Sanjeet Singh Dadwal

Background: Cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) prevents CMV reactivation after hematopoietic cell transplant (HCT). Trends in CMV-CMI using the QuantiFERON-CMV assay and its clinical utility in a Phase 3 study were evaluated. Methods: Cytomegalovirus-seropositive allogeneic HCT recipients who received letermovir prophylaxis through ∼100 days post-HCT were randomized to receive letermovir or placebo through ∼200 days post-HCT. QuantiFERON-CMV was performed at 100 days, 200 days, and Week 48 post-HCT. QuantiFERON-CMV results after prophylaxis completion (∼100 and ∼200 days post-HCT in placebo and letermovir groups, respectively) were evaluated for predicting postprophylaxis clinically significant CMV infection (CS-CMVi) through Week 48 post-HCT. Results: QuantiFERON-CMV assay positivity was similar at study entry between letermovir (n = 82) and placebo (n = 47) groups (30.5% vs 31.9%), higher for placebo group at 200 days post-HCT (48.8% vs 74.5%), and comparable between groups at Week 48 post-HCT (65.9% vs 74.5%). Postprophylaxis CS-CMVi occurred by Week 48 in 10.5% (6/57) of participants with a positive result versus 19.0% (8/42) with a negative result at 200 days post-HCT in the letermovir group and 10.3% (3/29) of participants with a positive result versus 20.7% (6/29) with a negative result at 100 days post-HCT in the placebo group. Assay sensitivity, specificity, positive predictive value, and negative predictive value were 60.0%, 57.1%, 89.5%, and 19.0% for tests at 200 days post-HCT (letermovir) and 53.1%, 66.7%, 89.7%, and 20.7% for tests at 100 days post-HCT (placebo). Conclusions: Positive QuantiFERON-CMV results increased after letermovir prophylaxis completion. Predictive utility of the QuantiFERON-CMV assay may be limited in the HCT setting.

The increasing emergence of antifungal resistance poses potential clinical challenges, particularly among immunocompromised patients with cancer at risk of invasive mold infections, but data on antifungal susceptibility trends specific to this population are few. We evaluated distributions of minimal inhibitory concentrations (MIC), including minimal effective concentrations (MEC) for echinocandins, of 11 antifungal agents for 523 mold isolates (395 Aspergillus spp.) from cancer patients. Based on published Clinical and Laboratory Standards Institute guidelines, isavuconazole had notably high rates of non-wild-type MICs for A. fumigatus (19.6%), A. flavus/oryzae (34.8%), A. niger complex (26.1%), and A. terreus complex (8.33%). Persistent low baseline resistance of A. fumigatus to voriconazole was observed across multiple years (2.4–11.5% per year, average 8.41%) without significant trends in MIC change over time. Itraconazole and posaconazole demonstrated the lowest MIC distributions (MIC₅₀ ≤ 0.06–0.5 µg/mL) of the azoles against Aspergillus spp. Amongst the A. niger complex, 29.4% (27/92) demonstrated non-wild-type MICs to itraconazole. While the A. nidulans group was less frequent (n = 24), bimodal peaks in MIC/MEC were noted for caspofungin (≤0.06 and 1 µg/mL). Non-Aspergillus molds of significance (Zygomycetes, Fusarium spp., Scedosporium spp., and Lomentospora prolificans) demonstrated variable but increased MICs to antifungal agents as previously described. Our results highlight increased rates of non-wild type MICs for Aspergillus spp. to isavuconazole and voriconazole, which are commonly used antifungal agents in cancer patients. Such AST trends should be closely monitored in populations with frequent antifungal use and encourage increased antifungal stewardship efforts.

Allogeneic hematopoietic cell transplantation (allo-HCT) recipients are susceptible to viral infections. We conducted a phase 2 trial evaluating the safety and rate of clinically significant infections (CSIs; viremia requiring treatment or end-organ disease) after infusion of posoleucel, a partially HLA-matched, allogeneic, off-the-shelf, multivirus-specific T-cell investigational product for preventing CSIs with adenovirus, BK virus, cytomegalovirus, Epstein-Barr virus, human herpesvirus-6, or JC virus. This open-label trial enrolled allo-HCT recipients at high risk based on receiving grafts from umbilical cord blood, haploidentical, mismatched, or matched unrelated donors; post-HCT lymphocytes of <180/mm3; or use of T-cell depletion. Posoleucel dosing was initiated within 15 to 49 days of allo-HCT and subsequently every 14 days for up to 7 doses. The primary end point was the number of CSIs due to the 6 target viruses by week 14. Of the 26 patients enrolled, only 3 (12%) had a CSI by week 14, each with a single target virus. In vivo expansion of functional virus-specific T cells detected via interferon-γ enzyme-linked immunosorbent spot assay was associated with viral control. Persistence of posoleucel-derived T-cell clones for up to 14 weeks after the last infusion was confirmed by T-cell–receptor deep sequencing. Five patients (19%) had acute graft-versus-host disease grade 2 to 4. No patient experienced cytokine release syndrome. All 6 deaths were due to relapse or disease progression. allo-HCT recipients at high risk who received posoleucel had low rates of CSIs from 6 targeted viruses. Repeat posoleucel dosing was generally safe and well tolerated and associated with functional immune reconstitution. This trial was registered at www.ClinicalTrials.gov as #NCT04693637.

Continuing antifungal prophylaxis (AFPx) to prevent invasive mold infections (IMIs) in recipients of allogeneic hematopoietic cell transplantation (alloHCT) after primary hospital discharge from alloHCT admission varies among transplant centers despite recommendations to continue prophylaxis through day +75. Characteristics driving AFPx prescribing at hospital discharge and outcomes are unknown. In this retrospective analysis, we reviewed patients continuing AFPx vs no AFPx at hospital discharge. We included patients with a hospital stay ≥7 days and ≤40 days. We excluded patients with a history of IMI prior to alloHCT, new IMI during admission, or death prior to discharge. Our primary objective was incidence of probable or proven IMI per the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Our secondary objectives were nonrelapse mortality at day +100, overall survival at day +100, and characteristics driving AFPx discontinuation at hospital discharge. Of the 430 patients identified, 387 met inclusion criteria. At discharge, 56% (217/387) continued AFPx, and 44% (170/387) had no AFPx. At day +100, 3 probable IMI cases occurred in the group with continued AFPx vs 1 probable IMI case in the no-AFPx group (no proven IMI). Univariate analysis showed no difference in cumulative incidence of probable IMI (P = .440), nonrelapse mortality (P = .072), and overall survival (P = .855) between groups. Multivariable logistic regression demonstrated that patients were less likely to continue AFPx if they had a diagnosis other than acute myeloid leukemia, a length of stay ≤30 days, acute graft-vs-host disease grade 0 or 1, and corticosteroid use ≤5 days. There was no difference in probable IMI at day +100 after alloHCT based on continuing vs discontinuing AFPx at hospital discharge after alloHCT admission supporting a risk-adapted prophylaxis approach.

Introduction Immunocompromised host pneumonia (ICHP) is an important cause of morbidity and mortality, yet usual care (UC) diagnostic tests often fail to identify an infectious etiology. A US-based, multicenter study (PICKUP) among ICHP patients with hematological malignancies, including hematological cell transplant recipients, showed that plasma microbial cell-free DNA (mcfDNA) sequencing provided significant additive diagnostic value. Aim The objective of this study was to perform a cost-effectiveness analysis (CEA) of adding mcfDNA sequencing to UC diagnostic testing for hospitalized ICHP patients. Methods A semi-Markov model was utilized from the US third-party payer’s perspective such that only direct costs were included, using a lifetime time horizon with discount rates of 3% for costs and benefits. Three comparators were considered: (1) All UC, which included non-invasive (NI) and invasive testing and early bronchoscopy; (2) All UC & mcfDNA; and (3) NI UC & mcfDNA & conditional UC Bronch (later bronchoscopy if the initial tests are negative). The model considered whether a probable causative infectious etiology was identified and if the patient received appropriate antimicrobial treatment through expert adjudication, and if the patient died in-hospital. The primary endpoints were total costs, life-years (LYs), equal value life-years (evLYs), quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio per QALY. Extensive scenario and probabilistic sensitivity analyses (PSA) were conducted. Results At a price of $2000 (2023 USD) for the plasma mcfDNA, All UC & mcfDNA was more costly ($165,247 vs $153,642) but more effective (13.39 vs 12.47 LYs gained; 10.20 vs 9.42 evLYs gained; 10.11 vs 9.42 QALYs gained) compared to All UC alone, giving a cost/QALY of $16,761. NI UC & mcfDNA & conditional UC Bronch was also more costly ($162,655 vs $153,642) and more effective (13.19 vs 12.47 LYs gained; 9.96 vs 9.42 evLYs gained; 9.96 vs 9.42 QALYs gained) compared to All UC alone, with a cost/QALY of $16,729. The PSA showed that above a willingness-to-pay threshold of $50,000/QALY, All UC & mcfDNA was the preferred scenario on cost-effectiveness grounds (as it provides the most QALYs gained). Further scenario analyses found that All UC & mcfDNA always improved patient outcomes but was not cost saving, even when the price of mcfDNA was set to $0. Conclusions Based on the evidence available at the time of this analysis, this CEA suggests that mcfDNA may be cost-effective when added to All UC, as well as in a scenario using conditional bronchoscopy when NI testing fails to identify a probable infectious etiology for ICHP. Adding mcfDNA testing to UC diagnostic testing should allow more patients to receive appropriate therapy earlier and improve patient outcomes.

Sequencing of plasma microbial cell-free DNA (mcfDNA) has gained increased acceptance as a valuable adjunct to standard-of-care testing for diagnosis of infections throughout the body. Here we report the analytical and clinical validation of a novel application of mcfDNA sequencing, the non-invasive detection of seven common antimicrobial resistance (AMR) genetic markers in 18 important pathogens with potential to harbor these markers. The AMR markers include SCC mec , mecA and mecC for methicillin, vanA and vanB for vancomycin, bla _CTX-M for oxyimino-cephalosporin and aztreonam, and bla _KPC for carbapenem resistance. The AMR markers are computationally linked to the pathogens detected, using a statistical model based on observed AMR gene and pathogen abundances. Analytical validation showed high reproducibility (100%), inclusivity (54 to100%), and exclusivity (100%), with limits of detection ranging from 425 to 6,107 pathogen mcfDNA molecules/μL for the different markers. Clinical accuracy was assessed with 115 unique plasma samples from patients at 7 study sites with concordant culture results for 12/18 (66.7%) target bacteria from a variety of specimen types and correlated with available phenotypic antimicrobial susceptibility test results and genotypic results when available. The positive percent agreement (PPA), negative percent agreement (NPA), overall percent agreement (OPA), and diagnostic yield (DY) were estimated for each AMR marker. The results for the combination of SCC mec and mecA for staphylococci were PPA 19/20 (95.0%), NPA 21/22 (95.4%), OPA 40/42 (95.2%), DY 42/60 (70.0%); vanA for enterococci were PPA 3/3 (100%), NPA 2/2 (100%), OPA5/5 (100%), DY 5/6 (83.3%); bla _CTX-M for gram-negative bacilli were PPA 5/6 (83.3%), NPA 29/29 (100%), OPA34/35 (97.1%), DY 35/49 (71.4%); and bla _KPC for gram-negative bacilli were PPA 0/2 (0%), NPA: 23/23 (100%), OPA23/25 (92.3%), DY 25/44 (56.8%). The addition of AMR capability to plasma mcfDNA sequencing should provide clinicians with an effective new culture-independent tool for optimization of therapy.