Poor outcome of patients with COVID-19 after CAR T-cell therapy for B-cell malignancies: results of a multicenter study on behalf of the European Society for Blood and Marrow Transplantation (EBMT) Infectious Diseases Working Party and the European Hematology Association (EHA) Lymphoma Group

Abstract Outcomes for patients with hematologic malignancy infected with COVID-19 have not been aggregated. The objective of this study was to perform a systematic review and meta-analysis to estimate the risk of death and other important outcomes for these patients. We searched PubMed and EMBASE up to 20 August 2020 to identify reports of patients with hematologic malignancy and COVID-19. The primary outcome was a pooled mortality estimate, considering all patients and only hospitalized patients. Secondary outcomes included risk of intensive care unit admission and ventilation in hospitalized patients. Subgroup analyses included mortality stratified by age, treatment status, and malignancy subtype. Pooled prevalence, risk ratios (RRs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Thirty-four adult and 5 pediatric studies (3377 patients) from Asia, Europe, and North America were included (14 of 34 adult studies included only hospitalized patients). Risk of death among adult patients was 34% (95% CI, 28-39; N = 3240) in this sample of predominantly hospitalized patients. Patients aged ≥60 years had a significantly higher risk of death than patients <60 years (RR, 1.82; 95% CI, 1.45-2.27; N = 1169). The risk of death in pediatric patients was 4% (95% CI, 1-9; N = 102). RR of death comparing patients with recent systemic anticancer therapy to no treatment was 1.17 (95% CI, 0.83-1.64; N = 736). Adult patients with hematologic malignancy and COVID-19, especially hospitalized patients, have a high risk of dying. Patients ≥60 years have significantly higher mortality; pediatric patients appear to be relatively spared. Recent cancer treatment does not appear to significantly increase the risk of death.

Patients with cancer have high mortality from coronavirus disease 2019 (COVID-19), and the immune parameters that dictate clinical outcomes remain unknown. In a cohort of 100 patients with cancer who were hospitalized for COVID-19, patients with hematologic cancer had higher mortality relative to patients with solid cancer. In two additional cohorts, flow cytometric and serologic analyses demonstrated that patients with solid cancer and patients without cancer had a similar immune phenotype during acute COVID-19, whereas patients with hematologic cancer had impairment of B cells and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses. Despite the impaired humoral immunity and high mortality in patients with hematologic cancer who also have COVID-19, those with a greater number of CD8 T cells had improved survival, including those treated with anti-CD20 therapy. Furthermore, 77% of patients with hematologic cancer had detectable SARS-CoV-2-specific T cell responses. Thus, CD8 T cells might influence recovery from COVID-19 when humoral immunity is deficient. These observations suggest that CD8 T cell responses to vaccination might provide protection in patients with hematologic cancer even in the setting of limited humoral responses.

To the Editor: Detection of replication-competent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the most reliable indicator of contagiousness. 1 Although the duration of live-virus shedding is well-characterized in immunocompetent patients with coronavirus disease 19 (Covid-19), little is known about how long immunocompromised patients are contagious. Consequently, the Centers for Disease Control and Prevention (CDC) guidelines on transmission-based precautions for immunocompromised patients are based on limited data. 2 In the current study, we used cell cultures to detect viable virus in serially collected respiratory samples (nasopharyngeal and sputum samples) obtained from 20 immunocompromised patients who had Covid-19 (Figure 1A). These patients included 18 recipients of hematopoietic stem-cell transplants or chimeric antigen receptor (CAR) T-cell therapy and 2 patients with lymphoma. Covid-19 was diagnosed between March 10 and April 20, 2020, with the use of a modified CDC nucleic acid amplification test. Live virus was isolated in Vero cells, and genetic variants were identified by whole-genome sequencing of nasopharyngeal and cultured specimens (see the Supplemental Methods section of the Supplementary Appendix, available with the full text of this letter at NEJM.org). The patients’ demographic characteristics, medical history, and clinical course of Covid-19 were abstracted from medical records (Table S1 in the Supplementary Appendix). Of the 20 patients, 15 were receiving active treatment or chemotherapy. Eleven had severe Covid-19. A total of 78 samples were collected from the 20 patients; 57 samples were obtained in the time periods shown in Figure S1. Viral RNA was detected for up to 78 days after the onset of symptoms (interquartile range, 24 to 64 days). Viable virus was detected in 10 of 14 nasopharyngeal samples (71%) that were available from the first day of laboratory testing. Follow-up samples obtained from 5 patients (Patients MSK-3, MSK-4, MSK-6, MSK-8, and MSK-9) grew virus in culture for 8, 17, 25, 26, and 61 days after the onset of symptoms (Figure 1). The 3 patients with viable virus for more than 20 days had received allogeneic hematopoietic stem-cell transplants (2 patients) or CAR T-cell therapy (1 patient) within the previous 6 months and remained seronegative for antibodies to viral nucleoprotein; 2 of these patients had severe Covid-19 and received investigational treatments. Whole-genome sequencing detected viral reads in all the samples and yielded more than 95% complete SARS-CoV-2 genomes for 37 of 57 nasopharyngeal samples obtained from 17 patients and all 18 cultured specimens (accession numbers, EPI_ISL_583426 to EPI_ISL_583480 [55 complete genomes]). Serial sample genomes were obtained for 11 patients, up to day 63 after the onset of symptoms. Each patient was infected by a distinct virus, and there were no major changes in the consensus sequences of the original serial specimens or cultured isolates (Figure 1B); these findings were consistent with persistent infection. Patients with profound immunosuppression after undergoing hematopoietic stem-cell transplantation or receiving cellular therapies may shed viable SARS-CoV-2 for at least 2 months. The current guidelines for Covid-19 isolation precautions may need to be revised for immunocompromised patients.