Prospective assessment of quality of life and patient-reported toxicities over the first year after CAR T-cell therapy.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has transformed survival outcomes in patients with relapsed and refractory large B-cell lymphoma, but it is associated with a variety of side effects OBJECTIVE: : This study examined changes in patient-reported quality of life (QoL) and toxicities, as well as risk factors for worse QoL and toxicities, in the first year after treatment STUDY DESIGN: : Patients with large B-cell lymphoma completed questionnaires assessing QoL and toxicity severity before infusion, and 90, 180, and 360 days after infusion. Mixed models were used to examine changes in QoL and toxicities over time, and clinical moderators of change in QoL and toxicities RESULTS: : Patients reported improvements in physical functioning and fatigue in the year after treatment (p-values<0.01), but there were no changes in pain, anxiety, or depression over time. Patients with active disease at day 90 reported more physical dysfunction at all post-infusion timepoints (ps≤0.01) compared to patients who responded to treatment. Similarly, patients with active disease at day 90 reported worsening depression over time, such that at day 360, depressive symptoms were worse for patients with active disease than patients without active disease (p=0.02). Patients treated with 4+ lines of prior therapy reported worsening pain and anxiety over time, such that at day 360, both pain and anxiety were significantly worse for patients previously treated with 4 of more lines of therapy than patients treated with fewer lines of therapy (ps≤0.01). Regarding toxicities, patients reported decreasing overall toxicity burden up to day 180, with subsequent worsening at day 360 (p=0.02). Most patients reported at least one or two grade 2 toxicities at each time point CONCLUSIONS: : Patients demonstrated unchanging or improved QoL after treatment with CAR T-cell therapy, but active disease and greater prior lines of therapy were associated with worse QoL outcomes over time. Toxicity severity also improved during the first 6 months post-treatment, but worsened thereafter, particularly among patients with active disease after treatment.

Novel prognostic scoring systems for severe CRS and ICANS after anti-CD19 CAR T cells in large B-cell lymphoma.

Autologous anti-CD19 chimeric antigen receptor (CAR) T cells are now used in routine practice for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Severe (grade ≥ 3) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) are still the most concerning acute toxicities leading to frequent intensive care unit (ICU) admission, prolonging hospitalization, and adding significant cost to treatment. We report on the incidence of CRS and ICANS and the outcomes in a large cohort of 925 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) in France based on patient data captured through the DESCAR-T registry. CRS of any grade occurred in 778 patients (84.1%), with 74 patients (8.0%) with grade 3 CRS or higher, while ICANS of any grade occurred in 375 patients (40.5%), with 112 patients (12.1%) with grade ≥ 3 ICANS. Based on the parameters selected by multivariable analyses, two independent prognostic scoring systems (PSS) were derived, one for grade ≥ 3 CRS and one for grade ≥ 3 ICANS. CRS-PSS included bulky disease, a platelet count < 150 G/L, a C-reactive protein (CRP) level > 30 mg/L and no bridging therapy or stable or progressive disease (SD/PD) after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 CRS. ICANS-PSS included female sex, low level of platelets (< 150 G/L), use of axi-cel and no bridging therapy or SD/PD after bridging. Patients with a CRS-PSS score > 2 had significantly higher risk to develop grade ≥ 3 ICANS. Both scores were externally validated in international cohorts of patients treated with tisa-cel or axi-cel.

Five-Year Follow-Up of Standard-of-Care Axicabtagene Ciloleucel for Large B-Cell Lymphoma: Results From the US Lymphoma CAR T Consortium.

PURPOSE: Axicabtagene ciloleucel (axi-cel) is an autologous CD19 chimeric antigen receptor (CAR) T-cell therapy that is approved for the treatment of relapsed or refractory large B-cell lymphoma. Little is known about the long-term survivorship after CAR T-cell therapy. METHODS: We previously reported the results of 298 patients who were leukapheresed with the intent to receive standard-of-care axi-cel (n = 275 infused) after two or more previous lines of therapy at a median follow-up of 12.9 months. Here, we report extended follow-up of this cohort to a median of 58 months, with a focus on late survivorship events. RESULTS: Among axi-cel-infused patients, progression-free survival at 5 years was 29% and overall survival (OS) at 5 years was 40%. The 5-year lymphoma-specific survival was 53% with infrequent late relapses. However, the 5-year nonrelapse mortality (NRM) was 16.2%, with over half of NRM events occurring beyond 2 years. Patients who were 60 years and older had a lower risk of relapse (P = .02), but a higher risk of NRM compared with patients younger than 60 years (NRM odds ratio, 4.5 [95% CI, 2.1 to 10.8]; P < .001). Late NRM was mainly due to infections and subsequent malignant neoplasms (SMNs). In total, SMNs occurred in 24 patients (9%), including therapy-related myeloid neoplasms (n = 15), solid tumors (n = 7), and unrelated lymphoid malignancies (n = 2). CONCLUSION: In the standard-of-care setting, axi-cel exhibits outcomes consistent with those reported in clinical trials, with sustained, durable responses observed at the 5-year time point. However, late infections and the development of SMN are key survivorship issues that reduce long-term survival after CAR T-cell therapy, particularly in the elderly.

Immune effector cell-associated haematotoxicity after CAR T-cell therapy: from mechanism to management.

Genetically engineered chimeric antigen receptor (CAR) T cells have become an effective treatment option for several advanced B-cell malignancies. Haematological side-effects, classified in 2023 as immune effector cell-associated haematotoxicity (ICAHT), are very common and can predispose for clinically relevant infections. As haematopoietic reconstitution after CAR T-cell therapy differs from chemotherapy-associated myelosuppression, a novel classification system for early and late ICAHT has been introduced. Furthermore, a risk stratification score named CAR-HEMATOTOX has been developed to identify candidates at high risk of ICAHT, thereby enabling risk-based interventional strategies. Therapeutically, growth factor support with granulocyte colony-stimulating factor (G-CSF) is the mainstay of treatment, with haematopoietic stem cell (HSC) boosts available for patients who are refractory to G-CSF (if available). Although the underlying pathophysiology remains poorly understood, translational studies from the past 3 years suggest that CAR T-cell-induced inflammation and baseline haematopoietic function are key contributors to prolonged cytopenia. In this Review, we provide an overview of the spectrum of haematological toxicities after CAR T-cell therapy and offer perspectives on future translational and clinical developments.

Autologous Hematopoietic Cell Transplantation Consolidation for First Response is Associated With Longer Survival Among Patients With Nodal Peripheral T Cell Lymphoma.

Nodal peripheral T cell lymphomas (PTCLs) are challenging subsets of non-Hodgkin lymphomas characterized by their heterogeneity and aggressive clinical behavior. Given the mixed outcomes reported in previous studies, the efficacy of autologous hematopoietic cell transplantation (auto-HCT) as a consolidation strategy following initial chemotherapy response remains uncertain. This study aims to evaluate the impact of upfront auto-HCT consolidation on overall survival (OS) and event-free survival (EFS) among patients with nodal PTCL who achieved a complete or partial response to initial chemotherapy. A retrospective cohort study was conducted at Moffitt Cancer Center, involving 123 patients with nodal PTCL treated between February 2005 and February 2021. Patients were stratified into 2 groups based on whether they received auto-HCT as part of their initial treatment strategy. Kaplan-Meier method and Cox proportional hazard models were used for statistical analysis to compare OS and EFS between groups. Patients undergoing auto-HCT after first response demonstrated significantly longer median OS (12.3 versus 4.3 yr; P = .035) and EFS (6.2 versus 2.2 yr; P = .003) compared to those who did not. Multivariate analyses indicated that auto-HCT at first response and younger age at diagnosis were favorable prognostic factors. The findings suggest that upfront auto-HCT consolidation can significantly improve long-term outcomes in patients with nodal PTCL, supporting the strategy of early auto-HCT consideration and referral following initial chemotherapy response. These results underscore the importance of integrating upfront auto-HCT into the treatment paradigm for nodal PTCL, emphasizing early referral to transplantation services to optimize patient outcomes.

Baseline Serum Inflammatory Proteins Predict Poor CAR T Outcomes in Diffuse Large B-cell Lymphoma.

A subset of patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 chimeric antigen receptor (CAR) T-cell therapy have poor clinical outcomes. We report serum proteins associated with severe immune-mediated toxicities and inferior clinical responses in 146 patients with DLBCL treated with axicabtagene ciloleucel. We develop a simple stratification based on pre-lymphodepletion C reactive protein (CRP) and ferritin to classify patients into low-, intermediate-, and high-risk groups. We observe that patients in the high-risk category were more likely to develop grade ≥3 toxicities and had inferior overall and progression-free survival. We sought to validate our findings with two independent international cohorts demonstrating that patients classified as low-risk have excellent efficacy and safety outcomes. Based on routine and readily available laboratory tests that can be obtained prior to lymphodepleting chemotherapy, this simple risk stratification can inform patient selection for CAR T-cell therapy. SIGNIFICANCE: CAR T-cell therapy has changed the treatment paradigm for patients with relapsed/refractory hematologic malignancies. Despite encouraging efficacy, a subset of patients have poor clinical outcomes. We show that a simple clinically applicable model using pre-lymphodepletion CRP and ferritin can identify patients at high risk of poor outcomes. This article is featured in Selected Articles from This Issue, p. 80.

Applying the EHA/EBMT grading for ICAHT after CAR-T: comparative incidence and association with infections and mortality.

ABSTRACT: Cytopenias represent the most common side effect of CAR T-cell therapy (CAR-T) and can predispose for severe infectious complications. Current grading systems, such as the Common Terminology Criteria for Adverse Events (CTCAE), neither reflect the unique quality of post-CAR-T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia. For this reason, a novel EHA/EBMT consensus grading was recently developed for Immune Effector Cell-Associated HematoToxicity (ICAHT). In this multicenter, observational study, we applied the grading system to a large real-world cohort of 549 patients treated with BCMA- or CD19-directed CAR-T for refractory B-cell malignancies (112 multiple myeloma [MM], 334 large B-cell lymphoma [LBCL], 103 mantle cell lymphoma [MCL]) and examined the clinical sequelae of severe (≥3°) ICAHT. The ICAHT grading was strongly associated with the cumulative duration of severe neutropenia (r = 0.92, P < .0001), the presence of multilineage cytopenias, and the use of platelet and red blood cell transfusions. We noted an increased rate of severe ICAHT in patients with MCL vs those with LBCL and MM (28% vs 23% vs 15%). Severe ICAHT was associated with a higher rate of severe infections (49% vs 13%, P < .0001), increased nonrelapse mortality (14% vs 4%, P < .0001), and inferior survival outcomes (1-year progression-free survival: 35% vs 51%, 1-year overall survival: 52% vs 73%, both P < .0001). Importantly, the ICAHT grading demonstrated superior capacity to predict severe infections compared with the CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant). Taken together, these data highlight the clinical relevance of the novel grading system and support the reporting of ICAHT severity in clinical trials evaluating CAR-T therapies.

Bridging therapy with axicabtagene ciloleucel for large B-cell lymphoma: results from the US Lymphoma CAR-T Consortium.

ABSTRACT: During the manufacturing period of autologous chimeric antigen receptor (CAR) T-cell therapy, patients may experience a decline in their condition due to cancer progression. In this study, we investigated the impact of bridging therapy (BT) on the outcome of patients with relapsed/refractory large B-cell lymphoma who received antilymphoma treatment between leukapheresis and axicabtagene ciloleucel (axi-cel) infusion. We conducted our analysis using data from the multicenter US Lymphoma CAR-T Consortium, with a median follow-up of 33 months (range, 4.3-42.1). Out of the 298 patients who underwent leukapheresis, 275 patients received axi-cel. A total 52% of patients (n = 143) who received BT had a higher baseline risk profile than patients who did not receive BT, and these patients, as a group, had inferior outcomes compared with those who did not receive BT. However, after propensity score matching between the 2 groups, there were no statistically significant differences in overall response rate (77% vs 87%; P = .13), complete response rate (58% vs 70%; P = .1), progression-free survival (hazard ratio [HR], 1.25; P = .23), and overall survival (HR, 1.39; P=.09) between the BT group and the no-BT group, respectively. Analyzing the effects of BT in the whole cohort that underwent leukapheresis regardless of receiving axi-cel (intention-to-treat analysis) showed similar results. Radiation BT resulted in outcomes similar to those observed with nonradiation BT. Our findings suggest that BT may be safe without a significant impact on long-term survival for patients who require disease stabilization during the manufacturing period. Moreover, our results suggest that there is no clear advantage to using radiation-based BT over nonradiation-based BT.

Simple Score of Albumin and CRP Predicts High-Grade Toxicity in Patients with Multiple Myeloma Receiving CAR-T Therapy.

Administration of chimeric-antigen receptor T-cell (CAR-T) therapy is complex and associated with unique toxicities. Identifying patients at risk for inferior outcomes is important for individualized management. The Glasgow-prognostic score (GPS) is a simple score shown to be highly prognostic of outcomes in the setting of traditional chemotherapy or checkpoint inhibitor administration. We sought to evaluate the value of the GPS to predict outcomes of patients with relapse refractory multiple myeloma (RRMM) receiving anti-BCMA CAR-T therapy. We included all patients treated with commercial CAR-T therapy for RRMM between 5/1/2021 and 2/1/2023 at the Moffitt Cancer Center. The GPS (CRP >1 mg/dL, 1 point; albumin <3.5, 1 point) was calculated for all patients at lymphodepletion (day -6) and patients were grouped as high-risk GPS (score = 2) or low-risk GPS (0 or 1). The primary endpoint was overall survival (OS) at day 100. A total of 139 pts were included, with a median follow-up of 6.7 months (95% CI, 6.2 to 8.9 months). Pts were treated with either idecabtagene vicleucel (83%) or ciltacabtagene autoleucel (17%). In total, 14% were classified with high-risk GPS, with significantly increased risk for grade 3 cytokine release syndrome (P = .003) and ICANS of any grade (P < .001). Patients in the high-risk GPS group had significantly lower day-100 OS (68.4% versus 97.3%, P < .001), OS at 6 months (56% versus 91.8% P = .0019) and PFS at 6 months (38.3% versus 72.3%, P = .03). The association of GPS with day-100 OS remained significant in a multivariable model. In conclusion, the GPS identifies a group of high-risk patients with RRMM receiving CAR-T therapy who experience increased rates of immune-mediated toxicity and are at higher risk for early mortality.

Severe hematotoxicity after CD19 CAR-T therapy is associated with suppressive immune dysregulation and limited CAR-T expansion.

Prolonged cytopenias after chimeric antigen receptor (CAR) T cell therapy are a significant clinical problem and the underlying pathophysiology remains poorly understood. Here, we investigated how (CAR) T cell expansion dynamics and serum proteomics affect neutrophil recovery phenotypes after CD19-directed CAR T cell therapy. Survival favored patients with "intermittent" neutrophil recovery (e.g., recurrent neutrophil dips) compared to either "quick" or "aplastic" recovery. While intermittent patients displayed increased CAR T cell expansion, aplastic patients exhibited an unfavorable relationship between expansion and tumor burden. Proteomics of patient serum collected at baseline and in the first month after CAR-T therapy revealed higher markers of endothelial dysfunction, inflammatory cytokines, macrophage activation, and T cell suppression in the aplastic phenotype group. Prolonged neutrophil aplasia thus occurs in patients with systemic immune dysregulation at baseline with subsequently impaired CAR-T expansion and myeloid-related inflammatory changes. The association between neutrophil recovery and survival outcomes highlights critical interactions between host hematopoiesis and the immune state stimulated by CAR-T infusion.

The CAR-HEMATOTOX score identifies patients at high risk for hematological toxicity, infectious complications, and poor treatment outcomes following brexucabtagene autoleucel for relapsed or refractory MCL.

CD19-directed CAR T-cell therapy with brexucabtagene autoleucel (brexu-cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common and clinically relevant side effects. In this multicenter observational study, we describe cytopenias and infections in 103 r/r MCL patients receiving brexu-cel. Furthermore, we report associations between the baseline CAR-HEMATOTOX (HT) score and toxicity events, non-relapse mortality (NRM), and progression-free/overall survival (PFS/OS). At lymphodepletion, 56 patients were HTlow (score 0-1) while 47 patients were HThigh (score ≥2). The HThigh cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p < .001) and an increased rate of severe infections (30% vs. 5%, p = .001). Overall, 1-year NRM was 10.4%, primarily attributed to infections, and differed by baseline HT score (high vs. low: 17% vs. 4.6%, p = .04). HThigh patients experienced inferior 90-day complete response rate (68% vs. 93%, p = .002), PFS (median 9 months vs. not-reached, p < .0001), and OS (median 26 months vs. not-reached, p < .0001). Multivariable analyses showed that high HT scores were independently associated with severe hematotoxicity, infections, and poor PFS/OS. In conclusion, infections and hematotoxicity are common after brexu-cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes.

Axicabtagene Ciloleucel in Combination with the 4-1BB Agonist Utomilumab in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Phase 1 Results from ZUMA-11.

PURPOSE: Chimeric antigen receptor (CAR) T-cell therapies have shown clinical benefit for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL), yet approximately 60% of patients do not respond or eventually relapse. We investigated the safety and feasibility of the CD19-directed CAR T-cell therapy axicabtagene ciloleucel (axi-cel) in combination with the 4-1BB agonist antibody utomilumab as an approach to improve efficacy of CAR T-cell therapy. PATIENTS AND METHODS: In phase 1 of the single-arm ZUMA-11 trial, patients with R/R LBCL received a single axi-cel infusion (target dose, 2 × 106 cells/kg) plus utomilumab 10 to 200 mg intravenously every 4 weeks for up to 6 months in a dose-escalation design. The primary endpoint was incidence of dose-limiting toxicities (DLT) with utomilumab. Key secondary endpoints were safety, antitumor activity, pharmacokinetics, and pharmacodynamics. RESULTS: No DLTs were observed among patients treated with axi-cel and utomilumab (n = 12). Grade ≥3 adverse events occurred in 10 patients (83%); none were Grade ≥3 cytokine release syndrome or neurologic events. The objective response rate was 75% and seven patients (58%) had a complete response. Peak CAR T-cell levels increased in a utomilumab dose-dependent manner up to 100 mg. Patients who received utomilumab 100 mg had persistently increased CAR T cells on days 57 to 168 compared with other dose levels. Utomilumab was associated with dose-dependent increases in IL2, IFNγ, and IL10. CONCLUSIONS: Utomilumab-mediated 4-1BB agonism combined with axi-cel therapy had a manageable safety profile. Dual 4-1BB and CD28 costimulation is a feasible therapeutic approach that may enhance CAR T-cell expansion in patients with LBCL.

Inferior Outcomes of EU Versus US Patients Treated With CD19 CAR-T for Relapsed/Refractory Large B-cell Lymphoma: Association With Differences in Tumor Burden, Systemic Inflammation, Bridging Therapy Utilization, and CAR-T Product Use.

Real-world evidence suggests a trend toward inferior survival of patients receiving CD19 chimeric antigen receptor (CAR) T-cell therapy in Europe (EU) and with tisagenlecleucel. The underlying logistic, patient- and disease-related reasons for these discrepancies remain poorly understood. In this multicenter retrospective observational study, we studied the patient-individual journey from CAR-T indication to infusion, baseline features, and survival outcomes in 374 patients treated with tisagenlecleucel (tisa-cel) or axicabtagene-ciloleucel (axi-cel) in EU and the United States (US). Compared with US patients, EU patients had prolonged indication-to-infusion intervals (66 versus 50 d; P < 0.001) and more commonly received intermediary therapies (holding and/or bridging therapy, 94% in EU versus 74% in US; P < 0.001). Baseline lactate dehydrogenase (LDH) (median 321 versus 271 U/L; P = 0.02) and ferritin levels (675 versus 425 ng/mL; P = 0.004) were significantly elevated in the EU cohort. Overall, we observed inferior survival in EU patients (median progression-free survival [PFS] 3.1 versus 9.2 months in US; P < 0.001) and with tisa-cel (3.2 versus 9.2 months with axi-cel; P < 0.001). On multivariate Lasso modeling, nonresponse to bridging, elevated ferritin, and increased C-reactive protein represented independent risks for treatment failure. Weighing these variables into a patient-individual risk balancer (high risk [HR] balancer), we found higher levels in EU versus US and tisa-cel versus axi-cel cohorts. Notably, superior PFS with axi-cel was exclusively evident in patients at low risk for progression (according to the HR balancer), but not in high-risk patients. These data demonstrate that inferior survival outcomes in EU patients are associated with longer time-to-infusion intervals, higher tumor burden/LDH levels, increased systemic inflammatory markers, and CAR-T product use.

The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma.

BACKGROUND: BCMA-directed CAR T-cell therapy (CAR-T) has altered the treatment landscape of relapsed/refractory (r/r) multiple myeloma, but is hampered by unique side effects that can lengthen hospital stays and increase morbidity. Hematological toxicity (e.g. profound and prolonged cytopenias) represents the most common grade ≥ 3 toxicity and can predispose for severe infectious complications. Here, we examined the utility of the CAR-HEMATOTOX (HT) score to predict toxicity and survival outcomes in patients receiving standard-of-care idecabtagene vicleucel and ciltacabtagene autoleucel. METHODS: Data were retrospectively collected from 113 r/r multiple myeloma patients treated between April 2021 and July 2022 across six international CAR-T centers. The HT score-composed of factors related to hematopoietic reserve and baseline inflammatory state-was determined prior to lymphodepleting chemotherapy. RESULTS: At lymphodepletion, 63 patients were HTlow (score 0-1) and 50 patients were HThigh (score ≥ 2). Compared to their HTlow counterparts, HThigh patients displayed prolonged severe neutropenia (median 9 vs. 3 days, p < 0.001), an increased severe infection rate (40% vs. 5%, p < 0.001), and more severe ICANS (grade ≥ 3: 16% vs. 0%, p < 0.001). One-year non-relapse mortality was higher in the HThigh group (13% vs. 2%, p = 0.019) and was predominantly attributable to fatal infections. Response rates according to IMWG criteria were higher in HTlow patients (≥ VGPR: 70% vs. 44%, p = 0.01). Conversely, HThigh patients exhibited inferior progression-free (median 5 vs. 15 months, p < 0.001) and overall survival (median 10.5 months vs. not reached, p < 0.001). CONCLUSIONS: These data highlight the prognostic utility of the CAR-HEMATOTOX score for both toxicity and treatment response in multiple myeloma patients receiving BCMA-directed CAR-T. The score may guide toxicity management (e.g. anti-infective prophylaxis, early G-CSF, stem cell boost) and help to identify suitable CAR-T candidates.

Cardiac events after standard of care idecabtagene vicleucel for relapsed and refractory multiple myeloma.

Idecabtagene vicleucel (ide-cel) is a type of B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor T-cell (CAR-T) approved for the treatment of relapsed and refractory multiple myeloma (RRMM). Currently, the incidence of cardiac events associated with ide-cel remains unclear. This was a retrospective single-center observational study of patients treated with ide-cel for RRMM. We included all consecutive patients who received standard-of-care ide-cel treatment at least 1-month follow-up. Baseline clinical risk factors, safety profile, and responses were examined based on the development of a cardiac event. A total of 78 patients were treated with ide-cel, and 11 patients (14.1%) developed cardiac events: heart failure (5.1%), atrial fibrillation (10.3%), nonsustained ventricular tachycardia (3.8%), and cardiovascular death (1.3%). Only 11 of the 78 patients had repeat echocardiogram. Baseline risk factors associated with the development of cardiac events included being female sex and having poor performance status, λ light-chain disease, and advanced Revised International Staging System stage. Baseline cardiac characteristics were not associated with cardiac events. During index hospitalization after CAR-T, higher-grade (≥grade 2) cytokine release syndrome (CRS) and immune cell-associated neurologic syndrome were associated with cardiac events. In multivariable analyses, the hazard ratio for the association of the presence of cardiac events with overall survival (OS) was 2.66 and progression-free survival (PFS) was 1.98. Ide-cel CAR-T for RRMM was associated with similar cardiac events as other types of CAR-T. Worse baseline performance status and higher-grade CRS and neurotoxicity were associated with cardiac events after BCMA-directed CAR-T-cell therapy. Our results suggest that the presence of cardiac events may confer worse PFS or OS; although because of the small sample size, the power to detect an association was limited.

Circulating tumor DNA adds specificity to PET after axicabtagene ciloleucel in large B-cell lymphoma.

We examined the meaning of metabolically active lesions on 1-month restaging nuclear imaging of patients with relapsed/refractory large B-cell lymphoma receiving axicabtagene ciloleucel (axi-cel) by assessing the relationship between total metabolic tumor volume (MTV) on positron emission tomography (PET) scans and circulating tumor DNA (ctDNA) in the plasma. In this prospective multicenter sample collection study, MTV was retrospectively calculated via commercial software at baseline, 1, and 3 months after chimeric antigen receptor (CAR) T-cell therapy; ctDNA was available before and after axi-cel administration. Spearman correlation coefficient (rs) was used to study the relationship between the variables, and a mathematical model was constructed to describe tumor dynamics 1 month after CAR T-cell therapy. The median time between baseline scan and axi-cel infusion was 33 days (range, 1-137 days) for all 57 patients. For 41 of the patients with imaging within 33 days of axi-cel or imaging before that time but no bridging therapy, the correlation at baseline became stronger (rs, 0.61; P < .0001) compared with all patients (rs, 0.38; P = .004). Excluding patients in complete remission with no measurable residual disease, ctDNA and MTV at 1 month did not correlate (rs, 0.28; P = .11) but correlated at 3 months (rs, 0.79; P = .0007). Modeling of tumor dynamics, which incorporated ctDNA and inflammation as part of MTV, recapitulated the outcomes of patients with positive radiologic 1-month scans. Our results suggested that nonprogressing hypermetabolic lesions on 1-month PET represent ongoing treatment responses, and their composition may be elucidated by concurrently examining the ctDNA.

Cardiac and inflammatory biomarker differences in adverse cardiac events after chimeric antigen receptor T-Cell therapy: an exploratory study.

BACKGROUND: Chimeric antigen receptor T- Cell (CAR-T) immunotherapy has been a breakthrough treatment for various hematological malignancies. However, cardiotoxicities such as new-onset heart failure, arrhythmia, acute coronary syndrome and cardiovascular death occur in 10-15% of patients treated with CAR-T. This study aims to investigate the changes in cardiac and inflammatory biomarkers in CAR-T therapy to determine the role of pro-inflammatory cytokines. METHODS: In this observational study, ninety consecutive patients treated with CAR-T underwent baseline cardiac investigation with electrocardiogram (ECG), transthoracic echocardiogram (TTE), troponin-I, and B-type natriuretic peptide (BNP). Follow-up ECG, troponin-I and BNP were obtained five days post- CAR-T. In a subset of patients (N = 53), serum inflammatory cytokines interleukin (IL)-2, IL-6, IL-15, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor (GM-CSF), and angiopoietin 1 & 2 were tested serially, including baseline and daily during hospitalization. Adverse cardiac events were defined as new-onset cardiomyopathy/heart failure, acute coronary syndrome, arrhythmia and cardiovascular death. RESULTS: Eleven patients (12%) had adverse cardiac events (one with new-onset cardiomyopathy and ten with new-onset atrial fibrillation). Adverse cardiac events appear to have occurred among patients with advanced age (77 vs. 66 years; p = 0.002), higher baseline creatinine (0.9 vs. 0.7 mg/dL; 0.007) and higher left atrial volume index (23.9 vs. 16.9mL/m2; p = 0.042). Day 5 BNP levels (125 vs. 63pg/mL; p = 0.019), but not troponin-I, were higher in patients with adverse cardiac events, compared to those without. The maximum levels of IL-6 (3855.0 vs. 254.0 pg/mL; p = 0.021), IFN-γ (474.0 vs. 48.8pg/mL; p = 0.006) and IL-15 (70.2 vs. 39.2pg/mL; p = 0.026) were also higher in the adverse cardiac events group. However, cardiac and inflammatory biomarker levels were not associated with cardiac events. Patients who developed cardiac events did not exhibit worse survival compared to patients without cardiac events (Log-rank p = 0.200). CONCLUSION: Adverse cardiac events, predominantly atrial fibrillation, occur commonly after CAR-T (12%). The changes in serial inflammatory cytokine after CAR-T in the setting of adverse cardiac events suggests pro-inflammation as a pathophysiology and require further investigation for their role in adverse cardiac events. TWEET BRIEF HANDLE: CAR-T related Cardiotoxicity has elevated cardiac and inflammatory biomarkers. #CARTCell #CardioOnc #CardioImmunology.

Mechanisms of Resistance and Treatment of Relapse after CAR T-cell Therapy for Large B-cell Lymphoma and Multiple Myeloma.

Although chimeric antigen receptor (CAR) T cell therapy (CAR-T) has altered the treatment landscape for relapsed/refractory B cell malignancies and multiple myeloma, only a minority of patients attain long-term disease remission. The underlying reasons for CAR-T resistance are multifaceted and can be broadly divided into host-related, tumor-intrinsic, microenvironmental and macroenvironmental, and CAR-T-related factors. Emerging host-related determinants of response to CAR-T relate to gut microbiome composition, intact hematopoietic function, body composition, and physical reserve. Emerging tumor-intrinsic resistance mechanisms include complex genomic alterations and mutations to immunomodulatory genes. Furthermore, the extent of systemic inflammation prior to CAR-T is a potent biomarker of response and reflects a proinflammatory tumor micromilieu characterized by infiltration of myeloid-derived suppressor cells and regulatory T cell populations. The tumor and its surrounding micromilieu also can shape the response of the host to CAR-T infusion and the subsequent expansion and persistence of CAR T cells, a prerequisite for efficient eradication of tumor cells. Here, focusing on both large B cell lymphoma and multiple myeloma, we review resistance mechanisms, explore therapeutic avenues to overcome resistance to CAR-T, and discuss the management of patients who relapse after CAR-T.