Clinical outcomes and frequency of persistent infection among immunosuppressed patients treated with bebtelovimab for COVID-19 infection at an ambulatory cancer center

Abstract

Background:

There are limited data on clinical outcomes associated with use of bebtelovimab for treatment of coronavirus disease 2019 (COVID-19) among cancer patients. We aimed to define the clinical characteristics and outcomes among patients receiving bebtelovimab as part of the COVID-19 therapeutics program at our cancer center.

Methods:

This is a retrospective cohort study of immunosuppressed adult patients who received bebtelovimab at Fred Hutchinson Cancer Center between March 2022, and November 2022. We reviewed medical records to capture date of first positive COVID-19 test, clinical characteristics, outcomes and follow-up COVID-19 testing for 60 days after first positive. Persistent infection was defined as a positive test beyond day 30; these patients were reviewed beyond day 60.

Results

Among 93 patients who received bebtelovimab, 64 (69%) had hematologic malignancy. Sixty-nine (74%) patients received bebtelovimab within 2 days after diagnosis. Two (2%) patients were hospitalized, none required ICU care, and one patient died on day 52; although it is unknown if death was directly related to COVID-19. Ten (11%) patients had persistent COVID-19 infection; of these, four received additional COVID-19 therapy with either nirmatrelvir/ritonavir or remdesivir, and five out of six patients with sequencing data available had spike protein mutations associated with bebtelovimab resistance.

Conclusion

A coordinated systems-based approach led to prompt initiation of bebtelovimab within two days of testing positive in most patients. We observed few hospitalizations or deaths. Persistent infection was noted in 11% of patients with four requiring additional therapies, highlighting a need for novel strategies to manage immunosuppressed patients.

Graphical Abstract

Favorable outcomes after treatment with bebtelovimab. A coordinated approach led to prompt initiation of monoclonal antibody therapy. Persistent infection noted in 11% of patients.

Background

Immunocompromised individuals, including those with hematologic malignancies or hematopoietic cell transplantation (HCT) recipients, are at increased risk of poor outcomes after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, including hospitalization and death. Mortality rates in patients with underlying hematologic malignancies and HCT have ranged from 12 – 48%^1,2 Additionally, some patients with hematologic malignancy experience persistent symptomatic infection accompanied by prolonged viral shedding.^1–6

Neutralizing monoclonal antibodies (mAb) directed against the SARS CoV-2 spike protein have been associated with a reduction in the rate of progression to severe COVID-19, time to viral clearance and death.^7–9Bebtelovimab is a recombinant neutralizing human IgG1λ mAb to the spike protein of SARS-CoV-2 that received emergency use authorization (EUA) from the Federal Drug Administration (FDA) in February 2022 for the treatment of mild-to-moderate COVID-19¹⁰; its EUA was rescinded in November 2022 as it was no longer expected to neutralize circulating variants¹¹.

There are limited data on clinical outcomes associated with use of bebtelovimab for treatment of mild to moderate COVID-19 among cancer patients. Furthermore, no studies have evaluated the effect of bebtelovimab on outcomes such as persistent COVID-19 infection, a distinct clinical entity among profoundly immunosuppressed patients with hematologic malignancy.^12,13 Although bebtelovimab is no longer authorized for treatment of COVID-19, understanding outcomes in the immunocompromised population may help guide development of novel mAb therapies. We aimed to characterize the clinical outcomes, including persistent infection among patients receiving bebtelovimab as part of the COVID-19 therapeutics program at our large comprehensive cancer center.

Methods

Study design

We performed a single center retrospective cohort study of immunosuppressed adult patients with COVID-19 infection who received bebtelovimab at Fred Hutchinson Cancer Center between March 31^st, 2022, and November 7^th, 2022. Patients were identified through our institution’s COVID-19 Therapeutics Program whereby an Infectious Diseases provider reviewed all daily reported positive COVID tests to determine eligibility for treatment with mAb therapy. At our center, bebtelovimab was offered to outpatients ≥18 years old with immunocompromise or other high-risk condition with mild-moderate COVID-19 infection diagnosed by either polymerase chain reaction (PCR) or rapid antigen test for whom alternative therapies (e.g., nirmatrelvir/ ritonavir and remdesivir) were not an option, due to significant drug-drug interactions with oral agents, and lack of availability of remdesivir in the outpatient setting.

We performed chart review to obtain demographics, clinical characteristics, outcomes, and laboratory test results. The primary outcome was hospitalization and/or death due to COVID-19 infection within 60 days after initial diagnosis (defined as the date of the first positive test). Secondary outcomes included intensive care unit (ICU) stay within 60 days after initial diagnosis and persistent COVID-19 infection. Persistent COVID-19 infection was defined as a positive PCR test beyond day 30; these patients were reviewed beyond day 60 for additional SARS-CoV-2 test results and therapies. This study was approved by the Fred Hutchinson Cancer Center Institutional Review Board.

Sequencing was performed as previously described^14,15. Briefly, RNA was extracted from residual clinical specimens using either Roche MagNA Pure 96 or ThermoFisher KingFisher platforms following manufacturer instructions. Sequencing libraries were prepared using multiplexed amplicon panels from Swift Biosciences (IDT) or Illumina COVIDSeq and sequenced on Illumina NextSeq 2000 or NovaSeq instruments using a 2×150 read format. Raw reads were processed using a custom bioinformatics pipeline (https://github.com/greninger-lab/covid_swift_pipeline) that performs adapter and quality trimming and filtering, masking of primers, generation of consensus sequences, and variant annotation. Phylogenetic lineage assignment was done using Pangolin (https://pangolin.cog-uk.io/) and Nextclade (https://clades.nextstrain.org/).

Statistical analysis

Data were summarized using descriptive statistics, including the median and range for continuous variables and frequency tabulations and percentages for categorical variables. SAS, version 9.4 (SAS Institute, Cary, NC) was used for all analyses.

Results

Patient population

A total of 93 patients (median age 65 years; 60% male) received bebtelovimab. Sixty-four (69%) had an underlying hematologic malignancy. Twenty-one (23%) had undergone HCT and one had received chimeric antigen receptor T-cell therapy. Seventy-four patients (80%) had received ≥ 2 doses of COVID-19 vaccination prior to their first positive test. More than half had received active treatment for their underlying malignancy in the two weeks prior to their first positive test. Sixty-nine (74%) patients received bebtelovimab within 2 days after first positive test; all patients received bebtelovimab within 7 days. Additional baseline characteristics are described in Table 1.

Table 1.

Baseline Characteristics of Patients Receiving Bebtelovimab¹

Characteristic	All Eligible Patients
Demographics
Age in years, median (range)	65 (21 – 88)
Sex
Female	37 (40%)
Race
White	75 (81%)
Asian	7 (8%)
Other	8 (9%)
Unknown	3(3%)
Clinical Characteristics
Underlying malignancy or condition
Acute lymphoblastic leukemia2	13 (14%)
Acute myeloid leukemia	12 (13%)
Chronic myeloid leukemia	1 (1%)
Chronic lymphocytic leukemia	13 (14%)
MDS/MPN	5 (5%)
Lymphoma	12 (13%)
Multiple Myeloma	8 (9%)
Other hematologic disorder3	4 (4%)
Solid tumor	25 (27%)
Comorbidities
Body Mass Index >25	48 (52%)
Chronic kidney disease	10 (11%)
Diabetes	17 (18%)
Cardiovascular disease	16 (17%)
Chronic lung disease	2 (2%)
Chronic liver disease	1 (1%)
Number of comorbidities4
1	33 (35%)
2	33 (35%)
≥3	27 (29%)
Number of COVID-19 vaccine doses received prior to COVID-19 diagnosis
0	9 (10%)
1	9 (10%)
2	22 (24%)
3	31 (34%)
4	20 (22%)
5	1 (1%)
Developed COVID – 19 symptoms	93 (100%)
Timing of symptom onset relative to COVID-19 diagnosis
Symptom onset before COVID-19 diagnosis	79 (85%)
Symptom onset after COVID-19 diagnosis5	4 (4%)
Symptom onset date unknown	10 (11%)
Days from symptom onset to COVID-19 diagnosis, median (range)6	1 (0–6)
Days from COVID-19 diagnosis to symptom onset, median (range)7	2 (1–4)
Days from most recent prior vaccination to COVID-19 diagnosis, median (range)	219 (0 – 564)
Days from COVID-19 diagnosis to Bebtelovimab administration
Same day	11 (12%)
1	36 (39%)
2	22 (24%)
≥3	24 (26%)
Cancer Related Treatments Received
Hematopoietic cell transplant recipient	21 (23%)
Chimeric antigen receptor T-cell recipient	1 (1%)
Receipt of anti-CD20 antibodies within 1 year prior to COVID-19 diagnosis	9 (10%)
Receipt of active treatment in 2 weeks prior to COVID-19 diagnosis8	51 (55%)
Receipt and dose of systemic steroids in 2 weeks prior to COVID-19 diagnosis
None	80 (86%)
Less than 1 mg/kg of prednisone equivalent	12 (13%)
1 or more mg/kg of prednisone equivalent	1 (1%)
COVID-19 Related treatments received
Receipt of nirmatrelvir/ritonavir at time of COVID-19 diagnosis9	4 (4%)

¹Among n=93 total patients. Baseline was date of COVID-19 diagnosis. Numbers shown are n(%) unless otherwise specified. Numbers may not add to totals due to missing data.

²Eleven were B-cell ALL and 2 were T-cell ALL

³Includes 2 patients with Waldenstorm’s macroglobulinemia and 2 patients with aplastic anemia.

⁴Includes underlying malignancy as a comorbidity.

⁵Symptom onset was before bebtelovimab initiation in all cases

⁶Among those with symptom onset before COVID-19 diagnosis

⁷Among those with symptom onset after COVID-19 diagnosis

⁸Includes chemotherapy, treatments for underlying malignancy.

⁹Two patients only received 2 doses of nirmatrelvir/ritonavir each, one patient received nirmatrelvir/ritonavir for 5 days, and one patient was intentionally treated with both nirmatrelvir/ritonavir and bebtelovimab.

Outcomes

Two (2%) patients required hospitalization directly related to their COVID-19 infection, none required ICU care, and one patient died on day 52, although it is unclear if the death was directly related to COVID-19. Twenty-six (28%) of 93 patients had a documented COVID-19 test obtained between day 30 and day 60; 10/93 (11%) individuals were known to have virologic evidence of persistent COVID-19 infection.

Among the 10 patients with persistent COVID-19 infection (Table 2), the median age was 66 years. Six (60%) had received active treatment for their malignancy in the two weeks prior to the first positive test. Half of the patients received bebtelovimab within two days of their positive test and one (10%) patient was unvaccinated at the time of their initial diagnosis. All 10 patients eventually tested negative. The median duration of COVID-19 test positivity was 47 days (range 33–155 days). Among these 10 patients, five had documentation of persistent symptoms; six had a negative test at or before day 60. Four remained positive after day 60 and four received additional COVID-19 therapy with either nirmatrelvir/ritonavir or remdesivir. None of these 10 patients developed serious complications requiring hospitalization or ICU admission for their persistent COVID-19 infection prior to day 60 or during the extended follow up period among those positive beyond day 60. One patient was admitted for remdesivir administration, due to logistical challenges with outpatient administration.

Table 2.

Characteristics of Patients with Persistent COVID-19 Infection¹

Patient	Age (years)	Sex	Underlying Diagnosis	On treatment for malignancy2	History of HCT	Number of vaccine doses3	Days to mAb administration	Duration of test positivity4	Persistent Symptoms5	Additional treatment	Bebtelovimab resistance mutations
1	64	Male	Myeloid sarcoma	Yes	No	2	1	33	No	-	N/A
2	63	Female	B-ALL	No	No	4	2	33	Yes	Nirmatrelvir/Ritonavir6	K444N, V445A
3	38	Male	Lymphoma	Yes	No	2	5	37	No	Remdesivir7	K444N
4	70	Male	AML	Yes	No	3	3	42	Unknown	-	None detected
5	65	Male	AML	Yes	No	3	Same day	46	No	-	N/A
6	79	Female	MM	Yes	No	3	5	47	No	-	N/A
7	67	Female	CLL	No	No	4	7	83	Yes	-	N/A
8	68	Female	B-ALL	Yes	No	3	3	83	Yes	-	K444N, V445F
9	70	Male	AML	No	Yes	0	1	111	Yes	Remdesivir8	K444N, V445F, G446R
10	55	Male	B-ALL	No	Yes	2	1	155	Yes	Nirmatrelvir/Ritonavir9	K444N

¹None of these patients had a COVID-19-related hospitalization, ICU stay, or died up to day 60

²Receipt of active treatment for malignancy in the 2 weeks prior to first positive COVID-19 test. Only patient #8 received anti-CD20 antibody therapy in the year prior to first positive COVID-19 test.

³Number of COVID-19 vaccine doses received prior to first positive COVID-19 test

⁴Number of days between first and last positive COVID-19 test

⁵Symptomatic more than 30 days after first positive COVID-19 test

⁶Received 2 doses on the day of first positive COVID-19 test which was stopped due to drug-drug interactions

⁷Although patient was asymptomatic, patient received a 10-day course on day 39 after first positive COVID-19 test due to his anticipated stem cell transplant

⁸Received a 5-day course on day 111 after first positive COVID-19 test

⁹Received an 18-day course on day 141 after first positive COVID-19 test

Abbreviations: Hematopoietic cell transplant (HCT), Monoclonal antibody (mAb), Acute Myelogenous Leukemia (AML), Multiple Myeloma (MM), B-cell Acute lymphoblastic leukemia (B-ALL),

Sequencing data

Sequence data was obtained for 6 out of the 10 patients with persistent infection with lineages 21K/BA.1 (n=1), 22C/BA.2 (n=2), and 22B/BA.5 (n=3) (Supplemental Table). Sequencing data for the index positive COVID-19 test was only available for one patient. In five out of six patients, the spike gene consensus sequence contained the K444N mutation, which is associated with resistance to bebtelovimab⁹. In one patient where sequence data was available for two time points, the mutation G446R went from 80% allele frequency to fixation. In addition, mutations V445F and V445A were present at low allele frequency (1–3%) in three patients. One patient did not have any mutations with known association with bebtelovimab resistance, however sequence data was only available for a single timepoint which was the day the patient tested positive for COVID -19 and received bebtelovimab.

Discussion

In this evaluation of patients at our cancer center treated with bebtelovimab for COVID-19, a coordinated systems-based approach led to prompt initiation of bebtelovimab within two days of testing positive in three-quarters of patients. We observed few hospitalizations or deaths in a population at high risk for poor outcomes. Persistent infection was noted among 11% of patients with 4 requiring additional therapies.

Neutralizing mAb therapies that target the SARS-COV-2 spike protein have played an important role throughout the COVID-19 pandemic for the treatment of high risk outpatients, particularly when nirmatrelvir-ritonavir use is precluded by significant drug-drug interactions^7,16. The initial data that led to the EUA for bebtelovimab came from in vitro neutralization studies and a phase 1/2 clinical trial conducted prior to the emergence of the Omicron variants and was not powered to determine differences in clinical outcomes.¹⁰ Since then, there have been a few published studies that examined outcomes of bebtelovimab therapy in high-risk patients^17–21,: none have focused exclusively on cancer patients.

McCreary et al found that treatment of high-risk patients with bebtelovimab was associated with 50% lower odds of hospitalization or death at 28 days compared with matched nontreated controls²². Razonable et al observed that bebtelovimab was associated with similarly low rates of severe outcomes as sotrovimab (1.3% vs 2.2%) and nirmatrelvir-ritonavir (1.4% vs 1.2%).^19,21 Yetmar et al found that solid organ transplant recipients who received bebtelovimab had similar rates of COVID-19 related hospitalization as those who received sotrovimab (3.3% vs 3.0)²⁰.

While our study shows similarly low rates of hospitalization and death^18,21 compared to previously published studies, to our knowledge, no study has evaluated outcomes with respect to persistent infection among those treated with monoclonal antibody therapy. We found that 11% of patients had evidence of persistent virologic detection beyond 30 days; half of whom had persistent symptoms. This group consisted predominantly of patients with hematologic malignancy, including those with B-cell dysfunction, similarly to other published reports of persistent COVID-19 infection^5,23–25. In contrast to other reports of persistent infection, none of our patients developed serious complications requiring hospitalization or ICU care^23,24,26,27. However, 4/10 patients required additional therapies including remdesivir and extended durations of nirmatrelvir-ritonavir, despite 3 of the 4 patients receiving bebtelovimab within 2 days of diagnosis^24,26,27.

Notably, 5 of 6 patients with persistent infection for whom we had sequence data had evidence of mutations in the spike protein associated with bebtelovimab resistance. As pre-bebtelovimab isolates were not available for sequencing, we were not able to determine whether these mutations developed as a result of intrahost viral evolution over the course of their persistent infection. Data regarding bebtelovimab resistance in the context of persistent infection is lacking. However, some studies have suggested that persistent infection in immunocompromised hosts treated with monoclonal antibody therapies may be a result of selection of resistance mutations in the spike protein. Huygens et al detected new key spike mutations associated with reduced in vitro susceptibility in 6 out of 16 (38%) patients after the administration of sotrovimab. Furthermore, 5 patients were found to have persistently high viral load after sotrovimab administration; spike mutations were found in 4 of these patients²⁸. Gliga et al also found emergence of viral spike protein mutations in 32% of their immunocompromised patients, which reduced sensitivity to sotrovimab in a pseudovirus neutralization assay²⁹. It is unknown whether early treatment with combination therapy (e.g., monoclonal antibody and antiviral therapy) could potentially modify the risk of resistance and persistent infection.

Studies have found that COVID-19 infection in patients with underlying hematologic malignancies may have a more protracted clinical course with delayed viral clearance and progressive or waxing and waning respiratory symptoms for weeks to months after initial diagnosis.^8,30 This may have a significant impact not only on an individual’s quality of life but also cancer care, leading to delays in chemotherapy or transplant; on a public health level, persistent infection among immunosuppressed individuals may lead to selection of globally significant viral variants transmissible to susceptible contacts. There are limited data describing the prevalence of persistent COVID-19 infection and outcomes among cancer patients following treatment of initial infection. Future studies of novel COVID-19 therapeutics should evaluate persistent COVID-19 infection as an outcome among immunosuppressed patients.

Limitations of this study include its retrospective nature which is subject to intrinsic sources of bias and confounding; the lack of a control group limits the ability to draw conclusions regarding the relative impact of bebtelovimab on clinical outcomes. The prevalence of persistent disease may be underestimated due to limited testing performed after day 30. However, we believe that we were able to capture clinically significant persistent infection as they presented for care and received additional therapies. Center-based selection may also have enriched for persistence due to the inclusion of a large number of hematologic malignancy patients. Lack of consistent longitudinal sampling for sequencing limits the ability to distinguish whether resistance mutations were acquired at infection versus those arising and sweeping to fixation during treatment.

Conclusions

Our retrospective review of patients at our ambulatory cancer center demonstrates low rates of hospitalization and death after treatment with bebtelovimab. A coordinated approach led to prompt initiation of this monoclonal antibody within 2 days of testing positive in most patients. Persistent infection was noted in 11% of patients, highlighting a need for novel strategies to manage highly immunosuppressed cancer patients.

Disclosures

Steven A Pergam: Receives research support from Global Life Technologies, Inc., and participate in clinical trials with F2G, Cidara and Symbio.

Catherine Liu: Site Investigator, clinical trial (Pfizer)

Abbreviations used:

COVID-19

coronavirus disease 2019

HCT

hematopoietic cell transplantation

SARS-CoV-2

severe acute respiratory syndrome coronavirus 2

mAb

monoclonal antibodies

EUA

emergency use authorization

FDA

United States Federal Drug Administration

PCR

polymerase chain reaction

ICU

intensive care unit