key: cord-0709728-aopaa4xt
authors: Duléry, Rémy; Lamure, Sylvain; Delord, Marc; Di Blasi, Roberta; Chauchet, Adrien; Hueso, Thomas; Rossi, Cédric; Drenou, Bernard; Deau Fischer, Bénédicte; Soussain, Carole; Feugier, Pierre; Noël, Nicolas; Choquet, Sylvain; Bologna, Serge; Joly, Bertrand; Philippe, Laure; Kohn, Milena; Malak, Sandra; Fouquet, Guillemette; Daguindau, Etienne; Taoufik, Yassine; Lacombe, Karine; Cartron, Guillaume; Thiéblemont, Catherine; Besson, Caroline
title: Prolonged in‐hospital stay and higher mortality after Covid‐19 among patients with non‐Hodgkin lymphoma treated with B‐cell depleting immunotherapy
date: 2021-05-12
journal: Am J Hematol
DOI: 10.1002/ajh.26209
sha: 1e6111ccfb1aa9e4e7ecb66ae6cb51a1fb62591c
doc_id: 709728
cord_uid: aopaa4xt

Prolonged Covid‐19 is an emerging issue for patients with lymphoma or immune deficiency. We aimed to examine prolonged length of in‐hospital stay (LOS) due to Covid‐19 among patients with lymphoma and assess its determinants and outcomes. Adult patients with lymphoma admitted for Covid‐19 to 16 French hospitals in March and April, 2020 were included. Length of in‐hospital stay was analyzed as a competitor vs death. The study included 111 patients. The median age was 65 years (range, 19–92). Ninety‐four patients (85%) had B‐cell non‐Hodgkin lymphoma. Within the 12 months prior to hospitalization for Covid‐19, 79 patients (71%) were treated for their lymphoma. Among them, 63 (57%) received an anti‐CD20 therapy. Fourteen patients (12%) had relapsed/refractory disease. The median LOS was 14 days (range, 1–235). After a median follow‐up of 191 days (3–260), the 6‐month overall survival was 69%. In multivariable analyses, recent administration of anti‐CD20 therapy was associated with prolonged LOS (subdistribution hazard ratio 2.26, 95% confidence interval 1.42–3.6, p < 0.001) and higher risk of death (hazard ratio 2.17, 95% confidence interval 1.04–4.52, p = 0.039). An age ≥ 70 years and relapsed/refractory lymphoma were also associated with prolonged LOS and decreased overall survival. In conclusion, an age ≥ 70 years, a relapsed/refractory lymphoma and recent administration of anti‐CD20 therapy are risk factors for prolonged LOS and death for lymphoma patients hospitalized for Covid‐19. These findings may contribute to guide the management of lymphoma during the pandemic, support evaluating specific therapeutic approaches, and raise questions on the efficacy and timing of vaccination of this particular population.

Patients with hematological malignancies have a higher risk of death from coronavirus disease 2019 (Covid-19) than the general population. 1, 2 Patients with lymphoma have an immune-deficiency due to the biological features of lymphoma per se (hypogammaglobulinemia, neutropenia, lymphopenia) and its treatments, leading to an increased incidence and severity of infections. 3, 4 High in-hospital mortality related to severe Covid-19 among patients with lymphoma has been reported in several countries, with 30-day overall survivals (OS) ranging from 625 to 81%. 2, [5] [6] [7] [8] [9] [10] The risk of early death for patients with severe Covid-19 and lymphoma increases with age and relapsed/refractory lymphoma disease. 5 The median length of in-hospital stay (LOS) for Covid-19 is reported to be 5 to 20 days depending on the requirement of intensive care. 11, 12 With longer hindsight, the persistence of SARS-CoV-2 appears to be an emerging clinical issue for immunocompromised patients: the persistence of SARS-CoV-2 replication for at least 2 months was recently reported in a series of 20 immunocompromised patients treated for hematological malignancies. 13 Hueso et al. also reported a series of 17 patients with profound B-cell depletion, prolonged Covid-19 symptoms, negative SARS-CoV-2 serology, and positive SARS-CoV-2 polymerase chain reaction (PCR) in blood. 14 Moreover, among lymphoma treatments, anti-CD20 monoclonal antibodies, such as rituximab and obinutuzumab, induce rapid B-cell depletion, which may alter the generation of antibody responses to new pathogens, 15, 16 possibly impacting the clinical course of Covid- 19 . Indeed, at least nine case studies have reported that patients with B-lineage hematological malignancies or auto-immune diseases treated with B-cell depletion experienced prolonged course of Covid-19 with persistence of SARS-CoV-2 replication. [17] [18] [19] [20] [21] [22] [23] [24] [25] The incidence, risk factors, and outcomes of prolonged forms of Covid-19 for patients with lymphoma are still only poorly assessed. In a previously published retrospective multicentric cohort, we reported a prolonged LOS of more than 30 days for 22% of patients with lymphoma and Covid-19. 5 By increasing the follow-up of this population from 1 to 6 months and following the inclusion of additional lymphoma patients from more centers in France, we aimed to examine prolonged LOS due to Covid-19, and assess its determinants and outcomes.

This retrospective multicentric study was conducted in 16 French hospitals. Briefly, adult patients with a past or current diagnosis of lymphoma, who were admitted for Covid-19 in March and April, 2020, were identified in each hospital, as previously described. 5 Living patients not discharged from the hospital at the time of the last follow up were censored at that time. The cumulative incidence of discharge from the hospital was estimated using the Kalbfleisch and Prentice method. 26 Factors associated with LOS were evaluated using a Fine and Gray proportional subdistribution hazard model. 27 Covariates considered in this analysis were gender, age (≥ 70 years vs (< 2 years vs ≥2 years), and lymphoma status (relapsed/refractory vs others). Multivariable analysis was performed from the subset of independent variables having univariate significance <0.1 and no missing data after a stepwise procedure of variable selection based on the Akaike information criterion. The impact of these selected variables on OS was also analyzed by a multivariable analysis using a Cox proportional hazard model. Statistical tests were two-tailed and p values <0.05 were considered to denote statistical significance. Statistical analysis was performed using the R language and environment for statistical computing version 4.03 (R Core Team (2020). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/.

The characteristics of the 111 included patients are summarized in Table 1 and Figure S1 . Briefly, their median age was 65 years and 63% were male. Ninety-four patients had B-cell NHL (85%) and half (50%) were diagnosed with lymphoma more than 2 years before Covid-19. The median LOS was 14 days (range, 1-235). After a median follow-up of 191 days (range, 3-260), the 6-month OS was 69% (95% Confidence Interval [CI] 60%-78%) ( Figure S2 ). Twentyfour patients died within 30 days after admission for Covid-19.

Among the 87 living patients 30 days after Covid-19 diagnosis, 55 had been definitively discharged from the hospital, 31 were still hospitalized for Covid-19 symptoms, and one was later re-hospitalized for Covid-19 symptoms recurrence. These 32 patients were considered as having prolonged LOS due to Covid-19 ( Figure S1 ).

The proportion of patients who had a prolonged LOS for Covid-19 symptoms (> 30 days) was 29%. Their median LOS was 58 days (range, 31-235). As shown in Table 1 Table S1 ).

The most common laboratory findings at admission were elevated C- 

Univariate and multivariable analyses of the factors associated with LOS are shown in (Figure 2 ). Figure S3 summarizes the clinical evolution of the patients who recently received or not an anti-CD20 monoclonal antibody.

Long-lasting Covid-19 symptoms are a major emerging concern for many individuals who have survived a SARS-Cov-2 infection. [29] [30] [31] Apart from mild-to-moderate long-lasting symptoms reported for the general population, several reports described the persistence of SARS-CoV-2 replication with severe symptoms for immunocompromised patients, including those with lymphoma. 13 none of the patients exposed to anti-CD20 antibodies within the 12 months prior to vaccination had an antibody-mediated response to BNT162b2 mRNA Covid-19 vaccine. 43 It may also hamper the formation of functional memory CD8+ T-cells 44 and the maintenance of follicular helper CD4+ T-cells responses. 45 Therefore, whenever possible, SARS-CoV-2 vaccination might be considered before the onset of anti-CD20 monoclonal antibody therapy although therapeutic B-cell depletion may also alter the efficacy of already established antiviral memory T-cell responses. 44 Likely, forthcoming studies will determine the optimal SARS-CoV-2 vaccination schedule in lymphoma patients.

Apart from B-cell depletion, other factors were found to contrib- 

We thank all the clinicians and patients in the participating centers for their contributions to this multicenter study. We are grateful to the Centre Hospitalier de Versailles, in particular Philippe Rousselot and Laure

Morisset for promoting the research and for supporting the editing. We thank France Lymphome Espoir for reviewing the study material, LYSA for discussions on the design of this study, and Sophie Rigaudeau and

Cécile Lauréana for their contribution to the collection of the cases.

The authors certify that there is no conflict of interest with any organization concerning the material presented in this manuscript. Lacombe reviewed the study design and the article. Caroline Besson designed the study, contributed to the analysis, and wrote the article.

The dataset supporting this article is available upon demand to the corresponding author and to the promoter (Centre Hospitalier de Versailles). DUL ERY ET AL.

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https://orcid.org/0000-0002-5024-1713Guillemette Fouquet https://orcid.org/0000-0002-3751-393X