Outcome of COVID-19 in allogeneic stem cell transplant recipients: Results from the EPICOVIDEHA registry

Background The outcome of COVID-19 in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is almost uniformely considered poor. The aim of present study was to retrospectively analyse the outcome and risk factors for mortality in a large series of patients who developed COVID-19 infection after an allogeneic HSCT. Methods This multicenter retrospective study promoted by the European Hematology Association – Infections in Hematology Study Working Group, included 326 adult HSCT patients who had COVID-19 between January 2020 and March 2022. Results The median time from HSCT to the diagnosis of COVID-19 was 268 days (IQR 86-713; range 0-185 days). COVID-19 severity was mild in 21% of the patients, severe in 39% and critical in 16% of the patients. In multivariable analysis factors associated with a higher risk of mortality were, age above 50 years, presence of 3 or more comorbidities, active hematologic disease at time of COVID-19 infection, development of COVID-19 within 12 months of HSCT, and severe/critical infections. Overall mortality rate was 21% (n=68): COVID-19 was the main or secondary cause of death in 16% of the patients (n=53). Conclusions Mortality in HSCT recipients who develop COVID-19 is high and largely dependent on age, comorbidities, active hematologic disease, timing from transplant and severity of the infection.

Background: The outcome of COVID-19 in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is almost uniformely considered poor. The aim of present study was to retrospectively analyse the outcome and risk factors for mortality in a large series of patients who developed COVID-19 infection after an allogeneic HSCT.
Methods: This multicenter retrospective study promoted by the European Hematology Association -Infections in Hematology Study Working Group, included 326 adult HSCT patients who had COVID-19 between January 2020 and March 2022.
Results: The median time from HSCT to the diagnosis of COVID-19 was 268 days (IQR 86-713; range 0-185 days). COVID-19 severity was mild in 21% of the patients, severe in 39% and critical in 16% of the patients. In multivariable analysis factors associated with a higher risk of mortality were, age above 50 years, presence of 3 or more comorbidities, active hematologic disease at time of COVID-19 infection, development of COVID-19 within 12 months of HSCT, and severe/critical infections. Overall mortality rate was 21% (n=68): COVID-19 was the main or secondary cause of death in 16% of the patients (n=53).
Conclusions: Mortality in HSCT recipients who develop COVID-19 is high and largely dependent on age, comorbidities, active hematologic disease, timing from transplant and severity of the infection.

Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was recognized in late 2019 and developed into a pandemic with lifethreatening disease documented in high-risk groups (1). Allogeneic hematopoietic stem cell transplantation (HSCT) has been increasingly adopted as a curative treatment option for a great variety of hematologic malignancies, however HSCT recipients are vulnerable to viral infections due to neutropenia, immunosuppressive treatments, graft-versus-host disease (GVHD) and incomplete immune reconstitution occurring in the post-transplant period. In this respect, efforts have been made not to postpone transplantation during the pandemic (2). To date, scattered case series of HSCT recipients with coronavirus disease 2019 (COVID-19) have been reported (3)(4)(5)(6)(7)(8)(9)(10)(11). Overall, the prognosis of HSCT recipients has been uniformly reported dismal with COVID-19-related mortality ranging between 20 and 39% (5,6,(12)(13)(14)(15)(16), much higher than in the general population. Advanced age, presence of active GVHD and a short time interval from HSCT to COVID-19 were identified as predictors of adverse outcome (3,5,14). These findings may be discouraging the treating physicians, fearing for the high fatality rate of HSCT recipients. On the other hand, the use of immunosuppressive agents may potentially mitigate the deleterious systemic inflammatory syndrome secondary to the cytokine storm unleashed by SARS-Cov-2 leading to multiorgan dysfunction and eventually death. According to this observation some studies have reported a lower mortality rate of allogeneic HSCT recipients as compared to non-stem cell transplant patients (18% vs 31%) (3). Hence, aim of our retrospective study was to address the outcome and risk factors for mortality in a large series of patients who developed COVID-19 infection after an allogeneic HSCT.

Study population
This is retrospective multicenter cohort study promoted by the European Hematology Association -Infections in Hematology Study Working Group (EHA-IDWP; EPICOVIDEHA survey, https:// pubmed.ncbi.nlm.nih.gov/34235404/). Data have been collected on all consecutive adult patients who received an allogeneic HSCT and had COVID-19 in more than 150 European centers between January 2020 and March 2022. Only patients for whom allogeneic HSCT represented the last treatment performed were included into the study. Each institutional review board independently approved the study.

Data collection
Researchers at each center collected data using an online questionnaire hosted at www.clinicalsurveys.net, EPICOVIDEHA is registered at http://www.clinicaltrials.gov, with the identifier NCT 04733729. Only de-identified data have been analyzed.
Data collected included: age at transplantation (dichotomized as <50 years and ≥50 years), sex (male vs female), time from HSCT to the diagnosis of COVID-19, immunosuppression within 6 months of COVID-19 diagnosis, conditioning intensity (myeloablative vs reduced intensity), GVHD prophylaxis, time to engraftment, development of acute or chronic GVHD before COVID-19 diagnosis and immunodeficiency scoring index (ISI) at the time of COVID-19 infection. Clinically significant outcomes (hospital admission and intensive care unit [ICU] admission, vital status) were also evaluated. We did not collect information on treatment strategies of COVID-19.

Definitions
Confirmed cases of COVID-19 were defined by a positive reverse transcription polymerase chain reaction (RT-PCR) assay of a specimen collected on a nasopharyngeal swab.
The severity of COVID-19 at admission is graded according to the China Center for Disease Control and Prevention definitions (17).
Disease status at the time of SARS-CoV-2 detection was defined according to each specific disease's revised criteria for leukemia, myeloproliferative neoplasm, multiple myeloma, and lymphoma. The ISI was calculated as previously described (4).

Endpoints and statistical analysis
The primary outcome of this analysis was overall survival 30 days after COVID-19 diagnosis.
Categorical variables were summarised in frequencies and percentages and continuous variables with median, interquartile range (IQR) and absolute range. Additionally, to determine which factors were associated to mortality in our sample, we performed a Cox regression, with the backwards Wald method. Those variables with a p value <0.1 in the univariable model were included into the multivariable analysis. A p<0.05 was considered significant. Overall survival probability has been plotted in a Kaplan-Meier survival curve. SPSSv25.0 was employed for statistical analyses (SPSS, IBM Corp., Chicago, IL, United States).

Demographics
Between January 2020 and March 2022, 326 patients receiving an allogeneic HSCT were diagnosed with COVID-19 infection and registered in EPICOVIDEHA.
COVID-19 severity was mild in 21% of the patients, severe in 39% and critical in 16% of the patients; 79 patients (24%) had asymptomatic infection.
Among the 184 patients who were hospitalized, 51 patients (28%) were admitted to ICU, and 34 patients required mechanical ventilation.
Patient characteristics at the time of COVID-19 diagnosis are summarized in Table 2.

Factors associated with mortality and outcome of COVID-19 infection
The results of Cox regression analysis for factors associated with mortality after COVID-19 diagnosis in allogeneic HSCT recipients are shown in Table 3.
In multivariable analysis factors associated with a higher risk of mortality were, age 50 years or older, presence of 3 or more comorbidities, active hematologic disease at time of COVID-19 infection, development of COVID-19 within 12 months of HSCT, and severe/critical infections. The type of HSCT, the intensity of preparative regimen, the presence of aGVHD and cGVHD before COVID-19 infection and ISI group were not associated with increased mortality.
Vaccination and the number of doses (one, two or more doses) administered did not have an impact on the outcome of the patients.

Discussion
To our knowledge, the present study includes the largest series of allogeneic HSCT recipients with COVID-19. The aim of our analysis HSCT, hematopoietic stem cell transplantation; AML, acute myeloid leukemia; MDS myelodysplastic syndrome; ALL, acute lymphoblastic leukemia; CR, complete remission; R/R relapse/refractory; RIC, reduced intensity conditioning; MUD, matched unrelated donor; BM, bone marrow; PBSC, peripheral blood stem cell; CB, cord blood; CI, calcineurin inhibitors; PT/ Cy, post-transplant cyclophosphamide. *Comorbidities included diabetes, liver disease, renal impairment, smoking history. was to evaluate the outcome of COVID-19 in a cohort of patients particularly susceptible to infectious complications and to investigate risk factors that may impact on mortality. Patients were at high risk for severe disease and adverse outcome from COVID-19: a large proportion of patients (70%) received HSCT from alternative donors, 16% had critical infection and required ICU admission. Even more importantly, the median time from HSCT to COVID-19 infection was 268 days, remarkably shorter when compared to other reports (474-790 days) (3,4,12,14). This finding might mirror the adoption of less stringent measures of stewardship among transplant centers after the 1 st and 2 nd COVID-19 wave. In fact, it should be recognized that one third of the patients had COVID-19 infection diagnosed during the 3 rd wave.
Our study demonstrated that COVID-19 infection is a severe complication in allogeneic HSCT recipients with an attributable mortality of 16%. Our results are roughly superimposable to those reported from other recent studies. The CIBMTR reported a COVID-19-related mortality rate of 20% in 184 allogeneic HSCT recipients (14), Piñana et al. analyzed the outcome of COVID-19 in 65 allogeneic HSCT patients and reported a mortality of 18% (3). An EBMT (European Society for Blood and Marrow Transplantation) and GETH (Spanish Group of Hematopoietic Stem Cell Transplantation) prospective study reported an overall mortality rate of 28% among 236 allogeneic HSCT recipients (12). Other smaller series documented similar mortality rates ranging from 20 to 25% (5)(6)(7)9). It is worthwhile recalling that mortality in the general population declined over the 2 nd and 3 rd waves: this observation should be considered when we consider that only 20% of our patients were diagnosed with COVID-19 during the first wave.
Multivariable analysis showed that age, comorbidities, active disease, and severe/critical infection have been associated with higher mortality, consistent with previous studies (3,4,12,14). Nevertheless, it should be noted that a consistent number of comorbidities and demographic characteristics (i.e. diabetes, BMI, race) potentially influencing the outcome of the patients were not available Similarly, time from HSCT to COVID-19 diagnosis of less than 12 months was a factor significantly associated with fatal outcome. Surprisingly, GVHD at the time of COVID-19 diagnosis did not impact on the outcome of our patients, however it should be underscored that only 5% of the patients had grade II-IV acute GVHD and 10% had moderate/severe chronic GVHD; in addition, data on the cumulative dose of steroids and the different immunosuppressive agents used were not available.
Likewise, mortality was not influenced by the use of immunosuppressive drugs and steroids during the 6 months preceding COVID-19 diagnosis, notwithstanding the number of patients on treatment was extremely high. Whether the administration of two to three doses of vaccine in 20% of the patients might have contributed to dampen the severity of the disease as documented in some studies (18,19), remains speculative. Regrettably, we do not have data on patient seroconversion and Bcell reconstitution underpinning the effectiveness of vaccination.
ISI did not result as an independent risk factor for poor outcome as shown by Ljungman et al, however several variables included in the ISI (ANC and ALC, GVHD) were poorly represented in our study group. Two studies including a small number of patients reported a favorable outcome of patients receiving PT/Cy as GVHD prophylaxis, since cytokine release syndrome (CRS) associated with haploidentical HSCT and COVID-19 share similar pathophysiology (10, 11). It is well known that a dysregulated, excessive immune response with increased pro-inflammatory cytokines levels during the later phases of COVID-19 infection may lead to multiorgan failure (20). Cy is an alkylating agent largely used in the setting of haploidentical HSCT due to its capacity of depleting rapidly proliferating T-cells while sparing regulatory-T cells (21). According to these observations, it has been postulated a potential effect of Cy in mitigating the COVID-19 infection (22), however in our cohort, we did not find any significant  relationship between the type of GVHD prophylaxis and mortality, including PT/Cy in 22% of the cases. ANC and ALC at the time of COVID-19 diagnosis did not result as significant factors for disease severity as shown in other studies (3,5), however a minority of our patients were neutropenic or had low ALC. We recognize limitations of our study inherent to the retrospective design. We cannot exclude a possible selection bias in the registration of the patients among such a large number of centers. Our study presents a significant heterogeneity in terms of different variants of concern, namely wild type, delta and omicron variants, each with distinctive transmission rates and infection associated mortality. Information on the treatment of COVID-19 were not available and the management of patients with COVID-19 across centers may differ profoundly, potentially influencing clinical outcome.  Kaplan-Meier overall survival curve after diagnosis of COVID-19 infection in 326 allogeneic HSCT recipients.

Conclusion
Our study on a large number of patients who developed COVID-19 infection following HSCT, shows a high mortality rate compared to the general population. In this respect, it is of upmost relevance to see whether vaccination of patients after HSCT and the availability of pre-and post-exposure prophylactic measures effectively mitigates the severity of the disease in this vulnerable group of patients.

Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement
The studies involving human participants were reviewed and approved by EPICOVIDEHA was approved by the local ethics committee of the Fondazione Policlinico Universitario Agostino Gemelli -IRCCS, Università Cattolica del Sacro Cuore of Rome, Italy (Study ID: 3226). The patients/participants provided their written informed consent to participate in this study.