Opportunistic Infections in Patients Receiving Daratumumab Regimens for Multiple Myeloma (MM)

Background Daratumumab-based treatment regimens for MM have improved outcomes for both transplant-eligible and ineligible patients. As a result, patients are receiving longer exposure to this CD38 targeting monoclonal antibody. Adverse events (AE) including hypogammaglobulinemia, neutropenia, and lymphopenia have been reported in both clinical trials and retrospective studies, but with limited and contrasting data on the associated risk of developing infections. Furthermore, there remains a paucity of data on the risk of developing opportunistic infections in this growing patient population. The aim of this study is to assess the association between daratumumab-containing regimens and the development of opportunistic infections as reported to the Food and Drug Administration's Adverse Events Reporting System (FAERS), a pharmacovigilance monitoring database. Methods/Materials FAERS was queried for AE reports to evaluate the association of Cytomegalovirus reactivation (CMVr), Hepatitis B reactivation (HBVr), progressive multifocal leukoencephalopathy (PML), Herpes Zoster (HZ), Tuberculosis (TB), Pneumocystis Jirovecii (PJP), and Bronchopulmonary Aspergillosis (BA) with daratumumab-containing regimens from 2015-2021. The strength of an association between an infection reported with daratumumab in MM was compared with all events reported in MM treated patients, and the composite of all reported AE cases in FAERS. Signal disproportionality was calculated by using the reporting odds ratio (ROR), with the precision of the ROR determined by 95% confidence intervals (95% CI). Associated p-values were calculated by using chi-squared or Fisher's Exact test, with a p-value <0.05 considered statistically significant. Other reported variables concomitantly reported with daratumumab-treated patients were collected, including reported chemotherapy, >1 MM regimen, proteasome inhibitor (PI) use, or lenalidomide use. Results Out of the 12,393,747 AE cases reported to FAERS, there were 288,294 (2.3%) AE reported with MM patients, of which 7,152 (2.5%) were reported with daratumumab. There were 195 (2.7%) opportunistic infections reported with daratumumab, with a median age of 64 (42-89) years, and 64 (32.8%) were females. HZ (N=49, 25.1%) was the most common, followed by CMVr (N=43, 22.0%), PML (N=35, 17.9%), PJP (N=34, 17.4%), BA (N=16, 8.2%), HBVr (N=13, 6.7%), and TB (N=5, 2.5%). Neutropenia was reported in 29 (14.9%) of these patients, lymphopenia in 6 (3.1%), and hypogammaglobulinemia in 1 (0.51%) case. With comparison to all reported events in the FAERS database, a significant signal disproportionality was found with HZ (ROR 3.48 [95% CI 2.63, 4.61], p<0.0001), CMVr (ROR 33.31 [95% CI 24.61, 45.08], p<0.0001), PML (ROR 16.69 [95% CI 11.96, 23.31], p<0.0001), PJP (ROR 12.87 [95% CI 9.18, 18.05], p<0.0001), BA (ROR 9.82 [95% CI 6.01, 16.06], p<0.0001), and HBVr (ROR 9.35 [95% CI 5.42, 16.14], p<0.0001). When comparing reported infections with AE associated with MM patients in FAERS, HZ (ROR 1.59 [95% CI 1.19, 2.11], p=0.0015), CMVr (ROR 28.82 [95% CI 19.44, 42.72], p<0.0001), PML (ROR 13.04 [95% CI 8.89, 19.12], p=<0.0001), PJP (ROR 9.58 [95% CI 6.59, 13.96],p<0.0001), BA (ROR 11.46 [95% CI 6.56, 20.01], p<0.0001), HBVr (ROR 4.41 [95% CI 2.49, 7.83],p<0.0001), and TB (ROR 6.15 [95% CI 2.39, 15.78], p<0.0001) met statistical significance (Table 1). The proportion of concomitant medications reported with daratumumab is reported in Figure 1. Conclusion This study suggests a significant association between daratumumab-based regimens and multiple opportunistic infections. Patients with known chronic viral infections or who are heavily pretreated should be monitored for these potential complications. FAERS data is beneficial in reporting associations between medications and AE but does not necessarily indicate causality. Further studies are needed to corroborate these findings. Figure 1 Figure 1. Disclosures Ganguly: Kadmon: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.

Impact Of Adaptive Natural Killer Cells, KLRC2 Genotype And Cytomegalovirus Reactivation On Late Mortality In Patients With Severe Covid-19 Lung Disease

Objective: COVID-19 infection results in severe lung disease in a small but significant number of infected patients. The etiopathogenesis in a subset of such patients, who continue to have progressive pulmonary disease following virus clearance remains unexplored. Methods: We investigated the role of NKG2C+/NKG2A- adaptive natural killer (ANK) cells, KLRC2 genotype and cytomegalovirus reactivation in 22 such patients. Results: The median duration of virus positivity was 23 days and the median duration of hospitalisation was 48 days. The overall survival at 60 days in this group was 50%. Older age and comorbidities impacted survival negatively. CMV viremia was documented in 11 patients, with a survival of 25% vs 80% in those without viremia with viral load correlating with mortality. ANK cells were markedly depressed in all patients at day 15. However, persistently low ANK cells at 30 days along with an inversely high NKG2C-/NKG2A+ inhibitory NK cells significantly correlated with high CMV viremia as well as mortality, irrespective of KLRC2 genotype. Day 30 ANK cells were significantly lower in KLRC2 deletion group. IFN-gamma and Perforin release were severely compromised in all patients at day +15, with significant improvement in the survivors at day +30, but not in those with adverse outcome. Conclusion: Patients with severe lung disease even after negative SARS-CoV-2 status, with persistently reduced and functionally compromised ANK cells, are more likely to have CMV reactivation and an adverse outcome, independent of KLRC2 genotype.

Features of repertoire diversity and gene expression in human cytotoxic T cells following allogeneic hematopoietic cell transplantation

Cytomegalovirus reactivation is still a critical concern following allogeneic hematopoietic cell transplantation, and cellular immune reconstitution of cytomegalovirus-specific cytotoxic T-cells is necessary for the long-term control of cytomegalovirus reactivation after allogeneic hematopoietic cell transplantation. Here we show the features of repertoire diversity and the gene expression profile of HLA-A24 cytomegalovirus-specific cytotoxic T-cells in actual recipients according to the cytomegalovirus reactivation pattern. A skewed preference for BV7 genes and sequential “G” amino acids motif is observed in complementarity-determining region-3 of T cell receptor-β. Increased binding scores are observed in T-cell clones with complementarity-determining region-3 of T cell receptor-β with a “(G)GG” motif. Single-cell RNA-sequence analyses demonstrate the homogenous distribution of the gene expression profile in individual cytomegalovirus-specific cytotoxic T-cells within each recipient. On the other hand, bulk RNA-sequence analyses reveal that gene expression profiles among patients are different according to the cytomegalovirus reactivation pattern, and are associated with cytokine production or cell division. These methods and results can help us to better understand immune reconstitution following hematopoietic cell transplantation, leading to future studies on the clinical application of adoptive T-cell therapies.

Cytomegalovirus reactivation in immunocompetent mechanical ventilation patients: a prospective observational study

Background Cytomegalovirus (CMV) reactivation is associated with adverse prognoses of critically ill patients. However, the epidemiology and predictors of CMV reactivation in immunocompetent patients receiving mechanical ventilation (MV) are not clear. The aim of this study was to investigate the epidemiology and predictors of CMV reactivation in immunocompetent patients requiring MV. Methods A single-center, prospective observational study (conducted from June 30, 2017 to July 01, 2018) with a follow-up of 90 days (September 29, 2018) that included 71 CMV-seropositive immunocompetent patients with MV at a 37-bed university hospital general intensive care unit (ICU) in China. Routine detection of CMV DNAemia was performed once a week for 28 days (Days 1, 7, 14, 21, and 28). CMV serology, laboratory findings, and clinical data were obtained during hospitalization. Results Among 71 patients, 13 (18.3%) showed CMV reactivation within 28 days in the ICU. The median time to reactivation was 7 days. CMV reactivation was related to various factors, including body mass index (BMI), sepsis, N-terminal pro-b-type natriuretic peptide (NT-proBNP), blood urea nitrogen (BUN), and hemoglobin (Hb) levels (P < 0.05). In the multivariate regression model, BMI, Hb level, and sepsis were independently associated with CMV reactivation patients (P < 0.05). Moreover, the area under the receiver operating characteristic (AUROC) of BMI, Hb, and BMI combined with Hb was 0.69, 0.70, and 0.76, respectively. The duration of MV, hospitalization expense, length of ICU stay, and 90 day all-cause mortality rate in patients with CMV reactivation was significantly higher than in those without CMV reactivation (P < 0.05). Conclusions Among immunocompetent patients with MV, the incidence of CMV reactivation was 18.3%. CMV reactivation was associated with several adverse prognoses. BMI, Hb, and sepsis were independent risk factors for CMV reactivation. BMI and Hb may predict CMV reactivation.

Cytomegalovirus Reactivation in Immunocompetent Mechanical Ventilation Patients: A Prospective Observational Study

Background: Cytomegalovirus (CMV) reactivation is associated with adverse prognoses of critically ill patients. However, the epidemiology and predictors of CMV reactivation in immunocompetent patients receiving mechanical ventilation (MV) are not clear. The aim of this study was to investigate the epidemiology and predictors of CMV reactivation in immunocompetent patients requiring MV.Methods: A single-center, prospective observational study (conducted from June 30, 2017 to July 01, 2018) with a follow-up of 90 days (September 29, 2018) that included 71 CMV-seropositive immunocompetent patients with MV at a 37-bed university hospital general intensive care unit (ICU) in China. Routine detection of CMV DNAemia was performed once a week for 28 days (Days 1, 7, 14, 21, and 28). CMV serology, laboratory findings, and clinical data were obtained during hospitalization.Results: Among 71 patients, 13 (18.3%) showed CMV reactivation within 28 days in the ICU. The median time to reactivation was 7 days. CMV reactivation was related to various factors, including body mass index (BMI), sepsis, N-terminal pro-b-type natriuretic peptide (NT-proBNP), blood urea nitrogen (BUN), and hemoglobin (Hb) levels (P < 0.05). In the multivariate regression model, BMI, Hb level, and sepsis were independently associated with CMV reactivation patients (P < 0.05). Moreover, the area under the receiver operating characteristic (AUROC) of BMI, Hb, and BMI combined with Hb was 0.69, 0.70, and 0.76, respectively. The duration of MV, hospitalization expense, length of ICU stay, and 90-day all-cause mortality rate in patients with CMV reactivation was significantly higher than in those without CMV reactivation (P < 0.05).Conclusions: Among immunocompetent patients with MV, the incidence of CMV reactivation was 18.3%. CMV reactivation was associated with several adverse prognoses. BMI, Hb, and sepsis were independent risk factors for CMV reactivation. BMI and Hb may predict CMV reactivation.