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Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. Significant unmet need remains for patients with relapsed/refractory FL after =3 lines of prior therapy. While recent advancements have likely improved the survival of patients with FL, most patients will eventually relapse. The treatment of patients with FL after multiple relapses or those with refractory disease has historically led to lower overall response rates (ORR) and shorter progressionfree survival (PFS) with each subsequent line of therapy. New treatments with high ORR and durable PFS are needed in this setting, particularly in patients that progress within 2 years of first line chemoimmunotherapy (POD24) and/or those refractory chemoimmunotherapy. Chimeric antigen receptor T-cell therapies targeting the B-cell antigen CD-19 have shown to be an efficacious treatment option for both heavily pretreated patients and/or patients with refractory FL, resulting in a high ORR and durable remissions. [ABSTRACT FROM AUTHOR]

Summary: Data describing outcomes of chimeric antigen receptor (CAR) T‐cell therapy in patients with secondary central nervous system (SCNS) involvement of mantle cell lymphoma (MCL) are limited. We identified 10 patients with MCL and SCNS involvement treated with anti‐CD19 CAR T‐cell therapy at three US academic centres. Frequent objective responses were observed in the CNS (86%) and systemically (90%), and the 1‐year progression‐free survival was 47%. Seven patients developed immune‐effector‐cell‐associated‐neurotoxicity‐syndrome (n = 2 Grade 1, n = 5 Grade 3). Our results suggest that anti‐CD19 CAR T‐cell therapy in this setting is feasible and additional data regarding neurotoxicity in this population may be warranted. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma is the most common subtype of lymphoma. First-line treatment with combination chemoimmunotherapy is successful in about 60% of patients. For those who have relapse, second-line therapy consists of additional chemoimmunotherapy followed by autologous stem cell transplant. But most of these patients do not have good outcomes. The U.S. Food and Drug Administration (FDA) has approved CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) for third-line treatment; CAR-T is also effective for relapsed disease. The study described in this article examines whether CAR-T could be used as second-line therapy. Visual Abstract. Second-Line Chimeric Antigen Receptor T-Cell Therapy in Diffuse Large B-Cell Lymphoma: Diffuse large B-cell lymphoma is the most common subtype of lymphoma. First-line treatment with combination chemoimmunotherapy is successful in about 60% of patients. For those who relapse, second-line therapy consists of additional chemoimmunotherapy followed by autologous stem cell transplant. But most of these patients do not have good outcomes. The U.S. Food and Drug Administration (FDA) has approved CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) for third-line treatment; CAR-T is also effective for relapsed disease. The study described in this article examines whether CAR-T could be used as second-line therapy. Background: First-line treatment of diffuse large B-cell lymphoma (DLBCL) achieves durable remission in approximately 60% of patients. In relapsed or refractory disease, only about 20% achieve durable remission with salvage chemoimmunotherapy and consolidative autologous stem cell transplantation (ASCT). The ZUMA-7 (axicabtagene ciloleucel [axi-cel]) and TRANSFORM (lisocabtagene maraleucel [liso-cel]) trials demonstrated superior event-free survival (and, in ZUMA-7, overall survival) in primary-refractory or early-relapsed (high-risk) DLBCL with chimeric antigen receptor T-cell therapy (CAR-T) compared with salvage chemoimmunotherapy and consolidative ASCT; however, list prices for CAR-T exceed $400 000 per infusion. Objective: To determine the cost-effectiveness of second-line CAR-T versus salvage chemoimmunotherapy and consolidative ASCT. Design: State-transition microsimulation model. Data Sources: ZUMA-7, TRANSFORM, other trials, and observational data. Target Population: "High-risk" patients with DLBCL. Time Horizon: Lifetime. Perspective: Health care sector. Intervention: Axi-cel or liso-cel versus ASCT. Outcome Measures: Incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (iNMB) in 2022 U.S. dollars per quality-adjusted life-year (QALY) for a willingness-to-pay (WTP) threshold of $200 000 per QALY. Results of Base-Case Analysis: The increase in median overall survival was 4 months for axi-cel and 1 month for liso-cel. For axi-cel, the ICER was $684 225 per QALY and the iNMB was −$107 642. For liso-cel, the ICER was $1 171 909 per QALY and the iNMB was −$102 477. Results of Sensitivity Analysis: To be cost-effective with a WTP of $200 000, the cost of CAR-T would have to be reduced to $321 123 for axi-cel and $313 730 for liso-cel. Implementation in high-risk patients would increase U.S. health care spending by approximately $6.8 billion over a 5-year period. Limitation: Differences in preinfusion bridging therapies precluded cross-trial comparisons. Conclusion: Neither second-line axi-cel nor liso-cel was cost-effective at a WTP of $200 000 per QALY. Clinical outcomes improved incrementally, but costs of CAR-T must be lowered substantially to enable cost-effectiveness. Primary Funding Source: No research-specific funding. [ABSTRACT FROM AUTHOR]

Objective: To develop an automated, physiologic metric of immune effector cell‐associated neurotoxicity syndrome among patients undergoing chimeric antigen receptor‐T cell therapy. Methods: We conducted a retrospective observational cohort study from 2016 to 2020 at two tertiary care centers among patients receiving chimeric antigen receptor‐T cell therapy with a CD19 or B‐cell maturation antigen ligand. We determined the daily neurotoxicity grade for each patient during EEG monitoring via chart review and extracted clinical variables and outcomes from the electronic health records. Using quantitative EEG features, we developed a machine learning model to detect the presence and severity of neurotoxicity, known as the EEG immune effector cell‐associated neurotoxicity syndrome score. Results: The EEG immune effector cell‐associated neurotoxicity syndrome score significantly correlated with the grade of neurotoxicity with a median Spearman's R2 of 0.69 (95% CI of 0.59–0.77). The mean area under receiving operator curve was greater than 0.85 for each binary discrimination level. The score also showed significant correlations with maximum ferritin (R2 0.24, p = 0.008), minimum platelets (R2 –0.29, p = 0.001), and dexamethasone usage (R2 0.42, p < 0.0001). The score significantly correlated with duration of neurotoxicity (R2 0.31, p < 0.0001). Interpretation: The EEG immune effector cell‐associated neurotoxicity syndrome score possesses high criterion, construct, and predictive validity, which substantiates its use as a physiologic method to detect the presence and severity of neurotoxicity among patients undergoing chimeric antigen receptor T‐cell therapy. [ABSTRACT FROM AUTHOR]

Summary: The use of CD19 chimeric antigen receptor T‐cell (CAR‐T) therapy for relapsed/refractory solid organ transplantation (SOT)‐related post‐transplant lymphoproliferative disorder (PTLD) is not well studied. We conducted a multicentre, retrospective analysis of adults with relapsed/refractory SOT‐associated PTLD. Among 22 relapsed/refractory SOT‐PTLD patients, the pathology was monomorphic B cell. Prior SOTs included 14 kidney (64%), three liver (14%), two heart (9%), one intestinal (5%), one lung (5%), and one pancreas after kidney transplant (5%). The median time from SOT to PTLD diagnosis was 107 months. Pre‐CAR‐T bridging therapy was used in 55% of patients, and immunosuppression was stopped completely before CAR‐T infusion in 64%. Eighteen (82%) patients experienced cytokine release syndrome: one (5%) each grade (G) 3 and G4. The immune effector cell‐associated neurotoxicity syndrome was observed in 16 (73%) patients: six (27%) G3 and two (9%) G4. The overall response rate was 64% (55% complete response). Three patients (14%) experienced allograft rejection after CAR‐T. The two‐year progression‐free survival and overall survival rates were 35% and 58%, respectively. Additionally, the achievement of CR post‐CAR‐T was strongly associated with survival. Collectively, the safety and efficacy of CD19 CAR‐T therapy in relapsed/refractory SOT‐related PTLD appeared similar to pivotal CAR‐T data, including approximately one‐third of patients achieving sustained remission. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T cells (CAR T) are groundbreaking therapies but may cause significant toxicities including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and cytopenias. Granulocyte colony-stimulating factor (G-CSF) is often used to mitigate neutropenia after CAR T, but there is no consensus recommended strategy due to hypothesized, but largely unknown risks of exacerbating toxicities. To investigate the impact of G-CSF, we retrospectively analyzed 197 patients treated with anti-CD19 CAR T for lymphoma and 47 patients treated with anti-BCMA CAR T for multiple myeloma. In lymphoma, 140 patients (71%) received prophylactic G-CSF before CAR T (mostly pegylated G-CSF) and were compared with 57 patients (29%) treated with G-CSF after CAR T or not exposed. Prophylactic G-CSF was associated with faster neutrophil recovery (3 vs. 4 days, P < 0.01) but did not reduce recurrent neutropenia later. Prophylactic G-CSF was associated with increased grade ≥2 CRS (HR 2.15, 95% CI 1.11–4.18, P = 0.02), but not ICANS. In multiple myeloma, prophylactic G-CSF was not used; patients were stratified by early G-CSF exposure (≤2 days vs. ≥3 days after CAR T or no exposure), with no significant difference in toxicities. Future trials should clarify the optimal G-CSF strategy to improve outcomes after CAR T. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary new form of immunotherapy for the treatment of hematologic malignancies. The two primary toxicities associated with CAR T-cell therapy include cytokine-release syndrome and neurotoxicity. Cytokine-release syndrome is generally self-limited but high-grade toxicities like hypotension and hypoxemia can be managed with agents that block the effects of IL-6, like tocilizumab, and/or corticosteroids. Although CAR T-cell therapy-associated neurotoxicity is a well-described clinical phenomenon, its pathophysiology remains inadequately understood; treatments and preventive strategies remain elusive. Animal models and clinical trial experience suggest the centrality of monocytes, endothelial dysfunction, and the blood-brain barrier in the development of CAR T-cell-associated neurotoxicity. Here we report what is known from preclinical models, clinical trials, and histopathologic studies regarding the pathophysiology of neurotoxicity, predictors of its incidence, and potential targets for the treatment and prevention of neurotoxicity. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T cell therapy has become an important tool in the treatment of relapsed and refractory malignancy; however, it is associated with significant neurological toxicity. We characterized the neurological toxicity associated with chimeric antigen receptor T-cell therapy in a consecutive series of 100 patients up to 2 months post transfusion, 28 of whom were obtained from chart review and the others by prospective observation. The underlying neoplasms were lymphoma (74%), myeloma (14%), leukaemia (10%), and sarcoma (2%). The median age of the cohort was 64.5 years old and 39% of patients were female. The most commonly occurring neurological symptoms were encephalopathy (57%), headache (42%), tremor (38%), aphasia (35%) and focal weakness (11%). Focal neurological deficits are frequently observed after chimeric antigen receptor T-cell therapy and are associated with regional EEG abnormalities, FDG-PET hypometabolism, and elevated velocities on transcranial Doppler ultrasound. In contrast, structural imaging was typically normal. As this form of treatment is more widely adopted, recognition of the frequently encountered symptoms will be of increasing importance for the neurologists and oncologists caring for this growing patient population. [ABSTRACT FROM AUTHOR]

CAR T cell therapy has revolutionized the treatment of a spectrum of blood-related malignancies. However, treatment responses vary among cancer types and patients. Accurate monitoring of CAR T cell dynamics is crucial for understanding and evaluating treatment efficacy. Positron emission tomography (PET) offers a comprehensive view of CAR T cell homing, especially in critical organs such as lymphoid structures and bone marrow. This information will help assess treatment response and predict relapse risk. Current PET imaging methods for CAR T require genetic modifications, limiting clinical use. To overcome this, we developed an antigen-based imaging approach enabling whole-body CAR T cell imaging. The probe detects CAR T cells in vivo without affecting their function. In an immunocompetent B cell leukemia model, CAR-PET signal in the spleen predicted early mortality risk. The antigen-based CAR-PET approach allows assessment of CAR T therapy responses without altering established clinical protocols. It seamlessly integrates with FDA-approved and future CAR T cell generations, facilitating broader clinical application. [ABSTRACT FROM AUTHOR]

Background Axi-cel is a US FDA-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for treatment of adult patients (pts) with relapsed or refractory large B cell lymphoma (LBCL) after ≥ 2 prior lines of therapy. The checkpoint proteins PD-1 and PD-L1 are expressed on CAR T cells and in the tumor microenvironment, and are upregulated after CAR T cell infusion (Cherkassky, et al. J Clin Invest. 2016; Galon, et al. ASCO 2017. #3025). This suggests that PD-L1 blockade could augment axi-cel activity. This end of Phase 1 analysis of ZUMA-6 examines the safety and preliminary efficacy of axi-cel in combination with the anti–PD-L1 antibody atezolizumab (atezo) in pts with refractory LBCL (NCT02926833). Methods Eligible pts (≥ 18 years) with refractory DLBCL must have received prior CD20-targeting and anthracycline-containing regimen and had ECOG ≤ 1 and adequate bone marrow and organ function. Pts received low-dose conditioning followed by axi-cel infusion (target dose of 2 × 106 cells/kg). Atezo was administered at 1200 mg every 21 days for 4 doses starting on Day 21, 14, and 1 post–axi-cel infusion for Cohorts 1, 2, and 3, respectively. Incidence of dose-limiting toxicities (DLTs) was the primary endpoint. Secondary endpoints included the frequency of adverse events (AEs), disease response, and pharmacokinetics. Results As of January 19, 2018, 12 pts have received axi-cel and ≥1 dose of atezo (3 in Cohort 1; 3 in Cohort 2, 6 in Cohort 3). Median age was 55 years (range, 30 – 66); median follow-up from axi-cel infusion was 4.4 months (range, 0.8 – 12.6). One pt in Cohort 3 experienced a DLT of Grade 4 thrombocytopenia and neutropenia lasting >30 days. All pts experienced at least 1 AE (92% Grade ≥ 3), with no apparent exacerbation or recurrence of axi-cel–related AE following atezo infusion. The most common grade ≥ 3 AEs were anemia (9/12, 75%), encephalopathy (5/12, 42%), and neutropenia (5/12, 42%). Grade ≥ 3 CRS and neurologic events occurred in 3 (25%) and 6 (50%) pts, respectively. The ORR in evaluable pts was 9/10 (90%), with 6 pts (60%) in CR and 3 (30%) in partial response (PR); 2/6 pts (33%) had converted to CR at month 6 and month 9 after initially achieving a PR. CAR T cell expansion (area under the curve D0-28) in pts with DLBCL was >2-fold higher in ZUMA-6 than the median observed in pts treated with axi-cel alone in ZUMA-1 (ZUMA-6: median, 823 cells/µL × days, range, 99 – 2301; ZUMA-1: median, 357 cells/µL × days, range, 5 – 11,507). Median CAR T cell levels remained higher than ZUMA-1 beyond 28 days. Conclusions PD-L1 blockade with atezo following axi-cel infusion has a manageable safety profile, with a low incidence of DLTs and no clinically significant increase in incidence of AEs. Encouraging efficacy results support the opening of Phase 2 of ZUMA-6 in which 22 pts will be treated according to the Cohort 3 schedule. Pharmacokinetic data suggest the potential for enhanced CAR T cell expansion. [ABSTRACT FROM AUTHOR]

Axicabtagene ciloleucel (YESCARTA; Kite Pharma, a Gilead Company, Los Angeles CA) and tisagenlecleucel (KYMRIAH; Novartis Pharmaceuticals Corp., Basel, Switzerland) are two CD19-directed chimeric antigen receptor (CAR) T cell products currently approved by the US Food and Drug Administration; the European Medicines Agency; Health Canada; Ministry of Health, Labor and Welfare (Japan); and Therapeutic Goods Administration (Australia) for treatment of specific subtypes of relapsed/refractory aggressive B cell non-Hodgkin lymphoma (NHL). Although this approval has been transformative in the use of cellular immunotherapy in lymphoma, there are concerns regarding appropriate use of this novel therapy and of short- and long-term toxicities. To address these issues, representatives of the American Society of Transplantation and Cellular Therapy convened to recognize and address key issues surrounding the clinical application of CD19 CAR T cell therapy in B cell lymphomas, in collaboration with worldwide experts. The aim of this article is to provide consensus opinion from experts in the fields of hematopoietic cell transplantation, cellular immunotherapy, and lymphoma regarding key clinical questions pertinent to the use of CD19 CAR T cell products for the treatment of NHL. As the clinical practice using CAR T cells grows worldwide, we anticipate that this guidance will be relevant for hematology/oncology physicians who care for patients with lymphomas. [ABSTRACT FROM AUTHOR]

Outcomes with salvage regimens in pts with MCL who progress after Bruton tyrosine kinase inhibitor (BTKi) therapy are poor. ZUMA-2 is a Phase 2, registrational, multicenter study evaluating KTE-X19, an autologous anti-CD19 CAR T cell therapy, in pts with R/R MCL (1-5 therapies, including a BTKi). We present interim efficacy and safety results. Evaluate efficacy and safety of KTE-X19 in R/R MCL. Eligible pts (≥ 18 y) with R/R MCL had an ECOG of 0-1 and ≤ 5 prior therapies, including chemotherapy, an anti-CD20 antibody, and a BTKi. Pts underwent leukapheresis and conditioning chemotherapy followed by KTE-X19 infusion at 2 × 106 cells/kg. Bridging therapy with dexamethasone, ibrutinib, or acalabrutinib was permitted. The primary endpoint was objective response rate (ORR; complete response [CR] + partial response) assessed by an Independent Review Committee per the Lugano Classification (Cheson, et al. J Clin Oncol. 2014). Interim efficacy endpoints were investigator-assessed using the revised IWG Response Criteria for Malignant Lymphoma (Cheson, et al. J Clin Oncol. 2007). Key secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), frequency of adverse events (AEs), and blood levels of CAR T cells and cytokines. Sixty pts received KTE-X19; here, we present results in pts with ≥ 1 y follow-up. Updated results in all 60 pts will be reported in the presentation. As of May 30, 2018, 28 pts received KTE-X19 with ≥ 1 y follow-up (median, 13.2 mo). The median age was 65 y; 43% of pts had an ECOG score of 1; 21% had blastoid morphology; 82% had stage IV disease; 50% had intermediate/high-risk MIPI; and 86% received a median of 4 prior therapies. In 20 of 28 pts with available data, the median Ki-67 index was 38%. Eight pts received bridging therapy; all had disease present post-bridging. Investigator-assessed ORR was 86% (95% CI, 67-96) with a CR rate of 57% (95% CI, 37-76). As of May 30, 2018, 75% of responders remained in response, and 64% of treated pts had ongoing responses. The 12-month rates of DOR, PFS, and OS were 83% (95% CI, 60-93), 71% (95% CI, 50-84), and 86% (95% CI, 66-94), respectively; medians were not reached. The most common Grade ≥ 3 AEs were anemia (54%), platelet count decreased (39%), and neutropenia (36%). Grade 3/4 cytokine release syndrome (CRS) assessed by Lee et al. (Blood. 2014) and Grade 3/4 neurologic events (NE) occurred in 18% and 46% of pts, respectively, with no Grade 5 events. CRS and NE were generally reversible. There was 1 Grade 5 AE of organizing pneumonia. Median CAR T cell levels measured by peak and area under the curve were 99 cells/µL (range, 0.4-2589) and 1542 cells/µL (range, 5.5-27239), respectively. With ≥ 1 y follow-up, KTE-X19 demonstrated significant and durable clinical benefit, with a manageable safety profile in pts with R/R MCL for whom there are no curative treatment options. [ABSTRACT FROM AUTHOR]