ABSTRACT
We do not know the precise figure for solid organ tumors diagnosed each year in Spain and it is therefore difficult to calculate whether there has been a decrease in cancer diagnoses as a consequence of the pandemic. Some indirect data suggest that the pandemic has worsened the stage at which some non-hematological neoplasms are diagnosed. Despite the lack of robust evidence, oncology patients seem more likely to have a poor outcome when they contract COVID-19. The antibody response to infection in cancer patients will be fundamentally conditioned by the type of neoplasia present, the treatment received and the time of its administration. In patients with hematological malignancies, the incidence of infection is probably similar or lower than in the general population, due to the better protective measures adopted by the patients and their environment. The severity and mortality of COVID-19 in patients with hematologic malignancies is clearly higher than the general population. Since the immune response to vaccination in hematologic patients is generally worse than in comparable populations, alternative methods of prevention must be established in these patients, as well as actions for earlier diagnosis and treatment. Campaigns for the early diagnosis of malignant neoplasms must be urgently resumed, post-COVID manifestations should be monitored, collaboration with patient associations is indisputable and it is urgent to draw the right conclusions to improve our preparedness to fight against possible future catastrophes.
ABSTRACT
Background: Oncohematological patients may have a lower immune response against SARS-CoV-2, both to natural infection and to vaccines. Most studies have focused on the analysis of the humoral response, which means that the information available on the cellular response against SARS-CoV-2 in these patients is limited. Current recommendations include vaccination against SARS-CoV-2 in patients undergoing autologous hematopoietic stem cell transplantation (AHSTC), regardless of whether they have been previously exposed to the virus. These recommendations are based on previous studies with other vaccines. Therefore, it is necessary to analyze the immune response that is developed in these patients in order to make specific recommendations for COVID-19 vaccination. Objective: To study the humoral and cellular immune response before and after AHSTC in patients with oncohematological neoplasms who were exposed to SARS-CoV-2 before the transplantation. Materials & methods: Nine patients with previous exposure to SARS-CoV-2 who underwent AHSTC (Table 1) and 8 healthy donors who recovered from mild COVID-19 were recruited from Hospital Ramón y Cajal and Primary Healthcare Center Pedro Laín Entralgo (Madrid, Spain), respectively. Specific direct cellular cytotoxicity (DCC) of PBMCs from these patients against Vero E6 cells infected with pseudotyped SARS-CoV-2 was determined. The activation of caspase-3 in Vero cells was measured after 1 hour of co-culture with PBMCs, in which cytotoxic cell populations were analyzed by flow cytometry. Antibody-dependent cellular cytotoxicity (ADCC) was analyzed by quantifying the binding of Annexin V to rituximab-coated Raji cells as targets of PBMCs. Results: 1) 66% of AHSTC patients did not develop detectable levels of IgGs against SARS-CoV-2 (Fig. 1). In 33% of these patients with detectable IgG, the titers decreased after AHSTC, as well as their neutralizing capacity (Fig. 1B and C). 2) AHSTC patients showed increased levels of immature B cells (9.5-fold;p=0.0586) and plasmablasts (28.8-fold), in comparison with healthy donors who had mild COVID-19, while naive and resting memory B cells decreased 1.7- and 6.9-fold, respectively. 3) Specific DCC against SARS-CoV-2-infected cells increased 1.5-fold in comparison with healthy donors (Fig. 2A). Cytotoxic populations with NK phenotypes (CD3-CD56+CD16+), NKT (CD3+CD56+CD16+), and CD8+ T cells (CD3+CD8+TCRγδ+) increased 1.9- (p=0.0311), 1.9- (p=0.0592), and 1.6-fold, respectively (Fig. 2B). ADCC increased 2.1-fold in PBMCs from AHSTC patients in comparison with healthy donors (p = 0.0592). Conclusions: Our data show for the first time how the humoral and cellular immune response against the natural infection by SARS-Cov-2 may be modified in patients who were subsequently subjected to AHSTC. Although the humoral response may be reduced after AHSTC, the specific cellular response showed an increased cytotoxic activity. These results could be extrapolated to patients who were vaccinated against COVID-19 prior to AHSTC. Therefore, this information could be useful to define the recommendations for COVID-19 vaccination after AHSTC. [Formula presented] Disclosures: Garcia-Gutiérrez: Pfizer: Research Funding;Incyte: Consultancy;Novartis: Consultancy;Bristol-Myers Squibb: Consultancy.
ABSTRACT
[Formula presented] Background: Oncohematological patients present a variable immune response against many vaccines, due to the immunodeficiency caused by the disease and its treatment. The experience of vaccination against COVID-19 in oncohematological patients is low and mostly limited to studies of humoral immunity. However, the humoral and cellular immune responses between different oncohematological diseases (OHD) have not been compared. Objective: To compare the humoral and cellular immune responses in four groups of patients with OHD after receiving the first dose of one COVID-19 vaccine. Materials & methods: We recruited 53 patients in four groups according to diagnosis: Chronic Lymphatic Leukemia (CLL) (n=14), Chronic Myeloid Leukemia (CML) (n=11), Multiple Myeloma (MM) (n=15), and Allogeneic Hematopoietic Stem Cell Transplantation (ASCT) (n=13) (Table 1). Samples were collected prior to vaccination and 3 weeks after receiving one dose of COMIRNATY (BioNTech-Pzifer), mRNA-1273 (Moderna), or AZD1222 (AstraZeneca). Twenty-six healthy donors with similar vaccination pattern were recruited. IgG titers against SARS-CoV-2 were quantified by Euroimmun-Anti-SARS-CoV-2 ELISA. Direct cellular cytotoxicity (DCC) was determined against Vero E6 cells infected with pseudotyped SARS-CoV-2, measuring caspase-3 activation after co-culture with PBMCs, in which cytotoxic populations were phenotyped by flow cytometry. Antibody-dependent cellular cytotoxicity (ADCC) analyses were performed using Annexin V on Raji cells as a target. Results: 1) Early humoral response against COVID-19 vaccination in patients with CML was 5.1- (p<0.0001), 2.8- (p=0.0027), and 3.2-fold (p<0.0001) higher than in patients with CLL, MM and HSCT, respectively, and 3.5-fold higher than in healthy donors (p=0.0460) (Fig. 1). 84% of CLL patients did not develop detectable IgG titers. Individuals with OHD developed lower titres of neutralizing antibodies than healthy donors. 2) Unspecific ADCC was overall reduced in patients with OHD, mostly in individuals with ASCT (3.2-fold lower (p<0,0001)), whereas ADCC was reduced 2.2- (p<0.0001), 1.8- (p=0.0040), and 2.2-fold (p<0.0001) in individuals with CLL, CML and MM, respectively (Fig. 2A). However, specific DCC was increased 4.7-, 8.1- (p=0.0189), and 2.1-fold, respectively, in PBMCs from patients with CLL, MM, or ASCT, in comparison with healthy donors, whereas patients with CML showed a very similar response than healthy donors (Fig. 2B). 3) Levels of CD3+CD8+TCRγδ+ T cells were increased 2.2-, 2.1-, 2.7-, and 4.3-fold (p=0.0394) in patients with CLL, CML, MM, and ASCT, respectively, in comparison with healthy donors. CD3+CD8-TCRγδ+ T cells were also increased in patients with OHD, expressing high levels of the degranulation marker CD107a. However, the levels of CD3-CD56+CD107a+ NK cells were reduced 4.2- (p=0.0003) and 3.6-fold (p=0.0010) in PBMCs from patients with MM and ASCT, respectively, in comparison with healthy donors. Conclusions: We found significant differences in the early humoral immune response after one single dose of COVID-19 vaccine depending on the OHD analyzed. It was observed for the first time that the early cytotoxic immune response is efficient in all groups of patients, although superior in those who were not exposed to ASCT. Most cytotoxic activity relied on CD8+ T cells. These data can be useful to determine the efficacy of COVID-19 vaccines in patients with OHD. [Formula presented] Disclosures: Garcia Gutierrez: BMS: Consultancy, Honoraria, Research Funding;Novartis: Consultancy, Honoraria, Research Funding;Incyte: Consultancy, Honoraria, Research Funding;Pfizer: Consultancy, Honoraria, Research Funding.
ABSTRACT
To our knowledge, there is no information on long-term follow-up of recovered patients with chronic myeloproliferative neoplasms (MPN) with COVID-19. It can be hypothesized that cytokine storm of the acute phase and the post-COVID persistence of a residual inflammatory state may contribute to elicit hematopoietic stem cell insults and continuous vascular endothelial damage, leading to MPN disease progression and persistent high risk of thrombosis. Aims: To describe sequelae of COVID-19 in surviving patients with MPN following COVID-19. Methods: MPN-COVID study involved 38 European blood centers, and accrued 180 patients with MPN diagnosed with COVID-19 from Feb to Jun 2020, assessing mortality and incidence of thrombosis and bleeding during the acute phase of the pandemic [Barbui T et al. Leukemia. 2021;35(2):485-493. Barbui T et al. Blood Cancer J. 2021;11(2):21]. One-hundred-twenty-five (69%) of these patients survived and were followed up for at least 6 months. Centers were asked to update symptoms, treatments, hematological changes, major outcomes (i.e., thrombosis, disease evolution and death). Results: Among the 125 surviving patients, all eligible for the follow-up update, with a median age 70 years (IQR: 58-79), the following phenotypes were registered: PV (n=38, 30%), ET (n=37, 30%), early PMF (n=14, 11%) and MF (n=36, 29%). During the acute phase of infection, 38 (30%) were managed at home, 80 (64%) in a regular ward and 7 (6%) in ICU. Symptoms (i)The 3 prevalent symptoms during the acute phase of the disease were fever (79%), cough (56%) and dyspnea (53%), while gastrointestinal, neurological, musculoskeletal symptoms, as well as fatigue and anosmia/ dysgeusia, were present in a minor proportion, ranging from 1.6% to 17%. (ii) In the post-acute COVID-19 phase, 36 of 125 patients (32%) declared the persistence of some of these symptoms, fatigue being the most frequent (19%), while none presented persistence of fever and only 10% of dyspnea. Major outcomes (i) Major thrombosis was documented in 5 patients and involved 3 patients with MF (one fatal intestinal ischemia, two non-fatal events: splenic infarction and peripheral artery thrombosis), one case in PV (acute myocardial infarction) and one with ET (DVT of the legs with pulmonary embolism). Age varied from 61 to 80 years. The first event occurred five months after COVID-19 recovery and the Kaplan Meier thrombosis-free survival probability after 9 months was 82%. (ii) Acute myelogenous leukemia (AML) was ascertained in 3 patients (1 in MF, 1 in early-PMF, 1 in ET);one was fatal and occurred in a 49-yearold patient, the other 2 in 78- and 82-year-old patients, respectively. One non-Hodgkin′s lymphoma (in ET) and one progression of a previous parotid carcinoma (in MF) were seen in two patients aged 60 and 77 years, respectively. (iii) Deaths were reported in 8 patients (6.4%), due to AML (n=1), thrombosis (n=1), progression to prior carcinoma (n=2, 1 suspected), multi organ failure (n=1) and heart failure (n=2);the cause was unknown in a single patient. Five deaths (63%) occurred in MF patients. (iv) Overall, the event-free survival pooling together thrombosis, disease evolution and death reached 66% after 9 months from COVID- 19 recovery, indicating that, during this time of observation, 1 out of 3 patients died or have experienced at least one of the other two severe events. Summary/Conclusion: These results indicate that MPN patients who have survived SARS-CoV-2 infection continue to experience severe events suggesting an increased vigilance in the post-COVID period.