Use Of Bridging Therapy Research Articles

Bridging With Low-Molecular-Weight Heparin Versus Antiplatelet Therapy in Patients Undergoing Noncardiac Surgery After Percutaneous Coronary Intervention: A Comprehensive Review.

This review article discussed the use of bridging therapy with low-molecular-weight heparin (LMWH) in patients who undergo noncardiac surgery (NCS) after percutaneous coronary intervention (PCI). Patients who undergo PCI are at an increased risk of thrombotic events due to their underlying cardiovascular disease. However, many of these patients may require NCS at some point in their lives, which poses a significant challenge for clinicians as they balance the risk of thrombotic events against the risk of bleeding associated with antithrombotic therapy. This review evaluates the current evidence on the use of bridging therapy with LMWH in patients undergoing NCS after PCI, focusing on outcomes related to the efficacy and safety of antithrombotic therapy. The article also discusses the limitations of the current evidence and highlights areas where further research is needed to optimize the management of antithrombotic therapy in this patient population. The goal of this review was to provide clinicians with a comprehensive summary of the available evidence to guide clinical decision-making and improve patient outcomes.

Absolute Lymphocyte Count and Outcomes of Multiple Myeloma Patients Treated with Idecabtagene Vicleucel: The US Myeloma Immunotherapy Consortium Real- World Experience

Idecabtagene vicleucel (ide-cel) has shown impressive efficacy in relapsed/refractory multiple myeloma (RRMM). This study aimed to investigate the impact of absolute lymphocyte count (ALC) on the survival outcomes of RRMM patients treated with standard of care (SOC) ide-cel. Data were collected retrospectively from 11 institutions in the U.S. Impact of ALC parameters including pre-apheresis (pre-A), pre-lymphodepletion (pre-LD), absolute and percent difference from pre-A to pre-LD on clinical outcomes after ide-cel were examined using survival analysis. A new ALC profile was created based on univariate analysis that comprises 3 groups: normal (≥1 × 109/L) pre-LD ALC (LDN), low (<1 × 109/L) pre-LD ALC (LDL) + percent reduction <37.5 (%RL), and LDL ALC + percent reduction ≥37.5 (%RH). A total of 214 SOC ide-cel recipients were included in this analysis. The median patient age was 64 years (interquartile range [IQR], 57 to 69 years), median number of prior therapies was 6 (IQR, 5 to 9), and median duration of follow-up was 5.4 months (IQR, 2.1 to 8.3 months). Most patients had both low pre-A ALC (75.3%) and pre-LD ALC (77.2%), and the reduction from pre-A to pre-LD (median, .65 to .55 × 109/L) was statistically significant. Univariate analysis showed that the LDL + %RH group had significantly worse progression-free survival (PFS) and overall survival (OS) compared to the LDL + %RL and LDN ALC groups (6-month PFS: 40% versus 67.6% and 60.9%; 6-month OS: 69.5% versus 87% and 94.3%). In multivariable analysis, after adjusting for age, performance status, cytogenetic risk, use of bridging therapy, and extramedullary disease, PFS did not maintain its statistical significance; however, OS remained significantly worse for LDL + %RH group compared to the LDN ALC group (hazard ratio [HR], 4.3; 95% confidence interval [CI], 1.1 to 17), but the difference between the LDL + %RH versus %RL groups was not statistically significant (HR, 1.7; 95% CI, .8 to 4.0). Our findings indicate that low pre-LD ALC with high %R from pre-A to pre-LD was associated with inferior survival outcomes, particularly OS, in patients who received SOC ide-cel.

Impact of extramedullary multiple myeloma on outcomes with idecabtagene vicleucel.

7508 Background: Idecabtagene vicleucel (Ide-cel) has demonstrated excellent efficacy in patients with relapsed/refractory multiple myeloma (RRMM). However, outcomes in patients with extramedullary disease (EMD) remain to be better characterized. Methods: We included patients from 11 US academic centers, who were evaluated for EMD and were infused with ide-cel between May 2021 and April 2023. Patients with soft tissue or visceral lesions non-contiguous from bony lesions were classified as having true EMD, with paraskeletal disease classified as non-EMD. Disease responses were evaluated using the IMWG criteria. Time-to-event analyses were performed from the date of ide-cel infusion. Results: Among 351 patients with RRMM treated with ide-cel, 84 (24%) had EMD prior to infusion. Median follow-up for the entire cohort was 18.2 months (95% CI: 17-19.3). Baseline characteristics at ide-cel infusion for EMD and non-EMD cohorts are depicted in the table. For the EMD and non-EMD cohorts, the Day 30 objective response rates (ORR) were 58% vs. 69% (p=0.1), Day 30 ≥complete response rates were 16% vs 24% (p=0.11), the Day 90 ORR were 52% vs 82% (p&lt;0.001), and best ORR were 58% vs 82%, respectively. The median progression-free survival (PFS) was 5.3 months (95% CI: 4.1-6.9) for the EMD cohort vs. 11.1 months (95% CI: 9.2-12.6; p&lt;0.0001) for the non-EMD cohort. The median duration of response for EMD among day 30 responders was 6.4 months (95% CI: 5.1-8.4). In a multivariable analysis, EMD was an independent predictor of inferior PFS [hazard ratio 1.8 (95% CI: 1.2-2.5), p&lt;0.001] after adjusting for ECOG status, revised ISS stage, penta-drug refractoriness, elevated ferritin, prior BCMA-directed therapy and use of bridging therapy. Pattern of progression in the EMD cohort (n=68/84) included EMD site only (21%), hematologic only (22%), or both (57%), with comparable PFS for type of progression (p=0.19). The median overall survival (OS) was 14.8 months [95% CI: 9-Not reached (NR)] for EMD and 26.9 months [95% CI: 26.3 vs NR, p=0.006)] for the non-EMD group. Rates of Grade ≥2 cytokine release syndrome or neurotoxicity syndrome were comparable between the two cohorts. Conclusions: Patients with EMD demonstrate significantly inferior Day 90 ORR and presence of EMD is an independent risk factor for inferior PFS. [Table: see text]

Impact of perioperative low-molecular-weight heparin therapy on clinical events of elderly patients with prior coronary stents implanted > 12 months undergoing non-cardiac surgery: a randomized, placebo-controlled trial

BackgroundLittle is known about the safety and efficacy of discontinuing antiplatelet therapy via LMWH bridging therapy in elderly patients with coronary stents implanted for > 12 months undergoing non-cardiac surgery. This randomized trial was designed to compare the clinical benefits and risks of antiplatelet drug discontinuation via LMWH bridging therapy.MethodsPatients were randomized 1:1 to receive subcutaneous injections of either dalteparin sodium or placebo. The primary efficacy endpoint was cardiac or cerebrovascular events. The primary safety endpoint was major bleeding.ResultsAmong 2476 randomized patients, the variables (sex, age, body mass index, comorbidities, medications, and procedural characteristics) and percutaneous coronary intervention information were not significantly different between the bridging and non-bridging groups. During the follow-up period, the rate of the combined endpoint in the bridging group was significantly lower than in the non-bridging group (5.79% vs. 8.42%, p = 0.012). The incidence of myocardial injury in the bridging group was significantly lower than in the non-bridging group (3.14% vs. 5.19%, p = 0.011). Deep vein thrombosis occurred more frequently in the non-bridging group (1.21% vs. 0.4%, p = 0.024), and there was a trend toward a higher rate of pulmonary embolism (0.32% vs. 0.08%, p = 0.177). There was no significant difference between the groups in the rates of acute myocardial infarction (0.81% vs. 1.38%), cardiac death (0.24% vs. 0.41%), stroke (0.16% vs. 0.24%), or major bleeding (1.22% vs. 1.45%). Multivariable analysis showed that LMWH bridging, creatinine clearance < 30 mL/min, preoperative hemoglobin < 10 g/dL, and diabetes mellitus were independent predictors of ischemic events. LMWH bridging and a preoperative platelet count of < 70 × 109/L were independent predictors of minor bleeding events.ConclusionsThis study showed the safety and efficacy of perioperative LMWH bridging therapy in elderly patients with coronary stents implanted > 12 months undergoing non-cardiac surgery. An alternative approach might be the use of bridging therapy with half-dose LMWH.Trial registrationISRCTN65203415.

Abstract WP98: Variability of Perioperative Anticoagulation Strategies in Patients With Atrial Fibrillation

Introduction: In patients with atrial fibrillation (AFib) whose anticoagulation (AC) requires being held prior to non-emergent surgery, ischemic stroke is an unfortunately familiar event. Current practices in the holding of anticoagulation pre-op and the use of bridging therapy are heterogeneous, the guidelines for which are often underutilized. Methodology: We surveyed cardiologists, general practitioners and surgical specialists across a single large academic-based healthcare institution regarding periprocedural AC practices in patients with AFib. Data were organized by provider type and experience. Chi-square, Fisher exact, and Student's t-tests were used to analyze differences in anticoagulation practices. Results: Of 2,604 surveys emailed, 14 cardiologist, 53 general practitioners and 70 procedural/surgical specialists participated. Average number of days surgical specialists required holding AC were 2.6 (SD = 1.2) for direct oral anticoagulant (DOAC) and 4.6 (SD=1.6) for warfarin. INR goal averaged 1.6 (SD 0.3). Surgical specialists required bridging therapy for DOAC significantly less often than they did for warfarin, 15.5% vs 44.3%, X 2 = 14.0, p &lt; 0.001. Timing of DOAC held and warfarin held did not differ between attendings and trainees, nor did threshold goal INR. In contrast, practices between non-surgical specialists widely differed. Cardiologists trended roughly 4 times less likely than general practitioners to prescribe bridging therapy while DOAC was held, X 2 = 3.3, p = 0.06, yet they also trended toward prescribing bridging therapy more often for patients who had history of ischemic stroke. Significantly, attendings were 5 times less likely than residents to prescribe bridging therapy for DOACs and 3x times less likely to do so for warfarin, X 2 = 14.9, p = 0.0001 and X 2 = 5.5, p = 0.01, respectively. Conclusion: Our data indicate that significant differences exist in pre-op anticoagulation recommendations across provider type as well as training level. These differences are most stark in the use of bridging therapy while anticoagulation is held. Surgeons demonstrated more consistency in their anticoagulation strategies than did non-surgical providers.

Impact of Patient Selection and Management over Different Time Periods on the Outcome of Patients with Large B-Cell Lymphoma Receiving Chimeric Antigen Receptor T-Cell Therapy

Introduction. Autologous chimeric antigen receptor (CAR) T-cell therapy targeting CD19 is an effective treatment for relapsed or refractory large B-cell lymphoma (LBCL). Real-world studies have reported improved outcomes in terms of safety and efficacy in comparison with pivotal trials. These differences have been associated to a learning curve in patient selection and adverse event control, but this hypothesis has not been proven. The aim of this study was to analyze patient selection and CAR T-cell management across different time periods and assess its impact on treatment outcomes Methods. This retrospective analysis included all consecutive LBCL patients receiving CAR-T cell therapy (axicabtagene-ciloleucel [axi-cel] and tisagenlecleucel) in the third line setting from approval in 2019 to 2023 and reported in the Spanish Registry. Patients were categorized in 3 consecutive time periods of 18 months each according to infusion date. Baseline characteristics, manufacturing times and production failures as well as efficacy and safety outcomes were compared across periods. An additional safety and efficacy analysis was conducted in patients receiving axi-cel. Results. The study included 458 patients: 117 (26%), 194 (42%) and 147 (32%) in the early (EP) (January 2019-June 2020), intermediate (IP) (July 2020-December 2021) and recent period (RP) (January 2022-June 2023), respectively. In terms of patient profile, baseline characteristics evolved overtime as patients in the RP had received less number of prior therapies, had less primary refractory disease, less bulky disease and had lower LDH at lymphodepletion. On the contrary, the RP had more patients with ECOG performance status ³2 and higher comorbidity burden. Regarding the product, the use of axi-cel increased overtime, from 45% in the EP to 83% in the RP (Table). The time from apheresis to infusion improved overtime, moving from 48 days in the EP to 38 days in the RP. Manufacturing failures (5%) and use of bridging therapy (81%) remained stable overtime. Regarding efficacy, overall (complete) response rates improved overtime (from 66% [25%] in the EP to 78% [52%] in the RP [p&amp;lt;0.001], respectively). Median PFS and OS for the whole cohort were 3.9 months (95% CI 3.23-5.83) and 18.5 months (95% CI 13.53 - 27.67) without differences across periods. In terms of toxicity, patients in the RP had more grade &amp;gt; or = 3 CRS and ICANS, received more tocilizumab and corticosteroids and required more ICU admission compared with the EP. These results were driven by the higher use of axi-cel in the RP. When focusing exclusively on axi-cel patients (n=301), the CR rate also improved overtime (32% in the EP; 37% in the IP and 55% in the RP, p=0.016) (Figure) while median PFS (6.63 months, 95%CI 3.90 - 11.43) and OS (25.73 months, 95%CI 18.57 - NA) remained stable. In the multivariable analysis, ECOG PS &amp;gt; 1 (HR 2.68, 95% CI 1.35-5.09, p=0.005) and LDH ³ 500 UI/L (HR 1.54, 95% CI 1.02-2.31, p=0.04) but not treatment period were associated with a shorter PFS. In terms of toxicity, the time to CRS onset (median of 3 vs. 1 days, p=0.001) and ICANS (median of 8 vs. 6 days, p=0.06) was later in the EP compared with the RP. The incidence of grade &amp;gt; or = 3 CRS and ICANS (ranging from 10% to 7% and 36% to 41%, respectively), the use of tocilizumab, corticosteroids, and anakinra as well as ICU admission rate and 12-month non-relapse mortality (2% vs 5%) remained stable across periods. Conclusion. The criteria for selecting patients for CAR T-cell therapy have evolved overtime towards a less aggressive disease profile and allowing less fit patients for therapy in recent times. Patients treated in the RP were more likely to respond to these therapies but this did not translate into prolonged survival or an improved safety profile.

A Novel Composite Endpoint of Toxicity-Free, Progression-Free Survival (TPFS) after CD19-Directed Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma

Background: CD19-directed chimeric antigen receptor T-cell (CAR T) therapy with axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), or lisocabtagene maraleucel (liso-cel) are FDA-approved for relapsed and/or refractory (r/r) large B-cell lymphoma (LBCL) after ≥2 prior lines of systemic therapy (all 3) or earlier after 1 line (axi-cel and liso-cel) based on durable remissions of 30-40%. Pivotal trials and real-world data demonstrated notable heterogeneity in toxicity and efficacy between CAR T products. To account for such differences, we have established a novel composite endpoint of toxicity-free, progression-free survival within 6 months (TPFS6) after CAR T-cell therapy. We also studied factors associated with TPFS6 across CAR T-cell products and its impact on long-term success of CAR T-cell therapy. Methods: This retrospective cohort analysis included 282 consecutive adult patients with r/r LBCL and its variants who received axi-cel (n=228), tisa-cel (n=47), or liso-cel (n=7) at Moffitt Cancer Center (05/2015-01/2022). TPFS6 was defined as absence of severe (≥Grade 3) cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), progressive disease (PD)/stable disease (SD) and non-relapse mortality (NRM) within 6 months of CAR T-cell infusion. CRS and ICANS were graded according to CTCAE or ASTCT Consensus grading. Factors associated with TPFS6 were assessed via logistic regression multivariate analysis (MVA). Landmark analysis at the 6-month point examined the impact of TPFS on overall survival (OS). All analyses were performed utilizing SAS and R. Results: For the entire cohort (median age=64 years [range, 19-86]; 60.3% males), the TPFS6 was 37% (95% confidence interval [CI] 31-43, Figure 1A) with no difference between the recipients of axi-cel, tisa-cel, or liso-cel ( p=0.97). Individual components of TPFS6 such as severe CRS/ICANS, NRM, and PD/SD accounted for 6.8%/30.3%, 1.7%, and 61.2%, respectively. Patients with TPFS6 differed from their counterparts by gender (males, 51% vs 65.7%, p =0.014), presence of bulky (8.7% vs 17.4%, p =0.045) or extra nodal (≥2 sites, 30.8% vs 46.6%, p=0.009) disease, ECOG performance (≥2, 7.7% vs 20.8%, p=0.004), prior autologous transplant (25% vs 13.5%, p=0.015), C-reactive protein (CRP) (&amp;gt;4 mg/dL, 10.6% vs 35.4%, p&amp;lt;0.001), ferritin (≥400 ng/mL, 37.5% vs 62.4%, p&amp;lt;0.001), lactate dehydrogenase (LDH) (≥225 U/L, 51% vs 76.4%, p&amp;lt;0.001) at lymphodepletion (LD). TPFS6 patients were comparable to those experiencing at least one of the TPFS6 endpoints according to age, race, number of prior lines or use of bridging therapy, LBCL variants, Ann Arbor staging, double/triple hit status, prior CNS involvement, and vein-to-vein time (all p&amp;gt;0.1). In logistic regression MVA, lower levels of baseline LDH (odds ratio [OR]=0.44, p=0.004), CRP (OR=0.33, p=0.004), ECOG&amp;lt;2 (OR=0.43; p=0.05) and female gender (OR=0.5; p=0.01) were associated with TPFS6. In the landmark Cox MVA of OS, TPFS6 was strongly associated with 5.2-fold survival difference ( p&amp;lt;0.001, Figure 1B) after adjustment for age (hazard ratio [HR]=1.24 per 10-year increment, p=0.077) male gender (HR=1.92, p=0.013), ECOG≥2 (HR=2.34, p=0.004), high LDH at LD (HR=2.63, p&amp;lt;0.001), and CAR T product (HR=1.67 for tisa-cel vs axi-cel, p=0.079). At 6 months, overall response and complete response rates were 48% and 45%, respectively. With median follow up of 15.4 months for surviving patients, the estimated 2-year OS and PFS were 54.5% and 39.3%, respectively. Conclusions: Only 37% of patients were alive at 6 months without experiencing a TPFS-defining event. TPFS6 was associated with known clinical risk factors such as CRP, LDH, ECOG and gender but not the type of CAR T product. TPFS6 encompasses clinically meaningful components associated with OS and it therefore represents an ideal recovery outcome by measuring initial treatment success without progression, major morbidity, and mortality. Thus, TPFS6 needs to be further explored as a uniform endpoint for evaluating CAR T-cell safety and efficacy in future clinical trials of r/r LBCL.

A Novel Composite Endpoint of Toxicity- and Progression-Free Survival after B-Cell Maturation Antigen (BCMA)-Directed Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Multiple Myeloma

Introduction: BCMA-directed chimeric antigen receptor T-cell therapy (CAR T), idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), are approved for patients with relapsed and/or refractory (R/R) multiple myeloma (MM). Pivotal KaRMMA and CARTITUDE-1 trials as well as real-world data demonstrated heterogeneity in toxicity and efficacy between ide-cel and cilta-cel. To account for such differences, we have established a novel composite endpoint of toxicity-free, progression-free survival within 3 months (TPFS3) after anti-BCMA CAR T therapy. We also studied factors associated with TPFS3 across ide-cel and cilta-cel and the impact of TPFS3 on overall survival (OS) after CAR T. Methods: We analyzed a retrospective cohort of 133 consecutive recipients of ide-cel or cilta-cel at Moffitt Cancer Center (05/2021-03/2023). TPFS3 was defined as absence of severe (Grade≥3) cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenia(s), myeloma progression/stable disease (PD/SD), and non-relapse mortality (NRM) within 3 months after CAR-T infusion. CRS and ICANS were graded according to ASTCT Consensus grading. Cytopenias were graded according to CTCAE v5.0 and defined as two (or more) timepoint uni- or multilineage cytopenia, including any Grade≥2 cytopenia at post-CAR T Day 30 deepening to at least Grade≥3 at Day 60 and/or Day 90. Factors associated with TPFS3 were assessed via multivariate logistic regression analysis (MVA). Landmark Cox survival analysis at the 3-month timepoint examined the impact of TPFS3 on subsequent overall survival (OS). All analyses were performed using SAS and R. Results: In total, 48.1% (N= 64; median age=66 years [range, 45-82]; male=44%) of the patients were alive, toxicity- and progression-free by 3 months after CAR T infusion. TPFS3 components included PD/SD (N=30, 43.5%), severe cytopenias (N=26, 37.7%), ICANS (N=8, 11.6%), CRS (N=3, 4.3%), and NRM (N=2, 2.9%) (Figure 1A). In the univariate analysis, TPFS3 patients differed from the rest of the cohort according to lower marrow burden ( p=0.025), revised international staging system (R-ISS) (I/II vs III; p=0.015), CRP ( p=0.019) and ferritin ( p=0.002) levels at lymphodepletion (LD). The use of ide-cel (N=109) vs cilta-cel (N=24) was not significantly associated with TPFS3 ( p=0.119). In the MVA logistic regression, lower ferritin level (median cut off=228 ng/mL) at LD was associated with TPFS3 (odds ratio [OR]=0.37 [95%CI, 0.18-0.78], p=0.008] after adjusting for age, myeloma marrow burden, presence of extramedullary disease, R-ISS, CAR T product (all p&amp;gt;0.1), and CRP (median cut off=0.41mg/dL) at LD (OR=0.51 for lower vs higher, [95%CI, 0.25-1.05], p=0.069) included in the final model together with ferritin. In the landmark Cox survival analysis at 3 months, TPFS3 was associated with 6.54-fold superior OS (hazard ratio [HR]=0.15, 95%CI 0.05-0.52, p=0.003) (Figure 1B) after adjustment for potential confounders (age, gender, CRP, CAR-T product, marrow burden, R-ISS, extramedullary disease; all p&amp;gt;0.1). Other prognostic risks associated with inferior OS in the final model of the landmark analysis included the use of bridging therapy (HR=3.98 [95%CI, 1.30-12.20], p=0.016), ECOG≥2 at LD (HR=4.53 [95%CI, 1.57-13.07], p=0.005) and higher ferritin level at LD (HR=2.60 [95%CI, 0.95-7.13], p=0.063). Conclusions: We found that 48.1% of anti-BCMA CAR T recipients with R/R MM were alive and free of TPFS3-defining events. Myeloma response failure, cytopenias and severe ICANS were the top leading components of TPFS3 which was best predicted by ferritin level at LD. TPFS3 independently predicted long-term OS. Thus, TPFS3 may serve as an ideal composite safety and efficacy endpoint in future myeloma trials with BCMA-directed CAR T.

Factors associated with refractoriness or early progression after idecabtagene vicleucel in patients with relapsed/ refractory multiple myeloma: US Myeloma Immunotherapy Consortium real world experience.

While response rates and survival outcomes have been very promising for idecabtagene vicleucel (ide-cel), a proportion of patients do not respond or relapse early after this B-cell maturation antigen (BCMA) targeted chimeric antigen receptor (CAR) T-cell therapy. Understanding the characteristics of these patients is important for patient selection and development of novel strategies to improve outcomes. We evaluated factors associated with early progression (progression or death due to myeloma ≤3 months after CAR T-cell infusion) in patients treated with standard of care ide-cel at 11 US academic centers. Among 211 patients that received ide-cel, 43 patients had a progressive event ≤3 months of infusion. Patients with a history of extramedullary disease, prior BCMA targeted therapy, elevated ferritin at lymphodepletion, use of bridging therapy, Hispanic ethnicity, plasma cell leukemia and t(4;14) were more likely to progress ≤3 months of infusion (P<0.05). Of these risk factors for early progression identified in univariate analyses, history of extramedullary disease, prior BCMA targeted therapy, elevated ferritin at lymphodepletion, plasma cell leukemia, and t(4;14) were associated with worse progression-free survival (PFS) in multivariable analysis. Presence of three or more of these factors had a significant negative impact on PFS (P<0.001; median PFS for ≥3 factors, 3.2 months vs. 0 factors, 14.1 months). This study helps identify patients at high risk of early progression after CAR T-cell therapy who may benefit from specific interventions pre and post CAR T-cell therpy to improve outcomes.

Improved outcomes of large B-cell lymphoma patients treated with CD19 CAR T in the UK over time.

The success of CD19 Chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off-the-shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the 'standard-of-care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020-2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression-free survival (1-year PFS 50% vs. 32%, p < 0.001) and overall survival (1-year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high-grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up-to-date clinical data when comparing CAR T against new treatment options for r/r LBCL.

Prognostic value of month 1 bone marrow and PET MRD status in CAR-T therapy for myeloma.

8024 Background: Minimal residual disease (MRD) is prognostic for survival in multiple myeloma (MM). MRD is usually assessed in the bone marrow (BM) by flow cytometry or NGS. MRD by FDG PET/CT provides a global representation of the tumor burden, including response assessment of extramedullary disease. We examined MRD status in MM pts using both BM and PET/CT at Mayo Clinic. Methods: Medical records were reviewed retrospectively for MM pts who received CAR-T between 4/2018 and 12/2022. All PET/CT scans were assessed by radiologists. BM MRD was assessed by flow cytometry with a sensitivity of 10-5. Progression-free survival (PFS) and overall survival (OS) were analyzed by Kaplan-Meier method. Results: Among the 157 CAR-T pts, including 89 pts who received FDA-approved CAR-T, median age was 63 years, 59% (92/157) were males, 42% (66/157) had high risk cytogenetics with median of 5 prior lines of therapy, 36% (57/157) had plasmacytoma. Incidence of CRS was 83%, 5% grade ≥ 3 CRS. Incidence of ICANS was 19%, 4% grade ≥ 3 ICANS. CR/sCR rate was 37%. One hundred and thirty-seven pts (87%) had evaluable BM at month (mo) 1, 85% (117/137) were BM MRDneg at mo 1. Baseline demographics were comparable between the two groups except age, % BM plasma cells and use of bridging therapy. Among the MRDneg pts, CR/sCR rate was 44% (51/117) and 95% (111/117) had sFLC below normal. At median follow-up of 13.8 months, median PFS among pts with BM MRDneg at 1 mo was 12 mo (95% CI: 11, 30) vs 3 mo (95%CI: 2, 7) for BM MRDpos (p&lt;0.001). Median OS among pts with BM MRDneg at 1 mo was 34 mo (95% CI: 24, NR) vs 22 mo (95%CI: 7, NA) for BM MRDpos (p&lt;0.01). At month 1, 112 pts had both BM and PET/CT assessments available, 64/112(57%) were both BM MRDneg/PET MRDneg, 38/112 (34%) were MRDneg for either BM or PET and 10/112 (9%) were positive for both BM and PET (MRDpos/PET MRDpos). Baseline demographics except age were comparable between the 2 groups (Table). Rate of conversion from MRDpos to MRDneg was low. Rate of sustained BM and PET MRDneg at mo 12 was 44% (8/18). The median PFS and OS for BM MRDneg/PET MRDneg was significantly longer as compared to others (Table). Conclusions: Achieving FLC below normal, BM MRDneg and PET MRDneg at 1 month, regardless of IMWG response at that time, is prognostic for both PFS and OS in MM pts receiving CAR-T. Failure to achieve any of these confers poor prognosis. [Table: see text]

Outpatient practice utilization for CAR-T and T cell engager in patients with lymphoma and multiple myeloma.

1533 Background: FDA-approved chimeric antigen receptor T-cell (CAR-T) and bispecific T cell engager (TCE) therapy are most commonly managed inpatient. Here we report our experience with hospital-based outpatient (HBO) management of patients (pts) receiving FDA-approved CAR-T or TCE and a predictive model for increased risk of early hospitalization (≤3 days post CAR-T). Methods: We reviewed the outcomes of pts who received FDA-approved CAR-T (axi-cel, brexu-cel, ide-cel, cilta-cel) or TCE (teclistamab) in the HBO unit between 3/2021 and 1/2023 at Mayo Clinic, Rochester. Results: HBO is closely integrated with inpatient practice and includes the same specialty trained clinical team. It is the first point of contact 24/7 for pts and triage evaluations. CAR-T and TCE are given on HBO followed by monitoring per REMS and as clinically needed until admission criteria is met. Remote patient monitoring (RPM) tools were used as part of outpatient monitoring. Out of 169 CAR-T pts, 87 (51%) were dosed with new indication/products (follicular lymphoma, mantle cell lymphoma, myeloma). Among those, 80 (92%) pts were dosed outpatient, among whom 21 (27%) were never hospitalized. CRS and ICANS incidences were comparable to that reported in registration studies. Median time to first admission from CAR-T infusion was 1 day (range, 0-9), with 31% (n=18/59) of admissions after day 3 post infusion. The most common cause of hospitalization was fever (n=40, 59%). Median length of hospital stay was 4 days (range, 1-49). Median time to tocilizumab (n=45, 80%), steroid (n=1, 2%), escalation of oxygen support (n=7, 12%), vasopressor (n=2, 3%), ventilator (n=1, 2%), hemodialysis (n=1, 2%) and ICU transfer (n=3, 5%) was 1 day (range, 0-31) after first admission. Use of bridging therapy, elevated CRP and LDH were predictive of early admission (ROC AUC 0.62). Four pts received teclistamab on HBO and enrolled in RPM. Data from more pts will be reported at ASCO. Conclusions: Our expanded study in CAR-T and TCE confirms that HBO is feasible and that CAR-T and TCE can be safely dosed outpatient. Approximately 31% of pts were admitted after 3 days from CAR-T infusion, and 27% of our pts were never admitted. Variables associated with aggressive disease can predict early hospitalization in pts receiving FDA-approved CAR-T. Extension of HBO practice to TCE is feasible.[Table: see text]

Outpatient Practice Pattern for Recently Approved CAR-T in Patients with Lymphoma and Multiple Myeloma

Background: FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy are commonly administered in the inpatient setting given the average onset of cytokine release syndrome (CRS) is within the first 3 days post infusion. We and a few other centers have reported on the safety and feasibility of hospital-based outpatient practice (HBO) for CAR-T (Bansal et al, ASCO 2021). In Mayo Clinic Rochester practice, we have found the use of bridging therapy, elevated CRP and LDH as predictors for early hospital admission i.e., within 3 days post CAR-T infusion in patients with aggressive lymphoma (Bansal et al, ASCO 2021). Here, we report our experience with feasibility and safety of hospital-based outpatient (HBO) management of patients receiving the following CAR-T therapies: anti-BCMA CAR-Ts for multiple myeloma (MM), axicabtagene ciloleucel (axi-cel) for follicular lymphoma (FL), and brexucabtagene maraleucel (brexu-cel) for mantle cell lymphoma (MCL). Methods: We retrospectively queried a prospectively maintained database of consecutive, adult patients with MCL, FL grade 1-3A (FL1-3A) and MM who received an FDA-approved CAR-T product between 3/2021 and 6/2022 at Mayo Clinic, Rochester. Clinical course from CAR-T infusion to the time that they were dismissed home from the treatment center was reviewed. To predict baseline risk factors for admission within 72 hours of infusion, a logistic regression model was fit. Variables were selected using stepwise AIC variable selection. Results: Hospital based outpatient practice (HBO) is staffed by the same inpatient Immune Effector Cell care team, including nurses, advanced practice providers and physicians. These providers oversee patients in the hospital and HBO unit daily and provide continuity of care as patients transition between inpatient and outpatient care. HBO is the first point of contact 24/7 for patients and triage evaluations for direct inpatient admissions. The standard of care is to give lymphodepletion chemotherapy and CAR-T infusion on HBO and continue daily monitoring till day 7 and thereafter, as clinically needed until admission criteria are met. Fever, elevated CRP within 24-hour or less doubling time, or new neurologic symptoms are among the admission criteria utilized. Among 50 CAR-T recipients, 39 (78%) pts were dosed outpatient, among whom 7 (18%) were not admitted (Table 1). Median length of hospital stay for the 32 patients who were admitted was 6 days (range, 2-49). Cytokine release syndrome (CRS) and immune cell associated neurologic syndrome (ICANS) incidences for the entire cohort were comparable to that reported in registration studies. There were 2 deaths due to CAR-T related toxicity within 30 days post infusion. The median time to first admission from CAR-T infusion was 1 day (range 0-9), with 8 (25%) of admissions after 3 days. The most common cause of hospitalization was fever (25, 79%), of which 56% (14/25) were non-neutropenic. Work-up for fever was positive for infection in 4 (12.5%) patients. The median time to tocilizumab (26/32, 81%), steroid (1/31, 3%), escalation of oxygen support (4/32, 12.55), vasopressor (1/32, 3%), ventilator (1/32, 3%), hemodialysis (1/32, 3%) and ICU transfer (3/32, 9%) was 1 day (range, 0-31) after first admission. We applied the previous model (use of bridging therapy, elevated CRP and LDH) to this cohort and found this to remain correlated with early hospital admission (ROC AUC was 0.948, Figure 1). Conclusion: Our expanded study in FL, MCL and MM confirms that HBO is feasible. Axi-cel, brexu-cel, Idecabtagene vicleucel and ciltacabtagene autoleucel can be safely dosed outpatient. Approximately 20% of the patients are never admitted. In addition, variables associated with aggressive disease appear to be applicable for prediction of early hospital admission in these new CAR-T products and indications. This could potentially be used to risk stratify patients for monitoring in outpatient CAR-T practices. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Race and Social Determinants of Health on Outcomes in Patients with Aggressive B-Cell Lymphomas Treated with Chimeric Antigen Receptor T-Cell (CART) Therapy

Background: Health care disparities, driven by multiple social, economic, and/or environmental factors lead to inequalities in health outcomes. With CAR T-cell therapy (CART), differences in response rates have been identified across race. However, data that address the convergence of race with other social determinants of health on outcomes with CART remain limited. We examined the impact of interactions between race, insurance status, clinical trial utilization, and age on access to care and outcomes in patients (pts) treated with CART for aggressive B-cell lymphomas (B-NHL). Methods: Adult pts with relapsed/refractory B-NHL treated with CD19 CART between 2015- 2021 across 13 US academic centers were identified. Insurance type, demographic and clinical data were collected and analyzed via Chi-squared and Kaplan-Meier analysis. Cox multivariable regression was used to determine impact of race/ethnicity and other variables on survival. Variables used in the multivariable analysis (MVA) included race, age, insurance type, prior autologous stem cell transplantation (autoSCT), CART on clinical trial, use of bridging therapy, IPI at CART infusion, and elevated LDH pre-CART. Race (Caucasian, African American (AA), Asian or Other with the latter cohort excluded from analyses) and ethnicity (Hispanic vs non-Hispanic) were self-reported by pts. Results: A total of 466 adult pts were included. Table 1 outlines demographic, clinical, and health care utilization parameters by race. 406 (87%) were Caucasian, 34 (7%) AA and 26 (6%) Asian; 9 (2%) were Hispanic (all Caucasian). Caucasians were older compared to AAs and Asians (median age 59 vs 55 vs 55 yrs; p=0.004). Median number of lines of therapy prior to CART were similar across race (p=0.44). Caucasians were more likely to have a prior autoSCT (p= 0.04). For Caucasians vs AAs vs Asians: rates of bridging were 44% vs 61% vs 46% (p=0.17) and rates of utilization of clinical trials for CART access were 29% vs 15% vs 19% (p=0.12), respectively. Median time from last relapse/progression pre-CART to CART was 2 vs 1.8 vs 1.2 mo (p=0.9) and median time from apheresis to CART was 1.1 vs 1.1 vs 0.9 mo (p=0.2), respectively. D180 ORR were 51% vs 46% vs 19% (p =0.01) with D180 CR rates of 43% vs 42% vs 19% (p = 0.17), respectively. No difference in grade >/= 3 CRS or ICANS was observed across race. Median follow-up after CART was 12.7 mo. Median PFS (mPFS) was longer for Caucasians (11.5 mo) than for AAs (3.5 mo, HR 1.56 [1.03-2.4], p=0.04) or Asians (2.7 mo, HR 1.7 [1.02-2.67], p=0.04). Differences in median OS (mOS) were not statistically different: mOS was 25.4 mo in Caucasians vs 30.4 mo in AAs (HR 1.0 [0.59 - 1.69], p=0.99) vs 16.8 mo in Asians (HR 1.42 [0.84 - 2.42], p=0.19). Rates for administration of therapy after CART failure were non-significantly higher for Caucasians vs AAs or Asians, (46% vs 25% vs 28%, p = 0.05). On MVA, race, insurance type, use of bridging, and elevated LDH pre-CART impacted PFS (p < 0.001 - 0.031, Table 2). As compared to Caucasians, AAs (but not Asians) had a worse PFS (HR 1.72 [1.05 - 2.82], p = 0.03). Race did not impact OS. Medicare, lack of bridging, and receipt of further therapy post CART failure positively impacted OS (p = 0.006 - 0.044). Insurance type did not impact median time from last relapse/progression to CART. However, there were significant differences in mPFS and mOS between payer groups: mPFS was 15.9 vs 4.2 vs 6.0 vs 0.9 mo (p<0.001) and mOS was 31.2 vs 12.8 vs 21.5 vs 3.2 mo (p<0.001) for Medicare (n=206) vs Medicaid (n=33) vs private insurance (n=219) vs self-pay (n=7). Conclusion: In our cohort, AAs and Hispanics were greatly underrepresented which underscores the presence of health care disparities across race and ethnicity for relapsed/refractory B-NHL. With CART, Caucasians had similar complete response rates but longer mPFS as compared to AAs and Asians warranting exploration of factors that may predict for early progression in racial minorities. No difference in OS was observed by race perhaps attributed to the effects of next line therapy after CART. Insurance type impacted both PFS and OS with best outcomes seen in pts with Medicare. Results do not capture pts facing insurance denial and/or poor access that would likely augment trends for race and socioeconomic disparities identified in our CART population. The interaction between race and insurance status and their relative contributions to access and outcomes with CART should be further explored. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Assessment of Durable Responses after Brexucabtagene Autoleucel (KTE-X19) in the ZUMA-2 Study in Relapsed/Refractory Mantle Cell Lymphoma (R/R MCL)

Introduction: Brexucabtagene autoleucel (brexu-cel, formerly known as KTE-X19) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the United States for the treatment of adults with R/R MCL and in the European Union for adults with R/R MCL after ≥2 prior therapies, including a Bruton tyrosine kinase inhibitor (BTKi). At a median 35.6-months (mo) follow-up in the Phase 2, multicenter ZUMA-2 study of brexu-cel in R/R MCL, the objective response rate was 91% (68% complete response [CR] rate), with a median duration of response (DOR) of 28.2 mo, and overall survival (OS) of 46.6 mo among all 68 treated patients (pts) and not reached in pts with a CR (Wang et al. J Clin Oncol. 2022). To identify factors associated with long-term response to KTE-X19, we evaluated patient and product characteristics by response status at 24 mo post infusion in ZUMA-2. Methods: Adults (≥18 years) with R/R MCL who had received ≤5 prior regimens including a BTKi underwent leukapheresis and conditioning chemotherapy followed by a single infusion of brexu-cel (2×106 anti-CD19 CAR T cells/kg). Post hoc assessments of patient, disease, pharmacokinetic, and product characteristics are reported by response status at 24 mo (ongoing vs relapsed). Results: At a median follow-up of 35.6 mo (range, 25.9-56.3), 62 pts had achieved a CR or partial response; 3 did not reach the 24-mo assessment visit and were excluded from this analysis. Of the 59 evaluable pts with response, 29 (49%) had ongoing responses at 24 mo (ongoing responders), and 30 (51%) had relapsed prior to 24 mo (relapsed responders). At baseline, the median age was 65 years and median number of prior therapies was 3 in both subgroups. Among ongoing vs relapsed responders, 66% vs 43% had ibrutinib as last prior therapy and 14% vs 13% had acalabrutinib as last prior therapy, with a median (range) time from last prior therapy of 63 (26-748) vs 64.5 mo (22-443), respectively. A smaller proportion of ongoing responders compared with relapsed responders received bridging therapy (21% vs 53%) and prior platinum therapy (10% vs 40%), respectively; while similar proportions received prior bendamustine therapy (45% vs 53%), prior proteosome inhibitor therapy (41% and 37%), and prior autologous stem cell transplant (48% vs 37%), respectively. At baseline, a greater proportion of ongoing responders had an ECOG score of 0 compared to relapsed responders (79% vs 57%, respectively), and the median (range) tumor burden (SPD) was 935.1 (260-6133) in ongoing responders and 4233.6 (386-14390) in relapsed responders. The incidence of high-risk features was similar between ongoing responders and relapsed responders, with 66% and 60% having a baseline Ki-67 proliferation index score of ≥30%, 10% of both subgroups having TP53 mutations, 45% and 37% having elevated lactose dehydrogenase levels (ULN to ≥1.5 ULN), and 10% and 13% having high-risk Simplified Mantle Cell Lymphoma International Prognostic Index scores (>6), respectively. The median (range) DOR in ongoing responders with CR (n=28) was not reached (46.7-not estimable) and was 8.3 mo (5-13.6) in relapsed responders with CR (n=15). Of the relapsed responders, 67% had received subsequent anticancer therapy by data cutoff, the most common of which were radiotherapy (23%), dexamethasone (23%), rituximab (23%), venetoclax (20%), and lenalidomide (20%; patients could have received multiple subsequent therapies and multiple lines of subsequent therapy). Median [range] peak (102.4 [0.3-2241.6] vs 59.9 [1.6-2589.5]) and area under the curve (1487 [3.8-16,700] vs 688.2 [19-27,200]) CAR T-cell levels were ~2x higher in ongoing responders than in relapsed responders, respectively. A modest increase in the median [range] total number of infused CCR7+ cells was observed in ongoing vs relapsed responders (119.8 [37-249.9] vs 89.1 [6.1-353.4]), suggesting a potential role of continuous memory T-cell differentiation in achieving durable responses. Conclusions: After ~3-years median follow-up, brexu-cel continues to demonstrate durable responses with 49% of patients in ongoing response at 24 mo post infusion. In summary, ongoing responders had lower ECOG scores and tumor burden, as well as less frequent use of bridging therapy and less intense regimens for previous relapses, suggesting the potential for greater benefit with brexu-cel if given in earlier course of disease.

Impact of conditioning chemotherapy on lymphocyte kinetics and outcomes in LBCL patients treated with CAR T-cell therapy.

Conditioning chemotherapy (CCT) has been shown to be essential for optimal efficacy of chimeric antigen receptor (CAR) T-cell therapy. Here, we determined whether the change in absolute lymphocyte count, referred to as delta lymphocyte index (DLIx), may serve as a surrogate marker for pharmacodynamic effects of CCT and whether it associated with germline genetic variants in patients with large B-cell lymphoma (LBCL). One-hundred and seventy-one patients were included, of which 86 (50%) received bridging therapy post-leukapheresis. Median DLIx was 0.5 × 109/L (range, 0.01-2.75 × 109/L) and was significantly higher in patients who achieved complete response (p = 0.04). On multivariate analysis, low DLIx was associated only with use of bridging therapy (odds ratio 0.4, 95% CI 0.2-0.8, p = 0.007). Low DLIx was independently associated with shorter progression-free (p = 0.02) and overall survival (p = 0.02). DLIx was associated with genetic variations related to drug metabolism and macrophage biology such as ABCB1, MISP and CPVL. The impact of CCT on lymphocyte count is affected by use of bridging therapy but change in lymphocyte count is independently associated with efficacy. Studies aimed at investigating macrophage biology in this setting may suggest strategies to increase the efficacy of CCT and improve outcomes.

A call to action for anticoagulation stewardship

A call to action for anticoagulation stewardship

Value of Reducing Wait Times for Chimeric Antigen Receptor T-Cell Treatment: Evidence From Randomized Controlled Trial Data on Tisagenlecleucel for Diffuse Large B-Cell Lymphoma

ObjectivesThis study aimed to quantify the value of reducing chimeric antigen receptor T-cell (CAR-T) treatment wait times on patients with refractory and relapsed aggressive blood cancer who can newly gain access to treatment or access treatment earlier in their disease course. MethodsUsing data from the JULIET clinical trial, we first identified the number of additional patients with diffuse large B-cell lymphoma that would have been treated with tisagenlecleucel CAR-T therapy if wait times were shortened. For these patients, we estimated mortality benefits using literature estimates of CAR-T effectiveness. Next, among patients who already received CAR-T, we estimated tumor burden progression over time using a linear probability regression model. The primary outcome variable was an indicator for having above-normal lactate dehydrogenase, and we controlled for time, use of bridging therapy, and time-invariant patient characteristics. The regression results, along with literature estimates relating lactate dehydrogenase to CAR-T effectiveness, were used to compute the survival benefits of earlier CAR-T treatment. ResultsReducing wait times by 2 months increased the number of eligible patients receiving CAR-T by at least 10.7%. For patients already receiving tisagenlecleucel CAR-T, a 2-month reduction in wait times generated a 3.3% increase in survival gains per treated patient. Thus, among patients seeking treatment, the combined treatment efficacy increased by 14%, with approximately one-quarter of survival benefits accruing to existing patients receiving faster treatment. ConclusionsDelays affected not only access to CAR-T treatments but also treatment effectiveness. Our results highlight the survival benefits of expediting treatment access and may help explain some observed differences in CAR-T effectiveness across countries.

Sequencing of Novel Therapies for Mantle Cell Lymphoma.

There is no standard approach to sequencing novel therapies in mantle cell lymphoma (MCL). For initial treatment, intensive induction chemotherapy followed by autologous stem cell transplant and rituximab maintenance remains our preferred approach in young, fit patients. We consider bendamustine plus rituximab or lenalidomide plus rituximab in patients who are ineligible for intensive chemotherapy-based approaches. Bruton's tyrosine kinase inhibitors are our preferred class of agents to use in the second-line setting. When patients inevitably relapse on one of these agents, we proceed with chimeric antigen receptor T-cell (CAR T) therapy in eligible patients, often with the use of bridging therapy with corticosteroids, lenalidomide, or venetoclax. We treat patients who are ineligible for CAR T or clinic trial with venetoclax, lenalidomide, or proteosome inhibitor-based regimens, although efficacy is expected to be limited in this setting with a shortened duration of response to each subsequent line of therapy. Allogeneic stem cell transplant remains an option for carefully selected patients who progress after autologous stem cell transplant and CAR T. Clinical trials involving combinations of novel agents in early lines of therapy are ongoing, and new compounds with unique mechanisms of action are in development. The results of ongoing clinical trials with novel agents will further change the treatment landscape for patients with MCL in the coming years.

Analysis of Factors Associated with Conversion to CR in Patients with Large B-Cell Lymphoma Achieving Day 30 PR after CAR T-Cell Therapy

Analysis of Factors Associated with Conversion to CR in Patients with Large B-Cell Lymphoma Achieving Day 30 PR after CAR T-Cell Therapy