Letermovir vs Valganciclovir for Prophylaxis of Cytomegalovirus in High-Risk Kidney Transplant Recipients: A Randomized Clinical Trial.

Importance: Valganciclovir for 200 days is standard care for cytomegalovirus (CMV) prophylaxis in high-risk CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor, but its use is limited by myelosuppression. Objective: To compare the efficacy and safety of letermovir with valganciclovir for prevention of CMV disease in CMV-seronegative kidney transplant recipients who receive an organ from a CMV-seropositive donor. Design, Setting, and Participants: Randomized, double-masked, double-dummy, noninferiority, phase 3 trial in adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor at 94 participating sites between May 2018 and April 2021 (final follow-up in April 2022). Interventions: Participants were randomized in a 1:1 ratio (stratified by receipt of lymphocyte-depleting induction immunosuppression) to receive letermovir, 480 mg, orally daily (with acyclovir) or valganciclovir, 900 mg, orally daily (adjusted for kidney function) for up to 200 days after transplant, with matching placebos. Main Outcomes and Measures: The primary outcome was CMV disease, confirmed by an independent masked adjudication committee, through posttransplant week 52 (prespecified noninferiority margin, 10%). CMV disease through week 28 and time to onset of CMV disease through week 52 were secondary outcomes. Exploratory outcomes included quantifiable CMV DNAemia and resistance. The rate of leukopenia or neutropenia through week 28 was a prespecified safety outcome. Results: Among 601 participants randomized, 589 received at least 1 dose of the study drug (mean age, 49.6 years; 422 [71.6%] men). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease; stratum-adjusted difference -1.4% [95% CI, -6.5% to 3.8%]). No participants who received letermovir vs 5 participants (1.7%) who received valganciclovir developed CMV disease through week 28. Time to onset of CMV disease was comparable between the groups (hazard ratio, 0.90 [95% CI, 0.56-1.47]). Quantifiable CMV DNAemia was detected in 2.1% of participants in the letermovir group vs 8.8% in the valganciclovir group by week 28. Of participants evaluated for suspected CMV disease or CMV DNAemia, none (0/52) who received letermovir and 12.1% (8/66) who received valganciclovir had resistance-associated substitutions. The rate of leukopenia or neutropenia through week 28 was lower with letermovir vs valganciclovir (26% vs 64%; difference, -37.9% [95% CI, -45.1% to -30.3%]; P < .001). Fewer participants in the letermovir group than the valganciclovir group discontinued prophylaxis due to adverse events (4.1% vs 13.5%) or drug-related adverse events (2.7% vs 8.8%). Conclusion and Relevance: Among adult CMV-seronegative kidney transplant recipients who received an organ from a CMV-seropositive donor, letermovir was noninferior to valganciclovir for prophylaxis of CMV disease over 52 weeks, with lower rates of leukopenia or neutropenia, supporting its use for this indication. Trial Registration: ClinicalTrials.gov Identifier: NCT03443869; EudraCT: 2017-001055-30.

The Lung-Liver Axis: A Requirement for Maximal Innate Immunity and Hepatoprotection during Pneumonia.

The hepatic acute-phase response (APR), stimulated by injury or inflammation, is characterized by significant changes in circulating acute-phase protein (APP) concentrations. Although individual functions of liver-derived APPs are known, the net consequence of APP changes is unclear. Pneumonia, which induces the APR, causes an inflammatory response within the airspaces that is coordinated largely by alveolar macrophages and is typified by cytokine production, leukocyte recruitment, and plasma extravasation, the latter of which may enable delivery of hepatocyte-derived APPs to the infection site. To determine the functional significance of the hepatic APR during pneumonia, we challenged APR-null mice lacking hepatocyte signal transducer and activator of transcription 3 (STAT3) and v-rel avian reticuloendotheliosis viral oncogene homolog A (RelA) with Escherichia coli in the airspaces. APR-null mice displayed ablated APP induction, significantly increased mortality, liver injury and apoptosis, and a trend toward increased bacterial burdens. TNF-α neutralization reversed hepatotoxicity, but not mortality, suggesting that APR-dependent survival is not solely due to hepatoprotection. After a milder (nonlethal) E. coli infection, hepatocyte-specific mutations decreased APP concentrations and pulmonary inflammation in bronchoalveolar lavage fluid. Cytokine expression in airspace macrophages, but not other airspace or circulating cells, was significantly dependent on APP extravasation into the alveoli. These data identify a novel signaling axis whereby the liver response enhances macrophage activation and pulmonary inflammation during pneumonia. Although hepatic acute-phase changes directly curb injury induced by TNF-α in the liver itself, APPs downstream of these same signals promote survival in association with innate immunity in the lungs, thus demonstrating a critical role for the lung-liver axis during pneumonia.

Regulation of acute graft-versus-host disease by microRNA-155.

Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic stem cell transplant (alloHSCT), underscoring the need to further elucidate its mechanisms and develop novel treatments. Based on recent observations that microRNA-155 (miR-155) is up-regulated during T-cell activation, we hypothesized that miR-155 is involved in the modulation of aGVHD. Here we show that miR-155 expression was up-regulated in T cells from mice developing aGVHD after alloHSCT. Mice receiving miR-155-deficient donor lymphocytes had markedly reduced lethal aGVHD, whereas lethal aGVHD developed rapidly in mice recipients of miR-155 overexpressing T cells. Blocking miR-155 expression using a synthetic anti-miR-155 after alloHSCT decreased aGVHD severity and prolonged survival in mice. Finally, miR-155 up-regulation was shown in specimens from patients with pathologic evidence of intestinal aGVHD. Altogether, our data indicate a role for miR-155 in the regulation of GVHD and point to miR-155 as a novel target for therapeutic intervention in this disease.

Functional implications of microRNAs in acute myeloid leukemia by integrating microRNA and messenger RNA expression profiling.

BACKGROUND: The expression of microRNAs (miRNAs) is deregulated in acute myeloid leukemia (AML), but the corresponding functional miRNA-controlled pathways are poorly understood. Integration of messenger RNA (mRNA) and miRNA expression profiling may allow the identification of functional links between the whole transcriptome and microRNome that are involved in myeloid leukemogenesis. METHODS: We integrated miRNA and mRNA expression profiles obtained from 48 newly diagnosed AML patients by using 2 different microarray platforms and performed correlation, gene ontology, and network analysis. Experimental validation was also performed in AML cell lines using miRNA oligonucleotide mimics and functional assays. RESULTS: Our analysis identified a strong positive correlation between HOX-related genes and miR-10 and miR-20a. Furthermore, we observed a negative correlation between miR-181a and miR-181b, miR-155, and miR-146 expression with that of genes involved in immunity and inflammation (eg, IRF7 and TLR4) and a positive correlation between miR-23a, miR-26a, miR-128a, and miR-145 expression with that of proapoptotic genes (eg, BIM and PTEN). These correlations were confirmed by gene ontology analyses, which revealed the enrichment of members of the homeobox, immunity and inflammation, and apoptosis biological processes. Furthermore, we validated experimentally the association of miR-145, miR-26a, and miR-128a with apoptosis in AML. CONCLUSION: Our results indicate that by integrating the transcriptome and microRNome in AML cells, it is possible to identify previously unidentified putative functional miRNA-mRNA interactions in AML.

Sp1/NFkappaB/HDAC/miR-29b regulatory network in KIT-driven myeloid leukemia.

The biologic and clinical significance of KIT overexpression that associates with KIT gain-of-function mutations occurring in subsets of acute myeloid leukemia (AML) (i.e., core binding factor AML) is unknown. Here, we show that KIT mutations lead to MYC-dependent miR-29b repression and increased levels of the miR-29b target Sp1 in KIT-driven leukemia. Sp1 enhances its own expression by participating in a NFkappaB/HDAC complex that further represses miR-29b transcription. Upregulated Sp1 then binds NFkappaB and transactivates KIT. Therefore, activated KIT ultimately induces its own transcription. Our results provide evidence that the mechanisms of Sp1/NFkappaB/HDAC/miR-29b-dependent KIT overexpression contribute to leukemia growth and can be successfully targeted by pharmacological disruption of the Sp1/NFkappaB/HDAC complex or synthetic miR-29b treatment in KIT-driven AML.