ABSTRACT
Introduction: CARTITUDE-2 (NCT04133636) is a phase 2, multicohort study evaluating cilta-cel, an anti-BCMA CAR-T therapy, in several multiple myeloma (MM) patient (pt) populations. Objective(s): To report updated results with longer follow-up on cohort C pts with previous exposure to a non-cellular anti- BCMA immunotherapy. Method(s): Cohort C pts had progressive MM after treatment (tx) with a proteasome inhibitor, immunomodulatory drug, anti-CD38 antibody, and non-cellular BCMA-targeting agent. A single cilta-cel infusion (target dose 0.75x106 CAR+ viable T cells/kg) was administered 5-7 days post lymphodepletion. Primary endpoint was minimal residual disease (MRD) negativity at 10-5. Secondary endpoints included overall response rate (ORR), duration of response (DOR), and adverse events (AEs). Result(s): As of June 1, 2022, 20 pts (13 ADC exposed;7 BsAb exposed) were treated with cilta-cel;4 pts did not receive cilta-cel due to either low cellular yield (n=2, 1 in each group) or death due to progressive disease (PD) prior to dosing (n=2, 1 in each group) and 6 pts received anti-BCMA tx as their last line of therapy (n=4 ADC, n=2 BsAb). During prior anti-BCMA tx, best responses included VGPR (ADC: 2 pts;BsAb: 1 pt), sCR (ADC: 1 pt), and CR (BsAb: 1 pt);the rest had best response of stable disease or PD (1 pt not evaluable). Baseline characteristics are presented in Figure 1A. Median time from last anti- BCMA agent to cilta-cel infusion was 195 d;median administered dose of cilta-cel was 0.65x106 CAR+ viable T cells/kg. At a median follow-up of 18.0 mo, 7/10 evaluable pts (70%) were MRD negative at 10-5 (ADC: 5/7 [71.4%], BsAb: 2/3 [66.7%]). ORR: full cohort, 60%;ADC, 61.5%;BsAb, 57.1% (Figure 1B). Median DOR: full cohort, 12.8 mo;ADC, 12.8 mo;BsAb, 8.2 mo. Median PFS: full cohort, 9.1 mo;ADC, 9.5 mo;BsAb, 5.3 mo. Cilta-cel responders had a shorter median duration of last anti- BCMA agent exposure (29.5 d) compared with non-responders (63.5 d). Responders also had a longer median time from last anti-BCMA tx exposure to apheresis (161.0 d) than non-responders (56.5 d). Most common AEs were hematologic. CRS: n=12 (60%;all Gr1/2), median time to onset 7.5 d, median duration 6.0 d. ICANS: n=4 (20%, 2 Gr3/4), median time to onset 9.0 d, median duration 7.0 d. No patient had movement or neurocognitive tx emergent AE/parkinsonism. There were 12 deaths (PD: 8;COVID-19 pneumonia: 2 [not tx related];subarachnoid hemorrhage: 1 [not tx related];C. difficile colitis: 1 [tx related]). (Figure Presented)(Figure Presented)Conclusions: Pts with heavily pretreated MM and previous exposure to a non-cellular anti-BCMA therapy had favorable responses to cilta-cel. However, depth and DOR appear lower than that seen in anti-BCMA-naive pts treated with cilta-cel (at 27.7 mo, median DOR was not reached in heavily pre-treated but anti-BCMA naive CARTITUDE-1 pts). These data may inform tx plans, including sequencing and washout period between BCMA-targeting agentsCopyright © 2023 American Society for Transplantation and Cellular Therapy
ABSTRACT
Background: The ZUMA-1 safety management Cohort 6 (N=40), which evaluated whether prophylactic corticosteroids and earlier corticosteroids and/or tocilizumab could improve safety outcomes, demonstrated an improved safety profile (no Grade >=3 cytokine release syndrome [CRS];15% Grade >=3 neurologic events [NEs]) vs pivotal Cohorts 1+2, without compromising response rate or durability (95% ORR, 80% CR rate, and 53% ongoing response rate with >=1 y of follow-up;Oluwole, et al. ASH 2021. 2832). Here, 2-y updated outcomes are reported. Method(s): Eligible pts with R/R LBCL underwent leukapheresis (followed by optional bridging therapy) and conditioning chemotherapy, then a single axi-cel infusion. Pts received corticosteroid prophylaxis (once-daily oral dexamethasone 10 mg on Days 0 [before axi-cel], 1, and 2) and earlier corticosteroids and/or tocilizumab for CRS and NE management vs Cohorts 1+2 (Oluwole, et al. Br J Haematol. 2021). The primary endpoints were incidence and severity of CRS and NEs. Secondary endpoints included ORR (investigator-assessed), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and chimeric antigen receptor (CAR) T-cell levels in blood. Result(s): As of December 16, 2021, the median follow-up time for the 40 treated pts was 26.9 mo. Since the 1-y analysis, no new CRS events were reported (no pts had Grade >=3 CRS to date). The incidence of Grade >=3 NEs increased from 15% to 18%between the 1-y and 2-y analyses. Two new NEs occurred in 2 pts: 1 pt had Grade 2 dementia (onset on Day 685 and ongoing at time of data cutoff;not related to axi-cel) and 1 had Grade 5 axi-cel-related leukoencephalopathy. Since the 1-y analysis, 6 new infections were reported (Grades 1, 2, and 5 COVID-19 [n=1 each], Grade 3 Pneumocystis jirovecii pneumonia [n=1], Grade 3 unknown infectious episode with inflammatory syndrome [n=1], and Grade 2 herpes zoster [n=1]). In total, 8 deaths occurred since the 1-y analysis (progressive disease [n=5], leukoencephalopathy [n=1], and COVID-19 [n=2]). The ORR was 95% (80% CR), which was unchanged from the 1-y analysis. Median DOR and PFS were since reached (25.9 mo [95% CI, 7.8-not estimable] and 26.8 mo [95% CI, 8.7-not estimable], respectively). Median OS was still not reached. Kaplan- Meier estimates of the 2-y DOR, PFS, and OS rates were 53%, 53%, and 62%, respectively. Of 18 pts (45%) in ongoing response at data cutoff, all achieved CR as the best response. By Month 24, 14/20 pts with evaluable samples (70%) had detectable CAR T cells (vs 23/36 pts [64%] in Cohorts 1+2). Conclusion(s): With 2 y of follow-up, the ZUMA-1 Cohort 6 toxicity management strategy continued to demonstrate an improved long-term safety profile of axi-cel in pts with R/R LBCL. Further, responses remained high, durable, and similar to those observed in Cohorts 1+2 (Locke, et al. Lancet Oncol. 2019).Copyright © 2023 American Society for Transplantation and Cellular Therapy
ABSTRACT
Background: The Pfizer/BioNTech BNT162b2 vaccine, employing mRNA technology, has been recently approved by both the FDA and EMA for the prevention of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, demonstrating a 94.6% protection rate in a phase 3 study. While this vaccine is recommended by the FDA, EBMT and ASH-ASTCT for immunosuppressed patients, data regarding protection efficacy and safety in patients undergoing immunologic cell therapy are scarce. Aims: We aimed to evaluate efficacy and toxicity of the BNT162b2 vaccine in patients that underwent hematopoietic cell transplantation and CAR-T therapy. Methods: All patients under active treatment at the long-term follow-up HCT clinic (n=124) at the Tel Aviv Sourasky Medical Center, were evaluated for immunologic recovery (CD19+, CD4+, and CD8+ cell blood levels) pre-vaccination and were recommended to receive the commercial vaccination based on the EBMT recommendations. Patients were prospectively followed for vaccination-safety profile (laboratory tests, GVHD monitoring, and symptom-based questionnaire). We evaluated the humoral immune response to vaccine, 7-14 days after the second vaccine dose, by in vitro quantitative determination of anti-SARSCoV- 2S antibodies using Elecsys. assay and cellular immune response by ELISpot, estimating IL-2 and IFN-gamma secretion in response to a pool of lyophilized SARS-COV-2 S and M peptides (PepTivator;Miltenyi). The trial was approved by the local Ethics Committee and was registered by the clinical trials network (NCT04724642). Results: From 23-Dec-2020 all sequential patients (allogeneic, n=101 and CAR-T, n=23) were assessed for eligibility based on the EBMT recommendations (Version 5.0, Feb 21, 2021). Of those, 100 patients were eligible and 79 patients (allogeneic, n=65 and CAR-T, n=14) were vaccinated per-protocol. Characteristics of patients are depicted in Table 1. Overall, the 2 vaccine doses were well tolerated. Adverse events were reported in 39% of allogeneic HCT recipients (4.6% grade ≥3) and 32% of CART recipients (7% grade ≥3). All events resolved within few days, with the exception of 1 secondary graft rejection which is still under investigation. Among the CAR-T group, 5 patients (36%) had humoral antibody response. Patients with CD19+ lymphocytes >0 had a higher likelihood to develop antibodies compared to those with B cell aplasia (67% vs. 12.5%, p=.036). Among the allogeneic HCT group - 47 patients (81%) had a humoral antibody response. Incidence of positive serology was lower in patients with concomitant high intensity immunosuppressive therapy (IST) compared to those with low intensity IST (69% vs. 94%, p=.016). Linear regressions identified that male sex (beta=-.380, p=.012) and high intensity IST (beta=-.497, p=.014) were associated with lower antibody titer, while age, months from HCT, intensity of conditioning, low CD19 cell count, and active GVHD did not predict response. Analysis of peptide induced cytokine release by ELISpot is ongoing and will be presented at the EHA meeting. Summary/Conclusion: Humoral response to the BNT162b2 mRNA COVID-19 vaccine in CAR-T patients with B cell aplasia is significantly impaired, while overall response in patients after allogeneic HCT is encouraging. Patients on concomitant high intensity IST had impaired humoral response to BNT162b2. Longer follow-up is mandatory to test persistence of antibodies, and general preventive practices should be continued until more data are available.
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Background: Chimeric antigen receptor T cells (CAR-T) cells targeting CD19, demonstrate highly effective anti-tumor response in Diffuse Large B Cell Lymphoma (DLBCL). However, can result in significant side effects such as prolong neutropenia and infections. The incidence of infections in the setting of real world data hasn't been completely identified. Aims: To perform a comprehensive analysis of infection rate and profile in the first month after CAR-T cells in a cohort of infirm patients treated with commercially available CAR-T cells. Methods: This is a retrospective, single center study conducted in the Bone marrow transplant unit, Tel Aviv, analyzing the infection rate in consecutive patients with DLBCL who were treated with commercially available axicabtagene ciloleucel or tisagenlecleucel. Following a local protocol, all patients were treated with prophylaxis with ciprofloxacin and fluconazole when neutrophil counts decreased below 0.5∗103/μl. Acyclovir was administered at conditioning initiation. Microbiology and clinical documented infections (MDI and CDI, respectively) were defined according to the ECIL guidelines. Following white blood cell recovery, patients carried out weekly full blood count, and monthly CMV and HHV-6. A logistic regression was performed for the association between baseline characteristics and documented infections. Results: From June 2019 to December 2020, we included 60 consecutive patients with DLBCL treated with axicabtagene ciloleucel (n=16, 27%) or tisagenlecleucel (n=44, 73%). The median age was 69.3 (range, 19.8-85.2) years and ECOG-Performance status(PS) was 2-3 in most patients (58%). Broad spectrum antibiotics was administered to patients experiencing neutropenic fever (n=53, 88%). Overall infections were noted in 27/60 patients (45%).Bacterial infections were seen in 16 patients (27%) and included CDI in 7 (Pneumonia, n=5;periodontal infection, n=1 and cellulitis, n=1) and MDI in 9 patients (Gram negative rod bacteremia (GNR), n= 5;Gram positive cocci(GPC) bacteremia, n= 3;Both GNR and GPC, n=1). Viral infection was described in 14 patients (23%). The most common viral infection was CMV reactivation (n=10, 17%) leading to initiation of anti-CMV treatment in 6 among these patients. None had CMV disease. HHV-6 was positive in 3 patients (5%) with one of these patients presenting with acute encephalitis. Other viral infections reported were RSV (n=2)COVID-19 (n=1). No fungal infection was documented. Incidence of documented infections was higher in patients with CRS/ICANS compared with patients without [23/44 (52%) vs 4/16 (25%), p=0.005]. While CRP levels predicted documented infections (p= 0.041), ferritin blood levels did not (p=0.130). In univariate analysis, ICANS (OR= 4.5, p = 0.018) was associated with higher incidence of bacterial infection while there was a trend for lower incidence of bacterial infections in patients with chemo-sensitive disease to bridging therapy (OR= 0.375, p= 0.074)(Table 1). Age or ECOG-PS were not associated with increased risk of bacterial infection. Patients with documented infection had an increase in hospitalization days compared to those without documented infection (26.44 vs 21.7 days, p= 0.085). Summary/Conclusion: Infections were common in the first month following CAR-T cell administration, however were not increased in elderly patients or those presenting with poorer PS. Patients refractory to bridging therapy and ICANS should be monitored cautiously for the occurrence of infections. CMV monitoring should also be considered.
ABSTRACT
Patients diagnosed with B-cell non-Hodgkin lymphoma (B-NHL), particularly if recently treated with anti-CD20 antibodies, are at risk of severe COVID-19 disease. Because studies evaluating humoral response to COVID-19 vaccine in these patients are lacking, recommendations regarding vaccination strategy remain unclear. The humoral immune response to BNT162b2 messenger RNA (mRNA) COVID-19 vaccine was evaluated in patients with B-NHL who received 2 vaccine doses 21 days apart and compared with the response in healthy controls. Antibody titer, measured by the Elecsys Anti-SARS-CoV-2S assay, was evaluated 2 to 3 weeks after the second vaccine dose. Patients with B-NHL (n = 149), aggressive B-NHL (a-B-NHL; 47%), or indolent B-NHL (i-B-NHL; 53%) were evaluated. Twenty-eight (19%) were treatment naïve, 37% were actively treated with a rituximab/obinutuzumab (R/Obi)-based induction regimen or R/Obi maintenance, and 44% had last been treated with R/Obi >6 months before vaccination. A seropositive response was achieved in 89%, 7.3%, and 66.7%, respectively, with response rates of 49% in patients with B-NHL vs 98.5% in 65 healthy controls (P < .001). Multivariate analysis revealed that longer time since exposure to R/Obi and absolute lymphocyte count ≥0.9 × 103/µL predicted a positive serological response. Median time to achieve positive serology among anti-CD20 antibody-treated patients was longer in i-B-NHL vs a-B-NHL. The humoral response to BNT162b2 mRNA COVID-19 vaccine is impaired in patients with B-NHL who are undergoing R/Obi treatment. Longer time since exposure to R/Obi is associated with improved response rates to the COVID-19 vaccine. This study is registered at www.clinicaltrials.gov as #NCT04746092.