Atallah‐Yunes, Suheil Albert

e19503 Background: The uptake of BCMA directed ADCs in MM has been hindered by ocular toxicity. Belantamab mafodotin (BM) and MEDI2228 (MEDI) are BCMA directed monoclonal antibodies conjugated to the microtubule inhibitor, monomethyl auristatin F and the alkylator, pyrrolobenzodiazepine, respectively. Differences in the ADCs payload, antibody specificity and linker stability influence ocular toxicity. We investigated the patterns of ocular toxicity and tolerability of BCMA directed ADC therapy. Methods: Retrospective study of MM patients who commenced treatment with a commercial or investigational BCMA directed ADC at the Mayo Clinic between 2019-22. Results: 111 patients were included, the median age was 69 and median follow up 40 months. The median number of prior treatments was 6, 87% of patients were triple class refractory, 50% penta class refractory, 14% had prior BCMA directed therapy and 24% had extraosseous disease. Treatments included BM (n=56, 50%), BM in combination with other MM therapy (n=12, 11%) and MEDI (n=43, 39%). The overall response rate was 30% for BM and 44% for MEDI. The median OS and PFS for BM was 8 and 2 months, the median OS and PFS for MEDI was 11 and 5 months. The median number of ADC cycles was 2.5. Ocular toxicity is summarized in the table 1. Keratopathy was more common with BM (p=0.004). Only 4 MEDI patients developed keratopathy, all grade 1 and associated with dry eyes and/or photophobia. In contrast, 60% of BM patients developed keratopathy (13% grade 3-4 keratopathy). The median time to keratopathy onset was 1 month with BM, and 2.8 with MEDI. The median time until keratopathy was 4.6 months for BM. Loss of best-corrected visual acuity (VA) was significantly more common with BM (p<0.001). The median time to any decline in VA was 1.5 months for BM and 2.3 for MEDI. The median time until VA returned to baseline was 2.4 months for BM and 2.3 for MEDI. The frequency of dose delays for ocular toxicity was comparable between ADCs, as was the number of dose reductions (16% BM vs. 12% MEDI, p=0.5). The most common reasons for treatment discontinuation were progression or death (BM=69%, MEDI=44%) and ocular toxicity (BM=18%, MEDI=30%). Conclusions: Treatment interruptions, dose reductions and drug discontinuation are common with BCMA directed ADC therapy. Further research to optimize the administration schedule of these agents is warranted. BM and MEDI produce distinct patterns of ocular side effects, namely keratopathy and reduced VA with the former, and photophobia and dry eyes with the latter. BM N = 68 MEDI N = 43 p-value 2 Prophylactic steroid eye drops 4 (6%) 28 (68%) <0.001 Prophylactic lubricant eye drops 42 (63%) 33 (80%) 0.051 Max grade keratopathy 0.004 1-2 29 (47%) 4 (19%) 3-4 8 (13%) 0 (0%) VA equal or worse than 20/40 26 (68%) 6 (20%) <0.001 Days of ADC treatment 59 (33, 167) 68 (41, 105) 0.9 Dose delay for ocular toxicity 19 (28%) 8 (19%) 0.2 n (%); Median (IQR); 2 Chisq test; Wilcoxon rank sum.

7032 Background: The impact of immune cell counts pre LD and during immune reconstitution on CAR T therapy outcomes is poorly understood. We investigated the association between CD4, CD8 and NK cell counts and CAR T therapy outcomes in patients with LBCL. Methods: Retrospective study of R/R LBCL patients who received CAR T cells between 2016-24 at Mayo Clinic, Rochester, were included in this analysis. Peripheral blood CD4, CD8 and NK counts were measured pre LD and at M1 post CAR T infusion. The receiver operating characteristic (ROC) curve was used to determine the optimal cutoff for pre LD and M1 immune cells to predict patients who were alive and in remission at 6 months (M6) post CAR T infusion. Patients who progressed or were lost to follow up prior to day 30 were excluded from M1 ROC analysis. Results: Of 140 patients, 81 were alive and in remission at M6 (Group A), while 59 had relapse or death (Group B). Axicabtagene ciloleucel was the CAR T product given in 81% of patients (114/140). Median pre LD CD4 counts were significantly lower in Group B compared to group A (143 vs 280 cells/µL, p = 0.001). No significant difference was observed in median pre LD CD8 counts (205 vs 221 cells/µL, p = 0.8). ROC analysis identified an optimal pre LD CD4 count of 124.5 cells/µL for M6 alive+remission. Lower pre LD CD4 counts (<124.5) predicted worse progression free survival (PFS) in univariate (HR = 3.02, 95% confidence interval [CI]: 1.73–5.27, p< 0.01) and multivariable analysis (MVA) adjusted for IPI and the number of prior lines (aHR = 2.54, 95% CI: 1.39–4.62, p< 0.01).Lower pre LD CD4 counts also predicted inferior overall survival (OS) in MVA (aHR = 2.27, 95% CI: 1.08–4.77, p = 0.03). (Table 1) On day 30 landmark analysis, ROC identified M1 optimal CD4 count of ≥ 99.5 cells/µL to be associated with a trend toward superior PFS (P=0.09), but not OS (p=0.90) in MVA. Median pre LD NK cell counts were significantly lower in Group B (73 vs 98 cells/µL, p = 0.04). ROC analysis identified an optimal pre LD NK count of 151 cells/µL for M6 alive + remission. Lower pre LD NK counts (<151) predicted worse PFS, both on univariate (HR = 4.17, 95% CI: 1.29–13.47, p = 0.02) and MVA (aHR = 4.64, p< 0.01). The lower pre LD NK cell count group had worse OS in MVA (aHR = 5.69, 95% CI: 1.16–28.1, p = 0.01). (Table 1) On D30 landmark analysis, M1 NK cell count of ≥ 128.5 cells/µL was associated with a trend toward superior PFS (P=0.08), but not OS (p=0.30) in MVA. Conclusions: Pre LD CD4 and NK cell counts are significantly associated with PFS and OS post CAR T therapy in patients with R/R LBCL. Pre-treatment immune subset levels may identify patients at higher risk of relapse or death after CAR-T therapy. Groups Median PFS 2 Year PFS Median OS 2 Year OS CD4 ≥124.5 cells/µL (N=75) NR 58% 3.31 years 67% CD4 <124.5 cells/µL (N=30) 2.2 months 22% 1.59 years 45% NK ≥151 cells/µL (N=17) NR 77% NR 84% NK <151 cells/µL (N=82) 10.6 months 44% 3.31 years 62%

Background: Beside fibril-forming proteins, amyloid deposits contain other proteins which can influence organ toxicity, disease initiation and clearance. We investigated the association between the amyloid plaque proteomic signature of diagnostic renal biopsies from patients achieving deep and sustained hematologic remissions and renal organ response in AL amyloidosis. Methods: Retrospective study of newly diagnosed AL amyloidosis patients between 2010-2020. Patients were eligible if; (1) they had a baseline renal biopsy which had undergone laser micro-dissection and mass spectrometry, (2) were assessable for renal response [RenR, non-selective proteinuria ≥1g /24 hours, predominantly albumin], (3) were not on renal replacement therapy and did not experience renal progression within 3-months of diagnosis and (4) had RenR measurements, at least twice annually in the first year from treatment and annually thereafter. Patients who did not obtain a renal complete response (RenCR) required a hematologic very good partial response (VGPR) or better within 6 months of treatment initiation, sustained for a minimum of 6 months. Hematological and renal responses were graded according to consensus criteria. Overrepresentation analyses of differentially expressed proteins were performed using the WebGestalt 2019 and the reactome pathway database. A false detection rate corrected p value &lt;0.05 was used to identify significantly overrepresented proteins and pathways. Results: We defined two organ response categories, to capture the extreme ends of the spectrum: renal suboptimal responders (n=24), patients for whom the best renal response was ≤partial response (RenPR), and renal complete responders (n=29), patients who obtained a RenCR at best response. Overall, the median follow-up was 6.7 years (IQR: 5.4-9.2), 6.6 years (IQR: 5.4-8.1) for complete responders, and 8.4 years (IQR: 6.1-11.3) for suboptimal responders. Between renal suboptimal responders and complete responders there was no significant difference in median age (63 vs 63 years, p=0.7), lambda light chain isotype (66% vs 79%, p=0.3), first-line therapy received and renal stage (Stage III: 14% vs 8%, p=0.9). The median time to RenCR was 52-months (IQR: 31-63). Protein pathways over-represented in renal complete responders included 14-3-3 proteins (YWHAG, YWHAH, YWHAQ, YWHAZ), early components of the complement cascade and complement regulatory proteins (C3, C4A, C4B, C8A, complement factor H), keratins, cytoskeletal proteins (tubulin, actin, filamen) and collagen IV. Protein pathways over-represented in renal suboptimal responders included terminal/effector components of the complement cascade (C5, C6, C8B, C9), amyloid signature proteins (ApoA1 and E, vitronectin, clusterin), proteoglycans (heparan sulfate proteoglycan), transgelin and metallopeptidase inhibitor 3. Proteins with the highest-fold increase in renal complete responders included serine protease inhibitor (SERPINA3) and F-box and leucine rich repeat protein (FBXL6), 9.0 x 106 & 7.7-fold, respectively. Proteins with the highest-fold increase in renal suboptimal responders included complement 6 and 8B, 3.5 & 3.6-fold, respectively. Conclusion: This is the first study to identify proteomic determinants of organ response in AL amyloidosis. Molecular chaperones involved in protein aggregate homeostasis, such as the 14-3-3 proteins are upregulated in renal complete responders, similar to what we have shown in our prior work. This suggests that organ responders may have a more favorable microenvironment which “primes” them for organ response after the amyloidogenic light chain has been cleared from the circulation. Renal suboptimal responders (≤RenPR) have elevated levels of terminal complement proteins including membrane attack complex proteins and reduced levels of early components or complement regulatory proteins, which may be responsible for reno-toxic and reno-protective effects, respectively.

Introduction: Light chain (AL) amyloidosis is a clonal plasma cell disorder characterized by tissue deposition of misfolded immunoglobulin light chains in the form of amyloid, leading to organ dysfunction. Halting the production of the amyloidogenic free light chains by achieving a deep hematologic response (HemR) is key to improving organ function, however, variation in organ responses exists. In this work, we investigated variables associated with liver response (LivR) in a large cohort of patients with AL amyloidosis. Methods: Retrospective study of newly diagnosed AL amyloidosis patients with liver involvement seen at Mayo Clinic within 90 days of diagnosis between January 2000 and December 2021. Patients were eligible if they (1) had liver involvement, defined as a baseline alkaline phosphatase (ALP) ≥ 1.5 x upper limit of normal (ULN) and (2) had LivR measurements at least twice annually in the first year from treatment and annually afterward. LivR was defined as a &gt;50% reduction in alkaline phosphatase (ALP) from baseline value or normalization of ALP. LivR was recorded at 6, 12, and 24 months from treatment initiation and at the best LivR achieved. Patients who died prior to landmark assessment were considered non-responders at subsequent milestone assessments. Covariates associated with LivR were identified by univariate and multivariable logistic regression analyses and a proportional subdistribution hazard (Fine-Gray) model for competing risk (treating death as a competing event). Multivariable logistic regression models for LivR were created using best subset selection, with calculation of odds ratio (OR) and 95% confidence interval (CI). Results: A total of 130 patients were included, with a median age of 60 years (IQR 53-66), male predominance (69%), and a median follow-up of 8.8 years. Sixty percent of patients had lambda isotype, the median ALP was 368 IU/mL (IQR 279-589), with 48% of patients having ALP ≥3 fold the upper limit of normal (ULN). Median bilirubin was 0.7 mg/dL (IQR 0.5-1.1). Forty-three percent of patients received front-line autologous stem cell transplant (ASCT) with or without prior induction therapy, and 5% received daratumumab-based therapy as their front-line treatment. Liver response rate increased with time, with 36 patients (28%) achieving a LivR at 6 months, 47 (36%) at 12 months, 63 (48%) at 24 months, and 94 (72%) at best response. The median time to liver response was 14 months (7.22-32.67). At the 24-month landmark, age &lt;60 years, ALP ≥3 fold ULN, and front-line ASCT were significantly associated with achieving a LivR on univariate logistic regression. On univariate logistic regression at best liver response, age &lt;60 years, ALP ≥3 fold the ULN, kappa isotype, ≥HemVGPR within 6 months, and front-line ASCT were significantly associated with obtaining a LivR. On multivariable logistic regression, at 24 months, ALP ≥3 folds of ULN (OR=2.9, 95% CI 1.4-6.3, P=0.004) was significantly associated with an increased likelihood of LivR. Achieving ≥HemVGPR and front-line ASCT were also associated with increased LivR likelihood, although not statistically significant (p=0.094, p=0.078, respectively). At best liver response, achieving ≥HemVGPR within 6 months (OR=5.2, 95% CI 1.9-14.8), kappa isotype (OR=3.2, 95% CI 1.1-10.0), ALP ≥3 folds of ULN (OR=3.3, 95% CI 1.3-9.9), and front-line ASCT (OR=5.3, 95% CI 1.9-16.7) were factors significantly associated with LivR. The Fine-Gray model demonstrated kappa isotype (HR=1.7), baseline ALP ≥3 folds of ULN (HR=2.1), ≥HemVGPR within 6 months (HR=1.9), and age &lt;60 years at diagnosis (HR=1.9) to be positively associated with achieving LivR (P&lt;0.05). Conclusions: In this large cohort of liver AL amyloidosis, LivR was achieved in 72% of patients, and amongst responders, the median time to response was 14 months from therapy initiation. Predictors of LivR included kappa isotype, deep hematological response in the first 6 months of initial therapy, ASCT usage, and higher baseline ALP levels. These findings better inform clinicians on the likelihood of achievement of liver response and may enable ways to improve its achievement.

Background Emerging evidence has demonstrated rare subacute to late neurological toxicities (NTs) after BCMA CAR T-cell therapy (CAR-T) in multiple myeloma (MM). These adverse events can be categorized as: 1) Parkinsonism (PD), 2) cranial nerve (CN) palsies, and 3) peripheral neuropathies/Guillan Barré syndrome (GBS). These toxicities can cause significant morbidity, but given their relative rarity in clinical trials, there is limited data regarding evaluation and treatment. To our knowledge, this is the largest and only global registry of delayed NTs after BCMA CAR-T. Methods We retrospectively established a registry of NTs via the Immune Therapy Working Committee of the International Myeloma Working Group (IMWG). We gathered data pertaining to demographics, MM characteristics, MM response, NT signs/symptoms, diagnostic workup, and treatment. Result A total of 52 patients with delayed neurotoxicity were included from 14 institutions and 6 countries; 92% received ciltacel, 4% idecel, and 4% investigational CAR-T. Median age at CAR-T infusion was 65 years; 69% were male and 88% were Caucasian. Median bone marrow plasma cell (PC) burden was 15% prior to CAR-T (range 0-95%). Patients received a median of 4 prior lines of therapy (LOT), with 67% progressing on last LOT. Seventeen percent had pre-existing neurological diagnoses (including stroke, epilepsy, migraines). We identified sixteen cases of PD (94% with movement disorder, 69% with cognitive impairment, 75% with personality changes), occurring at a median of 26 days (range: 15-87) after CAR-T. Ninety four percent had CRS (grade (G)1 50%, G2 38%, G3 6%, G4 0%), while 19% had ICANS (G1 13%, G2 6%, G3-G4 0%). Median peak absolute lymphocyte count (ALC) was 9.5 x 109/L, peak C-reactive protein (CRP) 60.9 mg/L, and peak ferritin 1893.5 ug/L within the first 30 days. Concurrently, 3 upper respiratory infections (URIs) and 2 low-level HHV7 in the cerebrospinal fluid (CSF) were detected. A median of 73% of T-cells in the CSF were CAR-T, based on a flow cytometry assay. Ten patients received steroids (median 19 days after symptoms, 70% partial response, 20% no response, 10% unknown), 2 received intrathecal (IT) methotrexate-based therapy (median 32 days after symptoms, 1 with no response, 1 unknown), 5 received intravenous (IV) cyclophosphamide (median 31 days after symptoms, 40% full response, 20% partial response, 40% no response), 4 received high-dose IVIG ≥1g/kg for one or more dose (50% partial response, 50% no response), and 6 received dopamine agonists. There were 37 CN palsies (76% CN7, 15% CN6, 7% CN5, 2% CN3), occurring at a median of 37.5 days (range: 7-482) after CAR-T. Eighty one percent had CRS (G1 68%, G2 14%, G3-G4 0%); 11% had G1 ICANS (G2-G4 0%). Median peak ALC was 4.1 x 109/L, CRP 25.4 mg/L, and ferritin 543 ug/L within the first 30 days. We identified 2 concurrent URIs, 4 CMV viremia (50% with viral load &gt;1500 IU/mL), 1 HHV6 viremia, and 1 HSV in the CSF. Thirty-two (86%) received steroids for a median duration of 12 days, 50% with full response, 3% with no response, and 47% with partial response (of which 43% had later full recovery without further intervention). One received IT methotrexate and another received IV cyclophosphamide without response. Thirteen (41%) received IVIG, of which 38% was high-dose IVIG. Four patients with CN palsies developed peripheral neuropathy/GBS. Eight patients (15%) in this cohort were not heavily pre-treated (≤1 prior LOT); 7 developed CN palsies (6 after ciltacel, 1 after investigational CAR-T) and 1 PD (after idecel). These patients had median &lt;5% PC; none had extramedullary disease. Median ALC was 4.14 x 109/L, CRP 33 mg/L, and ferritin 448.5 ug/L within the first 30 days. Conclusions Delayed NT requires prompt recognition, evaluation for alternative causes, and treatment. In our cohort, the majority of patients were male and Caucasian, suggesting that sex and race may impact the likelihood of developing NT. Individuals with PDs had greater inflammatory response (CRS, ALC, CRP, ferritin) compared to those with CN palsies. CN palsies responded to steroids and/or IVIG, whereas PD had at best partial response to steroids, prompting additional therapy. These toxicities notably did occur in less heavily pre-treated patients, perhaps driven by immune fitness and greater circulating T-cells rather than MM burden. At the time of the annual meeting, data will be updated with additional NTs from less heavily pre-treated patients.

Background Advancements in imaging techniques, diagnostic procedures, and increased routine health care visits are anticipated to lead to a higher number of patients with an incidental diagnosis of cancer, including the most common lymphoma DLBCL. In parallel, multiple cancer early detection (MCED) blood assays are emerging to screen for cancer in asymptomatic, average risk individuals. Assays that use methylated DNA markers (MDM) are of special interest and have been shown to detect evidence of DLBCL in the blood in 80% of DLBCL cases (Witzig TE et al ASCO 2022). While these MDMs are candidates for inclusion in MCED assays, the impact of early detection of lymphoma in general and DLBCL specifically remains controversial. Since the outcomes for patients with an incidental diagnosis of DLBCL have not been previously studied and to give further insight to the early detection question, we investigated clinical characteristics and outcome differences between patients with DLBCL found incidentally and those with symptoms or obvious signs of disease that led them to seek medical evaluation. Methods We conducted a retrospective analysis of newly diagnosed DLBCL patients enrolled into the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence from 2002-2015. We reviewed the medical records of the Mayo component to assign a mode of diagnosis (incidental vs symptomatic). We examined disease characteristics and impact on event-free survival (EFS) and overall (OS) survival according to the mode of diagnosis. EFS was the time from diagnosis to relapse, progression, retreatment, or death from any cause. OS was defined as the time from diagnosis to death from any cause. Results 1140 patients with DLBCL (90.6%), high grade B cell lymphoma (2.4%) or primary mediastinal B cell lymphoma (7.0%) were reviewed; 85 (7.5%) patients presented incidentally (incidental group), while 1055 (92.5%) presented with a lymphoma-related symptom or sign, e.g., palpation of a lump/mass, B symptoms and/or other symptoms caused by the lymphoma such as abdominal pain (symptomatic group). In the incidental group, 67.5% (65/85) of patients were diagnosed after an incidental finding on imaging or diagnostic/surgical procedure, 14.1% (12/85) were diagnosed after an incidental lab finding, and 9.4% (8/85) were diagnosed after a clinical health care professional incidentally identified a lump/mass. Compared to the symptomatic group, patients with incidental diagnosis were older at diagnosis (median age 66 vs 63 years, P=0.01) and more likely to present with an earlier stage I/II (62.4% vs 38.9%, P&lt;0.001). Patients who presented with symptoms were more likely to have ≥ 1 extra-nodal site involvement (29.8% vs 15.5%, P=0.005), elevated LDH level (55.4% vs 40.8%, P=0.01), and high-risk IPI score (13.7% vs 5.9% P=0.03) compared to the incidental group. The median diagnosis to treatment interval (DTI) was significantly longer in the incidental group (21 days, IQR 12-34) compared to the symptomatic group (15 days, IQR 9-24) (P = 0.0014). The median follow-up time was 152.3 months in the incidental group and 123.7 months in the symptomatic group. We observed no difference in early failure rates as measured by failure to achieve event-free status at 24 months (EFS24) for incidentally vs symptomatic diagnosis (25.9% vs 31.9%, P=0.25). There was no difference in EFS between the two groups in univariate (HR=1.08, 95%CI=0.8-1.45) or multivariable analysis adjusted for IPI (aHR=0.97, 95%CI=0.72-1.31). There was also no difference in OS in univariate (HR=0.98, 95%CI=0.72-1.34) or multivariable analysis adjusted for IPI (aHR=0.87, 95%CI=0.64-1.19). Conclusion In this large cohort of aggressive B-cell lymphoma, incidental diagnosis occurred in only 7.5% of cases and these patients had earlier stage, lower IPI score, lower LDH levels and less extranodal involvement. These differences in clinical characteristics did not translate into EFS or OS differences. Our findings are the first to describe presentation and outcomes of incidentally diagnosed DLBCL and provide data regarding what investigators may find with MCED assays. Finding more early stage DLBCL patients with lower tumor burden may influence type of treatment, enable the use of fewer chemotherapy cycles, and avoid symptoms and complications of advanced stage disease such as tumor lysis syndrome and organ compression.

Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment with high efficacy in treating relapsed or refractory (R/R) mantle cell lymphoma (MCL). However, with CAR-T therapy, refractory disease occurs and a continuous pattern of relapse over time has been observed. Limited data exist about post-CAR-T progression of disease (POD) management and outcomes in MCL. Such data would meaningfully inform practice and set a critical benchmark for future studies in the post-CAR-T setting. We characterized treatment patterns and outcomes for pts with POD after CD19 CAR-T therapy for R/R MCL. Methods: We queried institutional databases to identify pts with R/R MCL who received CD19-directed CAR-T therapy. Treatment may have occurred as standard-of-care or in a clinical trial. We performed chart review to extract variables and categorized therapies by mechanism(s) of action. We used descriptive statistics to characterize patient/disease characteristics and treatment patterns, the reverse Kaplan-Meier method to calculate follow-up, the Kaplan-Meier method to calculate survival, and Cox proportional hazards to associate clinical and disease features with survival outcomes. Results: Across 9 sites, we identified 306 pts who received CD19 CAR-T for R/R MCL, of which 104 (34%) experienced POD and were investigated in detail: pts with POD were mostly men (73%), had a median age of 67 yrs (range 36-86) at infusion, and had received a median of 3 lines of therapy pre-leukapheresis, including a BTK inhibitor (BTKi) in 97% of patients; 36% of BTKi-exposed patients had BTKi-unresponsive disease. High-risk tumor features were common pre-CAR-T: 47/68 (69%) with a TP53 mutation, 66/93 (71%) with Ki67 ≥50%, and 47/102 (46%) with blastoid/pleomorphic MCL. Most pts (75%) received bridging therapy. Pts received brexucabtagene autoleucel (88%) or lisocabtagene maraleucel (12%). Regarding best CAR-T response for pts with POD, 71% had a complete response (CR), 13% partial response (PR), and 15% had no response. The median time from CAR-T infusion to POD was 6 months (IQR 3-12). At time of POD, high-risk MCL features were again common: 55% blastoid/pleomorphic, 42/56 (75%) Ki67 ≥50%, 51/83 (61%) MIPIb high-risk, and 21/35 (60%) TP53-mutated MCL. Among 69 pts with CD19 assessed on a post-POD biopsy, 8 (12%) had CD19-negative disease. 30% of pts had an ECOG performance status of ≥2 at time of POD. After POD occurred, 15 pts received no anti-lymphoma therapy (Tx), 11 pts underwent excision or radiation, and 78 pts received systemic therapy. The most commonly used first-line systemic Tx post-CAR-T progression included: pirtobrutinib in 13 pts [overall response rate (ORR) 31%], chemoimmunotherapy in 12 pts (ORR 25%), venetoclax in 10 patients (ORR 20%), bispecific antibodies (BsAb) in 10 pts (ORR 60%), and small molecule combinations (at least 2 of BTK inhibitor, BCL2 inhibitor, and lenalidomide) in 8 patients with ORR 50%. The ORR to all first systemic Tx post-POD was 42%. The median follow-up from POD is 15.2 months among survivors. The median progression-free and overall survival (OS) from time of POD were 2.3 (95% CI 1.9-3.4) and 5.4 months (95% CI 4.5-9.4), respectively, and 1-year OS rate was 33%. TP53 mutations predicted inferior OS (HR 2.83, 95% CI 1.08-7.43, P = 0.026) as did age ≥65 years at time of POD (HR 1.83, 95% CI 1.07-3.15, P = 0.023), MIPIb high-risk (HR 3.56, 95% CI 1.08-11.7, P = 0.042), and non-response to CAR-T (HR 3.55, 95% CI 1.93-6.53, P &lt; 0.001). Discussion: Our data, the largest reported cohort of pts with POD post-CAR-T with R/R MCL, confirm the poor prognosis in this patient population, with a median OS of 5.4 months. BsAbs showed promise with an overall response rate of 60%. The presence of a TP53 mutation significantly predicted inferior OS, corroborating the prognostic importance of this finding in the post-CAR-T context. Data from pts treated at additional sites and updated analyses will be presented at the meeting.

Background: In the ZUMA2 study, a higher peak chimeric antigen receptor (CAR) T cell expansion correlated with better outcomes in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) receiving brexucabtagene autoleucel (brexu-cel). However, in clinical practice, peak CAR T cell expansion is not routinely assessed for. Since patients receive lymphodepleting agents prior to CAR T cell infusion, it is hypothesized that peak absolute lymphocyte count (ALC), which can be easily measured, in the first two weeks after CAR T cell infusion represents peak CAR T cell expansion. Our group previously showed that peak ALC was associated with response durability and outcomes in patients with R/R large B-cell lymphoma receiving axicabtagene ciloleucel. In this retrospective study, we assessed the association of peak ALC with clinical outcomes after brexu-cel infusion in patients with R/R MCL. Methods: Patients with R/R MCL who received brexu-cel between March 2020-March 2024 at Mayo Clinic were included in this analysis. Peak ALC was defined as maximum ALC value in the first 14 days after CAR T cell infusion. Progression-free survival (PFS) was defined as time from CAR T cell infusion to lymphoma relapse, progression, or death, and overall survival (OS) was defined as time from to CAR T cell infusion to death. The optimal cutoff point for peak ALC that correlated with PFS was determined by the log-rank method using the Cutoff Finder application, a computational method which fits Cox proportional hazard models to the dichotomized variable and survival. The optimal cutoff was the point with the most significant PFS split by log-rank test. Results: A total of 43 patients were identified. The median age at time of CAR T cell infusion was 68 years (IQR 58, 73). 34 (79%) were male, 28 (74%) had Ki-67 &gt;30%, 14 (33%) had blastoid or pleomorphic histology, and 19 (44%) had TP53 mutation or deletion. Median number of prior lines of therapy was 3 (IQR 2, 4) and 13 (30%) received prior autologous stem cell transplant. 32 (74%) received bridging therapy prior to CAR T cell infusion. All patients received fludarabine plus cyclophosphamide for lymphodepletion. The best overall response rate was 88%, with a complete response rate of 84%. After a median follow-up of 25.6 months (95% CI 14.4-31.4), the median PFS and OS were 16.6 (95% CI 8.6-NE) and 35.1 (95% CI 24.5-NE) months, respectively. The incidence of cytokine release syndrome (CRS) was 95% (4.7% grade ≥3). The median time to initial CRS and maximum grade CRS onset was 4.5 days (IQR 1, 6.25) and 5.5 days (IQR 2.75, 7), respectively. The incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) was 65% (18% grade ≥ 3). The median time to initial and maximum grade ICANS onset was 9 days (IQR 6, 11) and 10.5 days (IQR 7, 12), respectively. The median ALC at time of CAR T cell infusion was 0.03 x109/L (IQR 0.02, 0.05). Among 37 patients with identifiable ALC peaks, the median ALC peak was 0.84 (IQR 0.41, 2.45) and the median time to peak ALC was 12 days (IQR 9, 12). 6 patients had no identifiable peak ALC due to no frequent CBC differentials post CAR T cell infusion. A peak ALC of ≥0.45 × 109/L correlated significantly with PFS, with median PFS not reached for the group with peak ALC of ≥0.45 × 109/L (n=27) compared to 9.3 months for the group with peak ALC of &lt;0.45 × 109/L (n=10) and a 1-year PFS rate of 68% vs 33% (p=0.02). OS was also significantly higher in patients with a peak ALC of ≥0.45 × 109/L (median OS not reached vs 11 months, 1-year OS rate of 84% vs 44%, p=0.01). The incidence of ICANS was significantly higher (74% vs 30%, p=0.02) in patients with a peak ALC of ≥0.45 × 109/L. Numerically, the group with peak ALC of ≥0.45 × 109/L had a later onset of initial and maximum grade ICANS, but the difference was not statistically significant. Peak ALC was not associated with ICANS severity. There was a trend towards higher incidence of CRS (100% vs 80%, p=0.07) and earlier CRS onset (3 vs 5 days, p=0.07) in the high peak ALC group. There was no difference in CRS severity. Conclusion: Peak ALC after CAR T cell infusion was significantly associated with better PFS and OS and higher incidence of ICANS in patients with R/R MCL receiving brexu-cel. Peak ALC may serve as a surrogate measure for peak CAR T cell expansion in routine practice, but confirmatory studies are needed. Larger studies are warranted to confirm the association of peak ALC with PFS, OS and toxicities in patients with R/R MCL receiving brexu-cel.