The activity of anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) with Richter's transformation (RT) to aggressive large B cell lymphoma (LBCL) is largely unknown. In a multicenter ...retrospective study, we report the safety and efficacy of CAR T cell therapy in patients with RT (n=30) compared to patients with aggressive B cell lymphoma (n=283) and patients with transformed indolent Non-Hodgkins Lymphoma (iNHL) (n=141) between April 2016 and January 2023. Two-thirds of patients received prior therapy for CLL before RT and 89% of them received B-cell receptor and B-cell lymphoma 2 (BCL-2) inhibitors. Toxicities of CAR T cell therapy in RT were similar to other lymphomas, with no fatalities related to cytokine release syndrome or immune effector-cell associated neurotoxicity synderome. The 100-day overall response rate and complete response rates in patients with RT were 57% and 47%, respectively. With a median follow up of 19 months, the median overall survival (OS) was 9.9 months in patients with RT compared to 18 months in de-novo LBCL and not reached in patients with transformed iNHL. The OS at 12 months was 45% in patients with RT compared with 62% and 75% in patients with de novo LBCL and transformed iNHL, respectively. In a multivariate analysis, worse OS was associated with RT histology, elevated LDH, and more prior lines of therapy. CAR T cell therapy can salvage a proportion of patients with CLL and RT exposed to prior targeted agents; however, efficacy in RT is inferior compared to de novo LBCL and transformed iNHL
Background
Tisagenlecleucel and brexucabtagene autoleucel have demonstrated remarkable efficacy and safety results in adult patients with relapsed/ refractory acute B lymphoblastic leukemia (R/R ...B-ALL). Long term follow-up of the ZUMA-3 trial recently reported a median duration of response (DOR) of 14.6 months and an overall response rate of 71% (Hadjivassileva, EBMT 2023).
Methods and patients
We report results of a phase 1b/2 single center clinical trial (NCT02772198) involving point-of-care (POC) anti-CD19/CD28 costimulatory domain chimeric antigen receptor (CAR) T-cell therapy in adults with R/R B-ALL. Inclusion criteria were age ≥18 years, failure of at least 2 prior therapies, and a preserved organ function. Patients underwent a single leukapheresis procedure. Fresh CAR T products were delivered for immediate infusion. Lymphodepletion included fludarabine and cyclophosphamide. Cell dose was 1x10 6 CAR T cells/kg. Primary endpoints were 1-month disease response and safety. Secondary endpoints were the minimal residual disease (MRD) negativity rate, overall survival, progression-free survival (PFS), and production feasibility. Last follow-up was July 2023.
Results
Between 03/2017-05/2023, 28 patients enrolled. CAR T-cells were successfully produced in 27 patients (96%) who were included in the analysis. The median age was 33 years (range 19-77), and 7 (25%) patients had Karnofsky Performance Status <90%. Six patients (22%) had positive Philadelphia chromosome, and 14 patients (52%) had an extramedullary disease at leukapheresis. Nineteen patients (70%) had ≥3 prior lines of therapy, 18 patients (67%) underwent prior allogeneic hematopoietic stem-cell transplantation (allo-HCT), and 20 patients (74%) had prior exposure to inotuzumab-ozogamicin or blinatumomab. At leukapheresis, 16 patients (60%) had an active disease, while 11 patients (40%) were in complete morphological response (CR; MRD positive, n=7 26%, MRD negative or not evaluated, n=4 15%).
The median time between leukapheresis and cell infusion was 11 days (IQR 10-11). Only 3 patients (11%) received bridging chemotherapy. Grade 3-4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndromes were observed in 30% of the patients, each. Six (22%) and 16 (59%) patients were treated with tocilizumab or corticosteroids, respectively. Severe neutropenia (<0.5k/μl) and thrombocytopenia (≤50 K/μl) occurred in 81% and 70% of the patients, respectively, and anemia requiring blood transfusion occurred in 71%. Three patients (11%) had grade 3 cardiovascular events, and 1 patient (4%) had grade 3 pleural effusion. Bloodstream bacterial infection occurred in 3 (11%) patients. Cellular therapy-related mortality was observed in 2 (7%) patients (both due to septic shock).
The 1-month overall response rate was 88% (81% CR; MRD negative CR, 63%). MRD was evaluated by RT-PCR in most of the patients. The median follow-up was 19.7 months (IQR 4.7-43.2). Two-year overall survival and PFS were 62% (95% CI: 42-91), and 56% (95% CI: 38-84), respectively. The median DOR was not reached (95% CI: 6.1 months-not reached). PFS was not affected by prior exposure to inotuzumab-ozogamicin or blinatumomab (hazard ratio (HR) 0.7, 95% CI: 0.17-2.68, p=0.6). All eligible patients who achieved a response were offered consolidation with allo-HCT. Eight patients (30%) underwent allo-HCT (2 nd allo-HCT in 3 of them). The DOR was not affected by consolidation of CR with allo-HCT (HR 0.9, 95% CI: 0.2-4.1, p>0.9). Nevertheless, 2 patients (7%) died due to allo-HCT related complications while in CR.
Conclusion
Treatment with POC CAR T-cells, produced in an academic center, achieved high response and survival rates in adults with R/R B-ALL. These results are also comparable to the FDA approved CAR T-cells. The use of POC CAR T abrogates the need for cryopreservation and shipment of the cells, thus allowing a short vein-to-vein time without the need of bridging therapy in most patients.
Introduction
Pulmonary function tests (PFT) play a pivotal role in hematopoietic cell transplantation (HCT), with routine evaluation in HCT candidates. However, their predictive value in chimeric ...antigen receptor T-cell (CAR-T) therapy outcomes remains uncertain. To address this gap, we conducted a retrospective analysis of PFT metrics and pulmonary comorbidity definitions, following the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), in B-cell lymphoma patients treated with autologous CD19-CAR-T cell therapy.
Patients and Methods
In this retrospective analysis, we included adult patients (age ≥ 18 years) with B-cell lymphoma who received treatment at a tertiary medical center with commercially available or point-of-care (POC) anti-CD19 CAR T-cell therapy (Kedmi et al., Transplant Cell Ther. 2022) as their 3rd line of treatment or above, between 2017 and 2022. Patients underwent routine PFT assessment before CAR-T cell therapy, as part of institutional practice, including spirometry, body plethysmography, and single-breath diffusing capacity for carbon monoxide (DLCO). Patients were categorized into three pre-treatment pulmonary comorbidity groups (normal, moderate, severe) based on HCT-CI definitions for forced expiratory volume in 1 second (FEV1) and DLCO expressed as precent of predicted value (>80%, 66-80%, <66%, respectively).
Results
A total of 192 patients (median age, 60 range 46-69) were included. Aggressive B-cell lymphoma was the predominant diagnosis (n=166, 86%) followed by indolent B-cell lymphoma (n=18, 9.4%), and Mantle cell lymphoma (n=8, 4.2%). Most patients had a good performance status (KPS ≥ 90, 78%), although with high-risk disease features (pre-lymphodepletion LDH was elevated in 108 56%). Seventy-eight (41%) patients received bridging therapy. POC CAR-T were used in 56%, while 44% received commercial CAR-T (26% axi-cel, 18% tisa-cel).
Pre-CAR-T smoking history was documented in 25% of patients. The median pre-treatment measured-to-predicted DLCO and FEV1 were 96% and 92%, respectively. Seventy-four percent of patients had normal DLCO, and 77% had a normal FEV1. The calculated normal, moderate, and severe pulmonary comorbidity levels, per the HCT-CI, were 64%, 23%, and 13%, respectively.
With a median follow-up of 17.6 months (IQR 8.5-29.7), the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 7.6 months.
There was no correlation between pulmonary comorbidity level and the best overall response rate.
Categorical PFT results (FEV1 and DLCO) and pulmonary comorbidity (per-HCT-CI) were not associated with reduced OS (p=0.3, p=0.4, p=0.6, respectively) or reduced PFS (p=0.058, p>0.9, p=0.2, respectively) in a univariable Cox regression analysis. However, FEV1 as continuous measure and FEV1 categorized into 2 levels (normal vs. moderate-severe) were associated with reduced PFS ( Figure 1). FEV1 (as a continuous metric) association with PFS remained consistent (HR 0.99 95% CI 0.98-1, p=0.007) in a multivariable Cox regression adjusted for pre CAR T KPS score, elevated LDH level, and co-stimulatory CAR-T domain. Nevertheless, this association is minor, with unclear clinical significance. No association was observed between pulmonary function measures and immune-toxicities, including cytokine release syndrome grade >2 or immune effector cell-associated neurotoxicity grade > 2.
Conclusions
To the best of our knowledge, this is the first study evaluating the relationship between PFTs and the outcomes of CAR T-cell treatment. Our results indicate that among standard measures of pulmonary assessment, only FEV1 was predictive of poor PFS, though with minor association, with unclear clinical significance. We did not observe any association with overall survival. These findings suggest that pre-CAR-T pulmonary assessment may have limited utility in evaluating CAR-T candidates. Nevertheless, further validation in a multicenter setting is required.
Patients with relapsed/refractory follicular lymphoma (R/R-FL) often require multiple treatment lines. We performed a phase 1b/2 single-center clinical trial of autologous point-of-care anti-CD19 ...chimeric antigen receptor (CAR) T-cells in R/R-FL patients treated patients with ≥ 2 treatment lines. All 26 patients enrolled received CAR T-cell infusion at a median of 11 days after leukapheresis. Seventy-seven percent of patients had POD24. At enrollment, disease stage was III-IV in 85% of the patients, 77% had high-risk FLIPI score, and 77% had progressive disease. Grade III-IV cytokine release and immune effector cell-associated neurotoxicity syndromes occurred in 12% and 16% of the patients, respectively. Overall response rate at 1-month was 88%. The median follow-up was 15.4 months. One-year overall and progression-free survival were 100% and 63%, respectively. In conclusion, point-of-care CAR T-cell, manufactured within 11 days, induced a high response rate with an acceptable safety profile in patients with high-risk R/R-FL.
INTRODUCTION: CAR-T therapy is an effective treatment for hematological malignancies. However, in recent years there is a growing body of literature suggesting adverse cardiovascular (CV) events ...among patients treated with CAR-T therapy. Whether cardiovascular risk factors serve as determinants of CV complications and CAR-T outcomes is unclear. The aim of this study is to investigate the landscape and prognostic role of CV comorbidities in patients with non-Hodgkin lymphoma (NHL) treated with autologous CD19- CAR-T.
METHODS: We included patients with NHL treated with CD19-directed CAR-T across two tertiary care centers. Data collected included baseline demographics, CV risk factors, and outcomes. CV disease and risk factors included were: coronary artery disease (CAD), diabetes, hypertension (HTN), sleep apnea, smoking history, and stroke/ transient ischemic attack (TIA). CV events were defined as atrial fibrillation (AF), heart failure (HF), acute coronary syndrome (ACS), and cardiogenic shock. All CV events were adjudicated by a board certified cardiologist.
RESULTS: In the cohort of 345 patients, 87% had large B cell lymphoma (LBCL), 4% follicular lymphoma, and 9% mantle cell lymphoma (MCL). Predominant CV vulnerabilities included a history of smoking (41%), HTN (32%), diabetes (12%), sleep apnea (8%), history of CAD (7%), and history of stroke/TIA (5%). Patients were categorized based on number of CV risk factors or CV disease with 37% having 0, 35% with 1, and 28% with 2 or more. A total of 41 (12%) patients experienced a CV event within the first 100 days after CAR-T infusion, with 29 (8.4%) patients developing AF, 15 (4.3%) patients with HF, 2 (0.5%) patients with ACS, and 2 (0.5%) patients with cardiogenic shock. Five patients experienced more than one cardiac event.
Univariable logistic regression of CV vulnerabilities revealed that patients with a history of HTN (OR 2.23, 95% CI 1.15-4.33, p = 0.018), 1 CV risk factor (OR 2.57, 95% CI 1.05-6.91) and/or 2 or more CV risk factors (OR 3.67, 95% CI 1.51-9.88) were associated with an increased risk of CV event(s) (global p=0.012). Additional baseline characteristics increasing risk of CV events included older age (OR 1.04, 95% CI: 1.01 - 1.07, p = 0.004), Karnofsky performance scale < 90 (OR 2.31, 95% CI: 1.13-5.12, p = 0.021), or stage III-IV disease (OR 2.90, 95% CI 1.11-9.94, p = 0.028). The 1-year overall survival was 62%, with a trend towards worse overall survival (HR 1.59, 95% CI:1.0-2.54, p=0.053) among patients experiencing CV events (Figure 1).
CONCLUSIONS: In this largest analysis to date, we found that patients with NHL treated with CAR-T therapy had a high burden of CV comorbidities that increases their risk of CV events. Given the incidence of CV events and trend towards decreased OS signifies the importance of cardiac evaluation and CV stratification prior to CAR-T therapy. Further investigation is essential to define strategies to mitigate adverse CV complications during treatment.
Chimeric antigen receptor T‐cells (CAR‐T) are widely used for the treatment of relapsed/refractory diffuse large B cell lymphoma (DLBCL). The data for CAR‐T cell therapy in patients with extra‐nodal ...(EN) lymphoma is restricted. We included 126 consecutive patients with DLBCL treated with commercially available CAR‐T cells (tisagenlecleucel, n = 100, 79.4% and axicabtagene ciloleucel, n = 26, 20.6%). At lymphodepletion, 72 of 126 (57%) patients had EN disease, 42 of 126 (33%) patients had nodal disease (ND)‐only and 12 of 126 (10%) showed no disease assessed by PET‐CT. There were no significant differences in CAR‐T related toxicities and in the median Progression free survival (PFS) between EN patients and ND (10.76 95% CI: 7.8–13.6 vs. 14.1 95% CI: 10–18.1 months, p = .126). Similarly, median overall survival (OS) was not significantly different (15.36 95% CI 12.5–18.2 vs. 18.4 95% CI 14.8–22.1 months, p = .100). Subgroup analysis according to the number of EN involved sites showed that median PFS and OS were significantly higher in patients with <3 EN sites (12.3 months 95% CI 9–15.5 vs. 4.28 months 95% CI 0.6–7.9, p = .010) compared to patients with >2 EN sites, respectively (16.5 months 95% CI 13.4–19.6 vs. 8.7 months 95% CI 4.6–12.8, p = .05). In multivariate cox regression analysis, increased number sites of EN disease and high lactate dehydrogenase (LDH) at lymphodepletion negatively impacted PFS (p = .021 and <.001, respectively), while sex, type of product administered, age and performance status did not predict PFS and OS. Of note, all the patients with involvement of gastrointestinal tract (n = 9), urinary tract (n = 9), or pharynx (n = 3) at lymphodepletion, progressed or had an early relapse. In conclusions, patients with >2 EN sites at lymphodepletion have significantly worse clinical outcomes compared to patients with <3 EN sites. Patients with specific sites of EN disease may demonstrate grim prognosis.
