Understanding and Managing Large B Cell Lymphoma Relapses after Chimeric Antigen Receptor T Cell Therapy

Byrne, Michael; Oluwole, Olalekan O.; Savani, Bipin N.; Majhail, Navneet S.; Hill, Brian T.; Locke, F.

doi:10.1016/j.bbmt.2019.06.036

Cited by 68 publications

(52 citation statements)

References 66 publications

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“…CR is achieved in approximately 30% to 40% of patients [1,2,4]; thus, 60% to 70% of patients are expected to experience disease progression or relapse after CAR-T therapy. The mechanism of CAR-T failure that is best understood in NHL is loss of CD19 expression, whereas preliminary work has also implicated CAR-T exhaustion as a potential mechanism [2,23,[83][84][85][86]. Unlike chronic lymphocytic leukemia, failure of CAR-Ts because of poor expansion is a less common reason for treatment failure in aggressive B cell lymphomas.…”

Section: Treatment Options For Patients With Progression Of Disease Omentioning

confidence: 99%

Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy

Jain

Bar

Kansagra

et al. 2019

Biology of Blood and Marrow Transplantation

Self Cite

155

121

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

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Section: Treatment Options For Patients With Progression Of Disease Omentioning

confidence: 99%

Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy

Jain

Bar

Kansagra

et al. 2019

Biology of Blood and Marrow Transplantation

Self Cite

155

121

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“…CD19-targeted chimeric antigen receptor modified T-cell immunotherapy (CD19 CAR T cells) has shown excellent antitumor activity in patients with relapsed/refractory acute lymphoblastic leukemia (ALL) [1] and non-Hodgkin lymphoma (NHL) [2,3], which led to the approval of tisagenlecleucel (Kymriah, Novartis; New Jersey, USA) and axicabtagene ciloleucel (Yescarta, (Kite (A Gilead Company); Santa Monica, CA, USA) by regulatory agencies in the United States, Europe, Canada, Japan, and Australia. This approval has transformed the care of patients with relapsed/refractory ALL and aggressive B cell NHL [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Patient-Reported Neuropsychiatric Outcomes of Long-Term Survivors after Chimeric Antigen Receptor T Cell Therapy

Ruark

Mullane

Cleary

et al. 2020

Biology of Blood and Marrow Transplantation

116

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CD19-targeted chimeric antigen receptor (CAR) modified T cell immunotherapy is a novel treatment with promising results in patients with relapsed/refractory lymphoid malignancies. CAR T cell therapy has known early toxicities of cytokine release syndrome and neurotoxicity, but little is known about long-term neuropsychiatric adverse effects. We have used patient-reported outcomes, including Patient-Reported Outcomes Measurement Information System (PROMIS) measures, to assess neuropsychiatric and other patient-reported outcomes of 40 patients with relapse/ refractory chronic lymphocytic leukemia, non-Hodgkin lymphoma, and acute lymphoblastic leukemia 1 to 5 years after treatment with CD19-targeted CAR T cells. Mean T scores of PROMIS domains of global mental health, global physical health, social function, anxiety, depression, fatigue, pain, and sleep disturbance were not clinically meaningfully different from the mean in the general US population. However, 19 patients (47.5%) reported at least 1 cognitive difficulty and/or clinically meaningful depression and/or anxiety, and 7 patients (17.5%) scored 40 in global mental health, indicating at least 1 standard deviation worse than the general population mean. Younger age was associated with worse long-term global mental health (P = .02), anxiety (P = .001), and depression (P= .01). Anxiety before CAR T cell therapy was associated with increased likelihood of anxiety after CAR T cell therapy (P = .001). Fifteen patients (37.5%) reported cognitive difficulties after CAR T cell therapy. Depression before CAR T cell therapy was statistically significantly associated with higher likelihood of self-reported post-CAR T cognitive difficulties (P = .02), and there was a trend for an association between acute neurotoxicity and self-reported post-CAR T cognitive difficulties (P = .08). Having more post-CAR T cognitive difficulties was associated with worse global mental health and global physical health. Our study demonstrates overall good neuropsychiatric outcomes in 40 long-term survivors after CAR T cell therapy. However, nearly 50% of patients in the cohort reported at least 1 clinically meaningful negative neuropsychiatric outcome (anxiety, depression, or cognitive difficulty), indicating that a significant number of patients would likely benefit from mental health services following CAR T cell therapy. Younger age, pre-CAR T anxiety or depression, and acute neurotoxicity may be risk factors for long-term neuropsychiatric problems in this patient population. Larger studies are needed to confirm these findings.

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“…Relapses following CAR T unrelated to antigen escape are often due to limited persistence secondary to exhaustion, in part due to upregulated PD-1. 67 PD-1 antagonism with pembrolizumab in 12 patients with RR NHL relapsing following tisa-cel resulted in CAR T re-expansion in 75%, an ORR of 27%, and a CR rate of 17%. 68 Similar results occurred with pembrolizumab or nivolumab post-tisa-cel in children with ALL.…”

Section: Cd30 (Investigational)mentioning

confidence: 96%

Advances in CAR T Therapy for Hematologic Malignancies

Freyer

Porter

2020

Pharmacotherapy

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The introduction of chimeric antigen receptor T‐cell (CAR T) therapy has resulted in a paradigm shift in the management of relapsed/refractory B‐cell malignancies. Patients with acute lymphoblastic leukemia and non‐Hodgkin’s lymphoma who had exhausted all meaningful treatment options now have an opportunity for long‐term remission and possibly cure. CAR T is rapidly expanding into the treatment paradigm for multiple myeloma with approvals expected in the near future. CAR T for chronic lymphocytic leukemia may not be far behind, while CAR T studies in Hodgkin lymphoma and acute myeloid leukemia are ongoing. Such therapeutic success brings challenges in toxicity management related to cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome. Our understanding of these unique syndromes is evolving, with predictive models and additional treatment strategies on the horizon. This review aims to summarize the progress of CAR T therapeutics within malignant hematology thus far and highlight ongoing advances in the field.

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Understanding and Managing Large B Cell Lymphoma Relapses after Chimeric Antigen Receptor T Cell Therapy

Cited by 68 publications

References 66 publications

Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy

Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy

Patient-Reported Neuropsychiatric Outcomes of Long-Term Survivors after Chimeric Antigen Receptor T Cell Therapy

Advances in CAR T Therapy for Hematologic Malignancies

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