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INTRODUCTION We aim to identify factors that impact outcomes of venetoclax for patients with CLL treated in routine practice at a tertiary center. We report on the use of venetoclax in the most frequently encountered disease scenarios: first-line, relapsed/Bruton tyrosine kinase inhibitor (BTKi)-naïve, and relapsed/BTKi-exposed. METHODS We identified patients who received venetoclax therapy for CLL (between 4/2012-4/2023) from the Mayo Clinic CLL Database. Undetectable measurable residual disease (uMRD) was defined as <1 CLL cell per 10,000 leukocytes using 8-color flow cytometry on peripheral blood (PB) or bone marrow (BM). Overall survival (OS) was defined as the time from venetoclax start until date of death or last known to be alive. Treatment-free survival (TFS) after venetoclax was defined as the time from venetoclax start until the earliest of date of next treatment, or death. Kaplan-Meier was used to display OS and TFS. Multivariable Cox proportional hazards regression models were used to estimate associations of factors with time-to-event outcomes. RESULTS A total of 155 patients received venetoclax: firstline therapy (in combination with obinutuzumab, n=55) and relapsed CLL (n=100; 17 had relapsed/BTKi-naïve CLL, and 83 had previously received BTKi [55 with progression after BTKi], relapsed/BTKi-exposed). The median follow-up for the cohorts of first-line therapy, relapsed/BTKi-naïve, and relapsed/BTKi-exposed was 12.9 months, 37.0 months, and 27.6 months, respectively. Baseline characteristics at the time of venetoclax initiation for all patients are shown in Table 1. The median TFS for the overall cohort was 39.0 months. The median OS was 54.6 months. Among patients treated with venetoclax as first-line therapy (n=55), the 2-year TFS ( Figure 1) and 2-year OS rates were both 91%. MRD testing was performed in 28 patients and was uMRD in 23 (82%) patients (only PB assessed, n=7; only BM assessed, n=2; PB and BM assessed, n=14). Detectable MRD was identified in 3 patients, and 2 patients had discordant results (PB uMRD and BM detectable disease). Among patients treated with venetoclax in the relapsed/BTKi-naïve setting (n=17), the 2-year TFS rate was 73% ( Figure 1) and the 2-year OS rate was 100%. MRD testing was performed in 7 patients and was uMRD in all 7 (100%) (only PB assessed, n=3; only BM assessed, n=2; PB and BM assessed, n=2). The median time to first uMRD result was 14.1 months. Among relapsed/BTKi-exposed venetoclax-treated patients (n=83), the median TFS was 26.9 months ( Figure 1), and the median OS was 39.4 months.In this subgroup, the median TFS for patients with (n=55) and without (n=28) prior disease progression on prior BTKi were 22.3 and 42.3 months, respectively. Median TFS with venetoclax monotherapy (n=30) was 24.0 months, venetoclax in combination with rituximab (n=37) was 26.9 months, and venetoclax in combination with obinutuzumab (n=16) was 39.0 months. BTKi-exposed patients that were chemotherapy-naïve (n=27) and chemotherapy-exposed (n=56) had median TFS of 29.1 and 24.0 months, respectively. MRD testing was performed in 28 patients and was uMRD in 16 (57%) patients (only PB assessed, n=9; only BM assessed, n=2; PB and BM assessed, n=5). Detectable MRD was identified in 11 patients, and 1 had discordant results (PB uMRD and BM detectable disease). The median time to first uMRD result was 11.5 months. TP53 disruption, unmutated IGHV genes, older age, complex karyotype (CK; defined as more than 3 chromosomal aberrations on CpG stimulated karyotype), and disease progression on prior BTKi were associated with shorter TFS in the overall cohort on univariate analysis. TP53 disruption, older age, CK, and disease progression on prior BTKi were associated with shorter OS in the overall cohort on univariate analysis. Multivariable analysis was performed by including only those patients where all variables significant in univariable analysis were available (OS model n=65, TFS model n=53). In these models, only CK was significantly associated with shorter TFS (HR 8.5; 95%CI 2.5-29.1; P<0.001) and shorter OS (HR 4.1; 95%CI 1.2-14; P=0.03). CONCLUSIONS Patients with BTKi-exposed CLL, particularly those with prior disease progression on BTKi, had worse outcomes. Our study identified CK as one of the most important baseline predictors of adverse TFS and OS in the overall cohort of patients, supporting karyotype assessment for prognostication prior to venetoclax treatment.

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:Patients with R/R CLL/SLL who experience intolerance to or disease progression after Bruton tyrosine kinase inhibitor (BTKi) and venetoclax treatment have no established standard of care and poor outcomes, indicating a critical unmet need. Liso-cel, an autologous, CD19-directed, 4-1BB CAR T cell product, has demonstrated efficacy in large B-cell lymphoma and CLL/SLL. In the primary analysis of the phase 1/2, single-arm, multicenter TRANSCEND CLL 004 (NCT03331198) study, a single administration of liso-cel demonstrated rapid, deep, and durable responses and a manageable safety profile in patients with R/R CLL/SLL, including those with progression on previous BTKi and venetoclax failure (Siddiqi T, et al. Lancet 2023). The primary endpoint was met in the prespecified subset of efficacy-evaluable patients with disease progression on BTKi and venetoclax failure (primary efficacy analysis set [PEAS]) at a target dose of 100 × 10 6 CAR + T cells (null hypothesis: ≤ 5%) with the rate of complete response/remission (CR) and CR with incomplete marrow recovery (CRi) by an independent review committee (IRC) per 2018 International Workshop on CLL (iwCLL) criteria at 18.4% ( P = 0.0006). Here we report results from TRANSCEND CLL 004 with a median follow-up of 23.5 months. Methods: Patients must have received ≥ 2 prior lines of therapy, including a BTKi. Eligible patients received liso-cel at a target dose of either 50 × 10 6 (dose level [DL] 1) or 100 × 10 6 (DL2) CAR + T cells after lymphodepleting chemotherapy. The primary endpoint was CR/CRi in the PEAS at DL2. Key secondary endpoints were ORR and rate of undetectable MRD (uMRD; 10 −4 by next-generation sequencing) in blood. All null hypotheses were tested at the primary analysis and not retested in this analysis. Results:Of 137 leukapheresed patients, 118 received liso-cel (safety set), 97 (DL1 = 9; DL2 = 88) were efficacy evaluable, and 54 (DL1 = 4; DL2 = 50) were in the PEAS. In the safety set, median (range) age was 65 years (49-82), 83% had high-risk cytogenetics (del[17p], 42%; TP53 mutation, 47%; unmuted immunoglobulin heavy-chain variable gene, 47%; ≥ 3 chromosomal aberrations, 61%), median (range) lines of prior therapy was 5 (2-14), and all patients had prior BTKi. As of data cutoff (February 28, 2023), median (range) on-study follow-up was 23.5 months (0.4-59.6) for the safety set. In the PEAS at DL2, CR/CRi rate was 20% (95% CI, 10.0-33.7; Table 1). ORR was 44% (95% CI, 30.0-58.7). One patient who had best overall response (BOR) of partial response/remission (PR) at primary analysis had deepened to CR/CRi at 18 months without any additional therapy. Of 9 patients who had BOR of CR/CRi at the primary analysis, 8 had ongoing CR/CRi and 1 completed the study with the last assessment as CR/CRi. The uMRD rate was 64% (95% CI, 49.2-77.1) in blood and 60% (95% CI, 45.2-73.6) in marrow. Median (95% CI) duration of response was 35.3 months (12.4-not reached [NR]) and median duration of CR/CRi was NR. Median (95% CI) PFS was 11.9 months (5.7-26.2). Median (95% CI) OS was 30.3 months (15.0-NR). The efficacy outcomes were similar in the full population at DL2. Of 16 patients who had BOR of CR/CRi at primary analysis, 10 had ongoing CR/CRi. In the safety set, rates of any-grade and grade ≥ 3 treatment-emergent AEs were similar across age groups (Table 2). The rate of any-grade cytokine release syndrome (CRS) was 85% (grade 3, 8%; no grade 4/5) and neurological events (NE) was 45% (grade 3, 18%; grade 4, 1%; no grade 5); 69% received tocilizumab and/or corticosteroids for CRS/NEs. Median (range) time to onset and resolution was 4 days (1-18) and 6 days (2-37) for CRS and 7 days (1-21) and 7 days (1-83) for NEs, respectively. Prolonged cytopenia (grade ≥ 3 at Day 30 after liso-cel infusion), grade ≥ 3 infections, hypogammaglobulinemia, tumor lysis syndrome, second primary malignancy, and macrophage activation syndrome occurred in 54%, 18%, 15%, 11%, 9%, and 3%, respectively. Forty-five (33%) of 137 leukapheresed patients died after liso-cel infusion (disease progression, n = 27 [20%]; AE, n = 6 [4%]; other reasons, n = 12 [9%]). Conclusions: With longer follow-up, liso-cel continued to demonstrate durable CR/CRi, high uMRD rates, and a manageable safety profile in patients with heavily pretreated, high-risk R/R CLL/SLL. The safety results from longer follow-up were similar to those reported in the primary analysis with no new safety signals and were consistent across age groups.

Background: Dex is a key component of induction regimens for NDMM despite common toxicities including insomnia and anxiety. The E4A03 randomized trial (Rajkumar, Lancet Oncol 2010) demonstrated that dex dosed at 40 mg weekly outperformed higher-intensity dex and established this regimen as the standard of care for NDMM. In standard practice as well as clinical trials, however, dex doses are often reduced to 20 mg weekly or lower (if not stopped entirely) among older patients or among patients experiencing toxicities. As a first step toward establishing the equipoise of planned dex dose reductions in NDMM, we investigated outcomes with patients from two previous SWOG trials to understand the impact of dex dose reductions on post-induction outcomes. Methods: This was a secondary analysis of data from two completed NDMM studies, S0777 (comparing VRd vs Rd) and S1211 (comparing Elo-VRd vs VRd). For this secondary analysis, we analyzed the subset of patients who completed all eight 3-week cycles of induction (or six 4-week cycles in the S0777 Rd arm). As shown in Figure 1A, we defined DEX fullDose as patients for whom the starting dex dose (either 40 mg once per week or 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 of 21-day cycles) did not change during induction. In contrast, DEX lowered was defined as patients for whom the end-of-induction dex dose and/or frequency were lower than their starting values. As an exploratory analysis, we also compared PFS and OS between the DEX fullDose (no changes to dex strength during induction) and DEX veryLow (dex dosing reduced ≥50% during induction) subgroups. All analyses were landmarked from the end of induction, defined as 24 weeks from registration, to account for the time-dependent nature of dex treatment received. Survival curves were based on the Kaplan-Meier method and comparisons were made using the log-rank test. Results: Of 541 evaluable patients ( n = 441 from S0777, n = 100 from S1211), dex was reduced during induction in 76% ( n = 410). Compared to DEX fullDose patients, DEX lowered patients were more likely to be anemic (37% vs 26%, p = 0.02) but had similar distributions of age ≥70 (24% of DEX lowered vs 26% of DEX fullDose), Performance Status > 1 (15% vs 12%), ISS stage 3 disease (33% vs 27%), ≥ 60% bone marrow plasma cell burden (37% vs 31%), M-spike > 3 g/dL (48% vs 48%) platelets < 150,000 cells/mm 3 (18% vs 14%), baseline LDH ≥ 190 U/L (36% vs 41%), and baseline CRP ≥ 8 mg/L (27% vs 30%). PFS (Figure 1B) was comparable between DEX lowered (median 36 months, 95% CI 29 to 39 months) and DEX fullDose (median 33 months, 95% CI 24 to 48 months) with p = 0.90. Similarly, OS (Figure 1C) was comparable between DEX lowered [median 77 months, 95% CI 68 months to not reached (NR)] and DEX fullDose (median 92 months, 95% CI 65 months to NR) with p = 0.93. In the DEX veryLow subgroup with ≥50% reduction in dex dosing during induction, median PFS was 39 months (95% CI 34 to 50 months) and median OS was NR (95% CI NR to NR). As shown in Figure 1D and Figure 1E, PFS and OS were comparable between these patients and DEX fullDose patients. Discussion: To our knowledge, this is the first analysis of dex dosing strength in NDMM since E4A03. In two separate randomized trials, over half of patients required dex reductions below a starting dose of ~40 mg weekly. Dex dose reductions during induction had no impact on post-induction PFS and OS, even in the subset of patients who required significant dose reductions. Limitations of our post hoc analysis include heterogeneity between dex dosing schedules and lack of cytogenetic data for all patients. We could not discern specifically why dex was lowered, and it is possible that dex might have been lowered disproportionately commonly in patients who had achieved early responses and thus independently did better. Regardless, these results strongly suggest that maintaining dex 40 mg weekly for the entirety of NDMM induction may be unnecessary in the modern era. Cooperative efforts to study a planned dex de-escalation protocol (i.e., once no longer needed for symptom management or as a pre-medication) alongside patient-reported outcome assessments of symptom burden are being planned. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180821, U10CA180820; and in part by Millennium Pharmaceuticals, Inc. (now part of Takeda Pharmaceutical Company), and by Celgene.

Background CV mortality has been recognized as the preventable cause of death in most cancers. However, there is a scarcity of data exploring CV mortality in adults diagnosed with leukemia. Hence, understanding the timing, and quantifying the magnitude of CV mortality can facilitate strategies to reduce the burden of mortality in these patients. Methods Surveillance, Epidemiology, and End Results (SEER) database (2004-2018) was queried to obtain CV mortality (defined as deaths due to heart diseases, hypertension, cerebrovascular diseases, atherosclerosis, and aortic aneurysm and dissection) in adults (>18 years of age) diagnosed with leukemias including acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Standardized mortality ratios (SMRs) were calculated. SMR was defined as the observed deaths from each category divided by the expected number of deaths in the age-matched US population for the same period. SMR >1 indicated increased while <1 indicated decreased mortality. SMR was presented by latency periods of <2, 2-5, and >5 years after the initial diagnosis of leukemias and stratified by age (<50 years, 50-70 years, >70 years), race (White, Black, Asian/Pacific Islander, Native American), ethnicity (Hispanic, Non-Hispanic), and marital status (married vs single/divorced/widowed). Results This analysis included 120,193 leukemia patients. Of which, 61,763 had lymphocytic leukemia and 58,430 were diagnosed with myeloid leukemia. In overall population, a significant increase in mortality was observed in adults diagnosed with leukemia (SMR: 1.34, 95% CI: 1.27-1.40). The risk of CV death was highest <2 years of initial diagnosis (1.94, 1.87-2.01) as compared to the population who died 2-5 years (1.17, 1.11-1.23) and >5 years (1.07, 1.01-1.14) after the initial diagnosis. In terms of different subgroups, patients aged <50 years observed the highest risk of CV mortality within < 2 years (9.35, 6.54-13.38) compared to patients aged 50-70 years (2.73, 2.45-3.04), and aged >70 years (1.80, 1.73-1.88). Similarly, regarding race, Asians/Pacific islanders had the highest risk of CV mortality (4.41, 3.70-5.26) followed by Blacks (2.58, 2.26-2.94), and Whites (1.85, 1.78-1.92) within <2 years of initial diagnosis. There was a significant increase in observed mortality in Hispanic (2.83, 2.47-3.23) as well as in non-Hispanic (1.90, 1.83-1.97) population within <2 years of initial diagnosis. However, the magnitude was relatively higher in Hispanic as compared to non-Hispanics. The risk of CV death was observed to be higher in single/divorced/widowed patients (2.30, 2.00-2.20) compared to those who were married (1.81, 1.71-1.91). The CV mortality risk remained consistent for all subtypes of leukemias (ALL, CLL, AML and CML) in overall patient population and among subgroups of interest over different latency periods of <2, 2-5, and > 5years after the initial diagnosis. Small sample size in Native Americans precluded any meaningful statistics. Conclusions: Risk of CV mortality among adults with leukemia is observed to be highest among younger (<50 years), Asians, Hispanics, and single/divorced/widowed patients, especially within 2 years of initial diagnosis. A risk-adapted approach may be warranted for cardiovascular care in these patients. Targeted cardio-oncological strategies should be aimed at improving CV mortality in patients who are at the highest risk of death.

High dose chemotherapy followed by autologous hematopoietic cell transplantation (auto HCT) is a standard therapy for patients with plasma cell disorders (PCD). A barrier to improving candidate selection for auto HCT is appraisal of risk for transplant related complications. Electrocardiography (ECG) is a standard pre-HCT test to evaluate the potential for arrhythmia and structural heart disease. We hypothesized that an artificial intelligence (AI) based interpretation of ECG waveform data (AI-ECG) could enhance risk prediction for cardiac-specific and other outcomes following auto HCT for patients with PCD. To test this hypothesis, we used several AI-ECG tools developed using a deep-learning based approach that were trained to predict comorbidity (Attia et al, Lancet 2019 & Grogan et al, Mayo Clin Proc 2021). Model outputs include a scaled prediction value indicating increasing risk for atrial fibrillation/flutter (AF), reduced ejection fraction (EF), or cardiac amyloidosis. We evaluated this tool in 9,225 ECGs obtained from 849 patients (median 6 ECGs/patient, inter-quartile range: 3-12) who underwent first or subsequent auto HCT at Memorial Sloan Kettering Cancer Center between 2016-2022 and who had a diagnosis of multiple myeloma (N = 810), amyloidosis (N = 37), or other PCD (N = 2). The endpoints were to determine whether baseline AI-ECG prediction of AF risk correlated with peri-transplant AF events, and to explore whether model outputs correlated with survival and other cardiac clinical outcomes. The mean age of patients was 61.0 years (range 23.7 - 81.2) and median follow up was 2.7 years post auto HCT. Contributing cardiovascular risk factors included a prior history of AF (N = 101, 11.9%), coronary or cerebrovascular disease (N = 95, 11.2%), and diabetes mellitus (N = 98, 11.5%). Reduced dose melphalan (< 200 mg/m 2) was administered in 26%. The HCT-comorbidity index (HCT-CI) was high risk (≥3) in 52.7%. The one-year overall survival and progression-free survival in the whole cohort was 94% (95% confidence interval (95% CI): 92 - 95%) and 86% (84 - 89%), respectively. Among patients not in AF at pre HCT evaluation, the 90-day cumulative incidence of AF was 5.6% (4.2 - 7.3%). In univariable competing risk regression, baseline pre HCT AI-ECG appraisal of AF risk was strongly correlated with incidence AF in patients who were in sinus rhythm before HCT (hazard ratio (HR): 25.1, 95% CI: 11.7 - 53.7, p < 0.001). In a multivariable model adjusting for patient age and HCT-CI, AI-ECG AF predicted risk remained associated with incidence of post HCT AF (HR: 13.4, 95% CI: 5.9 - 30.4, p < 0.001). Considering a decision threshold identified during original model training, AI-ECG predicted AF events with an accuracy of 75% (Mcnemar's p < 2 x 10 -16). The precision, recall, and F1-score were 0.94, 0.77, and 0.85, respectively. AI-ECG predicted age correlated highly with actual patient age (Spearman rho = 0.59, p < 2 x 10 -16). Amyloid risk scores were highly correlated with a known clinical history of amyloidosis (median 0.45 versus 0.05, Wilcoxon rank-sum p < 0.001). Patients with EF < 50% had greater prediction scores for cardiomyopathy compared to patients with normal EF (median 0.23 versus 0.01, Wilcoxon rank-sum p <0.001). In univariable analysis, increasing AI-ECG predicted age (HR 1.02, CI: 1.003 - 1.04, p = 0.02) and predicted AF risk score (HR: 3.2, CI: 1.4 - 7.2, p = 0.006) were associated with risk for death, whereas predicted amyloid score and predicted low EF were not associated with decreased survival. In multivariable analysis of all patients that considered patient age, hematopoietic comorbidity index, and remission status at HCT, increasing predicted AF score trended towards association with increased risk for death (HR: 2.3, 95%CI: 1.0 - 5.5, p = 0.059). Predicted AF score correlated highly with the HCT-CI and patient age. Finally, we examined whether risk prediction for low EF correlated with peri-HCT fluid overload (FO) defined by absolute weight gain. The incidence of ≥ 10% weight gain (grade 2 FO) and ≥ 20% weight gain (grade 3 FO) at 180 days post HCT was 7.4% (95% CI: 5.8%, 9.3%) and 1.0% (95% CI: 0.5%, 1.8%), respectively. Predicted low EF was not associated with development of either grade 2 or grade 3 FO in this population. In summary, AI-ECG predicts episodes of AF in patients undergoing auto HCT for PCD and may augment transplant risk appraisal when considered in conjunction with other measures of comorbidity.

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: BCMA-directed CAR-T and Bispecific T-cell engager (BiTE) therapies have shown remarkable overall response rates in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). This has led to the approval of idecabtagene vicleucel, ciltacabtagene autoleucel and teclistamab by the FDA, EMA and other regulatory agencies. We performed a global survey on accessibility, practice patterns, and toxicity management of commercially available CAR-T and BiTE therapies. Methods: An online survey was completed by clinicians attending the International Myeloma Society's Immune Effector Cell Therapies in Multiple Myeloma Workshop, in-person or virtually, made available for 30 days after the meeting held in March 2023, Boston, MA. Results: 87 clinicians from 16 countries completed the survey, most practicing in an academic practice (86%) and in an urban environment (89%). Sixty-four percent of the respondents practice in North America followed by Europe (25.3%) including Germany, United Kingdom, Ireland, Italy, Netherlands, Spain, France, Greece, and Cyprus, and 6.9% from Asia and 3.4% from Australia. Seventy-seven percent reported CAR-T cell therapy was approved in their country with 44.8% treating 1-5 patients and 14.9% treating >5 patients per month; 67% reported BiTE therapy was approved in their country with 14.9% treating >5 patients per month. Of evaluable responses (n = 40), 62% administered CAR-T therapy inpatient and 15% administered CAR-T therapy outpatient ≥ 50% of the time. Length of time between decision to treat with CAR-T therapy to infusion was 6-12 weeks for 42% of responders and <6 weeks for only 20%. Most (75%) reported inpatient administration of BiTE therapy step-up dosing; 17.5% reported outpatient step-up dosing administered ≥ 50% of the time. Use of institutional or practice SOPs for CAR-T and BiTE therapy patient selection was reported by 85% and 58%, respectively, with the factors influencing SOP outlined in Table 1. Of available CAR-T therapies, 53% prefer cilta-cel and 23% reported CAR-T therapy preference depended most on patients' co-morbidities/frailty (89%), timing of next available apheresis (67%), age (56%), CNS disease (44%) and other factors. Maintenance therapy after CAR-T therapy was reportedly used by 25% and 5% of respondents in 1-10% and 11-50% of their patients, respectively, to “maintain level of response achieved” (50%) or “achieve a deeper level of response” (25%). About half (43%) of the respondents reported using an SOP or particular criteria for secondary Hemophagocytic Lympho-Histiocytosis/Macrophage Activation Syndrome/CAR-related-HLH (sHLH/MAS/CarHLH) management that varied between the use of ASTCT Working Group IEC associated HLH-like syndrome Criteria (47%) (Hines 2023), CARTOX HLH Criteria (24%) (Neelapu 2017) and HLH-2004 criteria (6%). Tocilizumab was used as cytokine release syndrome (CRS) prophylaxis only by one responder. Keppra neurologic prophylaxis was used by 47.5% and 15% of responders for CAR-T and BiTE therapy, respectively. Delayed neurotoxicity with CAR-T was reported in 1-5% of patients by 57.5% of responders and 6-10% of patients by 15% of responders; most common manifestations were other movement/neuromuscular disorder (62%), nerve palsy (55%), and Parkinsonism (45%). Infectious prophylaxis was used to protect against HSV (92.5%), PJP (90%), bacterial pathogens (55%), fungal pathogens (60%), and IVIG (77.5%). However, criteria for infectious prophylaxis use varies widely incorporating IgG levels, infectious history, CD4+ count, B-cell aplasia and cytopenias (48.1 - 88.9%). Most respondents (46.3 - 86.5%) reported completing an infectious work-up including CMV, EBV, Hep B/C, and HIV ( Table 2). Conclusions: Trends of CAR-T and BiTE therapy use and patterns of concurrent prophylactic and supportive care in MM vary widely among academic centers across the globe, demonstrating a need for further understanding of toxicity pathogenesis, toxicity management and consistent guidelines. This survey also demonstrates the great unmet need for access beyond urban centers among the international myeloma community. Prospective studies and claims data analysis should be utilized to evaluate the longitudinal cost of care, quality of life, duration of response and management of infectious disease, neurological or related complications of CAR-T and bispecific TCE therapies.

Our group has reported that transient CD19 antigen masking of leukemic cells with the CD19 monoclonal antibody (mAb), tafasitamab, resulted in reduction of CD19 chimeric antigen receptor T cell (CART19) apoptosis, enhanced CAR T proliferation, improved anti-tumor activity, diminished tumor pyroptosis, and reduced severity of cytokine release syndrome (CRS) in preclinical models. In this report, we aimed to study the mAb characteristics responsible for these observations. Specifically, we hypothesized that binding affinity of CD19 mAbs might affect the subsequent activation and apoptosis of CART19 as well as tumor cell pyroptosis in preclinical models. To test our hypothesis, we first determined the affinities of the CD19-targeting antibodies tafasitamab, HD37 and FMC63 to recombinant human CD19 protein. Tafasitamab demonstrated the strongest binding affinity among the three tested antibodies [tafasitamab ( K D: 1.0±0.2 nM), HD37 ( K D: 4.1±0.3 nM), FMC63 ( K D: 3.4±1.2 nM)]. Next, we studied CART19 apoptosis in the presence of these CD19 mAbs with different binding affinities. Here, we co-cultured CART19, CD19 + mantle cell lymphoma JeKo, and 400 μg/mL of CD19 mAb for 1 hour and measured CD3 + 7-AAD - Annexin V + T cells with flow cytometry. The number of apoptotic CART19 cells was significantly reduced by tafasitamab co-treatment compared to HD37, FMC63, or control IgG [control IgG (mean = 19.1, standard deviation (SD) = 0.8), tafasitamab (mean = 13.1, SD = 2.9), HD37 (mean = 17.8, SD = 0.8), FMC63 (mean = 18.4, SD = 1.0)]. We also performed an in vitro high mobility group box 1 (HMGB1) assay to assess if different affinities of the CD19 mAbs affect tumor cell pyroptosis triggered by CART19. Here, we co-cultured CART19, CD19 + JeKo, and 400 μg/mL of CD19 mAb for 24 hours and assessed HMGB1 on JeKo. In analogy to the apoptosis data, tafasitamab was the only mAb that prevented tumor cell pyroptosis, indicated by reduced HMGB1 expression (Fig 1A). Given these results, we aimed to study the impact of CD19 occupancy with different CD19 mAbs prior to CART19 infusion on tumor pyroptosis in vivo. We utilized a mouse model that mimics CAR T toxicities. Immunocompromised NSG mice were inoculated via tail vein with 5x10 6 leukemic cells derived from patients with relapsed/refractory acute lymphoblastic leukemia. Two weeks later (day -7), tumor burden was assessed by peripheral blood sampling. Leukemic cells were defined as murine CD45 -, human CD45 + CD19 + CD20 + via flow cytometry, and volumetric absolute number was calculated. Mice were then randomized according to tumor burden to receive IgG control [Group 1 (G1)], tafasitamab (G2), HD37 (G3), or FMC63 (G4) (5 mg/kg, ip) at day -7. CRS was determined by weight loss, development of motor weakness, poor body posture, and elevated serum cytokine levels. At day 0, all mice received 3x10 6 luciferase + CART19 via tail vein. Mice were monitored with daily bioluminescent imaging (BLI) to track and quantify CART19 expansion and physical assessment to detect toxicity. BLI on day 4 revealed that CART19 expansion in the tafasitamab-treated group (G2, mean = 1x10 7, SD = 2.3x10 7) was significantly lower than in the control group (mean = 3.5x10 7, SD = 9.3x10 7), the HD37-treated group (G3, mean = 4x10 7, SD = 6.6x10 7), and the FMC63-treated group (G4, mean = 2x10 7, SD = 3.59x10 7), [G1 vs G2: 95% confidence interval (CI) 3.5x10 7 to 1.1x10 8, p <0.0001, G1 vs G3: 95% CI -7.5x10 7 to -1.1x10 8, p=0.005, G1 vs G4: 95% CI -4.5x10 7 to 1.9x10 7, p=0.71] indicating that tafasitamab pretreatment significantly reduced early activation of CART19 compared to IgG control and HD37 in this model. Mice were bled on day 4 to analyze plasma cytokine. Tafasitamab-treated mice (G2) secreted significantly less IFNγ (Fig 1B), IL10 (Mean G1: 78, G2: 2.52, G3: 12.2, G4: 13.9 pg/mL), MDC (Mean G1: 4072, G2: 445, G3: 921, G4: 1364 pg/mL), and MIP1β (Mean G1: 283, G2: 59.1, G3: 148, G4: 123 pg/mL) compared to G1, G3, and G4. Satellite mice were euthanized on day 1 and spleens were harvested. Western blot analysis of splenocytes revealed that G1, 3, and 4 showed significantly lower expression of apoptosis-inducing protein gasdermin E on leukemic cells compared to G2, indicating reduced tumor pyroptosis in G2. In summary, application of the high affinity mAb tafasitamab prior to CART19 resulted in reduced CAR T apoptosis, diminished tumor cell pyroptosis, and reduction of CRS compared to lower affinity CD19 mAbs in preclinical models.

Introduction: Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is a rare form of large granular lymphocytic leukemia. The clinical characteristics and outcomes of patients (pts) with CLPD-NK in the literature are limited. We aim to describe the patient characteristics, laboratory features, and clinical outcomes of CLPD-NK by reporting on, to our knowledge, the largest single-center cohort of CLPD-NK in the United States. Methods: We retrospectively identified Mayo Clinic pts with CLPD-NK, defined per the WHO 5 th edition and 2022 International Consensus Classification. We conducted chart review to collect clinical and laboratory data. Overall survival (OS) was plotted using Kaplan-Meier. Time to first treatment (TTFT) was displayed using cumulative incidence methodology accounting for competing risk of death. Univariable Cox regression models investigated associations between patient characteristics and outcomes (OS and TTFT). Results: We identified 45 pts who were diagnosed with CLPD-NK between 1997 and 2022. The median age at diagnosis was 69 years (range: 25-90) and 32 pts (71%) were male. At the time of diagnosis, 10 pts (22%) had a concomitant autoimmune disorder and 9 (20%) had laboratory evidence of a serologic abnormality (monoclonal gammopathy, rheumatoid factor, etc.). In addition, 10 pts (22%) had a prior diagnosis of a hematologic malignancy and 12 (27%) had a prior diagnosis of a solid tumor. Clinically, 4 pts (9%) had B symptoms, 15 (33%) had splenomegaly, and 13 (29%) were transfusion dependent. At diagnosis, median hemoglobin (hgb) was 10.2 g/dL, with 25 pts (56%) showing a hgb <11g/dL and 8 (18%) demonstrating a hgb <8 g/dL. The median platelet count was 202x10^9/L, with 12 pts (27%) demonstrating a platelet count <150x10^9/L. The median white blood cell count was 5.8x10^9/L. The median absolute neutrophil count (ANC) was 1.2x10^9/L, with 29 pts (64%) demonstrating an ANC <1.5x10^9/L. The median absolute lymphocyte count (ALC) was 3.8x10^9/L, with 20 pts (44%) demonstrating an ALC >4x10^9/L. The median absolute abnormal NK cell count per flow cytometry was 2.2x10^9/L. Flow cytometry revealed killer cell immunoglobulin-like receptor (KIR) restriction in all pts, with 27 (61%) lacking KIR expression and 17 (39%) demonstrating KIR restriction in CD158a, CD158b, and/or CD158e. CD7 expression was present in 42 pts (93%; 31% dim/partial), CD8 expression was present in 22 (49%; 42% d/p), CD56 expression was present in 17 (39%; 23% d/p), CD57 expression was present in 26 (59%; 46% d/p), CD94 expression was present in 33 (77%; 7% d/p), and NKG2A expression was present in 21 (50%; 5% d/p). Bone marrow examination (n=30) revealed that the median number of NK infiltrate was 11% (range: 5-40%) of cellularity, with 20 demonstrating an intrasinusoidal infiltrative pattern. The median follow-up was 41 months (mo), and 23 pts required at least one line of treatment. Treatment indications included anemia (39%), neutropenia (4%), bi/pancytopenia (39%), lymphocytosis (4%), or other (13%). The median TTFT was 32 mo (95% CI 2-93 mo). Hgb <11g/dL was associated with a shorter TTFT (9.7 vs 187 mo); however, neutropenia and thrombocytopenia were not associated with TTFT. For first-line treatment, in addition to frequent steroid use, 16 pts (70%) received a methotrexate-based regimen, 6 (26%) received a cyclophosphamide-based regimen, and 1 (4%) received a cyclosporine-based regimen. The median TTFT was not reached. Of those who required systemic treatment, 9 pts required a second-line therapy. The median OS from diagnosis was 162 mo (95% CI: 84-not estimable, NE), with 33 pts alive at last follow-up (Figure 1a). Increasing age (HR 1.2, 95% CI 1.1-1.3, p=0.002) and lack of CD94 expression (HR 5.6, 95% 1.3-25.0, p=0.02) were associated with worse OS. In the 23 pts who required treatment, the median OS from treatment initiation was 84 mo (95% CI: 52-NE) (Figure 1b). Conclusions: In this large cohort of 45 pts, the majority had neutropenia and anemia, and approximately half required systemic treatment. Estimated median OS from diagnosis exceeded a decade for the entire cohort and was seven years after treatment initiation. Anemia was associated with a shorter TTFT, while increasing age and lack of CD94 expression were associated with worse OS. This rare disease warrants additional investigations to understand optimal management and improve outcomes, especially for those requiring treatment.