In 2023, although the attention on SARS-CoV-2 has diminished, the state of emergency we experienced and the urgent need to address the increased risk of death in cancer patients through preventive measures and vaccination campaigns have provided valuable learning experiences. Our retrospective study aims to describe the variables of interest in a cohort exclusively composed of patients undergoing anticancer therapy. It would be highly interesting to conduct future comparative analyses between healthy subjects and the oncological population undergoing active treatments to assess the impact of the disease and anticancer regimens compared to a baseline condition.

Cancer patients face a significantly higher risk of severe SARS-CoV-2 infection. Previous reports have indicated a mortality rate ranging from 5 to 30% in these patients [13,14,15]. Several factors contribute to the increased risk of death from SARS-CoV-2, including cancer- and treatment-related immunosuppression, hematological malignancies, particularly lung cancer, and non-cancer-related factors such as advanced age, metabolic disorders, and cardiovascular diseases. Endocrine-related diseases, which require specialized management during anticancer treatments and SARS-CoV-2 infection, also play a significant role, accounting for approximately 8% of cases in our series. The interaction between SARS-CoV-2 and existing endocrine dysfunctions can worsen the overall prognosis. Therefore, proper preventive measures and close attention are crucial, particularly during oncological (immune) treatments known to impact endocrine function [16].

Considering the high risk faced by cancer patients, the administration of SARS-CoV-2 vaccines is strongly recommended. While pre-marketing clinical trials provide limited data, an increasing amount of real-world evidence supports the safety and effectiveness of these vaccines, including the development of antibody responses.

In our study, we report the effects of SARS-CoV-2 vaccine administration on blood cells and the potential impact on oncological treatment in a well-characterized cohort of cancer patients. Most studies have primarily focused on safety and seroconversion, with few providing incidental reports regarding other outcomes. In our cohort, approximately 6% of patients experienced delays in treatment administration. We found a significant association between the administration of chemotherapy after the first vaccine dose and combined chemo-immunotherapy after the second dose with leukopenia. However, no statistically significant effects were observed in the general cohort of patients or those receiving immunotherapy alone. Furthermore, no significant alterations were noted in lymphocyte subpopulations, hemoglobin levels, or platelet counts.

Differential effects of various oncological treatments on white blood cells may explain these findings. Neutropenia, for instance, is predominantly observed 7–12 days after chemotherapy administration, while combined regimens may have a more delayed effect. An interesting report indicates a potential positive prognostic value of a single episode of neutropenia in lung cancer patients treated with chemo-immunotherapy, suggesting a reduced inhibitory effect on T-cells by suppressor neutrophils [17]. Several recognized risk factors, including age, low body mass index, baseline white blood cell counts, disease stage, and treatment lines, contribute to the development of neutropenia during oncological treatments. Notably, our cohort exhibited significant leukopenia but no significant neutropenia in correlation with chemotherapy and chemo-immunotherapy. Age, sex, and BMI did not show a statistically significant association with leukopenia, while immune-mediated diseases were significant predictors.

In a comparative evaluation conducted in Israel, a group of 232 cancer patients receiving various anticancer treatments and vaccinated with the SARS-Cov-2 BNT162b2 vaccine, along with 261 healthy subjects, reported a leukopenia rate of 39% among seronegative patients, without further details [7]. The prospective multicenter VOICE trial using the mRNA-1273 vaccine on patients with solid tumors undergoing chemotherapy, immunotherapy, or chemoimmunotherapy reported only one case of febrile neutropenia in the chemotherapy cohort, without providing data on the incidence of every grade of neutropenia [18].

Another study assessing the effects of the BNT162b2 vaccine in 154 cancer patients with solid tumors compared to a control group documented a delay in anticancer treatment in nine (6%) patients, primarily due to neutropenia (7 out of 9 patients) [19]. However, only a single episode of treatment delay was reported, and overall administration schedules were largely maintained. The incidence reported in this study aligns well with the delay observed in our cohort.

A recent study specifically focused on hematological abnormalities following the administration of inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac, Sinovac) and the mRNA vaccine BNT162b2 in healthy subjects reported an increased risk of leukopenia shortly after the second dose of BNT162b2 [20]. Similarly to our study, a significantly decreased leukocyte count, rather than neutrophils, was found. The authors hypothesized that leukopenia was due to reduced lymphocyte counts, but they could not support this hypothesis due to the unavailability of lymphocyte and WBC count data. In contrast, our study included these hematological parameters, but the small and heterogeneous patient sample size prevented the identification of statistically significant decreases in lymphocyte or neutrophil counts. Therefore, no conclusive evidence can be drawn regarding the specific white blood cell types involved in lower leukocyte counts. The reported global incidence of hematological abnormalities after SARS-CoV-2 vaccination ranges from 0.2 to 2.5 cases per 10,000 vaccine doses. Particularly, the study by Sing et al. observed an increased risk of leukopenia following the second dose of BNT162b2 [20]. Although subjects with cancer were not included in their study, Sing et al.‘s data support the presumed causal role of the SARS-CoV-2 vaccine in inducing temporary neutropenia. Food and Drug Administration Philippines received reports concerning hematological events [21], thus, raising interest in this matter. A case-controlled series coming from the national Philippines database and including children and adults reported on 268 individuals out of a total of 146,839,247 vaccine doses administered highlights that hematological events can be registered at a low rate without sequels and with confirmed safety [22]. In addition, another informative paper on 187 patients reports that following the second vaccine dose the neutrophil-to-lymphocyte ratio (NLR) was not significantly different in vaccinated patients versus non-vaccinated COVID-19 negative patients [23].

The variations in peripheral blood cell counts can be influenced by various factors, including the concurrent use of medications such as antiretrovirals, corticosteroids, antibiotics, and the presence of concomitant viral infections. In cancer patients undergoing chemotherapy, the use of granulocyte growth factors can also affect these variations. In our study, corticosteroids were gradually reduced before vaccination to potentially enhance seroconversion. White blood cell growth factors were used according to guidelines for high neutropenic regimens. However, the use of growth factors did not prevent the decrease in white blood cell counts, as two out of nine patients with treatment delays received pegylated factors.

Lymphocytopenia, a reduction in lymphocyte counts, is commonly observed during SARS-CoV-2 infection and is considered a poor prognostic factor [24, 25]. The interaction between the SARS-CoV-2 virus and lymphocytes is mediated through the Spike protein. We hypothesize that the vaccine-induced reaction, which characteristically leads to hypermetabolic lymph nodes [26] and potential drainage of lymphocytes, may contribute to the relative reduction of peripheral white blood cells [7]. Redistribution of white blood cells throughout the body has been documented after vaccine administration, ranging from approximately 14% to more than 50% [27], particularly highlighted after the SARS-CoV-2 vaccine. This redistribution has raised challenges in interpreting imaging results. A recent study reported 44% lymphopenia among 260 patients who underwent 18 F-FDG PET/CT scans [26]. The study found an inverse relationship between SARS-CoV-2 vaccine-induced hypermetabolic lymph nodes and lymphopenia, with the hypermetabolic pattern being more frequently associated with the absence of lymphopenia and possibly indicating a stronger immune response to the vaccine. This observation was independent of specific treatments, with 41% of the population being treatment-free and the others receiving various therapies including chemo-, immuno-, and targeted therapy.

Considering the significantly low leukocyte counts observed in patients receiving chemo- and chemo-immunotherapy, it is plausible to hypothesize that the vaccine and administered treatment have at least an additive effect. Previous studies have also highlighted a reciprocal bidirectional effect exerted by vaccination and immunotherapy [27]. The immune system is a complex network involving specialized cell populations and products, and its regulation occurs at epigenetic, genetic, and protein levels. Defects can occur in immune cells or their progenitors, leading to cancer development or an immune evasive phenotype that establishes an immune suppressive microenvironment. Therefore, we speculate on the potential reciprocal benefits of combining SARS-CoV-2 vaccination with immunotherapy in cancer patients. Further evaluation is warranted based on findings from this retrospective study.

Guidelines in oncology have recommended the use of growth factors to reduce the risk of febrile neutropenia when the risk exceeds 20% [28]. While most recommendations support this practice to minimize the risk of infection [29, 30], concerns have been raised regarding increased neutrophil extracellular traps, elevated levels of inflammatory cytokines, and the potential excess risk of thrombosis. In line with these considerations, the administration of prophylactic granulocyte colony-stimulating factor (G-CSF) should consider the increased risk of an inflammatory state and suggests the cautious use of short-acting G-CSFs [31,32,33]. Additionally, the administration of chemotherapy can influence the seroconversion induced by the vaccine, with poorer seroconversion observed when the interval between chemotherapy and vaccination is less than 15 days [34].

Serological testing provides valuable information about the immune response to SARS-CoV-2 following natural infection and vaccination. Most studies have used antigen S tests for assessing vaccine-induced immune response [7, 8]. On the other hand, tests based on anti-N antigen provide information about natural infection in vaccinated individuals. Detection of anti-N antibodies following vaccination is considered indicative of encountering the virus. A wide spectrum of cut-off index (COI) values has been observed in asymptomatic, mildly symptomatic, and severely symptomatic SARS-CoV-2 infected patients [35].

The S1 viral subunit plays a crucial role in binding to functional ACE2 receptors on susceptible human cells, enabling the virus to enter these cells. Blocking the virus’s entry through anti-spike antibodies significantly contributes to virus neutralization. Traditionally, higher levels of neutralizing antibodies targeting the spike protein of SARS-CoV-2 have been associated with greater vaccine-induced protection. However, with the increasing prevalence of spike protein mutations in variants, the induction of neutralizing antibodies against the N-protein may also be relevant for maintaining protection. The role of anti-N antibodies in conferring long-term immunity in individuals infected with the virus is still unknown [36]. Due to the retrospective nature of our study, we did not evaluate the anti-S response in this patient cohort.

In conclusion, although our study is limited by a relatively small sample size, it provides insights into the hematological changes following mRNA vaccines in patients with solid cancers undergoing active oncological treatments. Importantly, our findings suggest that the administration of mRNA vaccines does not compromise the scheduled delivery of oncological treatments. Despite its limitations, this study contributes to the growing body of evidence supporting the safe and effective use of mRNA vaccines in this specific patient population.