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Introduction: CAR-T (chimeric antigen receptor T-cell) therapy is known to be associated with immune-mediated toxicities including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). [18F]-Flurodeoxyglucose-positron emission tomography (FDG-PET) is frequently utilized for cancer staging before and after CAR-T therapy. Case series have demonstrated cerebral glucose hypometabolism (CGHM) on FDG-PET imaging in patients who developed CRS and ICANS. In this study, we aim to further characterize CART-CGHM. Methods: Patients who received CAR-T therapy at our institution from October 2019 to December 2023 were included. Clinical data was collected from retrospective review of the electronic medical record including patient age, sex, diagnosis, cancer stage, development of CRS or ICANS, and survival outcome. Standard of care whole body FDG-PET scans obtained before and approximately 30 days post CAR-T therapy were utilized. FDG-PET images of the brain were sub-selected and processed with dedicated imaging software (GE AW server 3.2 with Cortex ID, MIM Neuro, version 7.2.7). To identify CART-CGHM, visual and statistical comparison was made between the pre-CAR-T FDG-PET and the post-CAR-T FDG-PET using the age and gender matched normal cohort in the database as controls. Z-score changes > 1.5 were considered significant. Baseline variables were reported as frequency (%) and compared between patients with and without CGHM using Chi-squared test. Kaplan-Meier method was used to estimate the overall survival rate (OS) at different time points and log rank test was used to compare survival rates between the groups with and without CGHM. Multivariable Cox regression model was performed to evaluate the association between CGHM and OS with adjustment for ICANS. All tests were two-sided with p<0.05 considered statistically significant. Results: In total, 84 patients (41 women, 49%) were included. The median age at time of CAR-T therapy was 66 (33-85) years old. The most common diagnosis was multiple myeloma (n=39, 46%) followed by diffuse large B-cell lymphoma (n=33, 39%), follicular lymphoma (n=7, 8%), mantle cell lymphoma (n=3, 4%), and B-cell acute lymphoblastic leukemia (n=2, 2%). CART-CGHM was identified in 27 patients (32%). The pattern of CGHM was either global (n=15, 56%) or focal (n=12, 44%) with the prefrontal cortex predominantly affected. Of these 27 patients with CART-CGHM, 17 patients (63%) experienced ICANS and 23 patients (85%) experienced CRS. The diagnosis of lymphoma and development of ICANS were significantly associated with CGHM (p- 0.038 and <0.001 respectively). On univariate analysis, CGHM and ICANS were associated with negative impact on OS. The post-CAR-T 12-month OS for patients with CGHM was 76% versus 84% without CGHM (p-0.016), and 12-month OS for patients with ICANS was 64% versus 91% without ICANS (p-0.001). The post-CAR-T median OS for patients with CGHM, patients with ICANS, and patients with both CGHM and ICANS were 17.1 months, 13.5 months, and 12.6 months, respectively. On multivariate analysis, after adjusting for ICANS, CGHM alone did not have an impact on OS [HR 1.76 (0.71, 4.37); p-0.2250] but ICANS continued to have a negative impact on OS [HR 3.03 (1.21, 7.57); p-0.0178]. Conclusions: Our study represents the largest study to date on CART-CGHM. CART-CGHM was seen in 32% of CAR-T patients and had a strong association with ICANS and lymphoma patients. ICANS was found in 63% of CART-CGHM patients. ICANS alone or CGHM with ICANS were associated with a negative impact on OS. Although the underlying biological mechanism of CART-CGHM is not clear, it likely represents a significant immune-mediated reduction in cerebral glucose uptake. We suggest that CGHM represents a novel metabolic complication of CAR-T therapy and significantly contributes to CAR-T therapy associated neuro-cognitive toxicity. Although CART-CGHM can resolve completely, our study also showed patients with persistent CGHM on post-CART follow up FDG-PET scans. As such, CART-CGHM can potentially result in chronic neuro-cognitive complications. The current therapeutic interventions for CRS and ICANS do not appear to be adequately effective for CART-CGHM. Further research, involving multiple institutions, is urgently needed for better understanding of CART-CGHM and to develop specific therapeutic interventions.

Introduction: Outcomes from multidisciplinary lymphoma tumor boards in the molecular era are limited, and the effects of transitioning to virtual formats during the COVID-19 pandemic are not well-documented. This study evaluates how the transition of the Mayo Clinic Lymphoma Tumor Board to a virtual format has impacted its effectiveness and operations. The board, part of the International Mayo Clinic Care Network (MCCN), involves case presentations, subspecialist reviews, and collaborative recommendations. Methods: The Mayo Clinic Lymphoma Tumor Board, an integral part of the Mayo Clinic Care Network (MCCN), conducted a comprehensive review of lymphoma cases from 2014 to 2024. The board's review process involves a structured approach including the presentation of clinical case details, radiology and hematopathology findings, proposed treatment options, relevant literature review, and discussions. From 2014 to 2024, the Mayo Clinic Lymphoma Tumor Board reviewed a total of 722 patients. The review process involves a multidisciplinary team, including physicians, pharmacists, clinical research associates, and trainees. Recommendations and changes related to radiology interpretation, pathologic diagnosis, and treatment approaches were documented and tracked prospectively. In March 2020, the board transitioned to a virtual format due to the COVID-19 pandemic. This shift allowed for remote participation and continued collaborative review while maintaining the board's structured approach and documentation practices. Results: In a total of 722 patients, changes in care were identified in 423 patients, including 287 with newly diagnosed lymphoma and 136 with relapse or refractory disease. Among those who experienced changes, 94 had diffuse large B-cell lymphoma, 49 had follicular lymphoma, 39 had marginal zone lymphoma, 36 had classical Hodgkin lymphoma, and 29 had mantle cell lymphoma. Prior to the COVID-19 pandemic, 431 patients were analyzed, with 217 (50.3%) experiencing changes. A total of 268 changes were documented among these patients. Changes in radiologic interpretation occurred in 9 patients (2.1% of 431 total patients). Pathologic diagnosis changes were noted in 42 patients (9.7%). Additional testing was recommended for 73 patients (16.9%), and clinical management was altered for 144 patients (33.4%). After transitioning to a virtual format, 291 patients were reviewed post-COVID, with 206 (70.8%) having recommended changes. The total number of change recommendations was 322, reflecting increases across all components compared to previous data, with adjustments for varying numbers of patients reviewed. Specifically, radiologic interpretation changes occurred in 21 patients (7.2%), pathologic diagnosis changes in 57 patients (19.6%), additional testing recommendations for 85 patients (29.2%), and clinical management alterations in 159 patients (54.7%). Conclusion: Transitioning to a virtual format in the Mayo Clinic Lymphoma Tumor Board's continued to demonstrate the effectiveness, with increased changes in diagnostic interpretations and clinical management. These results illustrate the potential of virtual tumor boards to improve collaborative decision-making and adapt to evolving clinical needs.

Introduction: CD20xCD3 bispecific antibodies (BsAbs) represent a major advance in the treatment of relapsed or refractory (r/r) large B-cell lymphoma (LBCL). In their pivotal trials, epcoritamab (Epcor) and glofitamab (Glofi) showed an overall response rate (ORR) and complete response rate (CRR) of 52-63% and 39%, respectively, in patients (pts) with r/r LBCL after 2 or more prior lines of therapy (LOT). Data on the efficacy and safety of BsAbs in standard of care (SOC) setting is limited. Here, we report our multicenter retrospective study on SOC BsAbs for the approved indication in r/r LBCL. Methods: All pts who received SOC BsAbs for r/r LBCL at four cancer centers in Florida were included. Pts who died before the first response evaluation were considered to have disease progression. Median follow up time was calculated using reverse Kaplan Meier (KM) method. Univariate analysis (UVA) and multivariate analysis (MVA) of response rates were done using logistic regression. UVA and MVA of PFS and OS were done using Cox proportional hazard model. Median PFS (mPFS) and median OS (mOS) were estimated using KM method. Results: As of June 1, 2024, a total of 69 pts received SOC BsAbs for r/r LBCL (43 epcor and 26 glofi). Forty pts (58.0%) were male; median age was 66 years (range 32-89); ECOG >= 3 in 14 (20.3%) pts; transformed indolent lymphoma in 20 (29.0%); Richter transformation in 3 (4.4%); HGBL with MYC/BCL2 rearrangements (double-hit lymphoma [DHL]) in 12 (17.4%); bulky disease>10cm in 33 (47.8%); IPI score >= 4 in 15 (21.7%). Pts received a median of 3 prior LOT (range 2-12); 46 (66.7%) had primary refractory disease; 40 (58.0%) received prior CD19 CAR-T therapy; 35 pts (50.7%) would not have met the inclusion criteria of the pivotal trials due to: ECOG>=3 (n=14), thrombocytopenia (n=11), neutropenia (n=2), CNS involvement (n=6), recent infection (n=6), prior CAR-T within 30 days (n=1), and CrCL<45 (n=2). Among the 69 pts, 65 were evaluable for response. At a median follow up of 7 months, the ORR and CRR were 52.3% and 26.2%, respectively. Median PFS was 4.2 months (m) (95%CI: 2.8-6.9). Median OS was 6.2m (95%CI: 5.9-not reached [NR]). The ORRs in pts without prior CAR-T (CART-naive), progressed after achieving CR/PR to prior CAR-T (CART-R), and not achieving CR/PR to prior CAR-T (CART-NR) were 13/25 (52.0%), 18/24 (75%), and 3/16 (18.8%), respectively, p<0.01. In the UVA of ORR, the following factors were associated with lower response: CART-NR (18.8% vs 63.3%, p<0.01) and ECOG >=3 (21.4% vs 60.8%, p=0.01). Bulky disease, IPI >=4, DHL, >=4 prior lines of therapy, DLBCL subtype or BsAb type was not associated with response. In MVA, only CART-NR was a significant predictor of lack of response to BsAb (odds ratio 5.6, 95%CI: 1.3-24). In the UVA of PFS, CART-NR and ECOG >=3 were associated with shorter mPFS (1.9m [95%CI: 0.6-3] vs 5.4m [95%CI: 4.0-NR] in CAR-T non-responders vs responders; 1.1m [95%CI: 0.4-3.2] vs 5.4m [95%CI: 3.2-NR] in ECOG>=3 vs <3). In the MVA, CART-NR and ECOG>=3 were associate with shorter PFS (HR 2.7, p<0.01 and 2.5, p<0.02, respectively). One of the 3 pts with Richter transformation had continuous PR at 5 months. Cytokine release syndrome (CRS) occurred in 21 pts (36.2%), including 4 (5.8%) grade (Gr) >= 3. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 12 pts (17.4%) with 6 (8.7%) Gr >= 3. Gr3-4 neutropenia was observed in 18 pts (26.1%); Gr3-4 thrombocytopenia in 10 (14.5%). Infection all grades and Gr >= 3 occurred in 26 pts (37.7%) and 19 pts (27.5%), respectively. Among them, bacterial infection was identified in 13, COVID in 5, fungal in 2, and CMV in 1 patient. Conclusion: BsAbs had comparable efficacy in SOC setting as in the pivotal trials. CRS and ICANS were mostly low-grade; however, a high incidence of serious infection was observed. Pts with no response to prior CAR-T also had poor BsAbs response. This could reflect a common mechanism of resistance to immunotherapy, either due to tumor characteristics or host T-cell exhaustion. Longer follow-up is needed to evaluate the durability of response.

Background: Immunochemotherapy is the current standard-of-care frontline therapy for diffuse large B-cell lymphoma (DLBCL). Our group previously reported that addition of the mTOR inhibitor everolimus to R-CHOP resulted in excellent efficacy in the Alliance N1085 trial (Witzig TE et al, Blood Cancer J, 2017, 7(6):e576), with 23 of 24 patients achieving event-free survival at 24 months (EFS24), supporting further investigation of PI3K/mTOR targeting in DLBCL. New insights into molecular classification of DLBCL suggest that multiple genetic subtypes of DLBCL (eg, MCD, BN2, ST2, and EZB per LymphGen classification) may be susceptible to PI3K/mTOR targeting. Therefore, we conducted a phase 1/1b trial to investigate the safety and efficacy of combination therapy with a novel PI3K inhibitor parsaclisib and standard immunochemotherapy. Methods: Adult patients with newly diagnosed DLBCL were eligible if any of the following was present: 1) non-GCB subtype per the Hans algorithm; 2) protein expression of either MYC (≥40%) or BCL2 (≥50%) by immunohistochemistry; or 3) MYC rearrangement by FISH. Patients with high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements were also eligible. Phase 1 followed a 3+3 design to determine the maximum tolerated dose (MTD) of parsaclisib (plus R-CHOP) to be used in Phase 1b (dose expansion). The primary efficacy endpoint in phase 1/1b was complete response (CR) rate by PET. A polatuzumab vedotin (Pola) safety lead-in cohort was added later to explore the safety and efficacy of parsaclisib (at MTD) plus Pola-R-CHP. Results: From July 2020 to May 2023, 50 patients were enrolled; 1 patient withdrew consent before study treatment and was excluded from this analysis. Nine patients were treated in Phase 1, 33 in Phase 1b, and 7 in the Pola cohort. The median age at diagnosis was 66 years (range 20-86), and 20 (41%) were female. Two (4%) patients had ECOG PS ≥2, 26 (53%) had elevated LDH, 19 (39%) had >1 extranodal site, 37 (76%) had stage III/IV, and 25 (51%) had high-intermediate or high-risk International Prognostic Index (3-5). 23 (47%) had non-GCB subtype, 23 (46.9%) had MYC or BCL2 single expression, 21 (42.9%) had MYC/BCL2 double expression, and 6 (12%) had MYC rearrangement (2 with BCL2 and/or BCL6 rearrangements). In Phase 1, 3 patients were treated at dose level 1 (parsaclisib 20 mg QD, d1-10) and 6 at dose level 2 (parsaclisib 20 mg QD, d1-14). No dose limiting toxicity was observed. Therefore, dose level 2 for parsaclisib was the MTD and was used in Phase 1b. In the Pola cohort (n=7), only 1 of 6 evaluable patients experienced significant toxicity (grade 3 diarrhea). Among all 49 patients, the most common treatment-related adverse event (TRAE) of any grade included neutropenia (83.7%), thrombocytopenia (79.6%), leukopenia (77.6%), lymphopenia (71.4%), anemia (71.4%), nausea (63.3%), fatigue (40.8%), peripheral sensory neuropathy (36.7%), constipation (24.5%), and diarrhea (22.4%), and the most common grade ≥3 TRAE included neutropenia (71.4%), leukopenia (69.4%), lymphopenia (49.0%), thrombocytopenia (20.4%), anemia (16.3%), febrile neutropenia (6.1%), and diarrhea (6.1%). In Phase 1/1b (n=42), the overall response rate (ORR) to parsaclisib plus R-CHOP was 97.6%, and the CR rate was 90.5%. After a median follow-up of 28.5 months (95% CI 27.7-32.7), the estimated 2-year progression-free survival (PFS) rate was 84.6% (95% CI 73.9-96.8), and the estimated 2-year overall survival (OS) rate was 95.1% (95% CI 88.7-100.0). In the Pola cohort, the ORR to parsaclisib plus Pola-R-CHP was 100% and the CR rate was 100%. After a median follow-up of 15.6 months (95% CI 13.5-NE), 1 patient had disease relapse at 11.95 months, and all patients were alive. Conclusions: Addition of the PI3K inhibitor parsaclisib to R-CHOP or Pola-R-CHP immunochemotherapy is considered safe in patients with newly diagnosed DLBCL. Combination of parsaclisib and standard immunochemotherapy resulted in high ORR and CR rate and encouraging preliminary PFS and OS outcomes patients with high-risk DLBCL. These data support further investigation of PI3K/mTOR targeting in newly diagnosed DLBCL in future trials.

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 < 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: Mature T-cell lymphomas (MTL) are a heterogenous group of diseases representing about 10-20% of non-Hodgkin lymphomas (NHL). Standard treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy yields poor long-term outcomes. Allogeneic hematopoietic cell transplantation (allo-HCT) is often considered as consolidation to improve outcomes, especially in younger patients. Methods: The study included adult patients (pts) with MTL who received an allo-HCT at Mayo Clinic (Rochester, Arizona and Florida) and the City of Hope Cancer Center between 2007 and 2023. Patients with cutaneous T-cell lymphomas (mycosis fungoides/Sezary syndrome) were excluded. The primary aim of the study was to evaluate long-term outcomes of allo-HCT in patients with MTL. Primary endpoints included progression-free (PFS), overall survival (OS), relapse rates, non-relapse mortality (NRM), and cumulative incidence of acute and chronic graft vs host disease (aGVHD and cGVHD). Our second aim was to assess the impact of specific disease and transplant related factors on outcomes of allo-HCT in MTL. These included a) disease status prior to allo-HCT, b) the intensity of the conditioning regimen, c) inclusion of total body irradiation (TBI) in conditioning regimens and the use of posttransplant cyclophosphamide (PTCy) based GVHD prophylaxis Results: A total of 75 pts, median age 48 (22-72) years, with MTL underwent allo-HCT between 2007 and 2023 and were included in the study population. Peripheral T cell lymphoma not otherwise specified (PTCL-NOS; n=42, 56%) was the most common histology followed by angioimmunoblastic T cell lymphoma (AITL; n=13, 17%). Patients had a median of 3 (range 1-8) prior therapies and 26 (35%) pts had undergone a prior autologous HCT (auto-HCT). At the time of allo-HCT, 45 (63%) pts were in complete remission (CR) and 26 (36%) pts were in partial remission (PR). The most common donor source was HLA-matched unrelated donor (MUD; n=34, 45%) and matched related (MRD; n=24, 32%) followed by haploidentical donors (haplo; n=8, 10.7%), mistmatched unrelated donors (MMUD; n=7, 9.3%) and umbilical cord blood (UCB; n=2, 2.6%). Fifty-four pts (72%) received reduced intensity conditioning (RIC) and 20 (26.7%) received total body irradiation as part of their conditioning regimen. The median radiation dose was 1200cGy. Ten pts (13%) received PTCy-based GVHD prophylaxis. Median follow-up of was 3 yrs (0.05-11.34). The 5-yr PFS and OS were 64.2% (53.5%-77%) and 71.3% (61.3%-82.9%), respectively; cumulative incidence of relapse and NRM were 14.5% (5.2 - 23%) and 23.5% (12.2%-33.4%), respectively. Cumulative incidence of grade II-IV and grade III-IV aGVHD at 100 days was 45.3% (32.3%-55.9%) and 9.8% (2.6%-16.5%), respectively. One-year rate of all grade cGVHD was 50.7% (36.5%-61.8%). Patients who underwent allo-HCT while in complete remission compared to those in partial remission were noted to have superior survival with OS of 77.4% vs. 60.7% (p=0.022); no difference was noted between the two groups regarding PFS and incidence of relapse. No difference in long-term outcomes was observed based on the intensity of conditioning regimens but patients who received conditioning regimens containing TBI vs those who did not were noted to have inferior PFS of 44.9% vs 70.5% (p=0.019), with no difference in OS (58.4% vs 75.6% [p=0.059]), relapse rates (30.4% vs 10.7% [p=0.086]) and NRM (30.5% vs 20.3% [p=0.18]). Patients who received PTCy based vs. non-PTCy based GVHD prophylaxis had lower rates of chronic GVHD at 1 yrs (22% vs 56% [p=0.038]) with no difference in other outcomes. Conclusion: Results of our analysis show that allo-HCT represents a curative option for patients with MTL with excellent long-term outcomes. These outcomes were further improved for patients who achieved a complete remission prior to allo-HCT. The intensity of the conditioning regimen did not affect outcomes but TBI containing conditioning regimens were associated with adverse PFS. Within the limitations of a retrospective analysis and a relatively small sample, these data suggest that, a non-TBI RIC regimen, especially when combined with PTCy based GVHD prophylaxis can lead to long term disease control with limited morbidity.

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 >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 <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.

Background: Despite effective front-line therapies, DLBCL & MM have high relapse rates. Novel therapies like CAR-T & bispecific antibodies (BsAb) offer deep & durable remission compared to salvage therapies, but have a unique toxicity profile (TP) that requires monitoring. With no head-to-head trials, the rationale for therapy selection may vary. This study explores provider choices, sequencing preferences, & access barriers. Methods: Two anonymous surveys (MM and DLBCL) of US-based Hematologists were conducted from 2/2024 to 6/2024, on practice settings, CAR-T & BsAb availability, treatment preferences & barriers. Responses were analyzed to assess preferences across clinical scenarios. Results: Surveys were completed by 37 MM & 45 DLBCL providers. Most were at centers offering both CAR-T & BsAb. Most gave CAR-T inpatient, & BsAb outpatient. CAR-T was given by 73% MM providers & 66% DLBCL (92% used Cilta-cel, 96% used Ide-cel; 100% used Axi-cel, 90% used Liso-cel & 73% Tisa-cel). In MM, 78% used Teclistamab, 60% Talquetamab & 24% Elranatamab. In DLBCL, 62% used Epcoritamab & 40% Glofitamab. Providers preferred CAR-T over BsAb in MM after 4+ prior lines of therapy (LOT) (89%), & in DLBCL after 2+ prior LOT (93%). CAR-T was favored more among academic providers & those at CAR-T centers. Practice volume did not impact selection. Among providers at centers with BsAb-only, CAR-T was preferred by 60% (MM) and 50% (DLBCL). Providers at centers without both favored CAR-T (MM: 75%, DLBCL: 86%). CAR-T was chosen for better outcomes, short treatment, center choice, & prior experience. Other factors that influenced decisions were lower incidence of cytopenia/infection & “BsAb effective post-CAR-T, less so vice versa” (MM), & “curative potential of CAR-T” (DLBCL). Logistical barriers & institutional constraints influenced BsAb selection: CAR-T unavailability, access to specialized centers, referral complexity, insurance delay, manufacturing delay & hospitalization needs. In MM, 78% providers preferred Cilta-cel over Ide-cel, especially academic providers & those with CAR-T experience. CAR-T volume did not impact selection. Cilta-cel was preferred due to perceived better response rate (RR), more experience, “progression-free survival (PFS) benefit”, center choice, & logistical issues with Ide-cel. Ide-cel was selected due to center choice, favorable TP & insurance preference. Teclistamab was preferred by 78% due to more experience, better RR, TP & center choice, Elranatamab by 11% (better TP, RR, & “PFS”), & Talquetamab by 11% due to having a non-BCMA target. Academic providers preferred Teclistamab (89% vs 50%), & nonacademic providers preferred Talquetamab (38% vs 4%) and Elranatamab (13% vs 8%). In DLBCL after 2+ LOT, 69% favored Axi-cel due to prior experience, RR, center choice, & logistical issues with other products. Liso-cel & Tisa-cel were chosen by 27% & 2%, respectively, due to favorable TP. Axi-cel was also preferred 2nd line by 73% for similar reasons, while 24% favored Liso-cel for its favorable TP. Epcoritamab was preferred by 56% (subcutaneous injection, more experience & center choice) & Glofitamab by 42% (shorter treatment duration, easy administration, more experience, & center choice). Practice setting & volume did not impact selection between products in DLBCL. InBCMA-naïve MM pts, majority (97%) chose an anti-BCMA agent over GPRC5D due to better RR, TP, prior experience, & center choice. InBCMA-exposed pts, most (92%) favored an anti-GPRC5D agent. In contrast in DLBCL, 80% chose CD19 CAR-T after prior CD19-directed therapy, & 18% chose CD20 BsAb. Therefore, antigen escape was less of a concern in DLBCL vs MM. For relapse after 2nd line CAR-T in DLBCL, 78% preferred BsAb over other salvage options due to better RR, TP, & more experience. Providers prioritized RR, survival, & TP in decision making. Treatment logistics, duration, frequency, & cost were less crucial. MM providers also prioritized quality of life, which was less so in DLBCL. There were no differences in priority based on practice setting & experience with CAR-T. Conclusion: The study highlights factors influencing therapy choices in MM & DLBCL. Despite CAR-T's potential for better outcomes, significant access barriers exist. Efforts to streamline referral pathways, logistics, & expanding availability are crucial to improve outcomes. Understanding these preferences & barriers can guide future management strategies.

Abstract Unirradiated patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) who undergo anti-CD19 chimeric antigen receptor T-cell therapy (CART) have a predominant localized pattern of relapse, the significance of which is heightened in individuals with limited/localized disease before CART. This study reports on the outcomes of patients with R/R NHL and limited (<5 involved sites) disease bridged with or without radiotherapy. A multicenter retrospective review of 150 patients with R/R NHL who received CART with <5 disease sites before leukapheresis was performed. Bridging treatment, if any, was administered between leukapheresis and CART infusion. Study end points included relapse-free survival (RFS), event-free survival (EFS), and overall survival. Before CART infusion, 48 patients (32%) received bridging radiotherapy (BRT), and 102 (68%) did not. The median follow-up was 21 months. After CART infusion, BRT patients had higher objective response (92% vs 78%; P = .046) and sustained complete response rates (54% vs 33%; P = .015). Local relapse in sites present before CART was lower in the BRT group (21% vs 46%; P = .003). BRT patients had improved 2-year RFS (53% vs 44%; P = .023) and 2-year EFS (37% vs 34%; P = .039) compared with patients who did not receive BRT. The impact of BRT was most prominent in patients who had ≤2 pre-CART involved disease sites, with 2-year RFS of 62% in patients who received BRT compared with 42% in those who did not (P = .002). BRT before CART for patients with limited (<5 involved disease sites) R/R NHL improves response rate, local control, RFS, and EFS without causing significant toxicities.

Abstract T-cell/histiocyte–rich large B-cell lymphoma (THRLBCL) is a rare histologic variant of LBCL. Limited data regarding CD19–directed chimeric antigen receptor T-cell (CART) therapy in relapsed/refractory (R/R) THRLBCL suggest poor efficacy. We investigated CART outcomes for R/R THRLBCL through the Center for International Blood and Marrow Transplant Research registry. A total of 58 adult patients with R/R THRLBCL who received commercial CD19-CART therapy between 2018 and 2022 were identified. Most patients (67%) had early relapse of disease (45% primary refractory) with a median of 3 (range, 1-7) prior therapies and were treated with axicabtagene ciloleucel (69%). At median follow-up of 23 months after CART therapy, 2-year overall and progression-free survival were 42% (95% confidence interval [CI], 27-57) and 29% (95% CI, 17-43), respectively. In univariable analysis, poor performance status before CART therapy was associated with higher mortality (hazard ratio, 2.35; 95%CI, 1.02-5.5). The 2-year cumulative incidences of relapse/progression and nonrelapse mortality were 69% and 2%, respectively. Grade ≥3 cytokine release syndrome and immune effector cell–associated neurologic syndrome occurred in 7% and 15% of patients, respectively. In this largest analysis of CD19-CART therapy for R/R THRLBCL, ∼30% of patients were alive and progression free 2 years after CART therapy. Despite a high incidence of progression (69% at 2 years), these results suggest a subset of patients with R/R THRLBCL may have durable responses with CARTs.