To the Editor,

Despite coronavirus disease 2019 (COVID-19) vaccination reduced the mortality rate in patients with hematological malignancy (HM), it remains high [1,2,3]. Therefore, additional strategies to prevent COVID-19 progression are needed. The combination of two antibodies, tixagevimab and cilgavimab, evaluated to prevent COVID-19, succeeded with a reduction by 83% [4]. Thus, it was authorized in 2022 by European Medicines Agency (EMA) [5] and United States Food and Drug Administration (FDA) [6] for prophylactic intramuscular administration. So far, few studies have analyzed the efficacy of tixagevimab/cilgavimab to prevent COVID-19 and related complications in HM patients [7, 8].

Here, we report an analysis of breakthrough COVID-19 cases after prophylactic tixagevimab/cilgavimab administration that were matched-paired in sex, age (± 10 years), type of baseline malignancy, malignancy status at COVID-19 onset and number of SARS-CoV-2 vaccine before COVID-19 to controls from the EPICOVIDEHA registry (www.clinicaltrials.gov; NCT04733729) [9].

In total, we have identified 47 patients that had received prophylaxis with tixagevimab/cilgavimab. The main characteristics of the patients are summarized in Table 1.

Table 1 Characteristic of COVID-19 cases receiving tixagevimab/cilgavimab prophylaxis and their matched-paired controls
Full size table

Twenty-seven (57.4%) were male; the median age was 69 (range 41–87) and 28 (59.6%) patients had at least one comorbidity beyond HM. Lymphoproliferative disorders (44/47, 93.6%) were the main underlying HM. Only 2 (4.3%) patients each had severe neutropenia or lymphocytopenia. Ten (21.3%) patients had active HM at the time COVID-19 onset. SARS-CoV-2 strains were genotyped in 7 (14.9%) cases, and all belonging to the omicron variant. Forty (85.1%) patients had received mRNA-based vaccinations prior to tixagevimab/cilgavimab injection. Among vaccinated patients, 37 (92.5%) had received at least two doses. Seroconversion was assessed at the time of COVID-19 diagnosis in 27/40 (67.5%) patients, with undetectable antibody response to vaccination in 20/40 (50.9%) patients.

Eleven (23.4%) patients had a mild SARS-CoV-2 infection, 21 (44.7%) a moderate infection without need of hospital admission, while 7 (14.9%) had severe infection and 3 (6.4%) critical. Thirty-six (76.6%) patients were treated, either with monoclonal antibodies, antivirals, corticosteroids, or with combination schemes (Table 1). Overall, 10 (21.3%) were admitted to a hospital. Among these, three (6.4%) were transferred to intensive care unit (ICU). Overall, two deaths (4.3%) were reported, one (2.1%) from a patient not admitted to hospital and another one (2.1%) from a patient admitted to ICU. This patient was a 69-year-old male, vaccinated with 3 mRNA doses and underlying cardiopathy, diabetes, liver disease, pulmonary disease, and smoking history. He was diagnosed with Burkitt’s Lymphoma six months before and was under active chemotherapy at the time of COVID-19 diagnosis. The death was attributed to COVID-19 and HM.

Forty-five (95.7%) of the cases were matched to controls not receiving tixagevimab/cilgavimab to analyze the potential role of this prophylaxis administration in hospitalization, COVID-19 severity and mortality. As shown in Table 1, the proportion of hospitalizations in patients receiving tixagevimab/cilgavimab prophylaxis (n = 7, 15.6%) was significantly reduced compared to controls without such prophylaxis (n = 21, 46.7%; p = 0.001). In addition, the number of asymptomatic/mild cases was higher in cases with prophylaxis (n = 15, 33.3%) compared to controls (n = 13, 28.9%), while controls had more critical COVID-19 episodes (n prophylaxis = 3, 6.7%; n no prophylaxis = 6, 13.3%). Statistically significant differences between cases and controls were observed in COVID-19 treatment too. Cases receiving prophylactic tixagevimab/cilgavimab were more likely to receive no treatment or corticosteroids only (n = 23, 51.1%) compared to controls who were more often intaking antivirals (n = 24, 53.3%, p = 0.024). All-cause mortality was more than twice as high in controls (n = 6, 13.3%) not receiving tixagevimab/cilgavimab prophylaxis as in cases (n = 2, 4.4%) under with prophylaxis.

Patients with lymphoproliferative disorders accounted for almost all cases of our report, similarly to a previous monocentric report [11]. Most of our patients had a full vaccination course, and all the patients with malignancy treatment before COVID-19, except two who were treated with conventional chemotherapy, received immunotherapy or target therapy with or without chemotherapy 6 months before COVID-19, including two CAR-T procedures and one autologous transplant. The median age and the comorbidities, mainly respiratory and cardiovascular, were higher and more frequent than in other analyses carried by EPICOVIDEHA and other real-world settings [1, 2, 9]. Despite these parameters, COVID-19 severity and mortality in our subset does not seem to negatively affect the prognosis after prophylaxis with tixagevimab/cilgavimab, as noted in the matched-paired analysis. Moreover, a limited number of patients required hospitalization, short in most cases, while only two deaths were observed. One could hypothesize that the reduction in the SARS-CoV-2 progression to critical infections can be related to the protective synergistic action of the prophylactic antibodies and the vaccination approach, as previously shown [8]. The favorable clinical outcome obtained after passive immunization with tixagevimab/cilgavimab in our cohort is quite promising if we consider that severe breakthrough COVID-19 after vaccination showed a still high mortality rate [1, 2], even though this is lower in patients who received monoclonal antibodies, antivirals, or in combination. [10].

The present study has certain limitations, due to the retrospective observational design and the potential selection bias due to the lack of indication to register the cases of patients who received prophylactic tixagevimab/cilgavimab but who did not develop the infection. Reduced sample size may have restricted the significance level of our results too, although these are promising.

In conclusion, we report that the use of tixagevimab/cilgavimab prophylaxis may trigger a COVID-19 severity reduction, in terms of hospitalization and mortality in HM patients. Nevertheless, future studies should incorporate further HM patients to confirm the best drug administration strategies in this group at high risk. Seeking for novel and more effective monoclonal antibodies is necessary for prophylactic or therapeutic purposes in HM in light of the occurrence of emerging omicron sublineages (i.e., BQ.1.1) resistant to those currently available [11].