An international multicenter study comparing COVID‐19 omicron outcomes in patients with hematological malignancies treated with obinutuzumab versus rituximab

Abstract Objectives Hematological malignancy (HM) patients treated with anti‐CD20 monoclonal antibodies are at higher risk for severe COVID‐19. A previous single‐center study showed worse outcomes in patients treated with obinutuzumab compared to rituximab. We examined this hypothesis in a large international multicenter cohort. Methods We included HM patients from 15 centers, from five countries treated with anti‐CD20, comparing those treated with obinutuzumab (O‐G) to rituximab (R‐G) between December 2021 and June 2022, when Omicron lineage was dominant. Results We collected data on 1048 patients. Within the R‐G (n = 762, 73%), 191 (25%) contracted COVID‐19 compared to 103 (36%) in the O‐G. COVID‐19 patients in the O‐G were younger (61 ± 11.7 vs. 64 ± 14.5, p = 0.039), had more indolent HM diagnosis (aggressive lymphoma: 3.9% vs. 67.0%, p < 0.001), and most were on maintenance therapy at COVID‐19 diagnosis (63.0% vs. 16.8%, p < 0.001). Severe‐critical COVID‐19 occurred in 31.1% of patients in the O‐G and 22.5% in the R‐G. In multivariable analysis, O‐G had a 2.08‐fold increased risk for severe‐critical COVID‐19 compared to R‐G (95% CI 1.13–3.84), adjusted for Charlson comorbidity index, sex, and tixagevimab/cilgavimab (T‐C) prophylaxis. Further analysis comparing O‐G to R‐G demonstrated increased hospitalizations (51.5% vs. 35.6% p = 0.008), ICU admissions (12.6% vs. 5.8%, p = 0.042), but the nonsignificant difference in COVID‐19‐related mortality (n = 10, 9.7% vs. n = 12, 6.3%, p = 0.293). Conclusions Despite younger age and a more indolent HM diagnosis, patients receiving obinutuzumab had more severe COVID‐19 outcomes than those receiving rituximab. Our findings underscore the need to evaluate the risk–benefit balance when considering obinutuzumab therapy for HM patients during respiratory viral outbreaks.


| INTRODUCTION
Patients with hematological malignancies (HM) are at a higher risk for complications and mortality due to COVID-19. 1 Within these patients, those receiving anti-CD20 therapy are especially at risk for persistent disease, relapse, respiratory failure, and death. 2,3During the pandemic, nearing the end of 2021, the dominant SARS-CoV-2 variants were the Omicron lineage subvariants, 4,5 which are generally characterized by a lower case fatality rate, lower propensity for complications but substantially higher transmissibility 6 ; however, patients with HM remained at his risk for complications and mortality. 7,8Antivirals such as Nirmatrelvir-Ritonavir, Remdesivir, Molnupiravir, and monoclonal antibodies targeting SARS-CoV-2 became widely available during this period.These treatments benefit patients with HM who cannot mount an effective humoral response to SARS-CoV-2 infection or develop meaningful immunity following SARS-CoV-2 vaccines. 9,10n recent years, anti-CD20 treatments, rituximab, and obinutuzumab, have been widely used for HM.Alongside their beneficial anti-lymphoma effects, these antibodies neutralize B cells and suppress the humoral response to viral replication, 11 resulting in a higher risk for severe COVID-19. 23][14] Obinutuzumab is used (alone or with chemotherapy) mainly for previously untreated or relapsed follicular lymphoma (FL) or chronic lymphocytic leukemia (CLL).Obinutuzumabbased immunochemotherapy and maintenance resulted in more prolonged progression-free survival (PFS) for patients with advanced-stage FL, but there were more adverse events, including infections. 15previous single-center study 16 demonstrated that HM patients who had COVID-19 while on treatment with obinutuzumab rather than rituximab had worse clinical outcomes, including higher severe-critical illness (35% compared to 7% p = 0.017), hospitalization rate (60% compared to 25.9% p = 0.019), and all-cause mortality (3/20 vs. 0/27).This study aims to examine and validate this concept in a large international cohort.

| Study design and participants
We conducted a retrospective international multicenter cohort study across 15 centers from Israel, Turkey, Spain, Brazil, and the USA.The study period was between December 1, 2021, and June 30, 2022, when the Omicron lineage variants were predominant.We included patients with HM treated with either obinutuzumab or rituximab starting 6 months before and throughout the study.COVID-19 diagnosis was established based on a positive SARS-CoV-2 PCR test; all centers tested individuals who exhibited symptoms or were part of exposure tracing during epidemiological investigations.There was no formal screening for asymptomatic patients.We excluded patients diagnosed with COVID-19 before their first anti-CD20 treatment.

Conclusions:
Despite younger age and a more indolent HM diagnosis, patients receiving obinutuzumab had more severe COVID-19 outcomes than those receiving rituximab.Our findings underscore the need to evaluate the risk-benefit balance when considering obinutuzumab therapy for HM patients during respiratory viral outbreaks.

K E Y W O R D S
anti-CD20 monoclonal antibodies, COVID-19, hematological malignancies, obinutuzumab, rituximab or CHOP-like regimens.Indolent lymphoma included follicular lymphoma and marginal zone lymphoma.Patients in remission had a negative PET-CT scan before contracting COVID-19.The relapsed/refractory group included patients who received anti-CD20 therapy as a second or later line of treatment.

| Study outcomes
The primary outcome was the development of severe or critical COVID-19, defined as patients with SpO2 ≤94% on room air, including those on supplemental oxygen, oxygen through a high-flow device, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO) 17 .Secondary outcomes were hospitalization, ICU admission, COVID-19-related mortality, and all-cause mortality.

| Data collection
Baseline characteristics, including age, sex, Charlson comorbidity index (CCI), and medical history, were collected for all participants.We noted the use of tixagevimabcilgavimab (T-C) prophylaxis and COVID-19 vaccination status (number of doses received) when available.We recorded the hematological malignancy diagnosis, previous treatments, and the stage of HM treatments (induction or maintenance) when diagnosed with COVID-19.We collected COVID-19-related information, including COVID-19 severity (asymptomatic-mild-moderate or severe-critical) and the need for respiratory support (none, nasal cannula, facemasks with oxygen reservoir bag, high flow nasal cannula, noninvasive ventilation, invasive mechanical ventilation, and ECMO).We recorded the time from the last anti-CD20 therapy to the COVID-19 diagnosis and the duration of hospitalization.
Study data were collected and managed using REDCap (Research Electronic Data Capture) tools hosted at Ben-Gurion University. 18REDCap is a secure, web-based software platform that supports data capture for research studies.This study followed the STROBE guidelines 19 and complied with ethical and Good Clinical Practice guidelines and regulations.The study was approved, and a waiver of informed consent was granted by the Soroka Ethics in research committee (SOR-22-0198) and by each participating institution's committee.Patient information was deidentified and kept confidential throughout the study.

| Statistical analysis
Continuous variables were presented as mean ± standard deviation or median and interquartile range if non-normally distributed, while categorical data were presented as total patients (percentage of all patients).Continuous variables were compared using t-tests or the Mann-Whitney test, and categorical data were analyzed using chi-square (χ 2 ) or Fisher's exact tests.Multivariable analysis for severe COVID-19 and secondary outcomes was performed using a logistic regression model.Variables with clinical significance were incorporated in the model as comorbidities and age were shown to be related to COVID-19 outcomes in this population, 1 as well as T-C prophylaxis. 20Survival analysis was conducted using Kaplan-Meier's survival table and curve.A subgroup analysis was conducted specifically on patients with indolent lymphoma/CLL.Multivariate analysis within this group was conducted using logistic regression.Independent variables incorporated in this model were also selected upon a clinical basis, and included CCI and HM treatment stage at COVID-19 diagnosis. 1The statistical software SPSS version 25 (IBM Corp Armonk, NY, USA) was used, and a two-tailed p ≤0.05 was considered significant.

| RESULTS
During the study period, a total of 1048 patients with HM received at least one dose of anti-CD20, of which 762 (73%) received rituximab and 286 (27%) received obinutuzumab (Figure 1).Characteristics of the population corresponding to the anti-CD20 type are shown in Table 1.The majority of patients were treated in Israel (Table S1a,b).During the study period, 28.1% of the cohort (294/1048) contracted SARS-CoV-2, 191 (25.1%) in the rituximab group (R-G), and 103 (36.0%) in the obinutuzumab group (O-G).Median follow-up duration was 6.9 months (IQR 4.5-9.6).

| Subgroup analysis of patients with indolent lymphoma or CLL
Within the 469 patients with indolent lymphoma or CLL, we conducted a subgroup analysis of 162 patients who acquired COVID-19, which showed that O-G compared to R-G were younger (61.7 ± 11.0 vs. 67.9± 13.5 years p = 0.002), were in the maintenance therapy phase during COVID-19 diagnosis (64.6% vs. 46.7%,p = 0.028), and had a lower CCI (69.7% vs. 85.7% with CCI≥4, p = 0.020) (Table 4).While the overall proportion of severe-critical COVID-19 was similar between the two groups (31.3% O-G vs. 30.2%R-G, p = 0.877), the O-G had a higher incidence of critical disease indicators.Specifically, 11 patients (11.1%) in the O-G required invasive mechanical ventilation compared to only one patient (1.6%) in the R-G (p = 0.024).Additionally, there were 13 ICU admissions (13.1%) in the O-G group compared to three admissions (4.8%) in the R-G (p = 0.087).In the multivariable analysis, adjusting for CCI and therapy stage at COVID-19 diagnosis, obinutuzumab treatment was found to be independently associated with a 4.6-fold increased risk of ICU admission (OR 4.62, 95% CI 1.14-18.67),compared to rituximab (Table S3).Outcomes of COVID-19-infected patients during the induction and maintenance treatment phases separately, are presented in Table S4a,b.

| DISCUSSION
In this large, international cohort of patients with hematological malignancies receiving anti-CD20 therapy, we identified a distinct pattern of increased COVID-19  6.9, 5.4-6.96.9, 5.7-6.96.9, 5.6-6.90.600 severity in those treated with obinutuzumab compared to those treated with rituximab.Despite being younger, having a lower comorbidity burden, and less aggressive HM, patients receiving obinutuzumab were at an increased risk of severe and critical COVID-19 complications, including a higher hospitalization rate, ICU admission, and need for invasive mechanical ventilation.Previous research has suggested that anti-CD20 therapy might lead to a more severe course of COVID-19 due to impaired humoral immunity and decreased antibody response to the virus or the vaccine. 9,21,22Our findings align with this hypothesis, adding to the body of knowledge by showing a differential impact between various anti-CD20 therapies.While both obinutuzumab and rituximab lead to B-cell depletion, obinutuzumab induces a more prolonged and profound depletion, which might have contributed to our cohort's increased severity of COVID-19.
A recently published multicenter study on HM with FL performed in the pre-COVID-19 era (2016-2019) found no excess risk of infections among obinutuzumab patients in comparison to rituximab patients. 23The study demonstrated statistically similar viral infection rates among 21.7% of patients (rituximab group with 16/60 [26.7%] compared to 7/46 [15.2%]) in the obinutuzumab group (p = 1.0).Contrary to those results, in our cohort, among the subgroup of indolent lymphomas (n = 469), the incidence of COVID-19 was 27.1%, with significantly higher rates of infection and increased severity in those treated with obinutuzumab.Whether the differences we observed reflect the unique pattern of SARS-CoV-2 immunomodulation or the higher infection rate during the pandemic is not apparent.
Current practice favors obinutuzumab treatment for FL despite no significant impact on overall survival rates.Although the GALLIUM study demonstrated an improved progression-free survival (PFS) with obinutuzumab, adverse events, including infections and neutropenia, were more common.The rate of adverse events did not significantly differ between the induction and maintenance phases. 15The PRIMA study found a benefit in PFS without impacting overall survival when maintenance treatment with rituximab was compared to a placebo. 24e demonstrated an increased risk for severe outcomes in COVID-19 illness in patients treated with obinutuzumab.Thus, we raise the question of whether clinicians should reconsider treatment regimens containing obinutuzumab in the presence of a respiratory viral pandemic.
Despite recent evidence showing a modest increase in humoral response to a third vaccine dose, 25 we did not find that SARS-CoV-2 vaccination status or number of vaccine doses to be related to clinical outcomes.Furthermore, in line with previous studies, 10 we found that T-C monoclonal antibody prophylaxis was associated with a lower risk of severe COVID-19, suggesting an essential role for this intervention in protecting patients receiving anti-CD20 therapy.However, this option is currently unavailable, as these monoclonal antibodies have lost their neutralization ability against current variants. 26,27ur study has some limitations, including its retrospective nature with the possibility of unmeasured confounding factors.Additionally, treatment with obinutuzumab is mainly used for HM with indolent lymphomas and CLL, creating an inherent difference between the two groups; thus, it was not included in our multivariate analysis.To address this limitation, we performed a subgroup analysis of the patients with indolent lymphomas or CLL, which shows a similar trend in ICU admissions and mechanical ventilation as the larger cohort (Table S2a,b).Another limitation when assessing outcomes as admission rates (hospitalization or ICU admission) in a multicenter study is the different site-to-site criteria for these events.To address this variance, we defined the primary outcome as the disease severity, which relies on objective parament of oxygen dependence, and mechanical ventilation as an additional secondary outcome.Moreover, HM status as remission or relapsed/refractory disease depends on the availability of PET-CT scans.During the pandemic, access to nonemergency tests was limited and prone to extreme variation between the different sites.Therefore, we elected not to rely on this variable and focused on HM treatment status as a more reliable marker for disease status.Finally, most T A B L E 3 Multivariable analysis demonstrating the association between anti-CD20 treatment, patient characteristics, and COVID-19 outcomes.

Severe-critical COVID-19 a
Hospitalization a

Mechanical ventilation a
Obinutuzumab therapy (with rituximab as reference) In conclusion, our study suggests that patients with hematological malignancies receiving obinutuzumab are at a higher risk of severe and critical COVID-19 than those treated with rituximab.While further studies are needed to understand the mechanistic differences between these therapies better, our findings highlight an aspect of the infectious complications potentially arising from a more severe immune suppression by a new, more potent treatment.In this regard, COVID-19 may provide a signal that could apply to other respiratory viral infections.
Characteristics of positive COVID-19 patients with indolent lymphoma/chronic lymphocytic leukemia.