Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma

Wudhikarn, Kitsada; Palomba, M. Lia; Pennisi, Martina; García‐Recio, Marta; Flynn, Jessica; Devlin, Sean M.; Afuye, Aishat Olaide; Silverberg, Mervin; Maloy, Molly; Shah, Gunjan L.; Scordo, Michael; Dahi, Parastoo B.; Sauter, Craig S.; Batlevi, Connie Lee; Santomasso, Bianca; Mead, Elena; Seo, Susan K.; Perales, Miguel-Ángel

doi:10.1038/s41408-020-00346-7

Cited by 170 publications

(293 citation statements)

References 28 publications

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“…Treatments varied throughout the time period due to rapid iterative changes in clinical management algorithms. Documented secondary infections were uncommon, including in those patients who received IL-6-directed therapies, similar to CAR T recipients treated with tocilizumab for cytokine release syndrome (17,18). Interestingly, time from cellular therapy and many previously reported risk factors for disease severity were not significant in our analysis, though analyses were limited by the small number of events.…”

Section: Discussionmentioning

confidence: 67%

Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation

Shah¹,

DeWolf²,

Lee³

et al. 2020

Journal of Clinical Investigation

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111

209

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BACKGROUND. Understanding outcomes and immunologic characteristics of cellular therapy recipients with SARS-CoV-2 is critical to performing these potentially life-saving therapies in the COVID-19 era. In this study of recipients of allogeneic (Allo) and autologous (Auto) hematopoietic cell transplant and CD19-directed chimeric antigen receptor T cell (CAR T) therapy at Memorial Sloan Kettering Cancer Center, we aimed to identify clinical variables associated with COVID-19 severity and assess lymphocyte populations. METHODS. We retrospectively investigated patients diagnosed between March 15, 2020, and May 7, 2020. In a subset of patients, lymphocyte immunophenotyping, quantitative real-time PCR from nasopharyngeal swabs, and SARS-CoV-2 antibody status were available. RESULTS. We identified 77 patients with SARS-CoV-2 who were recipients of cellular therapy (Allo, 35; Auto, 37; CAR T, 5; median time from cellular therapy, 782 days; IQR, 354-1611 days). Overall survival at 30 days was 78%. Clinical variables significantly associated with the composite endpoint of nonrebreather or higher oxygen requirement and death (n events = 25 of 77) included number of comorbidities (HR 5.41, P = 0.004), infiltrates (HR 3.08, P = 0.032), and neutropenia (HR 1.15, P = 0.04). Worsening graft-versus-host disease was not identified among Allo recipients. Immune profiling revealed reductions and rapid recovery in lymphocyte populations across lymphocyte subsets. Antibody responses were seen in a subset of patients. CONCLUSION. In this series of Allo, Auto, and CAR T recipients, we report overall favorable clinical outcomes for patients with COVID-19 without active malignancy and provide preliminary insights into the lymphocyte populations that are key for the antiviral response and immune reconstitution.

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Section: Discussionmentioning

confidence: 67%

Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation

Shah¹,

DeWolf²,

Lee³

et al. 2020

Journal of Clinical Investigation

Self Cite

111

209

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“…Seven published manuscripts and abstracts describing IFIs after CAR-T-cell therapy were identified at the time of this review [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Overall, IFIs after CAR-T-cell therapy are uncommon and have been reported in 1–15% of patients, with 0–10% and 0–7% of patients developing yeast and mold infections, respectively.…”

Section: Epidemiology Of Fungal Infections After Car-t-cell Therapmentioning

confidence: 99%

“…In one study which reported infections occurring >90 days after CAR-T-cell infusion, IFIs developed in 9% of patients and included two invasive mold infections, one yeast infection, and one endemic mycosis ( Coccidioides immitis infection) [ 10 ]. Six studies reported infection-related deaths, of which mortality attributable to IFIs ranged from 0 to 5% [ 8 , 9 , 10 , 11 , 12 , 13 ].…”

Section: Epidemiology Of Fungal Infections After Car-t-cell Therapmentioning

confidence: 99%

“…Infections are among the indirect toxicities of CAR-T-cell therapy. CAR-T-cell recipients are at an increased risk of infection because of prior anti-neoplastic therapy, refractory malignancy, lymphodepleting conditioning chemotherapy (typically with fludarabine and cyclophosphamide), B-cell aplasia, the immune perturbations associated with CRS and ICANS, and their management with immunosuppressive therapies [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ]. Nosocomial bacterial and respiratory viral infections are the most common infections after CAR-T-cell therapy.…”

Section: Introductionmentioning

confidence: 99%

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Invasive Fungal Infections after Anti-CD19 Chimeric Antigen Receptor-Modified T-Cell Therapy: State of the Evidence and Future Directions

Garner

Samanta

Haidar

2021

JoF

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Studies describing invasive fungal infections (IFIs) after chimeric antigen receptor-modified T-cell (CAR-T-cell) therapy are limited. Although post-CAR-T-cell IFIs appear to be uncommon, they are associated with significant morbidity and mortality. Specific risk factors for IFIs in CAR-T-cell recipients have not been fully characterized and are often extrapolated from variables contributing to IFIs in patients with other hematologic malignancies or those undergoing hematopoietic cell transplant. Optimal prophylaxis strategies, including the use of yeast versus mold-active azoles, also remain ill-defined. Further research should investigate key risk factors for IFIs and establish an evidence-based approach to antifungal prophylaxis in these patients in order to improve clinical outcomes.

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“…Invasive mold infections were uncommon, ranging from 1 to 7% in CAR T-cell recipients [ 15 – 17 ]. In multivariate analyses, the use of systemic corticosteroids for the management of CRS or ICANS has emerged as a major risk factor of infection [ 18 ]. Certain inflammatory signatures – such as the “double peaks of IL-6” pattern observed in our patient – have been shown to confer an especially high risk of life-threatening infection [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy – a case report

et al. 2021

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Background Prolonged myelosuppression following CD19-directed CAR T-cell transfusion represents an important, yet underreported, adverse event. The resulting neutropenia and multifactorial immunosuppression can facilitate severe infectious complications. Case presentation We describe the clinical course of a 59-year-old patient with relapsed/refractory DLBCL who received Axicabtagene-Ciloleucel (Axi-cel). The patient developed ASTCT grade I CRS and grade IV ICANS, necessitating admission to the neurological ICU and prolonged application of high-dose corticosteroids and other immunosuppressive agents. Importantly, neutropenia was profound (ANC < 100/μl), G-CSF-refractory, and prolonged, lasting more than 50 days. The patient developed severe septic shock 3 weeks after CAR transfusion while receiving anti-fungal prophylaxis with micafungin. His clinical status stabilized with broad anti-infective treatment and intensive supportive measures. An autologous stem cell backup was employed on day 46 to support hematopoietic recovery. Although the counts of the patient eventually started to recover, he developed an invasive pulmonary aspergillosis, which ultimately lead to respiratory failure and death. Postmortem examination revealed signs of Candida glabrata pancolitis. Conclusions This case highlights the increased risk for fatal infectious complications in patients who present with profound and prolonged cytopenia after CAR T-cell therapy. We describe a rare case of C. glabrata pancolitis associated with multifactorial immunosuppression. Although our patient succumbed to a fatal fungal infection, autologous stem cell boost was able to spur hematopoiesis and may represent an important therapeutic strategy for DLBCL patients with CAR T-cell associated bone marrow aplasia who have underwent prior stem cell harvest.

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Infection during the first year in patients treated with CD19 CAR T cells for diffuse large B cell lymphoma

Cited by 170 publications

References 28 publications

Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation

Favorable outcomes of COVID-19 in recipients of hematopoietic cell transplantation

Invasive Fungal Infections after Anti-CD19 Chimeric Antigen Receptor-Modified T-Cell Therapy: State of the Evidence and Future Directions

Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy – a case report

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