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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 : Most older patients (pts) with relapsed or refractory (R/R) AML cannot tolerate intensive treatment and are not eligible for curative allogeneic hematopoietic cell transplant (alloHCT). 131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells while sparing toxicity to healthy organs. 131I-apamistamab led induction and conditioning can thus provide these pts with access to alloHCT. Methods: The SIERRA trial (NCT02665065) is a multi-center, randomized, controlled Phase 3 study comparing the rate of durable complete remission (dCR) lasting >6 months (mos) after complete remission with/without platelet recovery (CR/CRp) between two groups: 131I-apamistamab led induction and conditioning followed by alloHCT vs physician's choice of conventional care (CC). Pts were randomized (1:1) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. CR/CRp assessment was 28-56 days post alloHCT or 28-42 days post initiation of therapy on the CC group. Pts in the CC group not achieving leukemia-free state could crossover (CO) to 131I-apamistamab. Here we report the results of a post hoc analysis to determine if the presence of various risk factors (i.e., Karnofsky Performance Status (KPS) <90, HCT Comorbidity Index >3, age >65, adverse-risk cytogenetics, venetoclax failure prior to randomization) influenced achievement of dCR in pts treated with 131I-apamistamab. Results: In total, 153 pts were randomized (CC, n=76; 131I-apamistamab, n=77). All pts who received the therapeutic dose of 131I-apamistamab (n=66) underwent alloHCT vs 14 (18.2%) in the CC group. Of evaluable pts, dCR rates at 6 mos were 22% in the 131I-apamistamab group vs 0% in the CC group (95% CI;12.29, 34.73; p<0.0001). A total of 19 pts (13, 131I-apamistamab group; 6, CO) achieved dCR. Table 1 shows the pt, disease, and transplant characteristics of dCR vs. non-dCR pts. Eight of the 19 pts (42.1%) had primary induction failure and the median time to randomization from diagnosis was 5.4 mos. Approximately 50% of pts (9/19) had adverse-risk cytogenetics. Over 35% (7/19) of the pts had failed prior venetoclax and the median number of prior treatments was 3 (range 1-5). A total of 10/19 (52%) pts had KPS of <90% and a comorbidity index of >3. There was no difference in the rate of dCR when stratifying by number of risk factors for a given pt (0 to 5) with 27% for pts with 0-1 risk factors, 14% for pts with 2-3 risk factors, and 11% for pts with 4-5 risk factors (p=0.251). Conclusion: Pts with R/R AML who have multiple risk factors such as adverse risk cytogenetics, age >65, venetoclax failure, high comorbidity index or poor KPS are typically not considered for alloHCT due to high transplant-related mortality and post-transplant relapse rates. 131I-apamistamab was effective in achieving durable responses in R/R AML pts irrespective of the presence of multiple risk factors and successfully enabled alloHCT in such pts due to its targeted mechanism of action.

Background Teclistamab, the first-in-class B-cell maturation antigen (BCMA) x CD3 bispecific therapy was recently approved by the FDA for the treatment of triple-class exposed relapsed or refractory multiple myeloma (MM) after ≥ 4 prior lines of therapy. Because of the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), the step-up dosing (SUD) of teclistamab is commonly administered in an inpatient setting among early users. Mayo Clinic has a well-established hospital-based outpatient program for novel immunotherapies. Since the FDA approval, teclistamab SUD has been administered as part of this program. Each dose of the SUD is administered in an outpatient setting, and the patient is given a remote monitoring kit to regularly measure vital signs and stay connected with the command center for signs and symptoms of CRS and ICANS throughout the entire SUD period. This study aimed to evaluate early safety outcomes and healthcare resource utilization during SUD in real-world (RW) patients who initiated teclistamab under the outpatient administration model across 3 Mayo Clinic locations (Rochester, MN, Phoenix/Scottsdale, AZ, Jacksonville, FL). Methods This was a retrospective study using Mayo Clinic's electronic medical records from October 26, 2022 to June 12, 2023. Eligible patients were adults diagnosed with MM who had initiated commercial teclistamab at any of the 3 Mayo Clinic locations. Patient characteristics, rates and severity of CRS and ICANS, as well as healthcare resource utilization during SUD were described. Time between teclistamab administration and patient check-out was reported for SUD and treatment doses, respectively. Results At the time of data cutoff, 39 patients received at least 1 teclistamab dose across the 3 locations (median age 67.2 years; male: 74%; White: 87%; non-Hispanic: 92%), including 36 patients who initiated teclistamab SUD directly in an outpatient setting. A total of 8 (21%) patients had MM with high-risk cytogenetics and 14 (36%) had prior exposure to other BCMA-targeted therapies. Prevalent comorbidities prior to receiving teclistamab included anemia (77%), hypertension (56%), lytic bone lesions (51%), neutropenia (49%), and hypogammaglobulinemia (41%). Renal impairment or failure was observed in 31% of the patients (Table 1). Almost all patients received acetaminophen (95%), diphenhydramine (95%), and dexamethasone (92%) as pre-medications on the same day as teclistamab administrations during SUD. Of the teclistamab doses with clinic time data, the majority (62%) of doses during SUD required 30 minutes to 1 hour of clinic time for monitoring between administration and check-out. After SUD, the clinic time for weekly treatment doses decreased to less than 30 minutes for most (79%) doses (Figure 1). In patients who completed SUD by data cutoff (n = 37), most patients (70%) received the SUD on a 3-day dose interval (i.e., day 1, 4, 7). The mean time between the first and third doses was 6.3 days. Among the 37 patients with complete SUD, 12 (32%) developed CRS. The highest CRS grade was grade 1 for 10 patients; 1 patient had a grade 2 CRS, and 1 patient had a grade 4 CRS. The patient with grade 4 CRS concurrently decompensated during a dialysis session and all symptoms were considered for CRS grading. A total of 6 patients had recurrent CRS, including 1 patient with 3 events during SUD. All patients who developed CRS during SUD (n=12) were admitted to the hospital for treatment, with a total of 19 admissions across all patients and a median length of stay of 1.7 days per admission. Among patients who were admitted for CRS (n=12), the majority were treated with acetaminophen (92%), diphenhydramine (83%) and dexamethasone (83%); tocilizumab was given to the 2 patients with CRS grade 2 or higher. Only 1 ICANS event (grade 2) was observed in 1 patient during SUD, after dose 3, and the patient was admitted to the hospital for treatment. Conclusion This study evaluated early RW safety outcomes of teclistamab under an outpatient administration model and found the CRS rate and severity to be comparable with other RW evidence generated from various data sources. Outcomes related to teclistamab SUD from Mayo Clinic supported the safety and feasibility of outpatient administration model as a potential option to reduce healthcare resource utilization and improve treatment experiences.

Introduction: AutoHCT is an effective therapy for patients (pts) with DLBCL who are refractory or relapse following first-line chemotherapy, but long term outcomes remain suboptimal. The BTK inhibitor ibrutinib has shown promising activity in pts with ABC-DLBCL (Wilson et al, Nat Med 2015). In 2016 we launched a randomized phase III clinical trial to evaluate the addition of ibrutinib to AutoHCT as part of conditioning and as consolidation therapy for pts with relapsed/refractory ABC-DLBCL. Patients and Methods: Following assessment of open-label treatment in a safety cohort of 6 pts, we randomly assigned pts with chemotherapy-sensitive persistent or relapsed ABC-DLBCL to receive ibrutinib 560 mg [Arm A] or placebo [Arm B] concurrently with conditioning on days -6 to -1 of AutoHCT (Cycle 1). Following count recovery and resolution of acute toxicities, pts continued ibrutinib 560 mg in Arm A or placebo in Arm B for 12 additional 28-day cycles. Crossover to Arm A using single agent ibrutinib was allowed for pts progressing on Arm B. Central pathology review was performed for disease confirmation and subtype assignment. Initially, ABC subtype assignment was performed using the Nanostring Lymphoma Subtyping Test (LST) but the study was amended to use the IHC-based Hans classifier for non-GCB on 8/15/19. Other key eligibility criteria included receipt of no more than 3 prior regimens, no active CNS involvement, no need for long-term anticoagulation, and no prior progression on Ibrutinib. Pts were stratified by time to relapse (<=12 mos vs >12 mos), type of conditioning (BEAM or CBV) and prior ibrutinib use. The original design required 296 patients with 82% power to detect a difference in 2-year progression-free survival (PFS) rates of 67% vs. 50% with a two-sided alpha of 0.05. A revised statistical design allowed an interim futility analysis to be conducted after 40 pts were enrolled and followed for 2 years. Even though the study met criteria to continue accrual to a target of 160 pts, we decided to close it early due to declining accrual on 12/20/2022. We hereby present the primary analysis of the evaluable patients enrolled (data as of 07/17/2023). Results: Between 2/6/17 and 8/24/18, we screened 255 pts but enrolled only 34 (13%) largely due to long assay turnaround times and performance characteristics with the LST. Following the switch to the IHC-based Hans classifier (after 8/15/19), 60 out of 110 pts screened were enrolled (54%) in line with our a priori expectation. In total, 45 pts were randomized to Arm A vs. 43 to Arm B, with 39 and 38, respectively, being evaluable for the primary endpoint at this time. Median age was 61 years (range 20-75 years), median number of prior lines of therapy was 2, 46% of the pts were female, 21% were refractory or had early relapse, 94% were planned to receive BEAM conditioning. Overall, 87% of pts in Arm A and 88% in Arm B underwent conditioning while 70% and 67% respectively, started maintenance therapy. The median number of cycles received was 6 in Arm A vs. 5 in Arm B. The primary endpoint of 2-year PFS was 57.6% (95% CI: 42.1%, 78.8%) in Arm A vs. 40.8% (95% CI: 26.5, 62.8%) in Arm B (HR=0.54; 95% CI: 0.26, 1.10; log-rank p = 0.087). Median PFS was 26.5 months (95% CI: 10.2, not reached [NR]) in Arm A vs. 8.1 months (95% CI: 5.4, NR) in Arm B. Only one pt crossed over to Arm A after progression on Arm B. The most common grade 3-4 AEs in each of the arms were: neutropenia (A: 14%, B: 14%), febrile neutropenia (A: 11%, B: 9%), and thrombocytopenia (A: 11%, B: 7%). Rates of any grade atrial fibrillation were similar between arms (12.8% in Arm A vs. 10.5% in Arm B); one patient had grade 3 and one patient had grade 4 atrial fibrillation, both in Arm B. Six pts had reported grade 5 events (Arm A: 2 sepsis, 1 COVID-19, 1 respiratory failure and 1 disease progression and Arm B: 1 disease progression) but only one grade 5 event (sepsis, Arm A) was deemed probably related to treatment. Conclusions: Despite an early high rate of screen failures and declining accruals due to competition with CAR-T cell therapy, the primary analysis suggests that ibrutinib with and following AutoHCT in relapsed/refractory ABC-DLBCL is well-tolerated and may improve PFS in this high-risk patient population. This trial was supported by: U10CA180821, U10CA180882, U24CA196171; U10CA180820, UG1CA233234 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG) ClinicalTrials.gov Identifier: NCT02443077 https://acknowledgments.alliancefound.org

Introduction: Historically, older patients (pts) with relapsed/refractory large B-cell lymphoma (R/R LBCL) were often deemed ineligible for curative-intent autologous stem cell transplant (ASCT) due to age and concern for increased toxicity related to comorbidities. We previously demonstrated in the pivotal ZUMA-7 study that older pts with R/R LBCL can safely receive axicabtagene ciloleucel (axi-cel) as second-line (2L) therapy with improved event-free survival (EFS), response rate, and quality of life compared with standard of care (SOC) based on results from the primary EFS analysis (Westin, et al. Clin Cancer Res. 2023). At a median follow-up of 47.2 months (mo), results from the ZUMA-7 primary overall survival (OS) analysis demonstrated superior OS in the intention-to-treat (ITT) analysis (hazard ratio [HR], 0.73; 95% CI, 0.54-0.98; stratified two-sided log-rank P=0.03; Westin, et al. N Engl J Med. 2023; NCT03391466). We now report updated efficacy and safety results from the primary OS analysis among ZUMA-7 pts aged ≥65 years (y) and ≥70 y. Methods: Eligible pts were randomized 1:1 to axi-cel or SOC (2-3 cycles of platinum-based chemoimmunotherapy; responding pts proceeded to high-dose chemotherapy with ASCT). The primary OS analysis occurred 5 y after the first pt was randomized (01/25/2018) per protocol. Other endpoints included progression-free survival (PFS) per investigator assessment and safety. A planned subgroup analysis of pts aged ≥65 y was conducted in addition to an analysis for those ≥70 y. Multivariate analyses were performed to examine treatment efficacy with axi-cel compared with SOC after adjusting for multiple covariates, including sex, disease type, molecular subgroup, lactate dehydrogenase (LDH), tumor burden, and age; strata for these analyses included second-line age-adjusted International Prognostic Index (aaIPI), and relapsed vs refractory disease. Exploratory analyses were conducted to determine the association between OS and axi-cel product characteristics for pts aged ≥65 y. Results: A total of 109 pts were included in the analysis (axi-cel: 51 were ≥65 y, 26 of whom were ≥70 y, maximum age was 80 y; SOC: 58 were ≥65 y, 27 of whom were ≥70 y, maximum age was 81 y). Compared with SOC pts at baseline, more axi-cel pts had high-risk features, including aaIPI 2-3, elevated LDH, and high-grade B-cell lymphoma. At a median follow-up of 46.6 mo, OS was prolonged in the axicel vs SOC arm in pts aged ≥65 y (HR, 0.691; 95% CI, 0.401-1.190) and for those ≥70 y (HR, 0.330; 95% CI, 0.135-0.809). Similar results were observed using the piecewise Cox regression model. The median OS for axi-cel and SOC pts was 43.5 mo (95% CI, 20.9-not estimable [NE]) and 19.6 mo (95% CI, 12.3-NE), respectively, among those aged ≥65 y, and 24.7 mo (95% CI, 12.8-NE) and 11.2 mo (95% CI, 6.1-NE), respectively, among those aged ≥70 y. In the SOC arm, 57% and 52% of pts received subsequent cellular immunotherapy off protocol in pts aged ≥65 y and ≥70 y, respectively. Multivariate analyses demonstrated an even greater OS benefit with axi-cel over SOC when adjusting for differences in baseline characteristics in pts aged ≥65 y (HR, 0.526; 95% CI, 0.266-1.041) and in pts aged ≥70 y (HR, 0.184; 95% CI, 0.045-0.755). PFS assessed by investigator confirmed benefit of axi-cel over SOC in pts aged ≥65 y (HR, 0.406; 95% CI, 0.230-0.715) and in pts aged ≥70 y (HR, 0.206; 95% CI, 0.078-0.547). The median PFS for axi-cel and SOC pts was 28.7 mo (95% CI, 5.1-NE) and 5.0 mo (95% CI, 2.8-7.2), respectively, for those aged ≥65 y, and 11.4 mo (95% CI, 4.1-NE) and 2.7 mo (95% CI, 1.7-5.0), respectively, for those aged ≥70 y. No new treatment-related deaths occurred since the primary EFS analysis. There were no manufacturing failures for any pt who underwent leukapheresis. Similar associations between product characteristics and outcomes were observed among the elderly and overall populations, including improved OS associated with a greater (>median) proportion of juvenile or stem memory T-cell phenotype cells (CCR7+CD45RA+ T cells) in the axi-cel product among pts aged ≥65 y (HR, 0.369; 95% CI, 0.138-0.984). Conclusion: Axi-cel as 2L therapy prolonged survival over SOC in pts aged ≥65 y, including in pts aged ≥70 y. These findings confirm that age alone should not be a barrier for consideration of CAR T-cell therapy, supporting the use of axi-cel as a curative-intent 2L therapeutic option for older pts with R/R LBCL.

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.

INTRODUCTION: Luxeptinib (CG-806; LUX) is an orally active noncovalent kinase inhibitor of Bruton's tyrosine kinase (BTK), wild type and mutant forms of Fms-like tyrosine kinase 3 (FLT3) (including the internal tandem duplicates (ITD), tyrosine kinase domain (TKD), and F691L mutant forms), and growth receptors like KIT, CSF1R, PDGFRα, and TRKs. In prior studies, LUX has been shown to suppress aberrant proliferative signaling in B cell malignancies and acute myeloid leukemia (AML) via regulation of BTK, LYN, SYK, AKT, ERK, and MAPK. LUX is cytotoxic to primary AML cells insensitive to other FLT3 inhibitors and to malignant B-cells insensitive to ibrutinib, at pM and nM concentrations, respectively. AIMS: The primary objectives of these studies are to assess the safety, tolerability, and pharmacokinetics (PK) of LUX and determine recommended phase 2 doses for relapsed or refractory (R/R) AML and B cell malignancy patients. METHODS: In two studies (NCT04477291; NCT03893682), LUX (original formulation, G1) was administered continuously as oral capsules BID in 28-day cycles of ascending cohorts (relapsed or refractory de novo, secondary, or therapy-related AML or higher risk myelodysplastic syndrome (MDS), and relapsed and refractory for B cell lymphoma and chronic lymphocytic/small lymphocytic leukemia). A novel generation 3 (G3) formulation of LUX designed to increase bioavailability was tested at a single-dose (sub-study) for relative bioavailability (RBA), followed by continuous dosing in subsequent R/R AML patients. RESULTS: In the B-cell study (as of 15 th May 2023), LUX has been administered to 36 patients at dose levels from 150 mg to 900 mg BID in patients with a median of 3 lines of prior treatment, with 47.2% having received a BTK-inhibitor. Only one (2.8%) patient had a DLT of hypertension and 14 (38.9%) experienced at least one drug related ≥Grade3 treatment emergent adverse event (TEAE). Two patients (900 mg) are currently on study with no DLT and no ≥Grade 3 related TEAEs. A Follicular lymphoma patient is at cycle 28, and achieved a best response as partial response (PR) with a decrease in lesion size of 76.2%; an SLL patient is at cycle 13, and achieved stable disease (SD) showing a decrease in lesion size of 43.1% (Figure A). The overall best response achieved among the 17 patients who have been on treatment for more than 12 weeks are stable disease (SD) (n=11), partial response (PR) (n=3), minor response (n=2) and complete response (CR) (n=1). As of 5 th June 2023, in the AML trial, a total of 40 patients (16 (40%) FLT3-ITD, 21 (52.5%) FLT3-WT, 2 (5.0%) FLT3-TKD, and 1 (2.5%) unknown mutations) with a median of 3 prior treatments (range, 1 - 10) have been treated with LUX G1 formulation at dose levels from 450 mg - 900 mg BID (n=34) or with 50 mg BID of G3 formulation (n=6). Four (10%) experienced drug related SAE and 7 (17.5%) had a drug related grade ≥3 TEAEs. The most common related TEAEs were lymphocyte count decrease, platelet count decrease, and anemia (n=2; 5% patients each). One (2.5%) patient at 450 mg dose, reported complete remission without minimum residual disease (CRmrd) and remained on study for 56 weeks. In the RBA sub-study, G3 (50 mg) produced comparable exposures to G1 (450-900 mg range) (Figure B) and was, therefore, selected as the starting dose for use in the R/R AML study. Six patients were treated with a continuous dosing of 50 mg BID G3; with plasma levels of 274 ng/mL and 195 ng/mL LUX observed by the end of C1D15 and C1D22 respectively. No drug related Grade ≥3 TEAEs or DLTs were observed in 50 mg BID G3 LUX treated patients; with no new safety signals observed for the G3 formulation. Based on these findings and expected exposures for higher dose levels, the cohort safety review committee has approved escalation of G3 dosing to 200 mg BID at which dosing is ongoing. CONCLUSIONS: LUX has a favorable safety profile in patients at all tested dose levels, for multiple cycles, for both studies. Antitumor activity was observed in a heavily pretreated relapsed AML patient and in multiple B-NHL subtypes and CLL/SLL patients including several with prior ibrutinib exposure. Continuous dosing of patients with R/R AML and Higher-Risk MDS with the G3 formulation is ongoing; with updated clinical data (200 mg dose level) to be presented at the meeting.

Purpose The predominant pattern of relapse for patients with B-cell non-Hodgkin lymphoma (NHL) who undergo anti-CD19 Chimeric Antigen Receptor T-cell Therapy (CART) involves sites previously involved by NHL. Bridging radiotherapy (BRT) has shown to be an effective bridging treatment with excellent local control rates. Our previous work defined limited/oligometastatic lymphoma as disease involving <5 sites. This study is the first to report on the role of BRT for patients with limited (<5 involved sites) disease prior to CART. Methods Following Institutional Review Board approval, a retrospective review from 2018 to 2023 across 3 Mayo Clinic sites (Arizona, Florida, and Minnesota) was performed and identified 139 patients with relapsed/refractory (r/r) B-cell NHL without bone marrow involvement who received CART and had <5 disease sites prior to leukapheresis. Ann Arbor staging was used to define the number of involved disease sites. An involved disease site included the Ann Arbor anatomical lymph node region(s) harboring the pathological lymph node(s) or any extranodal lesion. Bridging treatment (radiation and/or systemic therapy) was defined as treatment administered between leukapheresis and CART infusion. The primary endpoint was event-free survival (EFS),defined from CART infusion to any disease progression or initiation of post-CART consolidative/salvage therapy. Secondary endpoints included progression -free survival (PFS),defined from CART infusion to any disease progression, and overall survival (OS), defined from CART infusion to death. Results Prior to CART infusion, 44 (32%) patients received BRT and 95 (68%) did not. Bridging systemic therapy was given to 5 (11%) and 34 (36%) patients in the BRT and no BRT groups, respectively (p=0.003). The median number of involved disease sites prior to leukapheresis was 2 (range: 1-4). There was no significant difference in the baseline characteristics prior to CART infusion between the BRT and no BRT groups, except for extranodal involvement that was more common in the BRT group (Table 1). The median equivalent 2 Gy dose was 27 Gy (Interquartile range 23-34), and the most common BRT regimen was 20 Gy in 5 fractions. Among the 44 BRT patients, 34 received radiation to all visible PET-avid disease sites, and 10 received radiation to some but not all disease sites. The median follow-up was 20 months. The rate of grade ≥2 cytokine release syndrome was 41% in both groups (p=0.99). The rate of grade ≥2 immune effector cell-associated neurotoxicity syndrome was 21% and 37% in the BRT and no BRT groups, respectively (p=0.059). There were no observed grade ≥3 BRT-related toxicities. Objective response rate by PET 5 point scale was higher in the BRT group (93% versus 79%; p=0.036). Crude rates of progression were 30% in BRT and 55% in no BRT patients, with 9/13 (69%) and 43/52 (83%) patients relapsing in pre-existing sites of disease present prior to CART infusion in the BRT and no BRT group, respectively. Seven (16%) BRT patients relapsed in the radiation field. The 2-year EFS was 50% in the BRT group and 39% in the no BRT group (p=0.01). The 2-year PFS was 55% in the BRT group and 45% in the no BRT group (p=0.017). The 2-year OS was 55% in the BRT group and 62% in the no BRT group (p=0.7). Intriguingly, patients who received BRT to all visible PET-avid disease sites (n=34) had further improvement in 2-year EFS (67% vs 39%, p=0.003) and 2-year PFS (71% vs 46%, p=0.008) compared to no BRT or patients who received BRT to some but not all visible disease sites (n=105). Nine patients (2 in BRT and 7 in no BRT groups) received consolidative radiotherapy for day 30 residual disease with only one patient subsequently experiencing progression. Twenty-five patients (6 in BRT and 19 in no BRT groups) received salvage/palliative RT for post-CART relapsed disease. Thirty-seven (39%) patients in the no BRT group remained without disease progression and did not receive radiation in the bridging, consolidative or salvage/palliative setting. Conclusion Bridging radiotherapy prior to CART infusion for patients with limited (<5 involved disease sites) r/r NHL appears to improve response rate, EFS, and PFS without causing significant toxicities. Approximately one third of patients who do not receive BRT will require subsequent post-CART radiation, and another third will remain free of radiation and disease progression.

Introduction: Preclinical studies have suggested synergism between lenalidomide (LEN) and ibrutinib (IBR) in multiple myeloma (MM). Both downregulate IRF4, a master transcriptional factor that regulates myeloma cell survival. Single agent oral IBR combined with dexamethasone proved well tolerated and active in advanced, steroid refractory relapsed MM as part of a large Phase1/2 study in 60 patients, with durable stabilization and minimal response seen in most evaluable patients (Richardson PG et al, BJH 2018). LEN is considered a standard of care in newly diagnosed MM, as maintenance and in relapsed disease, and a backbone of oral therapy in the MM treatment paradigm (Laubach JP et al, Leukemia 2016). Methods: We therefore conducted a 3+3 phase I trial to determine the maximum tolerated dose (MTD) of IBR in combination with LEN + dexamethasone (DEX) in patients with relapsed/refractory (RR) MM who had at least 2 prior lines of therapy. Three dose levels (DL) were planned. Cycle length was 28 days. IBR was administered orally daily at 560mg on DL1-2 and 840mg on DL3, LEN orally days 1-21 at 15mg on DL1 and 25mg on DL2-3, and DEX orally days 1, 8, 15, and 22 at 40 mg if age < 75 or 20 mg if ≥75 for DL1-3. Patients with GFR ≥ 30 and < 60 were treated according to manufacturer's instructions with lenalidomide dosed at 10mg/d. Dose limiting toxicities (DLT) included grade 4 thrombocytopenia; grade 4 neutropenia lasting more than 5 days or febrile neutropenia; grade 4 nausea, vomiting or diarrhea; grade 3 thrombocytopenia with bleeding or platelet transfusion; grade 3-4 hyperglycemia or thrombotic/embolic event, treatment delays ≥ 21 days for toxicity; and treatment related death. Due to changes in standard of care during the study, eligibility was modified to allow the enrollment of patients with RRMM who had at least 1 prior line of therapy. Response was assessed using IMWG/Uniform Criteria. Results: Fourteen patients (DL1-6 pts; DL2-3 pts; DL3-5 pts) registered to the study from March 2019 to May 2023, prior to its closure due to slow accrual. One patient on DL3 cancelled participation prior to start of treatment due to disease progression (PD). The remaining 13 patients are included in summary of toxicities and response but 2 patients on DL3 are excluded from determination of MTD due to discontinuing cycle 1 treatment due to COVID and receiving 280 mg/day of IBR instead of assigned 840 mg/day dose during cycle 1, respectfully. Twelve patients were evaluable for response. The median number of prior lines of therapy was 3 (range: 2-9), reflecting a heavily pretreated relapsed and refractory population. One of the 6 patient on DL1 developed a DLT, grade 3 non-viral hepatitis. None of the 3 patients on DL2 or the 2 patients on DL3 had a DLT. One patient on DL1 remains on treatment with stable disease for 42+ cycles. The median number of cycles administered was 3 (range: 1-42+). Severe toxicities reported included grade 3 lymphocytopenia (3), anemia (2), alanine aminotransferase increase (1), aspartate aminotransferase increase (1), blood bilirubin increase (1), hypocalcemia (1), hypokalemia (1) hypophosphatemia (1), febrile neutropenia (1), chronic kidney disease (1), non-viral hepatitis (1), soft tissue infection (1), and fatigue (1); grade 4 lymphocytopenia (1), and grade 5 sepsis (1). End of treatment reasons included: PD (7), toxicity (2), death [soft tissue infection that turned into sepsis considered to be likely related to DEX] (1), and concomitant conditions (2). Stable disease (SD) or better was achieved in 10 of 12 evaluable patients (83%), including one patient who achieved disease control for over 3.5 years. One patient (8%) on DL3 had a complete response (CR) but stopped treatment after 2 cycles due to reversible toxicity and comorbid conditions, based upon physician advice and patient choice. Conclusions: The combination of lenalidomide with Ibrutinib as an all-oral approach in RR MM proved feasible and generally tolerable, with the majority of discontinuation seen in this Phase I study due to disease progression. No COVID related - mortality was seen. SD or better was achieved in 83% of patients, including one CR. Potential future directions include combination approaches with next generation IMids such as pomalidomide, as well as other orally bioavailable novel agents with potent immune activating properties, such as CelMoDs. Support: AFT; Pharmacyclics; Clinicaltrials.gov Identifier: NCT03702725

Background: Anti-CD19 chimeric antigen receptor T-cell (CART) therapy is a standard of care in patients (pts) with relapsed or refractory (RR) large B-cell lymphoma (LBCL). However, it remains underutilized in elderly pts due to limited efficacy and safety data. We therefore evaluated real world outcomes of CART in such pts. Methods: Seven academic centers participated in this retrospective study. Pts aged ≥65 years with RR LBCL who received a commercial CART product were included. Baseline characteristics, treatment data, CART toxicity, and clinical outcomes were collected. Progression-free survival (PFS; time from infusion to disease progression or death) and overall survival (OS; time from infusion to death from any cause) were analyzed using Kaplan-Meier method. Cumulative incidences of non-relapse mortality (NRM) and disease relapse/progression were estimated accounting for competing risks. Statistical analyses were performed in JMP v15 and XLSTAT v2022.1.2. Results: 209 pts were identified. Baseline characteristics and treatment pattern are shown in Table. Median age at infusion was 71 years (range 65-89), and 25 (12%) were ≥80 years. 131 (63%) were male, 188 (90%) were white, and 27 (13%) had ECOG PS of ≥2. The median HCT-CI was 1 (range 0-6), and 39 (22%) pts had a score of ≥3. 165 (84%) had stage III-IV disease, 131 (70%) had extranodal involvement, 24 (18%) had bulky disease, and 24 (11%) had high grade B-cell lymphoma (HGBL; double- or triple-hit lymphoma, n=15; HGBL, NOS, n=9). The median number of prior lines of therapy was 2 (range 1-8), and 99 (48%) pts had ≥3 prior lines of therapy, 45 (22%) had prior bendamustine, and 44 (21%) had prior stem cell transplant (SCT; auto-SCT, n=41; allo-SCT, n=2; both auto- and allo-SCT, n=1). Bridging therapy was given to 100 (52%) pts; among those, 57 had chemotherapy, 20 had radiotherapy, 6 had both chemotherapy and radiotherapy, 10 had lenalidomide-based regimen, and 7 had CD20 antibody and/or corticosteroids. Axicabtagene ciloleucel (axi-cel) was most frequently used (63%, n=131), followed by lisocabtagene maraleucel (liso-cel) (24%, n=49) and tisagenlecleucel (tisa-cel) (13%, n=27). Cytokine release syndrome (CRS) occurred in 75% of pts, and a minority (6%) had grade ≥3. Immune effector cell associated neurotoxicity syndrome (ICANS) occurred in 55%, and 29% had grade ≥3. The management of CRS and ICANS included corticosteroids in 101 (49%) pts, tocilizumab in 116 (56%) pts, and other biologic agents (anakinra, siltuximab, basiliximab) in 8 (4%) pts. Day 30 response was evaluable in 195 pts with an objective response rate (ORR) of 84%, and a complete response rate (CR) of 52%. 82% of the responders continued to have a response at 3 month follow up. The ORR/CR rates were 86%/53% for axi-cel, 64%/44% for tisa-cel, and 89%/52% for liso-cel, respectively. At a median follow up of 19.1 months (95% CI 16.1-23.6) after infusion, the median PFS was 6.7 months (95% CI 5.1-11.5), with 6- and 12-month PFS rates of 54% (95% CI 47-61) and 43% (95% CI 35-50), respectively. The median OS was 16.5 months (95% CI 13.2-26.7), and the 6-and 12-month OS rates were 70% (95% CI 64-77) and 61% (95% CI 54-68), respectively. The NRM rate was 17% (95% CI 11-24) at 1 year, primarily due to infections including 5 COVID-19 related deaths. In univariate analysis, ECOG PS ≥2, bulky disease, elevated LDH, and the need for bridging therapy were associated with inferior PFS and OS. No significant difference in PFS and OS was seen based on age at infusion with a median PFS of 6.4 vs 9.6 vs 6.4 vs 6.0 months ( P=0.93) (Figure) and OS of 16.4 vs 19.2 vs 28.5 vs 12.7 months ( P=0.85) in age groups ≥65-69 vs ≥70-74 vs ≥75-79 vs ≥80-89. In addition, there was no statistically significant difference in PFS and OS based on type of CART with a median PFS of 6.4 vs 5.6 vs 12.7 months ( P=0.16) and OS of 15.1 vs vs 16.1 vs NR months ( P=0.24) in pts treated with axi-cel vs tisa-cel vs liso-cel. Conclusions: In this large multicenter study of elderly pts with RR LBCL, CART therapy demonstrated favorable efficacy and safety profile comparable to that in pivotal registration trials. Survival outcomes appeared similar regardless of patient age, including those aged ≥80 years, and type of CART product used. Similar to younger pts, high tumor burden and poor performance status at CART infusion were associated with inferior survival. This analysis confirms that older pts should not be excluded from receiving CART therapy solely due to chronological age.