ABSTRACT
We recently investigated incidence of SARS-CoV-2 infection and COVID-19 outcomes in MGUS patients during the early waves of pandemic, when vaccines were still not available (Sgherza N. et al Haematologica. 2022). In that study, we found that these subjects neither have an increased risk of contracting SARS-CoV-2, nor show poorer COVID-19 outcomes with respect to controls. Aiming to specifically address the clinical effects of vaccines, we compared incidence and outcome of SARS-CoV-2 infection of 1,454 previously described, not vaccinated MGUS patients (91 of whom were SARS-CoV-2 positive), with those observed in a similar population during the national vaccination campaign. So far, we have obtained retrospective information from 41 individuals found to be SARS-CoV-2 positive among 763 MGUS patients analyzed after at least two doses of anti-SARS-CoV-2 vaccine received between April 2021, and January, 2022. The mean age of this group was 64.1 +/-14.1 years (range 31-90);16 patients were female (39%), and 25 were male (61%). About MGUS-subtypes, the most frequent one was IgG-lambda (n=20;48.8%), followed by IgG-kappa (n=14;34.1%), IgA-kappa (n=3;7.3%), IgA-lambda (n=2;4.9%) and IgM-kappa (n=2;4.9%). Most of patients (39/41, 95%) were at low or low-intermediate risk, according to Mayo Clinic prognostic model. Twenty-one (51.2%) patients developed SARS-CoV-2 infection after two doses (5, 15 and 1 patients receiving ChAdOx1-S, BNT162b2 mRNA and mRNA-1273 vaccines, respectively), twenty (48.8%) after three doses (BNT162b2 mRNA or mRNA-1273 as 'booster' dose, repectively). The mean number of days between last dose of vaccine and SARS-CoV-2 infection was 98.8 +/-77.8 (range 2-240). The two populations of SARS-CoV2 positive MGUS patients (before and after vaccination) were comparable for age, sex and presence of co-morbidities (data not shown). Overall, rates of symptoms (59.3% vs 31.8%), hospitalization (20.9% vs 0%), and hospitalization in Intensive Care Unit (11% vs 0%) were significantly higher in still not vaccinated MGUS patients than in those who had received vaccines (Table 1). A strong trend toward a higher rate of deaths (8,8% vs 0%) was also observed in not vaccinated patients, although it did not reach statistical significance, probably due to the small number of evaluated patients. Interestingly, incidence of SARS-CoV-2 detection in vaccinated patients was not significally different from that of patients analyzed before vaccination (5.4% vs 6.2%, respectively) (p=0.402). Our data indicate that the possibility to be infected by SARS-CoV-2 is probably not significantly reduced by vaccination (even after three doses), likely also because of the higher diffusion capacity of the recently recognized Omicron viral variants. However, as observed in normal population and in other hematological contexts, the clinical outcome of COVID- 19 may be significantly improved after vaccination in MGUS patients, with less of one third of patients who were symptomatic and no case of hospitalization or death in our series. These observation reinforces the need to proceed with an active vaccination program in these patients. .
ABSTRACT
Despite SARS-CoV-2 transmission being a complex phenomenon, greater population density seems to be a risk factor. The aim of this study was to analyze through an epidemiologic urban health approach the relationship between population density and SARS-CoV-2 incidence using data which are comparable with regard to testing strategies. All 10,300 SARS-CoV-2 confirmed cases between October and December 2020 were included. We conducted separate analysis by gender standardizing and stratifying by age and month. In the Province Capital (p.d.=765 inhabitants/km2), standardized SARS-CoV-2 incidence rate was higher than the expected, both in men (SIR=1.17, 95%CI=1.12;1.22, p<0.0001) and women (SIR=1.20, 95%CI=1.15;1.25, p<0.0001). In municipalities with p.d. >200 inhabitants/km2, standardized SARS-CoV-2 incidence rate was similar to the expected (p>0.05). In municipalities with p.d. <200 inhabitants/km2, standardized SARS-CoV-2 incidence rate was lower than the expected, both in men (SIR=0.85, 95%CI=0.81;0.90, p<0.0001) and women (SIR=0.84, 95%CI=0.80;0.88, p<0.0001). Stratified analysis by months with likelihood ratio test showed heterogeneity of the p.d. effect in men and women (p<0.05). SARS-CoV-2 incidence rate seemed to be higher in most densely populated areas, both in men and women. Our results confirmed the great importance of restrictive measures as well as the importance of limiting the epidemic wave in the initial stages and could help guide pandemic management strategies according to urban context and population density.
ABSTRACT
Patients with hematological malignancies (HM) undergoing hematopoietic stem cell transplantation (HSCT) have an increased vulnerability to SARS-Cov-2 (Sharma et al, Lancet Haematology 2020;Ljungman et al, Leukemia 2021), the reason why international guidelines strongly support the need for a protective vaccination for these subjects. The most relevant data currently available on the response to a complete anti-SARS-Cov-2 vaccination cycle in HM patients after HSCT refer to 314 patients reported in a Lithuanian national survey (Maneikis et al, Lancet Haematol 2021). In this study, the median titers of antibodies against SARS-Cov-2, determined 7-21 days after the second vaccination, were comparable to that of healthy controls (HC) in both autologous and allogeneic groups, with no patient found below the protective threshold of 50 arbitrary units (AU)/ml. Notably, the large majority of patients had received the transplant more than 1 year before vaccination. In a prospective, cohort study, we compared 114 patients, who had received an autologous or allogeneic HSCT at least three months before the first dose of vaccination, to 107 HC, matched for age and sex. Study population and HC received two doses of BNT162b2 anti-SARS-Cov-2 mRNA vaccine on days 1 and 21, between April and May 2021. Serological tests were performed by a commercially available immunoassay for the quantitative determination of anti-spike IgG antibodies to SARS-Cov-2. The cut-off for defining responders was 50 or greater AU/ml. Patients and HC samples were collected four weeks after the second dose of the vaccine. Table 1 reports the main clinical characteristics of patients and HC. Eighteen of 114 patients (16%) did not respond (24% in the allogeneic group, 6% in autologous recipients). Overall, median antibodies titers did not differ between HC and the entire cohort of transplanted patients, recipients of allogeneic HSCT, all patients responding to the vaccine or responders in the autologous subgroup (Figure 1A). All autologous HSCT recipients had significantly lower titers of antibodies than HC, while higher levels were found in responders who had received allogeneic HSCT (Figure 1A). Responders in the allogeneic subgroup showed antibodies titers significantly higher than responders in the autologous subgroup (Figure 1B). We further stratified patients in three groups, according to the time elapsed from transplant to vaccination: G1:<1 year;G2:1-5 years;G3:>5 years. Higher antibodies titers were observed in HC compared to all transplanted patients in G1 (Figure 1C), including both allogeneic (Figure 1D) and autologous (Figure 1E) HSCT recipients. No differences emerged in G2 between HC and all patients (Figure 1C), allogeneic (Figure 1D) or autologous (Figure 1E) HSCT recipients. Finally, no differences were found in G3 when comparing HC with all patients (Figure 1C) or allogeneic recipients (Figure 1D), whereas patients in the autologous subgroup showed significantly lower titers than HC (Figure 1E). Myeloma patients with controlled disease showed higher titers than patients with active disease (Figure 1F). According to median age, autologous HSCT recipients older than 57 years had significantly lower antibody levels than younger patients (Figure 1G). Autologous vs allogeneic HSCT, age of all patients and of allogeneic HSCT recipients, sex, type of allogeneic HSCT, conditioning regimen, age and sex of donor, occurrence of GVHD, disease type and single vs double autologous HSCT did not significantly impact on antibody levels (data not shown). No relevant side effects were recorded after vaccination. With a median follow up of 12 weeks, no case of COVID19 occurred among vaccinated patients. In our single center study, patients with a previous history of HSCT tolerated well BNT162b2 vaccine and mounted a potentially protective immune response in the majority of cases one month after two doses of vaccine. However, lack of response was not rare, especially in the allogeneic setting. The main factor associated with the quality of response was the tim from HSCT, with lower responses within the first year from transplant and differences between autologous and allogeneic groups transplanted more than five years before vaccination. Here, a consolidated, complete immune reconstitution in allogeneic HSCT recipients, as well as age and a still active disease in the autologous setting, could have played opposite pivotal roles. [Formula presented] Disclosures: Delia: Gilead: Consultancy;Amgen: Consultancy;abbvie: Consultancy;Jazz pharmaceuticals: Consultancy.
ABSTRACT
Introduction. Monoclonal Gammopathy of Undetermined Significance (MGUS) is a pre-malignant plasma cell disorder reported in approximately 3% of individuals aged > 50 years, characterized by a low risk (about 1% per year) of evolution into “overt” myeloma or other lymphoproliferative diseases. It is classified as IgM-MGUS (15%) and non-IgM-MGUS (80-85%). MGUS is usually asymptomatic, but a higher risk of deep venous thrombosis and infection has been reported. In March 2020, “Coronavirus Disease 2019” (COVID-19) outbreak has been declared a pandemic by the World Health Organization. Regarding outcome of COVID-19 in patients with plasma cell dyscrasia, many papers have been published about multiple myeloma (MM), reporting a higher fatality rate respect to general population, while few data are available about the outcome of SARS-CoV-2 infection in patients with MGUS. Methods. We collected clinical data on MGUS Apulian patients with SARS- CoV-2 infection, tested by RT-PCR on nasopharyngeal swabs between March 1st, 2020 and April 30st, 2021. Among 1454 MGUS patients followed at our center, 91 were found SARS-CoV-2 positive, enrolled in this observational, retrospective study and compared with 182 age and sex-matched normal controls. Clinical data collected regarded: symptoms, hospitalization, hospitalization in intensive care unit, death. Calculations were carried out using Stata MP17. Results. Mean age of whole group (n. 273) was 65,3+/-13,3 years (range: 29-89), with no statistically-significant differences (p=0,734) observed between MGUS-group (65,6+/-13,3;range: 29-89 years) and controls-group (65,2+/- 13,4;range: 29-89 years). Mean number of comorbidities in the whole group was 1,2+/-1,2 (range: 0-5) and no statistically-significant differences (p=0,844) were found between MGUS-group (1,3+/-1,3;range: 0-5) and control group (1,2+/- 0,9;range: 0-3). About MGUS-subtypes, the most frequent was IgG-kappa (n=36;39,6%), followed by IgG-lambda (n=27;29,7%) and IgM-kappa (n=6;6,6%). Regarding MGUS risk-stratification, application of Mayo Clinic model identified 22 patients (24,2%) with low risk, 22 (24,2%) with low-intermediate risk, and 3 (3,3%) with high-intermediate risk;in 44 patients (48,3%) this data was missing. Immunoparesis was present in 13 cases (14,3%) and absent in 55 (60,4%), missing in 23 (25,3%). No patient developed MM or a lymphoproliferative disease progression during and immediately after COVID-19. Rates of symptoms (59,3% vs 56%), hospitalization (20,9% vs 14,3%), hospitalization in intensive care unit (11% vs 8,8%) and death (8,8% vs 5,5%) were slightly higher in MGUS group than controls (Table 1), but these differences were not statistically significant. A statistically significant association (p<0,05), was observed between higher age and death in both groups. Lastly, incidence of SARS-CoV-2 infection in MGUS patients (6,2%) was not statistically significant different from that observed in the population of the Puglia region (5,8%) in the same period. Conclusions. To our knowledge, this report is the largest study of patients with MGUS and SARS-CoV-2 infection to date. In our study patients with MGUS did not show an increased incidence of this infection compared to the general population and did not appear to represent a risk factor for poor outcome in COVID-19. [Formula presented] Disclosures: No relevant conflicts of interest to declare.
ABSTRACT
Cancer patients are at a higher risk of “Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)” infection than patients without cancer. In particular, Multiple Myeloma (MM) patients are at serious risk of contracting this severe infection because of many factors, such as immunosuppression, comorbidities, immune deregulation and frequent accesses to hospital. Several multicenter studies on MM patients and “Coronavirus Disease 2019” (COVID-19) have been published. At present, there are no proven agents for treatment or prevention of SARS-COV-2 infection, so single or combined therapeutic approaches repurposing existing anti-viral and anti-inflammatory drugs are currently utilized to treat patients with moderate to severe COVID-19. Among these, IL-6 inhibitors seem to be promising for the management of the massive cytokine storm associated with the development of the typical lung damage and consequent acute respiratory distress syndrome occurring in the most aggressive patterns of SARS-COV-2 infection. While different reports have been published about concomitant MM and Covid-19 infection, few data are available about the specific outcome of MM patients treated with IL-6 inhibitors. Available IL-6 inhibitors are siltuximab, tocilizumab and sarilumab. Siltuximab binds directly to IL-6, while tocilizumab and sarilumab target its soluble (sIL-6R) and membrane-bound receptors (mIL-6R). To our knowledge, from literature review, including case reports and case series, 49 patients (Table 1), with severe confirmed COVID-19 and MM, were treated with IL-6 inhibitors. The most used IL-6 inhibitor was tocilizumab, FDA approved for the management of CAR T-cell related Cytokine Release Syndrome (CRS) while no patient was reported treated with siltuximab. Clinical outcome (alive/deceased) is available for 40 on 49 patients with questionable results: 20 patients (50 %) died, 20 patients (50%) survived. Certainly, although this retrospective review includes a quite large cohort of patients (556), providing interesting information, several limitations to generalizability of findings are present. First, the number of patients with MM and COVID-19 infection treated with IL-6 inhibitors in the world, is certainly higher than one reported in case reports/case series. Second, data represent experiences of patients from different centers, treated differently in terms of drugs and according to their availability at different hospitals. Third, patients received also additional therapies for COVID-19 including hydroxychloroquine and anti-viral agents, so it is no possible distinguish absolutely the efficacy of tocilizumab (or other IL-6 inhibitors) from other drugs. An interesting aspect to focus on is the potential use of tocilizumab against MM. IL-6 is the major growth factor of human myeloma cells through an autocrine or a paracrine mechanism and tocilizumab was reported to inhibit their proliferation in vitro and to be effective in stabilize serum monoclonal protein in patients with systemic diseases (i.e. rheumatological disorders) and concomitant MM. So, in the subset of active MM patients with severe COVID-19 infection, in whom other anti-myeloma treatments could be not administrable, the possibility that tocilizumab could represent a treatment option with a double action against cytokine storm due to COVID-19 and MM itself would warrant to be verified.