NR); for BCMA-exposed pts, the mPFS was 6.8 mos (6.0-7.8; p=0.0002). For patients who received Talq as bridging prior to CART, the median PFS was NR (14.1 – NR); for those who did not receive Talq as bridging the mPFS was 6.5 mos (5.3-7.6; p<0.0001). In multivariable analyses, worse OS and PFS were associated with trial ineligibility [(HR 1.38, 95% CI 1.03-1.86; p=0.03) and (2.33, 1.31-4.14; p=0.004)], BMI<30 [(1.42,1.06-1.89; p=0.02) and (1.50, 1.01-2.22; p=0.045)] and true EMD at baseline [(1.95, 1.49-2.56; p<0.001) and (1.65, 1.16-2.36; p=0.005). On the other hand, use of Talq as bridging to CART was associated with better PFS (0.27, 0.17-0.43; p<0.001) and OS (0.13, 0.05-2.56; p<0.001). Ultra high-risk MM (1.40, 1.06-1.84; p=0.02) and baseline albumin <3 (1.68, 1.18-2.37; p=0.004) were associated with worse PFS; ECOG ≥2 (1.68, 1.18-2.40; p=0.004), and baseline Plt<50K (2.14, 1.48-3.10; p<0.0001) was associated with worse OS. Conclusions: In this large real-world analysis of 484 Talq recipients, the ORR was comparable to MonumenTAL-1 but the median PFS was shorter. This likely reflects differences in patient selection, with 70% of patients in our cohort being trial-ineligible. Patients who received Talq as pre-CAR-T bridging had superior survival outcomes. Rates of toxicities were similar to MonumenTAL-1, including >70% of patients developing dysgeusia.

Abstract Background Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is the most common leukemia in US adults and incidence increases with age. Although the treatment (tx) landscape has evolved, it is unclear whether tx selection differs for older patients (pts), given concerns around comorbidities, toxicity, and efficacy. There is a need to better understand pt characteristics, tx patterns, and biomarker use among pts aged ≥65 yrs with CLL/SLL in the current therapeutic era. Methods A retrospective longitudinal study was conducted using the de-identified 100% Medicare Fee-for-Service (FFS) Research Identifiable Files. Included pts were diagnosed with CLL/SLL at age ≥65 and initiated first-line (1L) tx 1/1/2020-9/30/2024 (with ≥12 mo in database prior to 1L tx start). Index date was defined as date of 1L tx start, and pts were followed to death, end of Medicare enrollment, or study end, whichever occurred first. 1L tx was defined as any CLL pharmacologic tx within the first 90 days of index date. Tx utilization was summarized as the number and proportion of pts who received each tx at each line. Descriptive statistics were used to summarize demographic and social characteristics and baseline comorbidities, in all pts and by 1L tx. Proportion and timing of documented biomarker orders any time prior to index were summarized by test type (CLL fluorescence in situ hybridization [FISH], TP53 DNA sequencing and immunoglobulin heavy chain variable region [IGHV] test) and by 1L tx. Results Of the 21,008 pts included, median age was 76.4 yrs at 1L tx, with 43% of pts aged 65-74 yrs, 43% aged 75-84 and 14% aged ≥85. The majority of pts were male (58%) and White (91%). About 8% and 9% of pts had dual eligibility status and low-income subsidy, respectively. Median Charlson Comorbidity Index (CCI) was 4 (range: 1-21), with 40% of pts having CCI ≥5. Covalent Bruton tyrosine kinase inhibitor (cBTKi) monotherapies (mono) were most common at 1L tx (41%), including 10% zanubrutinib (zanu), 15% ibrutinib (ibr), and 16% acalabrutinib (acala). B-cell lymphoma 2 (BCL2)+anti-CD20 monoclonal antibody (mAb) was less common (11%), and chemoimmunotherapy (CIT) was used by 13% of pts, mostly BR (8%) and FCR (3%). Other less common tx included cBTKi+anti-CD20mAb (6%) or cBTKi+BCL2 therapies (1%). Among remaining pts, most received anti-CD20mAb (22%). The use of cBTKi mono increased from 41.7% in 2020 (ibr 30.6%; acala 11.1%) to 47.6% in 2024, driven by increased use of zanu (27.8%; acala 15.7%; ibr 4.2%). BCL2+anti-CD20mAb increased from 9.2% in 2020 to 12.6% in 2024. Pts treated with cBTKi mono were older than those with BCL2+anti-CD20mAb (median age 77.2 vs 74.5), and more likely to have dual eligibility status (10% vs 4%) or low-income subsidy (11% vs 5%). More pts who received zanu mono had CCI ≥5 (39%) versus acala (36%), ibr (35%), or BCL2+anti-CD20mAb (32%). Pts with BCL2+anti-CD20mAb were less likely to have diabetes (23% vs 26%), congestive heart failure (CHF; 16% vs 19%), chronic pulmonary disease (23% vs 27%), and renal diseases (23% vs 27%). Pts with ibr were less likely to have myocardial infarction (29% vs 34%), coronary artery disease (22% vs 25%), CHF (16% vs 19%), and atrial fibrillation (12% vs 18%). Overall, 69% of pts had FISH testing prior to 1L tx, but test orders for TP53 (12%) or IGHV (28%) status were infrequent. Pts with ibr had the lowest rates of TP53 tests (6%), whereas pts with CIT had the lowest rates of IGHV tests (16%). The timing of tests showed a binomial distribution where most pts received FISH, TP53, or IGHV tests either ≤60 days prior to 1L tx (46%, 50%, 33%), or >1 yr before 1L tx (30%, 22%, 43%). Among pts who received ≥2 lines of therapy for CLL (n=4428; 21%), cBTKi mono was the most common in 2L (41%), including 14% zanu, 17% acala, and 10% ibr. CIT and BCL2+anti-CD20mAb were used in 12% and 9% of pts, respectively. Only 634 (3%) pts had 3L+ tx, of whom 33% received cBTKi mono, including 16% zanu, 12% acala, and 5% ibr (5%). Conclusion This large real-world study found that cBTKi mono was the most common 1L tx choice among pts aged ≥65 with CLL/SLL, with increased use of next-generation cBTKi. Pts with more baseline comorbidities were less likely to receive ibr or BCL2-based tx. FISH testing was not performed in nearly one-third of pts, and most pts did not have TP53 or IGVH sequencing prior to tx. Future studies are needed to continue to evaluate evolving tx paradigms in older pts with CLL/SLL.

Abstract Background Previous studies in aggressive B-cell lymphoma demonstrate that patients with shorter diagnosis-to-treatment intervals (DTI) represent those with higher risk disease. This suggests that patients enrolled in clinical trials may carry a selection bias as they often have longer DTI than patients in the general population. This has important implications for clinical research design and the generalizability of clinical trials in aggressive lymphomas. However, the prognostic implications of DTI have not been evaluated in peripheral T-cell lymphomas (PTCL). Therefore, we examined DTI and its association with clinical factors and outcomes in a prospective observational cohort of patients with PTCL from the United States within the LEO (Lymphoma Epidemiology and Outcomes) and MER (University of Iowa and Mayo Clinic Specialized Programs of Research Excellence Molecular Epidemiology Resource). Patients and Methods We evaluated patients enrolled to the MER (2002-2015) and LEO (2015-2020) cohorts with the following forms of PTCL: PTCL-not otherwise specified (PTCL-NOS, n=217), nodal T-follicular helper (TFH) cell lymphoma (nTFHL, n=153), anaplastic large cell lymphoma (ALCL), ALK positive (ALCL, ALK+, n=74), ALCL, ALK negative (ALCL, ALK-, n=95), enteropathy associated T-cell lymphoma (n=18), and monomorphic epitheliotropic intestinal T-cell lymphoma (n=2). Associations of DTI with clinical factors and outcomes were examined using Kaplan Meier and Cox models. Event free survival (EFS) was defined as the time from start of treatment to relapse/progression, start of 2nd line therapy, or death from any cause. Overall survival (OS) was defined as the time from start of treatment until death from any cause. DTI was defined as the number of days between the first diagnostic biopsy and the start of therapy. Patients who were initially observed or had DTI > 100 days were excluded. Results In 559 patients (229 MER and 330 LEO), median age was 60, 34% had IPI>2 and 71% were stage III/IV. 472 (84%) patients initially received anthracycline-based chemotherapy. Median DTI was 23 days (interquartile range (IQR): 12-39) and was similar in MER (21 days, IQR: 11-33) and LEO (25 days, IQR: 14-42). 168 (30%) patients had DTI 0-14 days, 178 (32%) 15-28 days, and 213 (38%) 29-100 days. Overall in the cohort, shorter DTI was associated with a worse 5-year OS (DTI 0-14 days: 43%; DTI 15-28 days: 53%; DTI 29-100 days: 58%, p<0.001) and 5-year EFS (DTI 0-14 days: 31%; DTI 15-28 days: 39%; DTI 29-100 days: 45%, p<0.001). In multivariable analyses, the association of DTI with outcomes remained consistent after adjusting for age and International Prognostic Index (IPI). Shorter DTI was strongly associated with adverse clinical factors, including elevated lactate dehydrogenase levels, poor performance status, B-symptoms, and higher IPI in both cohorts (all P < .003). DTI was not associated with age, sex, or distance from the LEO/MER center (all p>0.3). 6% patients with DTI of 0-14 days received 1L treatment on a clinical trial, compared to 11% with DTI 15-28 days and 13% with DTI 29-100 days, underscoring that patients with lower DTI may be underrepresented in clinical trials. When examining within PTCL subtypes, the association between short DTI (0-14 days) and inferior outcomes was most prominent in PTCL, NOS (OS HR=2.13, 95% CI: 1.52-2.94; EFS HR =1.49, 95% CI: 1.19-1.85). Associations between short DTI and outcomes were weaker in other subtypes: nTFHL (OS HR=1.28, 95% CI: 0.83-2.00; EFS HR =1.22, 95% CI: 0.82-1.81), ALCL, ALK-, (OS HR=1.30, 95% CI: 0.59-2.86; EFS HR =1.32, 95% CI: 0.68-2.56), ALCL, ALK+, (OS HR=1.05, 95% CI: 0.26-4.17; EFS HR =2.12, 95% CI: 0.84-5.26). Conclusion Shorter DTI is associated adverse prognostic clinical factors (LDH, stage, high IPI) and inferior EFS and OS in newly diagnosed PTCL. Patients with DTI ≤ 14 days, which represents approximately 1/3 patients with PTCL, may be underrepresented in clinical trials. Understanding of this selection bias should inform clinical trial design and interpretation. Future studies should consider strategies to minimize barriers to enrollment for patients with low DTI.

Abstract Background: IEC-HS is a potentially life-threatening complication following CAR-T therapy in RRMM. Reliable diagnostic biomarkers are needed to help expeditiously identify cases to initiate prompt treatment and supportive care. Serum ferritin, a routinely available laboratory parameter, is commonly elevated in IEC-HS and has been used to identify cases. However, ferritin can also be elevated in cytokine release syndrome (CRS) or secondary to baseline tumor-related inflammation. The optimal diagnostic threshold for post-CAR-T ferritin in IEC-HS in RRMM has not been previously established. Methods: This study used data from 15 centers within the US Multiple Myeloma Immunotherapy Consortium to identify the optimal post-CAR-T ferritin threshold to distinguish RRMM patients (pts) with and without a diagnosis of IEC-HS. Receiver operating characteristic (ROC) analysis was used to determine the optimal threshold based on Youden's Index. The performance of the threshold was evaluated overall and stratified by CAR-T product (cilta-cel, ide-cel). Additional analyses included the temporal relationship of peak ferritin and IEC-HS diagnosis, the evaluation of IEC-HS criteria according to ferritin levels, comparison of IEC-HS criteria co-occurrence, and comprehensive baseline characteristic comparisons across ferritin strata. Results: Of 1502 RRMM CAR-T recipients (ide-cel, n=712; cilta-cel, n=790), 74 patients (4.9%) had a provider-determined diagnosis of IEC-HS. A post-CAR-T ferritin threshold of 7470 ng/mL was identified as optimal for distinguishing pts with and without IEC-HS (AUC 0.938). Sensitivity (0.904) and specificity (0.934) were both very high, indicating high discriminatory ability. Stratified ROC analyses showed near-identical optimal thresholds for cilta-cel (7450 ng/mL; sensitivity 0.885, specificity 0.936, AUC 0.94) and ide-cel (7470 ng/mL; sensitivity 0.952, specificity 0.933, AUC 0.95), indicating minimal impact of CAR-T product on ferritin's prognostic utility. Baseline pt characteristics (N=1,413) differed significantly by ferritin threshold. Pts above the ferritin threshold of 7470 (N=154) were younger (median 64 vs 67 years; p=0.004), more frequently male (65% vs 56%; p=0.043), had higher baseline ferritin (1,300 vs 187; p<0.001), higher ECOG at apheresis (p=0.001), more likely penta-refractory (p=0.016), had higher baseline bone marrow plasma cell burden (p<0.001), and had higher R-ISS scores (p<0.001). Evaluation of IEC-HS criteria (Hines et al, TCT 2023) demonstrated significantly higher rates of laboratory and clinical criteria, including hepatic transaminase elevation (43% vs 15%), hypofibrinogenemia (53% vs 0%), cytopenias (95% vs 81%), hypertriglyceridemia (43% vs 8%), ICANS (52% vs 23%), renal insufficiency (20% vs 0%), and soluble IL-2 receptor elevations (47% vs 4%), in pts with ferritin >7500 ng/mL compared to those with lower ferritin. Heatmap visualization revealed distinct patterns of co-occurring criteria in high- and low-ferritin groups. Assessment of the timing of peak ferritin and IEC-HS diagnosis among IEC-HS cases revealed a median difference of 0 days (IQR: -1, 0), suggesting simultaneous occurrence. Median time to max ferritin was 9 days (IQR 8,12) in IEC-HS pts compared to 8 days (IQR 5,10) in non-IEC-HS pts (Wilcoxon p<0.05). Conclusions: In this analysis of over 1500 patients, a post-CAR-T ferritin level of 7500 ng/mL robustly identifies RRMM pts with IEC-HS following either cilta-cel or ide-cel. Pts exceeding this threshold demonstrate marked enrichment in IEC-HS diagnostic criteria and significant differences in baseline characteristics, warranting further study of the role of ferritin in IEC-HS diagnosis and early intervention.