Prognostic impact of corticosteroids on efficacy of chimeric antigen receptor T-cell therapy in large B-cell lymphoma.

Corticosteroids are commonly used for the management of severe toxicities associated with chimeric antigen receptor (CAR) T-cell therapy. However, it remains unclear whether their dose, duration, and timing may affect clinical efficacy. Here, we determined the impact of corticosteroids on clinical outcomes in patients with relapsed or refractory large B-cell lymphoma treated with standard of care anti-CD19 CAR T-cell therapy. Among 100 patients evaluated, 60 (60%) received corticosteroids for management of CAR T-cell therapy-associated toxicities. The median cumulative dexamethasone-equivalent dose was 186 mg (range, 8-1803) and the median duration of corticosteroid treatment was 9 days (range, 1-30). Corticosteroid treatment was started between days 0 and 7 in 45 (75%) patients and beyond day 7 in 15 (25%). After a median follow-up of 10 months (95% confidence interval, 8-12 months), use of higher cumulative dose of corticosteroids was associated with significantly shorter progression-free survival. More importantly, higher cumulative dose of corticosteroids, and prolonged and early use after CAR T-cell infusion were associated with significantly shorter overall survival. These results suggest that corticosteroids should be used at the lowest dose and for the shortest duration and their initiation should be delayed whenever clinically feasible while managing CAR T-cell therapy-associated toxicities.

Effect of delayed cell infusion in patients with large B-cell lymphoma treated with chimeric antigen receptor T-cell therapy.

Complications occurring after lymphodepleting chemotherapy (LDC) may delay chimeric antigen receptor (CAR) T-cell infusion. The effect of these delays on clinical outcomes is unclear. We performed a retrospective analysis of 240 patients with relapsed/refractory large B-cell lymphoma treated with standard-of-care axicabtagene ciloleucel (axi-cel) and identified 40 patients (16.7%) who had delay in axi-cel infusion. Of these, 85% had delay due to infection. At time of LDC initiation, patients with delayed infusion had lower absolute neutrophil count (p=0.006), lower platelets (p=0.004), lower hemoglobin (p5 days (4.6 vs. 8.2 months; p=0.036), but not 1 day (5.7 vs. 8.2 months; p=0.238). Following propensity score matching, patients with delayed infusion continued to have shorter median PFS (3.5 vs. 6.0 months; p=0.015). Levels of proinflammatory cytokines on day of infusion were significantly higher in patients with delayed infusion. Together, these findings suggest that delays in CAR T-cell administration after initiation of LDC are associated with inferior outcomes. Further studies are needed to guide strategies to improve efficacy in such patients.

Hematopoietic recovery and immune reconstitution after axicabtagene ciloleucel in patients with large B-cell lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 may be associated with long-term adverse effects such as cytopenia and immune deficiency. In order to characterize these late events, we analyzed 31 patients with relapsed or refractory large B-cell lymphoma treated with axicabtagene ciloleucel at our institution on two clinical trials, ZUMA-1 (clinicaltrials gov. Identifier: NCT02348216) and ZUMA-9 (clinicaltrials gov. Identifier: NCT03153462). Complete blood counts, lymphocyte subsets, and immunoglobulin levels were measured serially until month 24 or progression. Fifteen (48%) patients had grade 3-4 cytopenia, including anemia (five, 16%), neutropenia (nine, 29%), or thrombocytopenia (13, 42%) at day 30. Cytopenia at day 30 was not significantly associated with later diagnosis of myelodysplasia. Among patients with ongoing remission, grade 3-4 cytopenia was observed in one of nine (11%) at 2 years. While peripheral CD8+ T cells recovered early, CD4+ T-cell recovery was delayed with a count of <200/mL in three of nine (33%) patients at 1 year and two of seven (29%) at 2 years. Immunoglobulin G levels normalized in five of nine (56%) patients at 2 years. Thirteen (42%) patients developed grade 3-4 infectious complications, including herpes zoster and Pneumocystis jiroveci pneumonia. These results suggest the need for prolonged monitoring and prophylaxis against opportunistic infections in these patients, to improve the longterm safety of axicabtagene ciloleucel therapy.

Medical Error: Using Storytelling and Reflection to Impact Resident Error Response Factors.

Introduction: Medical error is common and has a significant impact on physicians, learners, and patients' perception of the medical system; however, residents receive little formal training on this topic. This curriculum aims to foster sharing of personal medical error stories, review and practice error management and coping strategies, and impact error response factors. Methods: Faculty identified factors related to effective physician error management and recovery in order to develop a targeted curriculum for family medicine residents. The curriculum consisted of three 1-hour didactic sessions in a medium-sized, urban program. Instructional methods included guided reflection after mentor storytelling, small-group discussion, role-play, and self-reflection. Results: Twenty-two out of 30 (73%) residents completed the premodule survey, and 15 out of 30 (50%) residents completed the post module survey. Fewer than half of residents reported they knew what to do when faced with medical error, but this increased to 93% after curriculum delivery, as did rates of reported error story sharing. Resident reported self-efficacy (I can be honest about the errors I make as a doctor.) and self-awareness (I acknowledge when I am at increased risk for making errors) also increased following the curriculum. Discussion: Family medicine residents are receptive to learning from peers and mentors about error management and recovery. A brief curriculum can impact the culture around disclosure and support. Future iterations should focus on the impact of targeted curricular interventions on patient-oriented outcomes related to medical error.

Medical Error: Using Storytelling and Reflection to Impact Error Response Factors in Family Medicine Residents.

I am a healer, yet sometimes I do more harm than good…David Hilfiker, 1984. Objectives: Medical error is common and significantly impacts patients, physicians, learners, and public perception of the medical system; however, residents receive little formal training on this topic. Research on error response in practicing physicians is limited, and even more so on medical education interventions to improve this. This study evaluates a curriculum developed to foster the sharing of faculty medical error stories, practice of constructive coping strategies, and growth in resident confidence in managing error. Methods: Researchers identified factors related to effective physician error management and recovery to develop a targeted intervention for family medicine residents. The intervention consisted of three one hour didactic sessions in a medium-sized midwestern, urban family medicine residency program over the course of 6 months. Instructional methods included guided reflection after mentor storytelling, small group discussion, role play, and self-reflection. Results: Of the 30 residents, 22 (73%) completed the preintervention survey, and 15 (50%) completed the postintervention survey. While most residents reported having experienced error (55%), fewer than half of the residents reported they knew what to do when faced with medical errors (46%). This increased to 93% after intervention. Personal error stories from mentors were the most desired type of training reported by residents preintervention, but this was surpassed by legal and malpractice concerns in the postintervention survey. Rates of reported error story sharing increased after the intervention. Residents reported self-efficacy (I can be honest about errors) and self-awareness (I acknowledge when I am at increased risk for error) also increased with intervention. However, these changes did not reach statistical significance. Conclusions: Family medicine residents are receptive to learning from peers and mentors about error management and recovery. A brief intervention can impact the culture around disclosure and support. Future research should focus on the impact of targeted interventions on patient-oriented outcomes related to medical error.

Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline.

PURPOSE: To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with chimeric antigen receptor (CAR) T-cell therapy. METHODS: A multidisciplinary panel of medical oncology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to develop the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 to 2021. RESULTS: The systematic review identified 35 eligible publications. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS: The multidisciplinary team issued recommendations to aid in the recognition, workup, evaluation, and management of the most common CAR T-cell-related toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, B-cell aplasia, cytopenias, and infections. Management of short-term toxicities associated with CAR T cells begins with supportive care for most patients, but may require pharmacologic interventions for those without adequate response. Management of patients with prolonged or severe CAR T-cell-associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid. On the basis of the potential for rapid decline, patients with moderate to severe immune effector cell-associated neurotoxicity syndrome should be managed with corticosteroids and supportive care.Additional information is available at www.asco.org/supportive-care-guidelines.

Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.

PURPOSE: To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) therapy. METHODS: A multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 through 2021. RESULTS: A total of 175 studies met the eligibility criteria of the systematic review and were pertinent to the development of the recommendations. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS: Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to the organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, except for some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert ≤ grade 1. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids. Corticosteroids should be tapered over the course of at least 4-6 weeks. Some refractory cases may require other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines.

Recognizing and Grading CAR T-Cell Toxicities: An Advanced Practitioner Perspective.

Over the past decade, chimeric antigen receptor (CAR) T-cell therapy has significantly improved the outlook for many patients with relapsed and/or refractory B-cell malignancies. The use of CAR T-cell therapy and other therapeutic immune effector cells will likely continue to expand with the development of other targets and use in solid tumors. Although these therapies have shown significant promise in the treatment of some malignancies, they can be associated with unique toxicities including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome which can be fatal if not identified early and treated appropriately. An understanding of how best to manage the toxicities associated with CAR T-cell therapy is continually evolving. Institutions providing CAR T-cell therapy have undergone changes in infrastructure and staffing models in order to safely care for patients receiving this novel therapy. As members of a multi-disciplinary health care team, advanced practice providers play significant roles in caring for this patient population and must be well-versed in the recognition, grading, and appropriate management of CAR T-cell therapy-related toxicities as these providers care for patients in multiple settings across the continuum of care.

Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lymphoma.

The recent development and clinical implementation of novel immunotherapies for the treatment of Hodgkin and non-Hodgkin lymphoma have improved patient outcomes across subgroups. The rapid introduction of immunotherapeutic agents into the clinic, however, has presented significant questions regarding optimal treatment scheduling around existing chemotherapy/radiation options, as well as a need for improved understanding of how to properly manage patients and recognize toxicities. To address these challenges, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in lymphoma to develop a clinical practice guideline for the education of healthcare professionals on various aspects of immunotherapeutic treatment. The panel discussed subjects including treatment scheduling, immune-related adverse events (irAEs), and the integration of immunotherapy and stem cell transplant to form recommendations to guide healthcare professionals treating patients with lymphoma.

Bridging therapy prior to axicabtagene ciloleucel for relapsed/refractory large B-cell lymphoma.

The impact of bridging therapy (BT) administered between leukapheresis and chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL) is unclear. We evaluated the influence of BT (systemic therapy [ST], radiation therapy [RT], or combined-modality therapy [CMT]) on outcomes of 148 LBCL patients who underwent leukapheresis for planned axicabtagene ciloleucel (axi-cel) infusion. The 55% (n = 81) of patients who received BT were more likely to have international prognostic index (IPI) score ≥3 (P ≤ .01), bulky disease (P = .01), and elevated lactate dehydrogenase (LDH; P ≤ .01). The 1-year progression-free (PFS) and overall survival (OS) rates were 40% and 65% in non-BT patients vs 21% and 48% in BT patients (P = .01 and .05, respectively). Twenty-four patients (16%) did not receive axi-cel, most commonly because of lymphoma progression (88%), despite 80% (n = 19) receiving BT. Among 124 patients who received axi-cel, 50% (n = 62) received BT with ST (n = 45), RT (n = 11), or CMT (n = 6); 1-year PFS and OS rates were not significantly different between BT and non-BT cohorts (P = .06 and .21, respectively). There was no difference in proportion of patients with IPI ≥3, limited-stage disease, or elevated LDH between ST, RT, and CMT groups. Compared with non-BT patients, 1-year PFS was inferior for ST-bridged patients (P = .01). RT-bridged patients had improved PFS compared with ST-bridged patients (P = .05). Despite the poor prognosis associated with requiring BT, RT can be an effective bridging strategy. Future studies are necessary to identify strategies that may improve access to CAR T-cell therapy and outcomes.

Clinical and radiologic correlates of neurotoxicity after axicabtagene ciloleucel in large B-cell lymphoma.

Neurotoxicity or immune effector cell-associated neurotoxicity syndrome (ICANS) is the second most common acute toxicity after chimeric antigen receptor (CAR) T-cell therapy. However, there are limited data on the clinical and radiologic correlates of ICANS. We conducted a cohort analysis of 100 consecutive patients with relapsed or refractory large B-cell lymphoma (LBCL) treated with standard of care axicabtagene ciloleucel (axi-cel). ICANS was graded according to an objective grading system. Neuroimaging studies and electroencephalograms (EEGs) were reviewed by an expert neuroradiologist and neurologist. Of 100 patients included in the study, 68 (68%) developed ICANS of any grade and 41 (41%) had grade ≥3. Median time to ICANS onset was 5 days, and median duration was 6 days. ICANS grade ≥3 was associated with high peak ferritin (P = .03) and C-reactive protein (P = .001) levels and a low peak monocyte count (P = .001) within the 30 days after axi-cel infusion. Magnetic resonance imaging was performed in 38 patients with ICANS and revealed 4 imaging patterns with features of encephalitis (n = 7), stroke (n = 3), leptomeningeal disease (n = 2), and posterior reversible encephalopathy syndrome (n = 2). Abnormalities noted on EEG included diffuse slowing (n = 49), epileptiform discharges (n = 6), and nonconvulsive status epilepticus (n = 8). Although reversible, grade ≥3 ICANS was associated with significantly shorter progression-free (P = .02) and overall survival (progression being the most common cause of death; P = .001). Our results suggest that imaging and EEG abnormalities are common in patients with ICANS, and high-grade ICANS is associated with worse outcome after CAR T-cell therapy in LBCL patients.

The Role of Advanced Practitioners in Optimizing Clinical Management and Support of Patients With Cytokine Release Syndrome From CAR T-Cell Therapy.

CAR T-cell therapy is rapidly emerging as a promising treatment for many hematologic malignancies. However, CAR T cells can be associated with unique toxicities, including cytokine release syndrome (CRS), which can be severe or fatal if not recognized promptly and treated appropriately. Therefore, it is essential that advanced practitioners caring for patients who have received CAR T-cell therapy to be knowledgeable regarding the signs and symptoms of CRS and understand how to grade and manage toxicities. Understanding the risk factors that may be associated with the development of toxicities as well as the incidence, severity, and timing of CRS with different CAR T-cell products will allow for earlier recognition and treatment, and therefore improvement of outcomes in patients receiving this novel therapy.

CAR T-Cell Therapy: Adverse Events and Management.

Chimeric antigen receptor (CAR) T-cell therapy is an exciting innovation in the treatment of cancer. However, CAR T-cell therapies have been associated with unique adverse events (AEs), including cytokine release syndrome (CRS) and neurologic events (also known as CAR T-cell-related encephalopathy syndrome [CRES] or, most recently, immune effector cell-associated neurotoxicity syndrome [ICANS]). Cytopenias and infection have also been observed. These AEs are treatable and reversible with appropriate treatment strategies but can become severe if not managed early. Therefore, it is essential for the advanced practitioner caring for patients undergoing these therapies to have a thorough understanding of the associated AEs, in particular their grading and management. Cytokine release syndrome and neurologic events can range in severity from low-grade symptoms that require supportive care only to a high-grade syndrome that can become life-threatening. While several grading and management recommendations have been used in clinical trials, until recently, there were no consistent grading and management guidelines. Here we provide the most recent recommendations, which have the ultimate goal of maintaining the benefits of CAR T-cell therapy, while minimizing life-threatening AEs. Improved understanding and management of AEs associated with CAR T-cell therapy will provide broader access to this innovative and potentially curative technology.

Adult Survivorship: Considerations Following CAR T-Cell Therapy.

BACKGROUND: Significant improvement in overall survival observed in patients on clinical trials and U.S. Food and Drug Administration approval of two chimeric antigen receptor (CAR) T-cell therapies have resulted in an increasing population of survivors who have undergone this therapy. Although adult survivors may experience similar physiologic and psychosocial sequelae to traditional cancer therapies, unique late effects and considerations are related to CAR T-cell therapy. OBJECTIVES: This article reviews survivorship considerations, with particular attention paid to the physical, psychosocial, and financial effects for adults who have undergone CAR T-cell therapy. METHODS: A review of the physiologic and psychosocial sequelae resulting from CAR T-cell therapy is presented, with a focus on late effects and financial toxicities of treatment. Physiologic concerns include B-cell aplasia and resulting hypogammaglobulinemia, as well as prolonged cytopenias and associated risk for infection. FINDINGS: To date, adult CAR T-cell therapy survivorship data are limited. However, data from clinical trials suggest expected late effects from treatment. As this survivor population grows, research can identify physiologic and psychosocial needs unique to adult survivors and evaluate evidence-based interventions.

Chimeric antigen receptor T-cell therapy - assessment and management of toxicities.

Immunotherapy using T cells genetically engineered to express a chimeric antigen receptor (CAR) is rapidly emerging as a promising new treatment for haematological and non-haematological malignancies. CAR-T-cell therapy can induce rapid and durable clinical responses, but is associated with unique acute toxicities, which can be severe or even fatal. Cytokine-release syndrome (CRS), the most commonly observed toxicity, can range in severity from low-grade constitutional symptoms to a high-grade syndrome associated with life-threatening multiorgan dysfunction; rarely, severe CRS can evolve into fulminant haemophagocytic lymphohistiocytosis (HLH). Neurotoxicity, termed CAR-T-cell-related encephalopathy syndrome (CRES), is the second most-common adverse event, and can occur concurrently with or after CRS. Intensive monitoring and prompt management of toxicities is essential to minimize the morbidity and mortality associated with this potentially curative therapeutic approach; however, algorithms for accurate and consistent grading and management of the toxicities are lacking. To address this unmet need, we formed a CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising investigators from multiple institutions and medical disciplines who have experience in treating patients with various CAR-T-cell therapy products. Herein, we describe the multidisciplinary approach adopted at our institutions, and provide recommendations for monitoring, grading, and managing the acute toxicities that can occur in patients treated with CAR-T-cell therapy.

Success factors in the long-term sustainability of a telediabetes programme.

We studied a telediabetes programme that had been in operation for 10 years, to identify the factors in its sustainability. We reviewed archive documents, conducted interviews with programme administrators and primary care providers, observed diabetes consultations and surveyed patient satisfaction. Three success factors were identified: the administration took a long-term view of the value of the telemedicine service; telediabetes enabled structured use of staff time and facilities; and service delivery followed national diabetes standards and a well defined cycle of care within a long-term quality improvement programme. However, the present study did not address the three other key theoretical dimensions of systems design beyond sustainability: size, scalability and scope.