Cell-free RNA Liquid Biopsy to Monitor Hematopoietic Stem Cell Transplantation.

Hematopoietic Stem Cell Transplantation (HSCT) is one of the oldest and most successful immunotherapies. Yet, despite long-standing success in the use of HSCT for the treatment of blood cancers and severe immune disorders, monitoring post-transplant complications remains a challenge due to a lack of informative diagnostic tests. Here, we investigate the utility of cell-free RNA (cfRNA) in plasma as a liquid biopsy to monitor allogeneic HSCT recipients during and after treatment. We assayed longitudinal samples from 92 HSCT recipients by cfRNA sequencing and show that cfRNA provides insight into treatment and recovery trajectories, immune dynamics in response to transplantation, infection, and solid-tissue injury associated with Graft-Versus-Host Disease. Collectively, our results provide support for the use of plasma cfRNA profiling to monitor complications of HSCT.

Safety and tolerability study of sotrovimab (VIR-7831) prophylaxis against COVID-19 infection in immunocompromised individuals with impaired SARS-CoV-2 humoral immunity.

BACKGROUND: Multiple vaccines have been approved since August 2021 to prevent infection with SARS-CoV-2; however, 20-40% of immunocompromised people fail to develop SARS-CoV-2 spike antibodies after COVID-19 vaccination and remain at high risk of infection and more severe illness than non-immunocompromised hosts. Sotrovimab (VIR-7831) is a monoclonal neutralizing antibody that binds a conserved epitope on the SARS-CoV-2 spike protein. It is neither renally excreted nor metabolized by P450 enzymes and therefore unlikely to interact with concomitant medications (e.g., immunosuppressive medications). In this open-label feasibility study protocol, we will define the optimal dose and dosing interval of sotrovimab as pre-exposure prophylaxis for immunocompromised individuals as well as its safety and tolerability in this population specifically. METHODS: We will enroll 93 eligible immunocompromised adults with a negative or low-positive (< 50 U/mL) SARS-CoV-2 spike antibody. In phase 1, the first 10 patients will participate in a lead-in pharmacokinetics (PK) cohort study to determine the optimal dosing interval. Phase 2 will expand this population to 50 participants to examine rates of infusion-related reactions (IRR) with a 30-min 500 mg sotrovimab IV infusion. Phase 3 will be an expansion cohort for further assessment of the safety and tolerability of sotrovimab. In phase 4, the first 10 patients receiving 2000 mg IV of sotrovimab on the second sotrovimab infusion day will comprise a lead-in safety cohort that will inform the duration of observation following administration of the drug. The patients will be followed for safety and COVID-19 events for 36 weeks after the second dose. DISCUSSION: In a previous phase III randomized, placebo-controlled pivotal trial, there were no significant differences in the prevalence of adverse events in patients receiving sotrovimab vs. placebo. Thus, we propose an open-label feasibility study protocol of sotrovimab as pre-exposure prophylaxis for immunocompromised individuals to evaluate its PK in immunocompromised individuals with impaired SARS-CoV-2 humoral immunity and define optimal dosing intervals. We also aim to determine COVID-19 infections over the study period and self-reported quality of life measures throughout the study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05210101.

Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Immunogenicity among Chimeric Antigen Receptor T Cell Therapy Recipients.

Patients receiving chimeric antigen receptor T cell (CAR-T) therapy may have impaired humoral responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinations owing to their underlying hematologic malignancy, prior lines of therapy, and CAR-T-associated hypogammaglobulinemia. Comprehensive data on vaccine immunogenicity in this patient population are limited. A single-center retrospective study of adults receiving CD19 or BCMA-directed CAR-T therapy for B cell non-Hodgkin lymphoma or multiple myeloma was conducted. Patients received at least 2 doses of SARS-CoV-2 vaccination with BNT162b2 or mRNA-1273 or 1 dose of Ad26.COV2.S and had SARS-CoV-2 anti-spike antibody (anti-S IgG) levels measured at least 1 month after the last vaccine dose. Patients were excluded if they received SARS-CoV-2 monoclonal antibody therapy or immunoglobulin within 3 months of the index anti-S titer. The seropositivity rate (assessed by an anti-S assay cutoff of ≥.8 U/mL in the Roche assay) and median anti-S IgG titers were analyzed. Fifty patients were included in the study. The median age was 65 years (interquartile range [IQR], 58 to 70 years), and the majority were male (68%). Thirty-two participants (64%) had a positive antibody response, with a median titer of 138.5 U/mL (IQR, 11.61 to 2541 U/mL). Receipt of ≥3 vaccines was associated with a significantly higher anti-S IgG level. Our study supports current guidelines for SARS-CoV-2 vaccination among recipients of CAR-T therapy and demonstrates that a 3-dose primary series followed by a fourth booster increases antibody levels. However, the relatively low magnitude of titers and low percentage of nonresponders demonstrates that further studies are needed to optimize vaccination timing and determine predictors of vaccine response in this population.

The Relationship Between Antibiotic Agent and Mortality in Patients With Febrile Neutropenia due to Staphylococcal Bloodstream Infection: A Multicenter Cohort Study.

Background: Methicillin-susceptible Staphylococcus aureus (MSSA) is a common cause of bloodstream infection (BSI) in patients with febrile neutropenia, but treatment practices vary, and guidelines are not clear on the optimal regimen. Methods: We conducted a multicenter retrospective cohort study of MSSA BSI in febrile neutropenia. We divided patients into 3 treatment groups: (1) broad-spectrum beta-lactams (ie, piperacillin-tazobactam, cefepime, meropenem); (2) narrow-spectrum beta-lactams (ie, cefazolin, oxacillin, nafcillin); and (3) combination beta-lactams (ie, both narrow- and broad-spectrum). We used multivariable logistic regression to compare 60-day mortality and bacteremia recurrence while adjusting for potential confounders. Results: We identified 889 patients with MSSA BSI, 128 of whom had neutropenia at the time of the index culture: median age 56 (interquartile range, 43-65) years and 76 (59%) male. Of those, 56 (44%) received broad-spectrum beta-lactams, 30 (23%) received narrow-spectrum beta-lactams, and 42 (33%) received combination therapy. After adjusting for covariates, including disease severity, combination therapy was associated with a significantly higher odds for 60-day all-cause mortality compared with broad spectrum beta-lactams (adjusted odds ratio [aOR], 3.39; 95% confidence interval [CI], 1.29-8.89; P = .013) and compared with narrow spectrum beta-lactams, although the latter was not statistically significant (aOR, 3.30; 95% CI, .80-13.61; P = .071). Conclusions: Use of combination beta-lactam therapy in patients with MSSA BSI and febrile neutropenia is associated with a higher mortality compared with treatment with broad-spectrum beta-lactam after adjusting for potential confounders. Patients in this study who transitioned to narrow-spectrum beta-lactam antibiotics did not have worse clinical outcomes compared with those who continued broad-spectrum beta-lactam therapy.

Low incidence of invasive fungal disease following CD19 chimeric antigen receptor T-cell therapy for non-Hodgkin lymphoma.

CAR T-cell therapy has revolutionized the treatment of hematologic malignancies, although its use may be complicated by toxicities, including cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infections. Invasive fungal disease (IFD) has been reported after CAR T-cell therapy, but the incidence in the absence of antifungal prophylaxis is unknown. Optimal prophylaxis strategies are widely debated. We performed a single-center retrospective study of 280 adults receiving CD19 CAR T-cell therapy for non-Hodgkin lymphoma (NHL) from December 2017 through September 2021. Patients did not receive routine antiyeast or antimold prophylaxis. IFD was identified between day of cell infusion and last follow-up. Cumulative incidence functions were calculated at 100 days and 18 months based on time to IFD, using dates of IFD-free death, initiation of salvage treatment, and hematopoietic cell transplantation as competing risks. Eight patients (2.9%) developed IFD, including 3 Pneumocystis jirovecii pneumonia, 3 invasive mold infections (IMIs), and 2 invasive yeast infections (IYIs). The 100-day cumulative incidence of IFD accounting for competing risks was 1.8% (95% confidence interval [CI], 0.8% to 4.4%). Among the 280 patients, early toxicities including CRS (85%) and ICANS (55%) and late toxicities after day 30 including grades 3 and 4 neutropenia (41%) and low CD4 T-cell count (20%) were common. IFD was rare among patients who received CD19 CAR T-cell therapy for NHL in the absence of routine antifungal prophylaxis, despite frequent toxicities. These results suggest that, in settings with low institutional rates of IFD, routine antifungal prophylaxis may not be indicated.

Clarithromycin-Rifampin-Based Treatment for Nontuberculous Mycobacteria Infections in Immunocompromised Patients who Require Concomitant CYP-Metabolized Medications.

Clarithromycin (CYP inhibitor) can be used instead of azithromycin for nontuberculous mycobacteria therapy in patients requiring CYP substrates to mitigate rifampin's CYP induction. We found no differences in adverse events (10/13 vs 14/17; P = .73), drug intolerability (1/5 vs 4/11; P = 1), or 90-day mortality (0/13 vs 1/17; P = 1) in patients receiving clarithromycin vs azithromycin.

Triazole antifungal use for prophylaxis and treatment of invasive fungal diseases for patients receiving gilteritinib.

Gilteritinib is primarily metabolized via cytochrome P450 (CYP). Therefore, concomitant administration of strong CYP3A4 inducers or inhibitors is not recommended. We evaluated the incidence of gilteritinib-related adverse events (AEs) in 47 patients who received gilteritinib with or without antifungal triazoles which are known inhibitors of CYP3A4. Reasons for coadministration were antifungal prophylaxis or treatment of suspected or confirmed fungal diseases. Gilteritinib-related AEs were similar in the gilteritinib-triazole group compared to the gilteritinib without triazole group (75 % vs. 55.5 %, P = 0.23). Additionally, severity of AEs, gilteritinib dose reductions (15 % vs. 14.8 %) or discontinuation due to AEs (10 % vs. 22.2 %), and 90-day mortality (35 % vs. 11.1 %) were similar in both groups. Thus, concomitant gilteritinib and triazole therapy is feasible and is not associated with clinically meaningful increase in gilteritinib-related AEs.