Bennani, N. Nora

Introduction: Diffuse Large B-cell Lymphoma (DLBCL) are aggressive B-cell non-Hodgkin lymphomas (NHL). One particular subtype, Primary Mediastinal B-cell Lymphoma (PMBCL), is often grouped with DLBCL, but it possesses distinct biological and clinical characteristics. While initial therapy successfully cures approximately two-thirds of patients (pts), those who do not respond or experience progression within the first two years have a poor prognosis despite novel cellular therapies and bispecifics and ultimately succumb to their disease. There is a pressing need for more effective therapeutic approaches in this patient population. Recent advances in the understanding of DLBCL pathogenesis have led to the targeting of various signaling pathways, including the PI3K-AKT-mTOR pathway. One such drug, copanlisib (C), a pan-PI3K inhibitor with potent PI3K-α/PI3K-δ inhibition, exhibited activity in both indolent and aggressive NHL. In preclinical studies using a DLBCL mouse model, treatment with C effectively reduced the immunosuppressive tumor-infiltrating T-regulatory cells (Tregs). Moreover, when combined with a surrogate anti-mouse programmed death -1 (PD-1) blocker, C demonstrated significant in vivo responses (75%) compared to the monotherapy groups (0%). These findings support the rationale for exploring the combination of nivolumab, a PD-1 blocker, and copanlisib (C-N) in DLBCL. Thus, a phase 2 prospective study has been developed, focusing on two relapsed/refractory (RR) cohorts (DLBCL and PMBCL), treated with the combination of C-N. A prespecified interim analysis was planned upon enrollment of 14 pts. Herein, we report outcomes of the 12 enrolled pts, as the study was halted prematurely due to a safety signal deemed possibly related to the combination. Study design: C 60 mg was given intravenously on days 1, 8, and 15 during cycles 1-8, and on days 1 and 15 in subsequent cycles. N 240 mg IV was given on days 1 and 15 during cycles 1-8, and 480 mg on day 1 on subsequent cycles. Each treatment cycle is 28 days. Therapy was given for up to 2 years, as long as there is no disease progression or unacceptable side effects. The primary objective of the study is to determine the ORR, which includes complete and partial responses (CR+PR). Secondary objectives include evaluating the safety of the combination, as well as assessing progression-free survival (PFS), duration of response (DOR), CR, and overall survival (OS). The study plan was to enroll a maximum of 106 pts, including a safety cohort of 6 pts. The study received funding from Bayer and conducted through NCI-CTEP (NCI Protocol #10193; NCT03484819). Results: Twelve pts who received at least one cycle of C-N were included in this analysis. Pt characteristics are illustrated in table 1. All enrolled pts had DLBCL histology. Only one patient received a prior autologous stem cell transplant. Interestingly 4/12 received prior chimeric antigen receptor T-cell therapy (CART). Of the 12 enrolled pts, seven were evaluated for response. The ORR was 25% (3/12) (95% CI: 5 - 57%), all CR. The median number of cycles received was 2.5 (range 1-24) with two pts receiving 23 and 24 cycles. Observed grade 3 and higher adverse events (AEs) were as follows: non-hematologic AEs in 10/12 (83.3%), while hematologic AEs were seen in 5/12 (41.7%) pts. A relatively higher incidence of cardiac events (4/12) were noted including one cardiac arrest after one cycle of therapy, and four atrial fibrillation events, all grade 3, but only two were deemed possibly attributed to therapy. The cardiac arrest was deemed unrelated to therapy. Conclusions: C-N combination had modest clinical activity in pts with R/R DLBCL with some prolonged responses. However, due to the relatively high number of cardiac events and the changing therapeutic landscape with recent approvals, a decision was made to halt the study. These findings likely reflect possibly older and sicker patient population. Biomarker studies for predictors of response are under consideration.

Introduction While chimeric antigen receptor (CAR)-T cell therapy has transformed the management of hematologic malignancies, it requires frequent monitoring for acute toxicities, almost universally achieved through mandatory hospitalizations, therefore utilizing a significant amount of healthcare resources. At Mayo Clinic in Rochester, MN, our standard practice is administering CAR-T cell therapy in the outpatient setting through a multi-disciplinary hospital-based outpatient (HBO) unit and remote patient monitoring (RPM) program. Our CAR-T RPM program consists of in-home, electronic health record-integrated technology to monitor vital signs and neurologic symptoms for 30 days post CAR-T infusion. Here we report the healthcare utilization outcomes of CAR-T patients managed in the outpatient setting enrolled in the RPM program. Methods Patients undergoing FDA-approved CAR-T cell treatment in the outpatient setting and participating in the CAR-T RPM program at Mayo Clinic Rochester were included in this IRB-approved study. Patient characteristics, healthcare utilization metrics, inpatient interventions, and patient satisfaction data regarding the RPM program were reviewed. Length of stay (LOS) includes any hospitalizations for which the admission date falls within the RPM monitoring period (CAR-T cell infusion to day +30), even if the hospitalization continued past day +30. Results A total of 123 patients participated in the CAR-T RPM program and underwent treatment in the outpatient setting. Median age at CAR-T infusion was 63 years (range 22 - 83), and most patients were male (n=78, 63%). Non-Hodgkin lymphoma was the most common diagnosis (n=74, 60%), followed by multiple myeloma (n=47, 38%), ALL (n=1, 1%) and other (n=1, 1%). During the PRM monitoring period, 19 (16%) patients were managed entirely in the outpatient setting. The remaining 104 (84%) patients required at least one hospitalization, with most patients (n=70, 57%) hospitalized only once [26 (21%) patients were hospitalized twice, and 7 (6%) patients were hospitalized 3 times, and 1 (1%) patient hospitalized 4 times during the monitoring period]. When considering the first hospitalization post CAR-T infusion, the median LOS was 6 days (range 2 - 47). When considering all hospitalizations post CAR-T, the median LOS was 8 days (range 2 - 47). Only 7 (6%) patients required an ICU stay, with a mean ICU stay of 0.2 days (standard deviation 0.9). Cytokine release syndrome (CRS) was noted in 92 (75%) of patients at a median of 3 days (range 0 - 18) post CAR-T infusion. All patients with CRS received tocilizumab, at a median of 4 days post CAR-T infusion. Steroids for CRS were administered in 63 (68%) of these patients. Neurotoxicity was reported in 45 (37%) patients at a median of 7 days (range 1 - 19) post CAR-T infusion. During the RPM monitoring period, patients were seen in our HBO unit with a median of 18 outpatient visits (range 4 - 30). Patient survey data, obtained at the end of the RPM monitoring period, were available from 37 patients. The majority of patients felt that the RPM program helped them feel comfortable managing their health at home, were able to reach a team member, and receive an appropriate response promptly. The majority of patients felt comfortable using the RPM equipment and interacting with providers virtually. Overall, 83% of patients were satisfied with the RPM program and 6% were neither satisfied nor dissatisfied. When asked about the reason for disappointment, technical difficulties/issues with the devices were the themes mentioned by the few patients (11%) who were unsatisfied with the RPM program. Conclusion: Despite the complexities and frequent monitoring associated with CAR-T cell therapy, outpatient CAR-T cell treatment is a feasible model of care. As the standard practice at our institution, the CAR-T RPM program was part of the management of nearly all patients undergoing an FDA-approved CAR-T product in the outpatient setting. RPM in the acute setting post CAR-T infusion is a well-received practice initiative by the majority of patients, including a high level of comfort utilizing the RPM equipment and virtual interaction with the RPM providers.

Background: Patients (pts) receiving FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy or Bispecific antibody Teclistamab (Tec) are commonly managed in the inpatient setting given the common adverse events such as cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome ICANS. We have previously reported that hospital-based outpatient (HBO) management of pts receiving CAR-T is feasible and safe (Bansal et al, ASH2022). In 2023, HBO management at our institution began incorporating home health visits and management of grade 1 CRS in outpatient setting for select pts receiving standard of care (SOC) CAR-T. Here, we report outcomes of our updated practice. Methods: We retrospectively analyzed medical records and remote monitoring data of adult pts who received SOC CAR-T or Tec between 10/2020 and 7/2023 at Mayo Clinic, Rochester under an IRB approved protocol. Results: In 3/2023, pts deemed to be low risk for severe CRS (fever onset >= 3 days from infusion, CRP<100) received HBO management for grade 1 CRS, including outpatient administration of tocilizumab. If CRS improved or resolved, outpatient monitoring was continued. If CRS persisted within the observation period on HBO, pts were admitted. Recurrent CRS after the first episode were all managed inpatient. Nine pts met these criteria for HBO CRS management and their outcomes were compared to those who received initial inpatient (INPT) CRS management (INPT, n=17) during the same timeframe, as well as the outcome of 164 pts who had CRS management INPT prior to our practice change (Table 1). Two-third of the pts with initial management of CRS outpatient did not require hospitalization. Median time to hospitalization trended later than those managed inpatient at the onset of CRS. The duration of hospitalization was comparable for all pts admitted between initial HBO and INPT CRS management. However with fewer admissions in the initial CRS HBO group, the average hospitalization days (LOS) per patient treated for that group was lower compared to initial INPT CRS management. Data on additional pts will be presented at ASH. In 1/2023, pts on RPM with no ongoing CRS symptoms, no language barriers, and no compliance concerns received home health visits during weeks 3 and 4 post CAR-T infusion in place of clinic visits on HBO. Home health visit team communicated with HBO staff to review assessment and plan. Changes in HBO utilization will be presented. Finally, 24 pts received 223 Tec infusions on HBO. Median age was 66 years, 15 (61%) were males, 9 (38%) had high risk cytogenetics. The median prior lines of therapy was 5. Among these pts, 220/223 (99%) doses were performed on HBO and 204/220 (93%) infusions never required admission for management. Twenty pts enrolled in RPM (Figure 1). An average of 2 alerts were generated per patient during the 2 week period and median time from infusion to alert was 1.5 days. Majority of alerts were resolved over a phone call and only 13/114 (11%) alerts required a physician visit/hospital admission. Of the 16 Tec infusions resulting in admission, 4/16 (25%) required re-admission resulting in a total of 20 hospitalizations. Admissions mostly occurred during step-up dosing (18/20; 90%). Most common reason for first admission was fever (13/16, 85%) and median time to admission was 1 day from infusion. Median LOS was 1.5 days (range, 0-12). In terms of CRS, majority were Grade 1 (12/13, 93%) which were managed with steroids (dexamethasone/ prednisone) alone. One patient had CRS grade 4 event, in the setting of concurrent decompensation during dialysis, and was treated with steroids, tocilizumab, vasopressor, CRRT, thoracentesis, intubation and mechanical ventilation. The rate of second CRS event after management of first CRS with steroid (dexamethasone/ prednisone) was 15% (2/13). These second CRS episodes also resolved with steroid alone. Data on additional pts receiving Tec will be presented at ASH. Conclusion: Our data showed that additional advances in outpatient practice, including initial outpatient management of CRS and outpatient administration of Tec step up dosing are feasible, safe and reduce hospital resource utilization.

Background: Oncolytic virotherapy, an innovative immunomodulatory therapeutic approach, is currently being investigated for its potential in treating relapsed refractory (R/R) hematologic malignancies. This study focuses on the use of an engineered Vesicular Stomatitis Virus called VSV-IFNβ-NIS, a bullet-shaped rhabdovirus which encodes both interferon beta (IFNβ) and sodium iodine symporter (NIS) with particular tumor cell tropism. Viral IFNβ serves as an indicator of viral proliferation and boosts the host's anti-tumor immune response. This is a phase 1 clinical trial with the identifier NCT03017820, wherein patients (pts) with R/R multiple myeloma (MM), and non-Hodgkin lymphoma (NHL) are treated with a single systemic administration of VSV-IFNβ-NIS. Study Design and Methods: Patient Eligibility Criteria: The Mayo Clinic Institutional Review Board approved the protocol. The study includes adult patients with relapsed or refractory multiple myeloma (MM), or T-cell lymphoma (TCL). For MM or plasmacytoma, patients should have <15% plasma cells and a largest diameter of <5 cm. TCL patients should have a mass <5 cm. Study Design: This is a single-center phase 1 trial aiming to determine the maximum tolerated dose of VSV-IFNβ-NIS in patients with R/R MM, and TCL. Secondary objectives included assessing the safety profile and estimating the clinical response rate of VSV-IFNβ-NIS. Correlative objectives involved monitoring viral replication through plasma IFN-β transgene levels and using SPECT/CT imaging with the NIS gene. Viral genomes were measured through quantitative reverse transcription (qRT) polymerase chain reaction (PCR) of VSV RNA, and any virus shedding was examined in body fluids. The tested doses were 5 × 109 TCID50, 1.7 × 1010, 5 × 1010, and 1.7 × 1011 TCID50. The virus was administered via IV infusion over 30 minutes, and patients received 650 mg acetaminophen and 50 mg diphenhydramine hydrochloride before infusion and every 6 hours for 24 hours to manage fever and hypotension. Two expansion cohorts at DL4 have been added (20 additional PTCL, 10 B-cell lymphoma and histiocytic neoplasms) to obtain additional data on tolerability and efficacy and biomarkers of response in these histologies. Safety and Response Assessments: All patients undergo toxicity evaluation, and adverse events (AEs) assessment using the Common Terminology Criteria for Adverse Events (CTCAE) version 4 criteria, except for cytokine release syndrome (CRS) grading, which follows the 2014 Lee criteria. Dose escalation and tolerability are based on the standard 3+3 phase 1 trial design. Ruxolitinib is added from days 2-5 or day -1 to day 9 depending on the arm to mitigate IFNβ toxicity. Response assessment followed the International Myeloma Working Group criteria for MM and the Lugano Classification for NHL and histiocytic neoplasms. Pharmacodynamic and Pharmacokinetic Analyses: For viremia and viral shedding assessment, RNA is isolated from whole blood, mouth rinse, buccal swabs, and urine samples. Quantitative RT-PCR determined VSV-nucleocapsid (N) RNA copy number, and virus shedding is assessed through coculturing samples on Vero cells. Anti-VSV antibodies are evaluated using the standard plaque reduction neutralization assay. Plasma cytokine levels are measured with a 30-plex human cytokine kit, and human IFN-β levels is quantified using an enzyme-linked immunosorbent assay (ELISA) kit. Statistical Analysis: Incidence of dose-limiting toxicities and AEs are tabulated by dose level (DL). AEs are summarized by type, maximum grade, and duration across patients in each DL. Spearman rank correlation tests are used evaluated correlations between laboratory-based measures, and Wilcoxon rank sum tests compared continuous measures between response groups. Response rates will be summarized by DL and disease group, with estimated response rates and corresponding 95% binomial confidence intervals calculated.

Background: Cytopenias are a common complication of and prolonged (beyond month 3 post CAR-T infusion), severe (grade 3 or higher) cytopenias can be difficult to manage. Stem cell boosts have been reported to restore hematopoiesis; however, stem cells would need to be available prior to CAR-T therapy for potential use post CAR-T. Most lymphoma patients and limited number of myeloma patients may have pre-collected stem cells in storage. Identifying patients at high risk for prolonged and severe cytopenia post CAR-T at the time of CAR-T evaluation (baseline), before leukapheresis, can help identify the patients for coordination of stem cell collection during CAR-T manufacturing and increase the likelihood that the collected stem cells would be used. In this study, we aim to identify clinical variables at the time of CAR-T evaluation, prior to leukapheresis, that are associated with severe cytopenias at month 3 post CAR-T infusion and identify patients who could be considered for pre-emptive stem cell collection prior to CAR-T therapy. Methods: We conducted a retrospective analysis of patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) who received CAR-T products at Mayo Clinic from 01/2016 to 06/2022. Patients with progressive disease in the first year post CAR-T were excluded from the analysis. Baseline (at CAR-T evaluation, prior to leukapheresis) variables were compared between those with and without severe cytopenia at month 3 post CAR-T. Severe cytopenias were defined as hemoglobin (Hg) < 8 g/dL, absolute neutrophil count (ANC) < 0.5 x 10 9/L, and/or platelet count (PLT) < 50 x 10 9/L. Statistically significant variables (p<0.05) by analysis were examined for statistical significance in multivariate analysis (MVA). Results: Among the 166 patients who received CAR-T (88 NHL, 78 MM) during the study period, 31 (18.67%) had a severe cytopenia at month . Twenty baseline variables were examined; HGB, PLT, ANC, and c-reactive protein (CRP) We devised a cytopenia risk score using 1 point each for Hg<10 or PLT<100k at baseline, with a range of 0 to 2. Demographics and clinical outcome by cytopenia risk score is shown in Table 1B. A higher percentage of patients with a score of 1 or 2 had a severe cytopenia at month 3 (Figure 1). In particular, there was a . In addition Conclusion: Baseline cytopenias before leukapheresis may identify patients with increased risk for severe cytopenias at month 3 post CAR-T. These patients can have continued slow hematopoietic recovery in the first year. Stem cell collection, if feasible, could be considered before CAR-T to alleviate post-CAR-T severe prolonged cytopenias.

Background Mantle cell lymphoma (MCL) is an incurable form of aggressive non-Hodgkin lymphoma. Treatment choice at diagnosis is based on tolerability of cytarabine and high-dose chemotherapy. With a median age of 60-70 years, many patients are ineligible for aggressive treatment. Bendamustine and rituximab (BR) is a reasonable treatment option (E1411, Smith MR et al. ASH 2022) for this patient population and venetoclax (VEN) has shown pre-clinical evidence of synergy with chemoimmunotherapy. PrECOG 0405 was designed to evaluate the addition of VEN to BR in previously untreated patients with MCL aged over 60 years. Methods Eligible patients included those that were previously untreated and diagnosed with MCL as defined as the presence of t(11;14) by FISH or cyclin D1 expression by IHC. Patients must have been at least 60 years of age or older on D1C1 of therapy with a good performance status (ECOG 0-2). Adequate marrow and organ function was required, specifically a creatinine clearance of ≥ 40 mL/min. Treatment administration is summarized in Figure 1. Dose of bendamustine was either 90mg/m 2 D1&2; or, for subjects over the age of 75 years, 70mg/m 2 was allowed per investigator discretion. VEN was dose escalated during Cycle 1 to 200mg. At the time of C2, BR was repeated and VEN was also escalated to 400mg. With C2-6, VEN 400mg PO daily was given D1-10 only. Primary endpoint was PET-negative complete response (CR) rate at end of treatment (EOT) by Lugano Criteria. A negative bone marrow biopsy was required to confirm CR if involved at screening. Minimal residual disease (MRD) by next-generation sequencing was performed at the EOT. Maintenance rituximab was encouraged per investigator discretion. This was a single arm study with an original accrual goal of 53 subjects to detect a 15% improvement in CR rate compared to historical data. However, due to slow study accrual during COVID pandemic and preliminary efficacy data from E1411 study, the statistical parameters were updated after 25 subjects had been accrued. The revised accrual goal was 33 patients to obtain 32 eligible and treated patients, which provided 81.8% statistical power to detect a 17% difference in CR rate (from 60% [E1411 data] to 77%) using an exact binomial test with a 1-sided alpha of 11.6%. This combination regimen will be considered promising if 23 or more (out of 32) patients attain CR. Results From January 2020 to March 2022, 33 subjects enrolled and were treated on study. Subject characteristics are listed in Table 1. Seven (21%) unique subjects were treated with 70mg/m 2 of bendamustine during induction cycles. Laboratory tumor lysis syndrome (TLS) was seen in 2/33 during C1 only; clinical TLS was not seen. Treatment was generally well tolerated with treatment-related adverse events (TRAE) of Grade ≥3 and occurring in >10% of subjects being neutropenia (n=5, 15%), thrombocytopenia (n=5, 15%) and lymphopenia (n=9, 27%). Other common non-hematologic TRAE of all grades were nausea/vomiting (n=26, 79%), diarrhea (n=10, 30%), and fatigue (n=17, 52%). There were 4 (12%) instances of COVID-19/COVID-19 pneumonia considered treatment related. Dose adjustments and delays for any drug occurred in 36% and 67% of subjects respectively. 22/33 (66.7%) subjects completed 6 cycles of BR-VEN. Maintenance rituximab was administered in 19/33 (57.6%) of subjects. Overall response rate was 97% (32/33) and PET-negative bone marrow biopsy confirmed CR Rate at EOT was 85% (28/33), achieving the primary endpoint (≥23 CRs). MRD at EOT is under analysis. With a median survival follow up of 21.5 months (mo), Median PFS and OS were not reached; estimated 2-year PFS and OS was 69.7% and 81.1% respectively. During follow up, there have been 6 deaths, 4 from COVID-19 (all in remission), one from influenza A (in remission), and one from disease progression (non-responding pt). There have been 2 other progression events who are alive. Conclusions BR-VEN was generally well-tolerated in this older patient population though GI toxicities were common. With a PET-negative CR rate of 85%, the combination is promising but longer follow-up is needed. There was a competing risk of death related to upper respiratory viruses identified, mostly COVID-19, as has been seen in other BR-based protocols during the COVID-19 pandemic. MRD analysis and survival data will be updated.

Introduction Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy that induces durable responses in patients with relapsed or refractory large B-cell lymphoma. At a median of 63.1 months follow-up on the ZUMA-1 trial, median overall survival (OS) was 25.8 months with 5-year OS and PFS (progression-free survival) estimates of 42.6% (95% CI, 32.8-51.9) and 31.8% (95% CI, 22.9-41.1), respectively (Neelapu, Blood 2023). We previously reported outcomes of axi-cel patients treated with standard of care therapy, including 42% who did not meet eligibility criteria for ZUMA-1 based on co-morbidities (Nastoupil, JCO 2020). Here we report results from this cohort at a median follow up of 58 months, as well as late outcomes of interest. Results The US Lymphoma CAR-T Consortium is comprised of 17 US academic centers who contributed data independent of the manufacturer. Two hundred and ninety-eight patients underwent leukapheresis with intent to manufacture standard of care axi-cel (n=298) as of September 30, 2018. In infused patients (n=275), OS and PFS were calculated from date of infusion. After a median follow-up of 58 months, median OS was 34.9 months (95% CI 23.4 - 44.8) with the OS at 3, 4, and 5 years of 49.1% (95% CI 42.9 - 54.9%), 43% (95% CI 36.8 - 48.9%), and 40.3% (95% CI 34.2 - 46.4%), respectively. The median PFS was 8.7 months (95% CI 5.87 - 16.6) and the 3-,4-, and 5- year PFS were 36.1% (95% CI 30.4 - 41.8%), 30.7 (95% CI 25.2 - 36.4%), and 28.5% (95% CI 23 - 34.2%), respectively. Results of multi-variable modeling were similar to our prior analysis: male sex (HR 1.56, 95% CI 1.08 - 2.27, p =0.02); LDH above the upper limit of normal (HR 1.6, 95% CI 1.12 - 2.30, p = 0.01); ECOG status of 2-4 (HR 2.02, 95% CI 1.33 - 3.07, p = <0.001); and elevated bilirubin > 1.5 (HR 5.68, 95% CI 2.21 - 14.6, p = <0.001) were associated with decreased OS. Factors associated with decreased PFS included male sex (HR 1.68, 95% CI 1.20 - 2.37, p = 0.003), LDH above the upper limit of normal (HR 1.82, 95% CI 1.31 - 2.53, p = <0.001), ECOG status of 2-4 (HR 1.93, 95% CI 1.30 - 2.86, p = 0.001), elevated bilirubin (HR 3.68, 95% CI 1.45 - 9.37, p = 0.006) and receipt of 3 or more prior lines of therapy (HR 1.49, 95% CI 1.03 - 2.13, p = 0.032). We also assessed events of interest including late PFS events and causes of non-relapse mortality (NRM). One hundred and ninety-one PFS events occurred after axi-cel infusion during the follow-up period, 151 due to lymphoma progression and 40 NRM. In the first 12 months post infusion, 131 progression events occurred,13 between 1 and 2 years post infusion, and 7 relapses after 2 years with the latest occurring 46.4 months after infusion. Thirteen NRM events occurred in the 1st year post infusion, 6 between 1- and 2-years post infusion and 21 occurring later than 2 years after infusion. Of the 40 NRM events, 21 were secondary to infection including fungal infections (n = 3, 2 candidemia, 1 candidemia and pneumocystis jiroveci pneumonia), JC encephalitis (n=1) and COVID-19 (n = 2). Nine deaths were attributed to secondary malignancy. Other causes of NRM included cerebral edema (n=1), HLH (n=1), intracranial hemorrhage (n=1), suicide (n=1), and unknown (n=6). The 5-year cumulative risk of relapse was 55.2% and the 5-year risk of non-relapse mortality was 16.2%. Excluding non-melanoma skin cancers, twenty-three of 275 (8%) patients were diagnosed with subsequent malignancy after axi-cel treatment: 14/275 (5%) patients were diagnosed with myeloid malignancies (MDS (n=11), AML (n=2), CMML (n=1)); other malignancies included anal squamous cell carcinoma (ca) (n=1); histiocytic sarcoma (n=1); prostate ca (n=1); endometrial ca (n=1); lung ca (n=1); merkel cell ca (n = 1), mesothelioma (n=1), B-ALL (n = 1), and AITL (n=1). Conclusion This multi-center retrospective study showed similar 5-year results to the ZUMA-1 trial with a 5-year PFS and OS of 28.5% and 40.3%, despite including patients who did not meet ZUMA-1 eligibility criteria based on comorbidities. Non-relapse mortality was primarily due to infection and secondary malignancy. This report supports the curative potential of axi-cel but highlights the competing risk of NRM in this high-risk patient population.

Background Central nervous system (CNS) involvement is a rare complication (<5% of cases) of mantle cell lymphoma (MCL) and is associated with poor outcomes, highlighting the need for novel treatment approaches. We report the outcomes of a large cohort of patients (pts) with CNS MCL from Mayo Clinic and Memorial Sloan Kettering Cancer Center (MSKCC). Methods MCL pts with CNS involvement seen at Mayo Clinic and MSKCC between 1/2000-1/2021 were included. CNS involvement was defined by histologically confirmed CNS MCL, CSF analysis demonstrating lymphoma cells, and/or neuroimaging findings compatible with CNS lymphoma. Medical records were reviewed for baseline characteristics, treatment, and outcomes. First-line MCL chemotherapy was categorized into higher intensity chemotherapy (i.e., anthracycline-based +/- high-dose cytarabine), moderate intensity chemotherapy (i.e., bendamustine-based regimens or single agent chemotherapy), and other. CNS treatment regimens were categorized as intrathecal (IT) therapy alone, systemic therapy (with CNS penetration such as IV cytarabine or IV methotrexate) with/without IT therapy, regimens with Bruton's tyrosine kinase inhibitors (BTKi), chimeric antigen receptor T cell (CAR-T) therapy, or radiation alone. Kaplan-Meier method was used for time to event analysis. Forest plots were developed using univariable Cox proportional hazards models. Results Seventy patients were included in the cohort, 34 from MSKCC and 36 from Mayo Clinic. Median age at MCL diagnosis was 65 years (range 56-72) and 52 were male (74%). MIPI score was available in 60 pts: low (n=10, 17%), intermediate (n=20, 33%), and high (n=30, 50%) risk. First line therapy included: higher intensity chemotherapy (n=42, 60%), moderate intensity chemotherapy (n=25, 36%) and other (n=3, 4%). Twenty-five (36%) pts underwent autologous hematopoietic cell transplantation in CR1. Median time from initial MCL diagnosis to CNS involvement was 24 months (m) (range 0-167). Four (6%) pts had CNS involvement at initial diagnosis. Abnormal CNS imaging was reported in 53 (76%) pts: leptomeningeal (n=37), leptomeningeal and parenchymal (n=4), parenchymal (n=8), orbital (n=4). The most common regimen following CNS diagnosis was systemic therapy with or without IT therapy (n=34, 54%) followed by treatment including BTKi (n=13, 21%), IT alone (n=10, 16%), radiation alone (n=3, 5%), and treatment including CAR-T (n=3, 5%). Three patients elected hospice care and four patients had missing/unknown CNS treatment. The overall CNS response to therapy was available in 54 patients: CR in 22 (41%) pts, PR in 8 (15%), SD in 11 (20%), and PD in 13 (24%) pts. Of the 70 patients, 63 died. Median follow up was 6.9 years (range: 1.6-11.2) from initial MCL diagnosis and 2.1 years from CNS diagnosis (range: 0.4-7.9). Median OS from MCL diagnosis was 3.4 years (95% CI: 2.4-4.6). In univariable Cox models, sex, stage, performance status, Ki67, or first line systemic chemotherapy type were not significantly associated with OS from MCL diagnosis. Low risk MIPI score (score < 5.7) was associated with favorable OS (HR 0.31, 94% CI: 0.12-0.77; p value 0.01) compared to high risk. First-line treatment and treatment intensity were not associated with a significant difference in OS. Median PFS for the first CNS-directed therapy was 2.4 m (95% CI: 1.7-4.3). Cause of death was disease-related in a majority (n=49, 78%) of pts and therapy-related in 10% (n=6). The remaining 8 deaths had cause of death reported as missing or other (13%). Median OS from CNS involvement was 5.1 m (95% CI: 3.3-10.0) (Figure 1). When assessing OS from time of CNS diagnosis, treatment regimens incorporating BTK inhibitors were associated with a more favorable OS compared to systemic therapy +/- IT therapy (HR=0.37, 95% CI: 0.16-0.89, p value=0.03) (Figure 2). Conclusions Our dual center series confirms patients with CNS involvement by MCL have poor outcomes. When evaluating OS from the time of CNS diagnosis, novel therapies, including BTKi and CAR-T, may be more effective than CNS-penetrant chemotherapy for treatment of CNS relapse suggesting newer therapeutic approaches are required to improve outcomes.

AbstractAnti‐CD19 chimeric antigen receptor T‐cell therapy (CART) has revolutionized the outcomes of relapsed and/or refractory B‐cell non‐Hodgkin lymphoma. However, CART is still limited by its availability, toxicity, and response durability. Not all patients make it to the CART infusion phase due to disease progression. Among those who receive CART, a significant number of patients experience life‐threatening cytokine release syndrome toxicity, and less than half maintain a durable response with the majority relapsing in pre‐existing sites of disease present pre‐CART. Radiation therapy stands as a promising peri‐CART and salvage treatment that can improve the outcomes of these patients. Evidence suggests that bridging radiotherapy prior to CART controls the disease during the manufacturing period, augments response rates and local control, cytoreduces/debulks the disease and decreases the severity of cytokine release syndrome, and may prolong disease‐free intervals and survival especially in patients with bulky disease. Consolidative radiotherapy for residual post‐CART disease alters the pattern of relapse and improves local recurrence‐free and progression‐free survivals. Salvage radiotherapy for relapsed post‐CART disease has favorable survival outcomes when delivered comprehensively for patients with limited relapsed disease and palliates symptoms for patients with diffuse relapsed disease. The biology of the disease during the peri‐CART period is poorly understood, and further studies investigating the optimal timing and dosing of radiation therapy (RT) are needed. In this review, we tackle the most significant challenges of CART, review and propose how RT can help mitigate these challenges, and provide The Mayo Clinic experts' approach on incorporating RT with CART.