Received Chimeric Antigen Receptor T-cell Therapy Research Articles

Abnormal Coagulation Function in CD19-Targeted CAR-T Therapy

Cytokine release syndrome (CRS), central nervous system (CNS) abnormalities and B-cell aplasia have been widely reported in recent clinical trials for chimeric antigen receptor T-cell (CAR-T) therapy. In our study, we also note that patients who received CAR-T therapy were easily to develop coagulopathy, even disseminated intravascular coagulation (DIC), which increased the risk of treatment related mortality (TRM) and required timely intervention. Therefore, it is important to pay attention to the symptom and find out the way to improve it.In our phase-1 clinical trial (NCT02965092) for B-cell acute lymphoblastic leukemia (B-ALL), we dynamically monitored the coagulation indicators and treated coagulopathy. Twenty-five patients (median age 28, [10-61]) were recruited into the trial and they underwent leukapheresis on day -11. Then they were subjected to the lymphodepleting regimens (fludarabine + cyclophosphamide, n=22; fludarabine, n=2; cyclophosphamide, n=1) on day -7~-5. Finally, they received the infusions of anti-CD19 CAR-T cells at a median dose of 4.5×106/kg (3.2-8.3×106/kg) on day 0~2. Excluding 3 patients who quitted from the trial for rapid progression of disease, and 3 patients who have not reached one-month follow-up time point yet, the overall one-month response rate for the evaluable 22 patients was 86.36%. Up to date, the longest leukemia free survival (LFS) was 16 months (median 5 months, [1-16]). As for side effects, 12 patients developed grade 2-3 CRS, 2 patients suffered from CNS symptoms, and no patients experienced serious infections. Besides, the obvious coagulopathy caught our attention. Eleven patients (11/22, 50%) developed coagulation dysfunction, manifested as petechiae and abnormal laboratory indicators (Table 1), such as deceased platelet count and fibrinogen, increased D-Dimer and fibrin degradation products, prolongations of activated partial thromboplastin time, prothrombin time and thrombin time. According to Chinese DIC Scoring System (CDSS), 5 of these 11 patients should be diagnosed as DIC (Table 2).Furthermore, we collected patients' plasma to measure the concentrations of tissue factor (TF) and platelet endothelial cell adhesion molecular-1 (PECAM-1), which are 2 vascular endothelial molecules that may play important roles in inflammation and coagulation. It was observed that coagulation disorders were more common in patients who developed severe CRS. Here we present the experiment results of 3 patients who experienced severe CRS and DIC at the same time. As shown in Figure 1, when the concentration of interleukin 6 rose and indicated CRS, the coagulopathy happened. At the same time, the TF concentration rose and PECAM-1 concentration dropped. Taken together, these data indicate that there is a relationship between CRS and DIC. We hypothesize that the cytokines released from inflammatory cells during CRS could cause dysfunction of endothelial cells and destroy the integrity of endothelial barrier, thus resulting in coagulopathy. However, the mechanism remains poorly understood, more in vivo experiments should be conducted to identify the mechanism, which may suggest novel therapeutic targets for coagulopathy.In conclusion, our data demonstrate that coagulation disorders are common side effects in CAR-T therapy, and suggest that TF and PECAM-1 are critical parameters in the pathogenesis of CRS-related coagulopathy. Investigators should pay more attention to coagulopathy and take preventive measures to avoid DIC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcomes in patients treated with chimeric antigen receptor T-cell therapy who were admitted to intensive care (CARTTAS): an international, multicentre, observational cohort study

Chimeric antigen receptor (CAR) T-cell therapy can induce side-effects such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), which often require intensive care unit admission. The aim of this study was to describe management of critically ill CAR T-cell recipients in intensive care. This international, multicentre, observational cohort study was done in 21 intensive care units in France, Spain, the USA, the UK, Russia, Canada, Germany, and Austria. Eligible patients were aged 18 years or older; had received CAR T-cell therapy in the past 30 days; and had been admitted to intensive care for any reason. Investigators retrospectively included patients admitted between Feb 1, 2018, and Feb 1, 2019, and prospectively included patients admitted between March 1, 2019, and Feb 1, 2020. Demographic, clinical, laboratory, treatment, and outcome data were extracted from medical records. The primary endpoint was 90-day mortality. Factors associated with mortality were identified using a Cox proportional hazard model. 942 patients received CAR T-cell therapy, of whom 258 (27%) required admission to intensive care and 241 (26%) were included in the analysis. Admission to intensive care was needed within median 4·5 days (IQR 2·0-7·0) of CAR T-cell infusion. 90-day mortality was 22·4% (95% CI 17·1-27·7; 54 deaths). At initial evaluation on admission, isolated cytokine release syndrome was identified in 101 patients (42%), cytokine release syndrome and ICANS in 93 (39%), and isolated ICANS in seven (3%) patients. Grade 3-4 cytokine release syndrome within 1 day of admission to intensive care was found in 50 (25%) of 200 patients and grade 3-4 ICANS in 38 (35%) of 108 patients. Bacterial infection developed in 30 (12%) patients. Life-saving treatments were used in 75 (31%) patients within 24 h of admission to intensive care, primarily vasoactive drugs in 65 (27%) patients. Factors independently associated with 90-day mortality by multivariable analysis were frailty (hazard ratio 2·51 [95% CI 1·37-4·57]), bacterial infection (2·12 [1·11-4·08]), and lifesaving therapy within 24 h of admission (1·80 [1·05-3·10]). Critical care management is an integral part of CAR T-cell therapy and should be standardised. Studies to improve infection prevention and treatment in these high-risk patients are warranted. Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique.

Chimeric Antigen Receptor T-Cell Emergencies: Inpatient Administration, Assessment, and Management.

Chimeric antigen receptor (CAR) T-cell therapy is a genetically modified cellular therapy approved for the treatment of acute lymphocytic leukemia and B-cell lymphoma. This therapy requires patients to remain hospitalized for at least 7 days to monitor for two black-box warnings: cytokine release syndrome and neurotoxicity. Both toxicities require astute monitoring and early treatment to prevent complication. We use a case study to illustrate the assessment and toxicity management of a patient receiving CAR T-cell therapy for diffuse large B-cell lymphoma at an academic medical center. Cytokine release syndrome and neurotoxicity are two common, potentially life-threatening toxicities that can be reversed with early nursing identification and treatment using evidence-based interventions. Objective assessment and consensus grading is essential for identification and management of CAR T-cell toxicities.

Cytokine release syndrome and neurological event costs in lisocabtagene maraleucel–treated patients in the TRANSCEND NHL 001 trial

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated high response rates in patients with relapsed/refractory large B-cell lymphoma (LBCL); however, these therapies are associated with 2 CAR T cell–specific potentially severe adverse events (AEs): cytokine release syndrome (CRS) and neurological events (NEs). This study estimated the management costs associated with CRS/NEs among patients with relapsed/refractory LBCL using data from the pivotal TRANSCEND NHL 001 trial of lisocabtagene maraleucel, an investigational CD19-directed defined composition CAR T-cell product with a 4-1BB costimulation domain administered at equal target doses of CD8+ and CD4+ CAR+ T cells. This retrospective analysis of patients from TRANSCEND with prospectively identified CRS and/or NE episodes examined relevant trial-observed health care resource utilization (HCRU) associated with toxicity management based on the severity of the event from the health care system perspective. Cost estimates for this analysis were taken from publicly available databases and published literature. Of 268 treated patients as of April 2019, 127 (47.4%) experienced all-grade CRS and/or NEs, which were predominantly grade ≤2 (77.2%). Median total AE management costs ranged from $1930 (grade 1 NE) to $177 343 (concurrent grade ≥3 CRS and NE). Key drivers of cost were facility expenses, including intensive care unit and other inpatient hospitalization lengths of stay. HCRU and costs were significantly greater among patients with grade ≥3 AEs (22.8%). Therefore, CAR T-cell therapies with a low incidence of severe CRS/NEs will likely reduce HCRU and costs associated with managing patients receiving CAR T-cell therapy. This clinical trial was registered at www.clinicaltrials.gov as #NCT02631044.

Prevalence and factors associated with anxiety and depressive symptoms among patients hospitalized with hematological malignancies after chimeric antigen receptor T-cell (CAR-T) therapy: A cross-sectional study

Background: We conducted a survey to investigate the prevalence and factors associated with anxiety and depressive symptoms among patients hospitalized with hematological malignancies after chimeric antigen receptor T-cell (CAR-T) therapy. Methods: In total, 130 eligible patients completed the Self-Rating Anxiety Scale and Self-Rating Depression Scale at week 4 after CAR-T cell infusion. We collected sociodemographic information during the same period. We studied factors associated with anxiety and depressive symptoms using logistic regression analysis. Results: The prevalence of anxiety and depressive symptoms at week 4 after infusion were 13.8% and 40.0%, respectively. A cutoff value of 50 or above indicates significantly anxiety and depressive symptoms. Binary logistic regression analysis showed that high school education and above (OR = 0.22, 95% CI = 0.06–0.78) and middle age (OR = 0.16, 95% CI = 0.03–0.90) were associated with lower risk of anxiety symptoms, and increased odds of depressive symptoms was associated with old age (OR = 11.39, 95% CI = 2.50–51.88), non-manual occupations before illness (OR = 3.72, 95% CI = 1.20–11.58), and higher healthcare expenditure (OR = 3.93, 95% CI = 1.50–10.33), while lower risk of depressive symptoms was associated with rural household location (OR = 0.25, 95% CI = 0.08–0.76) and being cared for by spouse (OR = 0.12, 95% CI = 0.02–0.63). Conclusions: Patients receiving CAR-T therapy with lower education background, old ages, urban household location, or who used to work as non-manual workers require more attention and psychological care. Support from a spouse and medical expense deductions from the government may help patients develop positive attitudes.

Cellular Therapy During COVID-19: Lessons Learned and Preparing for Subsequent Waves

An evidence-based triage plan for cellular therapy distribution is critical in the face of emerging constraints on healthcare resources. We evaluated the impact of treatment delays related to COVID-19 on patients scheduled to undergo hematopoietic cell transplantation (HCT) or chimeric antigen receptor T-cell (CAR-T) therapy at our center. Data were collected in real time between March 19 and May 11, 2020, for patients who were delayed to cellular therapy. We evaluated the proportion of delayed patients who ultimately received cellular therapy, reasons for not proceeding to cellular therapy, and changes in disease and health status during delay. A total of 85 patients were delayed, including 42 patients planned for autologous HCT, 36 patients planned for allogeneic HCT, and 7 patients planned for CAR-T therapy. Fifty-six of these patients (66%) since received planned therapy. Five patients died during the delay. The most common reason for not proceeding to autologous HCT was good disease control in patients with plasma cell dyscrasias (75%). The most common reason for not proceeding to allogeneic HCT was progression of disease (42%). All patients with acute leukemia who progressed had measurable residual disease (MRD) at the time of delay, whereas no patient without MRD at the time of delay progressed. Six patients (86%) ultimately received CAR-T therapy, including 3 patients who progressed during the delay. For patients with high-risk disease such as acute leukemia, and particularly those with MRD at the time of planned HCT, treatment delay can result in devastating outcomes and should be avoided if at all possible.

Megakaryocyte aplastic thrombocytopenia after CAR T-cell therapy in a patient with multiple myeloma: A case report

Abstract Chimeric antigen receptor (CAR) T-cell therapy is an effective new treatment strategy for hematologic malignancies. The success of CAR T-cell therapy in treating leukemia and lymphoma has promoted its development for multiple myeloma (MM), and the initial results of CAR T cell therapy have been encouraging. CAR T-cell therapy target antigens that have been clinically evaluated in MM; these antigens include CD19, B cell maturation antigen (BCMA), CD38, and CD138. A barrier to the widespread use of CAR T-cell therapy is its toxicity, primarily cytokine release syndrome (CRS), and neurologic toxicity. This study reports a patient with refractory MM who also developed megakaryocyte aplastic thrombocytopenia after receiving CAR T-cell therapy; such a case or the unusual side effects involving medications are yet unreported. There are risks in using cyclosporine and other immunosuppressants that may lead to MM recurrence as the use of such substances is contradictory to previous treatments; therefore, we temporarily administered platelet infusion as supportive care. Thus far, the condition of the patient has been steady and the patient regularly takes blood test in the hospital.

216 - The Impact of Bridging Therapy Prior to CAR-T Cell Therapy on Clinical Outcomes of Patients with Relapsed Refractory Large B-Cell Lymphoma

Introduction:Chimeric antigen receptor T-cell (CAR-T) therapy has become an important treatment modality for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, many of these patients have aggressive disease and require a form of bridging therapy (BT) for disease control during CAR-T manufacturing. There is limited data in the literature on the most appropriate form of BT and the impact of BT on clinical outcomes. Methods:We retrospectively analyzed data on 75 patients that received CAR-T therapy at our institution. BT was defined as therapy administered between apheresis and CAR-T infusion. 52 patients received bridging therapy (BT) and 23 did not receive BT (NBT). BT included 10 high dose (HD) steroids, 28 chemotherapy-based regimen (CT), and 14 radiation therapy (RT). CT included cytotoxic chemotherapy, immunotherapy, and targeted therapy. IRB approval was obtained for this study. Statistical analysis was conducted with SAS v9.4. Univariate analysis Cox proportional hazard model was used and p-values for response rate were generated from Fisher's exact test. The methods of generalized linear model and logistic regression were used to associate the toxicity grades and cytopenias with BT, respectively. Results:Many patient and disease characteristics between BT and NBT groups were similar, with minor, non-statistically significant differences (See Fig. 1a). Although while the incidence of stage III/IV patients in the BT and NBT group was comparable (p=0.79), in subgroup analysis, there were significantly more stage III/IV patients in the CT subgroup and NBT than in the RT and HD steroids subgroups (p=0.03). There was a higher incidence of bulky disease (≥10cm) in the BT and all BT subgroups versus (vs) NBT, although this was not significant (p=0.58 and p=0.92). The number of prior lines of therapy was comparable between the BT and NBT groups (p=0.99). However, in subgroup analysis there were significantly more patients in the CT subgroup and NBT that received ≥4 lines of therapy compared with RT and HD steroids subgroups (p=0.02). There was no significant difference in overall response rate (ORR) at last follow up between BT vs NBT and BT subgroups vs NBT with approximately 50% being in complete remission in all cases (p=0.48 and p=0.54). Progression free survival (PFS) and overall survival (OS) were similar in the BT vs NBT (one-year rates of 67% vs 64% and 83% vs 75%, respectively) and this was not statistically significant (p=0.52 and 0.89), see Fig. 1b and 1c. In subgroup analysis PFS was comparable in the BT subgroups (CT 69% and HD steroids 68%) vs NBT group (67%) while RT was lower (51%), although this was not statistically significant (p=0.54). In subgroup analysis OS was slightly worse in the BT subgroups (CT 77%, RT 76%, and HD steroids 72%) vs NBT group (83%) although was not statistically significant (p=0.93). The development of cytokine release syndrome (CRS) was comparable in the BT vs NBT group and in BT subgroups vs NBT (p=0.18 and p=0.53). The median grade of immune effector cell-associated neurotoxicity syndrome (ICANS) was higher in BT than NBT (grade 2 vs 0) and trended towards statistical significance (p=0.09). The development of cytopenias at day +180 following CAR-T therapy was significantly higher in BT (50%) vs NBT (13.3%) and was statistically significant (p= 0.038). Subgroup analysis also showed significantly increased cytopenias at day +180 in CT (58.3%) and RT (57.1%) subgroups (p= 0.04). Conclusion:In our single-institution experience, BT prior to CAR-T therapy is feasible and may preserve CAR-T candidacy in patients with rapidly progressive LBCL. BT does not appear to significantly affect ORR, PFS, and OS. The incidence of CRS was comparable, although there was a higher incidence of ICANS in BT, which trended towards significance, and could be contributed to higher tumor bulk in the BT group. BT patients receiving CT and RT for BT were more likely to experience prolonged cytopenias, likely due to the myelosuppressive impact of BT and previous lines of chemo-immunotherapy agents. In conclusion, in high-risk patients with advanced and/or aggressive disease, BT may provide disease stabilization to CAR-T with a similar toxicity profile compared to NBT patients, although BT patients are more likely to experience prolonged cytopenias after CAR-T therapy. Download : Download high-res image (352KB) Download : Download full-size image Disclosures Kansagra:Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics:Other: Advisory Board.Hardy:Incyte Corporation:Other: Advisory Board Member;American Gene Technologies:Other: DSMB Member;Kite/Gilead:Other: Advisory Board Member.

Response to CAR-T Therapy Can be Monitored Using Genome-Wide Sequencing of Cell-Free DNA in Patients with DLBCL

Response to CAR-T Therapy Can be Monitored Using Genome-Wide Sequencing of Cell-Free DNA in Patients with DLBCL

The Impact of Bridging Therapy Prior to CAR-T Cell Therapy on Clinical Outcomes of Patients with Relapsed Refractory Large B-Cell Lymphoma

Introduction:Chimeric antigen receptor T-cell (CAR-T) therapy has become an important treatment modality for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, many of these patients have aggressive disease and require a form of bridging therapy (BT) for disease control during CAR-T manufacturing. There is limited data in the literature on the most appropriate form of BT and the impact of BT on clinical outcomes. Methods:We retrospectively analyzed data on 75 patients that received CAR-T therapy at our institution. BT was defined as therapy administered between apheresis and CAR-T infusion. 52 patients received bridging therapy (BT) and 23 did not receive BT (NBT). BT included 10 high dose (HD) steroids, 28 chemotherapy-based regimen (CT), and 14 radiation therapy (RT). CT included cytotoxic chemotherapy, immunotherapy, and targeted therapy. IRB approval was obtained for this study. Statistical analysis was conducted with SAS v9.4. Univariate analysis Cox proportional hazard model was used and p-values for response rate were generated from Fisher's exact test. The methods of generalized linear model and logistic regression were used to associate the toxicity grades and cytopenias with BT, respectively. Results:Many patient and disease characteristics between BT and NBT groups were similar, with minor, non-statistically significant differences (See Fig. 1a). Although while the incidence of stage III/IV patients in the BT and NBT group was comparable (p=0.79), in subgroup analysis, there were significantly more stage III/IV patients in the CT subgroup and NBT than in the RT and HD steroids subgroups (p=0.03). There was a higher incidence of bulky disease (≥10cm) in the BT and all BT subgroups versus (vs) NBT, although this was not significant (p=0.58 and p=0.92). The number of prior lines of therapy was comparable between the BT and NBT groups (p=0.99). However, in subgroup analysis there were significantly more patients in the CT subgroup and NBT that received ≥4 lines of therapy compared with RT and HD steroids subgroups (p=0.02). There was no significant difference in overall response rate (ORR) at last follow up between BT vs NBT and BT subgroups vs NBT with approximately 50% being in complete remission in all cases (p=0.48 and p=0.54). Progression free survival (PFS) and overall survival (OS) were similar in the BT vs NBT (one-year rates of 67% vs 64% and 83% vs 75%, respectively) and this was not statistically significant (p=0.52 and 0.89), see Fig. 1b and 1c. In subgroup analysis PFS was comparable in the BT subgroups (CT 69% and HD steroids 68%) vs NBT group (67%) while RT was lower (51%), although this was not statistically significant (p=0.54). In subgroup analysis OS was slightly worse in the BT subgroups (CT 77%, RT 76%, and HD steroids 72%) vs NBT group (83%) although was not statistically significant (p=0.93). The development of cytokine release syndrome (CRS) was comparable in the BT vs NBT group and in BT subgroups vs NBT (p=0.18 and p=0.53). The median grade of immune effector cell-associated neurotoxicity syndrome (ICANS) was higher in BT than NBT (grade 2 vs 0) and trended towards statistical significance (p=0.09). The development of cytopenias at day +180 following CAR-T therapy was significantly higher in BT (50%) vs NBT (13.3%) and was statistically significant (p= 0.038). Subgroup analysis also showed significantly increased cytopenias at day +180 in CT (58.3%) and RT (57.1%) subgroups (p= 0.04). Conclusion:In our single-institution experience, BT prior to CAR-T therapy is feasible and may preserve CAR-T candidacy in patients with rapidly progressive LBCL. BT does not appear to significantly affect ORR, PFS, and OS. The incidence of CRS was comparable, although there was a higher incidence of ICANS in BT, which trended towards significance, and could be contributed to higher tumor bulk in the BT group. BT patients receiving CT and RT for BT were more likely to experience prolonged cytopenias, likely due to the myelosuppressive impact of BT and previous lines of chemo-immunotherapy agents. In conclusion, in high-risk patients with advanced and/or aggressive disease, BT may provide disease stabilization to CAR-T with a similar toxicity profile compared to NBT patients, although BT patients are more likely to experience prolonged cytopenias after CAR-T therapy. Disclosures Kansagra: Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics:Other: Advisory Board.Hardy:Incyte Corporation:Other: Advisory Board Member;American Gene Technologies:Other: DSMB Member;Kite/Gilead:Other: Advisory Board Member.

Gut Bacterial Diversity Associates with Efficacy of Anti-CD19 CAR T-Cell Therapy in Patients with Large B-Cell Lymphoma

Gut Bacterial Diversity Associates with Efficacy of Anti-CD19 CAR T-Cell Therapy in Patients with Large B-Cell Lymphoma

Significant Long-Term Benefits of CAR T-Cell Therapy Followed By a Second Allo-HSCT for Relapsed/Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (B-ALL) Patients Who Relapsed after an Initial Transplant

Introduction Current available treatments are limited once patients with B-ALL relapse following allogeneic hematopoietic stem cell transplantation (allo-HSCT). While chimeric antigen receptor (CAR) T-cell therapy offers a chance of remission, long-term outcomes for these patients remain poor. The benefit of bridging into a second transplant after CAR T-cell therapy remains inconclusive and available data are limited. Here, we report the long-term outcomes of 23 B-ALL patients who chose to undergo a second allo-HSCT after achieving complete remission (CR) from CAR T-cell therapy. Methods From April 2017 to April 2020, 23 R/R B-ALL patients (median age of 20 years, ranging from 3 to 58 years) who relapsed after first allo-HSCT received CAR T-cell therapy. The data were aggregated from seven different clinical trials (www.clinicaltrials.gov NCT03173417, NCT02546739 NCT03825718, NCT03825731, NCT03952923, NCT04100187 and www.chictr.org.cn ChiCTR1800016541). Patients' first transplant sources were HLA-identical sibling (n=5), matched-unrelated donor (MUD) (n=1), and haploidentical donors (haplo) (n=17). Eight of the 23 patients had disease relapse within 6 months following the first transplant. The median time from first transplant to CAR T-cell infusion was 261days (range: 117~2181 days). Before CAR T-cell infusion, patients' median bone marrow (BM) blasts by morphology were about 72.5% (1.5%-94.5%) including 12 patients with BM blasts >70% (5 with BM blasts >90%). Three of the 23 patients (13%) had received at least one prior donor lymphocyte infusion. No patients had active graft-versus-host disease (GVHD) prior to CAR T-cell therapy. Second generation CAR T-cells were generated by using purified T-cells from transplant donors (n=15) or patients (n=8). Twenty-two patients received T-cells modified with CD19-targeting CAR T-cells containing either a 4-1BB (n=18) or a CD28 co-stimulatory domain (n=4), and one patient received CD19-CD22 dual specificity CAR T-cells. All patients received a conditioning regimen of IV fludarabine (30mg/m2/d) and cyclophosphamide (250mg/m2/d) for 3 days followed by a single CAR T-cell infusion with a median dose of 3×105 cells/kg (1×105-6×105 cells/kg) in 21 patients. Two patients received a second CAR T-cell infusion in 2-3 months (1/3×105 cells/kg dose). Post CAR-T therapy, all patients bridged into a consolidation second transplantation with conventional myeloablative pre-transplantation conditioning regimens including 15 patients who received total body irradiation-based and 7 patients that received a busulfan-based conditioning regimen. Cyclosporin A, short-term methotrexate, and mycophenolate mofetil were used for GVHD prophylaxis. Results Patients' characteristics are shown in Table 1. On Day 30 post CAR-T-cell infusion, 23/23 (100%) patients achieved minimal residual disease (MRD)-negative CR. A total of 16/23 (69.6%) patients developed cytokine release syndrome (CRS) of which 14/23 (60.9%) had Grade I-II and 2/23 (8.7%) had Grade III CRS. Two patients had Grade III neurotoxicity. All patients with MRD-negative status subsequently bridged into a second transplant (2 from MUD and 21 from haplo donors) with a median interval time of 67 days (39- 329 days) from CAR T-cell therapy to a second transplant. At a median follow-up time of 258 days (84-978 days), no patients relapsed, which was encouraging. Five of 23 patients (21.7%) died from transplant-related mortality (TRM) at a median time of 295 days (103-372 days) (1 from GVHD and 4 from infection). The 1-year overall survival (OS) was 68.0% and 2-year OS was 54.4% (Fig.1). While there was a trend towards a more efficacious OS for patients whose CAR T-cells were derived from donors rather than from patients themselves but the number are too small to reach statistical significance (1-year OS 83.9% vs. 64.3%, 2-year OS 83.9% vs. 42.9%, P=0.739. Fig.2). After the 2nd transplant, four patients developed GVHD. Conclusions Our study demonstrates that even for R/R B-ALL patients who have relapsed following a first allo-HSCT , an MRD-negative CR status can still be achieved through CAR T-cell cell therapy without increasing CRS or neurotoxicity, making consolidation second allo-HSCT feasible for these patients. CAR T-cell therapy combined with a consolidation second HSCT are effective for these heavily pre-treated patients with an encouraging prospect for long-term survival. Disclosures No relevant conflicts of interest to declare.

Abstract PO-55: Single-center experience of chimeric antigen receptor T-cell (CAR-T) immunotherapy in relapsed/refractory large B-cell lymphoma identifies association of acute toxicities with inferior disease outcomes

Abstract Chimeric antigen receptor T (CAR-T) cells are an emerging approach for the treatment of hematologic and solid tumor malignancies. Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel were the first FDA-approved CAR-T therapies targeting CD19 for patients with relapsed/refractory (r/r) large B-cell lymphoma. Pivotal studies showed complete response (CR) rates of 58% and 40%, respectively, and we sought to investigate if the data are similar to our single-center results. We carried out a retrospective analysis of patients diagnosed with r/r diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, or mantle cell lymphoma who were treated with axi-cel or tisagenlecleucel at Sylvester Comprehensive Cancer Center in Miami, FL between January 2016 and October 2019. Primary objectives were to identify clinical characteristics associated with improved overall and progression-free survival (OS and PFS). Secondary analyses included incidence of post-CAR-T toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Our analysis included 44 patients: 32 received FDA-approved commercial product and 12 received axi-cel through clinical trials. Median age at time of CAR-T therapy was 62 years, and 70% of patients were male. Median number of prior treatments was 4, and 14 patients had undergone prior hematopoietic stem cell transplantation (12 autologous, 2 allogeneic). By day-30 post-treatment PET scan, 25 patients (57%) achieved CR or partial response (PR), while 16 (36%) had progressive (PD) or stable disease (SD). The remaining 3 patients decompensated rapidly post-infusion. Overall, patients with a CR or PR at 30 days had significantly improved OS and PFS compared to patients with PD or SD (OS p = 0.009, PFS p < 0.001). Univariate analyses showed patients requiring aggressive supportive measures in the post-infusion period had decreased OS compared to those who did not: requirement for ICU care (p = 0.018), vasopressor use (p = 0.01), and steroid treatment (p = 0.018) were all associated with inferior survival. There was no survival difference in DLBCL patients classified as double expressor or double hit; however, patients with germinal center B-cell (GCB) DLBCL trended strongly towards improved OS (p = 0.073) compared to non-GCB patients. CRS affected 35 patients (80%), while 24 patients (55%) experienced ICANS. Incidence of toxicities did not vary significantly in patients who received CAR-T commercially or in clinical trials. Patients who did not experience CRS had improved OS (p=0.061), and of patients who had CRS or ICANS, SD/PD patients had significantly worse PFS (p= <0.001, p= 0.024). This single-center retrospective analysis of patients receiving CAR-T therapy for r/r large B-cell lymphoma showed that incidence and management of toxicities and factors such as tumor subtype associate with treatment response. Further investigations into these factors may provide more insight into optimal management of patients undergoing CAR-T therapy. Citation Format: Fahmin Basher, Caroline A. Coughlin, Deukwoo Kwon, Lazaros Lekakis, Jonathan Schatz. Single-center experience of chimeric antigen receptor T-cell (CAR-T) immunotherapy in relapsed/refractory large B-cell lymphoma identifies association of acute toxicities with inferior disease outcomes [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-55.

Prolonged neurotoxicity in a lymphoma patient after CD19‐directed CAR T‐cell therapy: A case report and brief review of the literature

As the field of cancer therapeutics moves increasingly toward targeted and cellular therapies, this evolution comes with new hurdles. Toxicity of these therapies can result in serious adverse events that can become life-threatening. In particular, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are now the most common adverse effects resulting from chimeric antigen receptor (CAR) T-cell therapy. Furthermore, CAR T cells are reported to cause hyperactivation of macrophages, which in extreme cases results in hemophagocytic lymphohistiocytosis (HLH). These toxic effects result from cytokines released as a direct effect of the therapy. Physicians are evaluating inflammatory markers to monitor longitudinally cytokine stimulation and immune activation after therapy, which can help predict and gauge the severity of the cytokine storm. Prompt recognition of toxic effects and rapid intervention are essential in the management of patients receiving CAR T-cell therapy. Despite intervention, some patients still experience severe and prolonged ICANS. Herein we present a patient with lymphoma who developed prolonged ICANS and reviewed the literature on neurotoxicity and macrophage activation resulting from CD19-directed CAR T-cell therapy.

Recommendations for screening, monitoring, prevention, and prophylaxis of infections in adult and pediatric patients receiving CAR T-cell therapy: a position paper

Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising emerging treatments for B-cell malignancies. Recently, two CAR T-cell products (axicabtagene ciloleucel and tisagenlecleucel) have been approved for patients with aggressive B-cell lymphoma and acute lymphoblastic leukemia; many other CAR-T constructs are in research for both hematological and non-hematological diseases. Most of the patients receiving CAR-T therapy will develop fever at some point after infusion, mainly due to cytokine release syndrome (CRS). The onset of CRS is often indistinguishable from an infection, which makes management of these patients challenging. In addition to the lymphodepleting chemotherapy and CAR T cells, the treatment of complications with corticosteroids and/or tocilizumab increases the risk of infection in these patients. Data regarding incidence, risk factors and prevention of infections in patients receiving CAR-T cell therapy are scarce. To assist in patient care, a multidisciplinary team from hospitals designated by the Spanish Ministry of Health to perform CAR-T therapy prepared these recommendations. We reviewed the literature on the incidence, risk factors, and management of infections in adult and pediatric patients receiving CAR-T cell treatment. Recommendations cover different areas: monitoring and treatment of hypogammaglobulinemia, prevention, prophylaxis, and management of bacterial, viral, and fungal infections as well as vaccination prior and after CAR-T cell therapy.

Efficacy and safety of anti-CD19 CAR T-cell therapy in 110 patients with B-cell acute lymphoblastic leukemia with high-risk features

AbstractAnti-CD19 chimeric antigen receptor (CAR) T-cell therapy is effective in patients with advanced B-cell acute lymphoblastic leukemia (B-ALL). However, efficacy data is sparse in subgroups of patients with high-risk features such as BCR-ABL+, TP53 mutation, extramedullary disease (including central nervous system leukemia) or posttransplant relapse. It is also uncertain whether there is an added benefit of transplantation after anti-CD19 CAR T-cell therapy. We conducted a phase 1/2 study of 115 enrolled patients with CD19+ B-ALL. A total of 110 patients were successfully infused with anti-CD19 CAR T cells. In all, 93% of patients achieved a morphologic complete remission, and 87% became negative for minimal residual disease. Efficacy was seen across all subgroups. One-year leukemia-free survival (LFS) was 58%, and 1-year overall survival (OS) was 64% for the 110 patients. Seventy-five nonrandomly selected patients (73.5%) subsequently received an allogeneic hematopoietic stem cell transplant (allo-HSCT). LFS (76.9% vs 11.6%; P < .0001; 95% confidence interval [CI], 11.6-108.4) and OS (79.1% vs 32.0%; P < .0001; 95% CI, 0.02-0.22) were significantly better among patients who subsequently received allo-HSCT compared with those receiving CAR T-cell therapy alone. This was confirmed in multivariable analyses (hazard ratio, 16.546; 95% CI, 5.499-49.786). Another variate that correlated with worse outcomes was TP53 mutation (hazard ratio, 0.235; 95% CI, 0.089-0.619). There were no differences in complete remission rate, OS, or LFS between groups of patients age 2 to 14 years or age older than 14 years. Most patients had only mild cytokine release syndrome and neurotoxicity. Our data indicate that anti-CD19 CAR T-cell therapy is safe and effective in all B-ALL subgroups that have high-risk features. The benefit of a subsequent allo-HSCT requires confirmation because of nonrandom allocation. This trial was registered at www.clinicaltrials.gov as #NCT03173417.

Economic Evaluation of Chimeric Antigen Receptor T-Cell Therapy by Site of Care Among Patients With Relapsed or Refractory Large B-Cell Lymphoma

Chimeric antigen receptor (CAR) T-cell therapies are currently administered at a limited number of cancer centers and are primarily delivered in an inpatient setting. However, variations in total costs associated with these therapies remain unknown. To estimate the economic differences in the administration of CAR T-cell therapy by the site of care and the incidence of key adverse events. A decision-tree model was designed to capture clinical outcomes and associated costs during a predefined period (from lymphodepletion to 30 days after the receipt of CAR T-cell infusion) to account for the potential incidence of acute adverse events and to evaluate variations in total costs for the administration of CAR T-cell therapy by site of care. Cost estimates were from the health care practitioner perspective and were based on data obtained from the literature and publicly available databases, including the Healthcare Cost and Utilization Project National Inpatient Sample, the Medicare Hospital Outpatient Prospective Payment System, the Medicare physician fee schedule, the Centers for Medicare and Medicaid Services Healthcare Common Procedure Coding System, and the IBM Micromedex RED BOOK. The model evaluated an average adult patient with relapsed or refractory large B-cell lymphoma who received CAR T-cell therapy in an academic inpatient hospital or nonacademic specialty oncology network. The administration of CAR T-cell therapy. Total cost of the administration of CAR T-cell therapy by site of care. The costs associated with lymphodepletion, acquisition and infusion of CAR T cells, and management of acute adverse events were also examined. The estimated total cost of care associated with the administration of CAR T-cell therapy was $454 611 (95% CI, $452 466-$458 267) in the academic hospital inpatient setting compared with $421 624 (95% CI, $417 204-$422 325) in the nonacademic specialty oncology network setting, for a difference of $32 987. After excluding the CAR T-cell acquisition cost, hospitalization and office visit costs were $53 360 (65.3% of the total cost) in academic inpatient hospitals and $23 526 (48.4% of the total cost) in nonacademic specialty oncology networks. The administration of CAR T-cell therapy in nonacademic specialty oncology networks was associated with a $29 834 (55.9%) decrease in hospitalization and office visit costs and a $3154 (20.1%) decrease in procedure costs. The potential availability of CAR T-cell therapies that are associated with a lower incidence of adverse events and are suitable for outpatient administration may reduce the total costs of care by enabling the use of these therapies in nonacademic specialty oncology networks.

Psychosocial care for children receiving chimeric antigen receptor (CAR) T-cell therapy.

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). However, this new paradigm has introduced unique considerations specific to the patients receiving CAR T-cell therapy, including prognostic uncertainty, symptom management, and psychosocial support. With increasing availability, there is a growing need for evidence-based recommendations that address the specific psychosocial needs of the children who receive CAR T-cell therapy and their families. To guide and standardize the psychosocial care offered for patients receiving CAR T-cell therapy, we propose the following recommendations for addressing psychosocial support.

Differences in the Symptom Experience and Quality of Life of Children and Adolescents Undergoing Hematopoietic Stem Cell Transplantation Compared to Chimeric Antigen Receptor T-Cell Therapy

<h3>Background</h3> Allogeneic hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor (CAR) T-cell therapy are therapeutic options for children with recurrent or refractory malignancies. High symptom burden and poor quality of life (QoL) can occur secondary to these therapies. The purpose of this study is to compare the symptom, QoL trajectories of children undergoing allogeneic HSCT to those receiving CAR T-cell therapy. <h3>Methods</h3> A longitudinal, repeated measures design was used for this multi-site study. English or Spanish-speaking children ages 2-18 years with planned allogenic HSCT or CAR T-cell therapy were eligible. Children completed the Memorial Symptom Assessment Scale (MSAS) and the PedsQL Cancer Module at 4 timepoints: pre-HSCT or CAR T-cell infusion, and day+30, +60, +90 post. Parents completed corresponding parent proxy measures for younger children. Linear mixed effects models were used to test for associations between treatment (CAR-T vs allogenic HSCT) and child self-report outcomes. <h3>Results</h3> To date, 99 children were enrolled across 4 sites: 77 children received allogeneic HSCT, 22 received CAR T-cell therapy. Child mean age was 8.3 years (SD=4.9), 55.4% were male. Child symptom burden and QoL improved from pre-cell infusion through day +90 (Table 1). Child QoL was lowest and symptom burden was highest pre-cell infusion for children in both treatment groups. Children in the CAR-T group experienced significantly lower symptom burden compared to children undergoing allogeneic HSCT (p <.05) based on child self-report and parent proxy. Child QoL, based on both children self-report and parent proxy, did not significantly differ between based on the child's therapy type. <h3>Conclusion</h3> Children receiving allogeneic HSCT experience more frequent, severe and bothersome symptoms compared to children undergoing CAR T-cell therapy. Routine and comprehensive symptom assessment with multimodal interventions are needed to improve the symptom experience, particularly for children undergoing HSCT. Differences patient-reported outcomes, such as symptom burden, may be considered when discussing therapeutic options with patients and families.

Measuring the Effectiveness of CAR T-CELL Therapy Nursing Education

Topic Significance & Study Purpose/Background/Rationale Chimeric antigen receptor (CAR) T-Cell therapy standardized professional education is critical to help oncology team members understand the science behind this cellular immunotherapy and best practices for managing side effects. A multidisciplinary approach to education optimizes the focus of patient and caregiver centered care designed to meet not only the physical but emotional and educational needs. Interprofessional education (IPE) is thought to best prepare nurses and other health professionals for successful collaborative practice. Methods, Intervention, & Analysis Two short, highly interactive IPE 30-minute elearning modules were developed to serve as foundational CAR T-Cell therapy education for the five Sarah Cannon Blood Cancer Network Cellular Therapy Programs. The CAR T-Cell Therapy: A New Frontier module provides an overview of CAR T-Cell therapy, while the CAR T-Cell Therapy Toxicities module focuses on assessment and management of key side effects. Short term outcomes measurements assess current practice and intent to change practice immediately upon completion of the module. Findings & Interpretation The majority of participants included inpatient staff nurses, between the ages of 25-34 years of age with a bachelor's degree, and less than 3 years of oncology experience. Participants indicated an increase in confidence of understanding immune effector cell therapy and the process/timeline after completion of the Frontier module (N = 408) with 39% and 42% improvement respectively. After completion of the toxicity module (N = 195), there was significant intent to improve toxicity management (31% - 66%), patient education (33% - 64%), and psychosocial support (33-68%). Discussion & Implications Analysis at 3 months after the initial launch of these online modules demonstrates an improvement in self-reported knowledge. Evaluation is ongoing as more professionals complete the modules with over 1000 participant responses to be presented with the 2019 year-end data. Other outcomes measurements are being explored to measure the impact of this education. Overall, these modules are providing key information that nurses and other oncology team members need to care for patients receiving CAR T-Cell Therapy. These 2 modules are the first of a larger blood cancer oncology nursing curriculum aimed at standardizing education across a large network to improve outcomes for staff and patients.