Patients Receiving Chimeric Antigen Receptor T-cell Therapy Research Articles

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

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.

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.

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.

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.

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.

Acute Kidney Injury and Electrolyte Abnormalities After Chimeric Antigen Receptor T-Cell (CAR-T) Therapy for Diffuse Large B-Cell Lymphoma

Cytokine release syndrome is a well-known complication of chimeric antigen receptor T-cell (CAR-T) therapy and can lead to multiorgan dysfunction. However, the nephrotoxicity of CAR-T therapy is unknown. We aimed to characterize the occurrence, cause, and outcomes of acute kidney injury (AKI), along with the occurrence of electrolyte abnormalities, among adults with diffuse large B-cell lymphoma receiving CAR-T therapy. Case series. We reviewed the course of 78 adults receiving CAR-T therapy with axicabtagene ciloleucel or tisagenlecleucel at 2 major cancer centers between October 2017 and February 2019. Baseline demographics, comorbid conditions, medications, and laboratory values were obtained from electronic health records. AKI was defined using KDIGO (Kidney Disease: Improving Global Outcomes) criteria. The cause, clinical course, and outcome of AKI events and electrolyte abnormalities in the first 30 days after CAR-T infusion were characterized using data contained in electronic health records. Among 78 patients receiving CAR-T therapy, cytokine release syndrome occurred in 85%, of whom 62% were treated with tocilizumab. AKI occurred in 15 patients (19%): 8 had decreased kidney perfusion, 6 developed acute tubular necrosis, and 1 patient had urinary obstruction related to disease progression. Thosewith acute tubular necrosis and obstruction had the longest lengths of stay and highest 60-day mortality. Electrolyte abnormalities were common;hypophosphatemia, hypokalemia, and hyponatremia occurred in 75%, 56%, and 51% of patients, respectively. Small sample size; AKI adjudicated by retrospective chart review; lack of biopsy data. In this case series of patients with diffuse large B-cell lymphoma receiving CAR-T therapy, AKI and electrolyte abnormalities occurred commonly in the context of cytokine release syndrome.

Impact of Increasing Wait Times on Overall Mortality of Chimeric Antigen Receptor T-Cell Therapy in Large B-Cell Lymphoma: A Discrete Event Simulation Model.

The development of chimeric antigen receptor (CAR) T cells has transformed oncology treatment, with the potential to cure certain cancers. Although shown to be effective in selected populations and studies, CAR T-cell technology requires considerable health care resources, which may lead to additional wait times to access this type of treatment in future. The objective of our study was to estimate the potential impact of increasing wait times on CAR T-cell therapy effectiveness compared with standard chemotherapy for patients with relapsed/refractory diffuse large B-cell lymphoma. A health system-level discrete event simulation model was developed to project the potential impact of wait times on CAR T-cell therapy for patients with relapsed/refractory diffuse large B-cell lymphoma. Waiting queues and health states related to treatment and clinical progression were implemented. Using data from the literature, we evaluated nine scenarios of using CAR T-cell therapy with wait times ranging from 1 to 9 months. The outcome of interest was 1-year all-cause mortality. Increasing the wait time of receiving CAR T-cell therapy from 1 to 9 months increased the predicted 1-year mortality rate from 36.1% to 76.3%. Baseline 1-year mortality was 34.0% in patients receiving CAR T-cell therapy with no wait times and 75.1% in patients treated with chemotherapy. This resulted in an increased relative mortality rate of 6.2% to 124.5% over a 1- to 9-month wait time compared with no wait time. We found that modest delays in CAR T-cell therapy significantly hinder its effectiveness. Because CAR T-cell therapy offers a potential cure, it is expected that the uptake rate will be substantially increased once the therapy is regularly funded by a health care system. Wait times may be prolonged if system resource availability does not match the demand. Strategies must be developed to minimize the impact of delays and reduce complications during waiting.

An international survey on the management of patients receiving CAR T-cell therapy for haematological malignancies on behalf of the Chronic Malignancies Working Party of EBMT

Purpose of the studyTwo chimeric antigen receptor (CAR) T-cell therapies - Tisagenlecleucel (Kymriah™) and Axicabtagene ciloleucel (Yescarta™) - have been approved for commercial use. In order to inform forthcoming EBMT guidelines on the management of adults and children undergoing autologous CAR T-cell therapy, we undertook a survey of experienced clinicians. MethodsAn online survey with a dual focus on (1) ‘real world’ patient eligibility criteria and (2) models of care for patient follow-up was sent to experienced physicians. ResultsThere were 41 respondents (10 countries) and 93% worked in FACT-JACIE-accredited transplant centres. Most felt that a history of malignancy (57%), prior allo-HCT for B-NHL (78%–81%) and prior treatment with anti-CD19/CD3 BiTE antibodies (76%–86%) do not constitute contra-indications to CAR T therapy. Clinicians were divided as to whether CNS involvement represented an exclusion criterion. There was agreement that patients with viral infections (HIV, Hepatitis B or Hepatitis C) are not eligible. There is no common model of care for long-term follow-up. Most respondents believed that patients should attend the hospital two (43%) to three (33%) times weekly during the first month following discharge. A majority (69%) of respondents work in centres where there is an MDT meeting with a specific focus on follow-up following CAR T Therapy. Follow-up care is currently delivered either in HCT or haematology-oncology outpatient clinics. ConclusionThe responses reveal wide variation in perceived patient eligibility criteria and highlight the need for consensus guidelines. The findings also illustrate the embryonic nature of current follow-up arrangements.

Receptor-triggered lymphocyte apoptosis PC to replace Cy/Flu PC for CART.

e14011 Background: Chimeric antigen receptor T-cell (CAR-T) therapy is a relatively novel regimen for the treatment of acute lymphoblastic leukemia that has already shown promising results. Two FDA-approved CAR-T therapies, Kymriah and Yescarta have an 80% success rate in sending patients into remission. However, both of these treatments require preconditioning (PC) with chemotherapy to ensure CarT expansion and engraftment. Chemotherapy severely compromises patient’s immune-system, a further economic burden up to $70K per patient due to hospitalization, and fuels side effects of CAR-T therapy such as cytokine release syndrome (CRS) and neuroedema, driven by the release of IL-6 and GM-CSF respectively. Also, up to one third of cancer patients are too frail to tolerate chemotherapy and do not qualify for potentially life-saving therapies. A single acute dose of AVM0703 induces lymphodepletion equivalent to chemotherapy, and transiently eliminates the sites in the spleen where therapeutic cells accumulate without inducing toxicities associated with chemotherapy. Methods: Mice with subcutaneously implanted melanoma were preconditioned with AVM0703 prior to treatment with a mouse Pmel CAR-T therapy. Tumor growth was tracked and spleens were analyzed after dissection for binding of labeled CAR-T cells. In a separate study, four human patients were dosed with low doses of AVM0703 and the levels of released cytokines in the blood were quantified. Results: The mice demonstrated reduced T-cell sequestration in the spleen as noted by a reduction of fluorescently labeled cells. AVM0703 alone significantly delayed tumor growth, and as PC before Pmel T-cells, dramatically improved CAR-T-driven delay of tumor growth. In humans, a significant increase in beneficial IL-2 and IL-15 was observed, as well as a lack of released IL-6. In addition, existing literature demonstrate that AVM0703 reduces the release of GM-CSF. Conclusions: AVM0703 shows efficacy as preconditioning agent in a mouse solid tumor model of melanoma, reduces the binding of CAR-T cells in the spleen, and stimulates the release of beneficial cytokines. AVM0703 could be a non-toxic, effective preconditioning agent for patients receiving CAR-T therapy.

Educating Multidisciplinary Care Teams, Patients, and Caregivers on CAR T-Cell Therapy.

Two anti-CD19 chimeric antigen receptor (CAR) T-cell therapies are approved for adults with relapsed or refractory large B-cell lymphoma after more than two lines of therapy. Although CAR T-cell therapy has demonstrated significant efficacy for some patients, the treatment process can be long and complex and each phase is associated with unique challenges. Care for patients receiving CAR T-cell therapy also involves many health-care players, including physicians, advanced practitioners, nurse coordinators, nurse educators, apheresis nurses, inpatient and outpatient nurses, cellular therapy technologists, case managers, social workers, and many more. Dedicated educational efforts for patients, caregivers, and clinical providers that make up the multidisciplinary care team are warranted for optimal treatment. Here we present an overview of key elements for education along the treatment journey with CAR T-cell therapy, including considerations for each stage of therapy and specific recommendations for care teams, patients, and caregivers. We also present examples of educational programs that have been implemented at our institution.

Sublingual Microcirculatory Imaging As a Novel Tool to Monitor for Cytokine Release Syndrome after Chimeric Antigen Receptor T-Cell Therapy

Background:Chimeric antigen receptor T-cell (CAR-T) therapy is an FDA-approved therapy for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL). A common side effect of CAR-T therapy is cytokine release syndrome (CRS), and its severity ranges from mild to severe, and occasionally resulting in death. Patients at particularly high risk for severe CRS may benefit from earlier supportive care and rescue therapies, such as tocilizumab. Although the median onset of CRS has been reported as two days, no existing prognostic tools adequately assist the bedside clinician with triaging which patients will decompensate and warrant escalation of care. For example, biomarkers such as CRP and ferritin are ineffective in predicting CRS severity. Evaluation of the sublingual microcirculation of patients receiving CAR-T therapy may serve as a valuable surveillance tool.The sublingual microcirculation (defined as blood vessels <20um) has been investigated clinically in various inflammatory settings (e.g., sepsis, hemorrhage, surgery). Persistent alterations in microcirculatory flow correlate with worse clinical outcomes. We have used a handheld dark-field microscope, the Cytocam (Bradeus, Netherlands) to image and analyze the sublingual microcirculation of patients receiving CAR-T therapy.Methods:Video images are collected in real time. Prior to interpretation, all video clips were assessed for quality based on the current microcirculation consensus document. Each acceptable clip was then analyzed by using two point-of-care (POC) scoring systems: 1) the microvascular flow index (MFI) and 2) the point-of-care microcirculation (POEM) score. The MFI is determined by dividing the video monitor into four equal quadrants and grading the overall flow of each quadrant with a score from 0-3 (0 = no flow; 1 = intermittent flow; 2 = sluggish flow; 3 = normal flow). The POEM score utilizes an ordinal 1-5 scale (1 = critically impaired; 2 = impaired; 3 = normal with marked heterogeneity; 4 = normal with mild heterogeneity; 5 = normal) that is a composite of four measurements assessing flow impairment and heterogeneity. For each enrolled patient, a baseline measurement was made immediately prior to CAR-T cell infusion with follow up measurements occurring every six hours beginning at hour 18 after cell infusion until hour 72. After hour 72, measurements were made daily until they were deemed no longer at risk for CRS.Results:At this time there is mature data on 7 patients. All patients received Axicabtagene Ciloleucel- a CD19 directed CAR-T cell therapy (Yescarta, Kite Pharma). All patients had normal baseline microcirculation (MFI > 2.6, POEM=5) and normal or near-normal microcirculation at the end of the study period. No patients developed severe CRS (grade 3 and above). Three patients developed grade 2 CRS that required tocilizumab. Patients #1 and #2 both had significant microcirculatory impairments ≥12 hours prior to developing symptoms severe enough to warrant tocilizumab. Patient #3 had normal microcirculation through the first four days of therapy and developed hypotension on day six. We captured a subtle change from a normal MFI and POEM score to mild impairment with both scoring algorithms on day five, one day prior to clinical manifestations of decompensation. For logistical reasons, subsequent data were unable to be obtained. MFI and POEM scores for all patients are listed below in Table 1. The remaining four patients developed grade 1 CRS with associated mild microcirculatory changes.Conclusions:In this pilot study, POC microcirculatory assessments were successfully used to monitor patients undergoing CAR-T therapy. Patients with more severe CRS manifested lower MFI and POEM scores and maintained their nadir longer than those with milder CRS. Our data suggest that CAR-T patients developing CRS manifest early signs of sublingual microcirculatory dysfunction. Moreover, these microcirculatory defects present prior to the development of standard clinical abnormalities, such as macrocirculatory derangements. While further investigation is ongoing, this tool could be used for earlier identification of patients at risk for CRS in order to deliver earlier appropriate therapies, and ultimately to improve patient outcomes. DisclosuresNo relevant conflicts of interest to declare.

Tisagenlecleucel: The First CAR on the Highway to Remission for Acute Lymphoblastic Leukemia

Tisagenlecleucel is a first-in-class chimeric antigen receptor (CAR) T-cell therapy approved by the US Food and Drug Administration in 2017 for relapsed/refractory (RR) acute lymphoblastic leukemia (ALL) in patients up to 25 years of age. Tisagenlecleucel is an autologous T-cell therapy that is genetically engineered with a lentiviral vector to seek and eliminate CD19-expressing B cells throughout the patient's body and retain antitumor immune surveillance following remission. This groundbreaking cellular therapy brings unprecedented single-agent efficacy to patients with RR ALL, citing complete response rates of greater than 80% and 6-month relapse-free survivals exceeding 60% in a patient population with poor prognosis and few treatment options. Patients receiving CAR T-cell therapy are at risk for cytokine release syndrome (CRS), neurotoxicity, and infections, along with other toxicities that may be severe or life-threatening. The cornerstone of the management of moderate to severe CRS is treatment with the interleukin-6 antagonist tocilizumab, with dramatic responses often occurring within 24 hours. The optimal management of neurotoxicity following tisagenlecleucel remains undefined. It is critical that providers caring for patients receiving tisagenlecleucel understand the multistep process to prepare a patient for therapy, how to closely monitor patients for toxicity, and how to manage emergent adverse events following cell infusion.