Severity of SARS-CoV-2 infection and the safety of COVID-19 vaccination in patients receiving HSCT

The coronavirus pandemic has put a great strain on worldwide healthcare systems. Patients with hematologic malignancies have been at greater risk than the general population of experiencing severe COVID-19 and are more likely to succumb to this infection.

One of the major tools in the arsenal of weapons against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are vaccines. The speed at which vaccines have been produced to combat the COVID-19 pandemic has been impressive; however, little investigation has been carried out to assess the effectiveness of these vaccines in patients with a compromised immune response such as those who have received hematopoietic stem cell transplantation (HSCT). In addition, whether the vaccines can trigger or exacerbate graft-versus-host disease (GvHD) in patients who had undergone HSCT is unclear and required investigation.

Two recent studies have assessed the impact of SARS-CoV-2 infection,¹ and the safety of vaccination,² in patients who have undergone cellular therapy.

Mushtaq, et al. studied the impact of SARS-CoV-2 infection on patients who had undergone HSCT or been treated with chimeric antigen receptor (CAR) T-cell therapy, and assessed the clinical characteristics that were associated with poor outcomes (active GvHD, therapy, HSCT type).¹

Ali, et al. assessed the safety of two of the emergency-use authorized vaccines for SARS-CoV-2 in patients who had undergone HSCT.²

Study by Mushtaq, et al. on the severity of SARS-CoV-2 infection¹

Study design

To assess the severity of SARS-CoV-2 in patients, a single center prospective study that included 58 adult patients with COVID-19 who had received HSCT/CAR T-cell therapy was carried out. The baseline characteristics of the patients involved are shown in Table 1. The study also estimated the number of patients who were at risk of infection with SARS-CoV-2 after HSCT/CAR T-cell therapy, which was 756 between January 2019 and May 2021. The timeframe for including patients was calculated from the median time from HSCT/CAR T-cell therapy to infection, which was 17.7 months.

Only 5% of patients were treated with CAR T-cell therapy, 55% were given an allogeneic (allo) transplant and the remaining 40% received an autologous (auto) transplant (p = 0.027). Most patients underwent myeloablative conditioning (62%) and in 45% of patients the donor type was listed as self (p = 0.054). Out of all patients included, nine died from COVID-19. Factors that increased the chance of severe COVID-19 and death included: patients with myeloid disorders (p = 0.042), allo-HSCT recipients (p = 0.027), and those with a history of acute GvHD (p = 0.017).

Table 1. Baseline patient characteristics*

Results

The clinical characteristics of the 58 patients with COVID-19 infection were assessed and the characteristics that were associated with increased severity of disease and death included:

• active GvHD (p = 0.033)
• being on immunosuppressive therapy (p < 0.001)
• current immunotherapy (p = 0.019)
• lymphopenia (p = 0.049)
• high serum ferritin level (p = 0.02)
• high neutrophil: lymphocyte ratio (p = 0.040)
• high platelet: lymphocyte ratio (p = 0.008)

The number of patients estimated to be at increased risk of COVID-19 infection was 756, with an incidence of 8% out of the total cohort. Patients receiving allo-HSCT alone were more likely to get COVID-19 with an incidence of 11% compared with auto-HSCT and CAR T-cell recipients for whom the incidence was 6% and 3%, respectively. In addition, allo-HSCT patients were more likely to develop severe COVID-19 compared with CAR T-cell or auto-HSCT recipients (34% vs 17%; p = 0.013).

The severity of COVID-19 infection, treatment, and outcomes for patients receiving HSCT or CAR T-cell therapy are shown in Table 2. COVID-19 infection was fatal in 16% of patients surveyed and severe in a further 12%. All patients who experienced fatal SARS-CoV-2 infection had received allo-HCT. In the allo-HCT cohort, 16% required mechanical ventilation and 28% were admitted to an intensive care unit. In the auto-HCT group these numbers were reduced, with only 4% requiring ventilation and 9% intensive care unit admission. In the allo-HCT group, 72% recovered from infection compared with the auto-HCT group which showed 100% recovery.

Table 2. Disease severity, treatments, and outcomes in at risk patients*

Vaccine study by Ali, et al.²

A retrospective study of 113 adult patients who had received HSCT and been given at least one dose of either the BNT162b2 or mRNA-1273 vaccine was undertaken. The study also investigated the incidence of new onset GvHD or worsening of any existing GvHD symptoms.

The patient characteristics for this study are given in Table 3. Patients included had a median age of 66.5 years and 69% were male. The primary diagnosis was acute myeloid leukemia in 45.1%, with myelodysplastic syndromes and myelofibrosis the second and third most prevalent diagnoses, respectively. At the time of vaccine administration 66% of patients were receiving immunosuppressive therapy for GvHD prevention or treatment. Out of the patients included, four had history of a positive COVID-19 PCR test before vaccination. Of these patients two subsequently tested negative before vaccination but the results of the other two patients are unknown.

Table 3. Baseline patient characteristics*

Patient-reported adverse effects (AEs) were recorded for 40 days following the final dose of vaccination. The AEs experienced by patients are recorded in Table 4, but no details on severity of AEs were given. In total, 36 (31.9%) patients responded to the survey to assess AEs after vaccination. This was made up to 52 and 48 patients being evaluable after the first and second dose, respectively, with physician documentation of patient-reported AEs.

Table 4. Adverse effects following COVID-19 vaccination*

The most common AE experienced after the first dose was injection site pain (40.4%) followed by fatigue (15.4%) and myalgias/arthralgias (7.7%). Following the second dose of vaccination the rates of AEs reported increased in almost all categories with injection site pain being recorded in 43.8%, fatigue in 29.2%, and myalgia/ arthralgia in 14.6%.

The laboratory results showed the most common AE to be hepatic impairment (18.6%), with the majority of patients only experiencing Grade 1 severity. Neutropenia (13.3%), thrombocytopenia (11.5%), lymphopenia (8.8%), and eosinophilia (4.4%) were also recorded (Table 5).

Table 5. Clinical laboratory adverse effects following COVID-19 vaccination*

The effect of vaccination on GvHD incidence and severity was also investigated. In the patients included in this study the baseline level of chronic GvHD was 39.8%, predominantly involving the skin (68.9%) or with an oral focus (37.8%).

New cases of chronic GvHD occurred in 9.7% whereas existing GvHD symptoms deteriorated in 3.5% and two patients experienced both new and worsening symptoms of GvHD. These patients are now all well controlled with improving or resolved symptoms after a later follow-up.

Conclusion

Infection with SARS-CoV-2 can be severe in patients receiving stem cell transplants especially for allo-HSCT recipients with a fatality rate of almost 30% in this group. In addition, severity of COVID-19 was linked to history of Grade 2–4 aGvHD and immunosuppression therapy. In terms of vaccination, both vaccines examined in patients undergoing HSCT appear to be well tolerated with no new safety signals being recorded following at least one dose of the vaccination. There was an incidence of 9.7% of new cases of chronic GvHD and a low rate of worsening chronic GvHD symptoms (3.5%), though causality to the vaccines could not be established given the retrospective nature of the study. While the efficacy of these vaccines remains unclear in this patient population, given the increased risk of severe or fatal COVID-19 in allo-HSCT recipients, vaccination is a good option for this group despite any potential activation of inflammatory pathways and immune-related adverse events. Vaccination in patients receiving allo-HSCT is supported by recommendations from the American Society of Hematology, the National Comprehensive Cancer Network and the American Society for Transplantation and Cellular Therapy.²