ABSTRACT
Background: In 2009, a novel Influenza A(H1N1) virus caused the first pandemic of the twenty-first century. Patients commonly presented mild phenotypes, similar to seasonal influenza, however some developed complications requiring hospitalisation. Often critically ill patients exhibited major renal sequalae of acute kidney injury (AKI), leading to renal failure. Injury progression is poorly understood, with debates over development originating from direct viral infection of renal cells or pre-renal systemic inflammation. Method(s): Renal tissue and urine was taken from Babraham pigs (n=54) either daily (0-13 days) or weekly (0-3 weeks) following intranasal Influenza A(H1N1)pdm09 infection. IHC determined histological status of kidney tissue. Influenza A mRNA and nucleoprotein were detected by in situ hybridisation and IHC, respectively. Presence of H1N1 mRNA within urine was determined using qRT-PCR. Localised renal pro-/antiinflammatory cytokine expression profiles were developed using qRT-PCR. CD4+ and CD8alpha+ T-cell infiltration and IgA deposition were detected by IF. Result(s): Viral mRNA and protein was detected within kidney tissue at 1-6 days post-infection, similar to the timeline in respiratory tissue. Despite this, IHC revealed microscopic renal structure to be unchanged at all time points, with no evidence of necrosis/fibrosis. Consistent with this, pro-inflammatory cytokine mRNA decreased oneweek post-infection (TNF-alpha, IFN-beta, IFN-gamma, and IL-4;p<0.05). Expression recovers after 7-14 days, often reaching levels greater than control (TNF-alpha, IFN-gamma, IL-2, IL-4;p<0.05). Interstitial infiltration of CD4+ and CD8alpha+ cells, together with glomerular deposition of IgA, follows a similar trend (CD4 and IgA p<0.05). Urine samples were absent of H1N1 mRNA. Conclusion(s): This work creates an infection timeline within the porcine renal system and highlights the ability of the influenza A(H1N1)pdm09 virus to reach the kidney without causing direct injury. Viral presence within renal tissue is cleared one-week postinfection, corresponding with a localised dampening of the immune system. This work demonstrates a direct role of Influenza A(H1N1)pdm09 in the kidney, and with current literature documenting AKI in COVID-19 patients, it is important to understand how respiratory viruses can contribute to AKI and mortality.
ABSTRACT
Background: Venetoclax (Ven) in combination with hypomethylating agents, such as azacitidine (Aza) and low dose cytarabine (LDAC) has been shown to be effective therapy in acute myeloid leukaemia (AML) and has become standard of care for newly-diagnosed patients unfit for intensive chemotherapy (DiNardo et al., 2020;Wei et al., 2019;Pollyea et al., 2020). Efficacy has also been shown in the relapsed/refractory (R/R) setting in more limited data sets (Báez-Gutiérrez et al., 2021;Pollyea et al., 2020, Stahl et al., 2020;DiNardo et al., 2019). Ven combination therapy has become widely used in newly-diagnosed patients in the UK since its approval during the COVID-19 pandemic as an alternative to intensive chemotherapy and subsequently for patients unfit for intensive therapy. Aims: We describe the characteristics and outcomes of patients with AML or high risk myelodysplastic syndrome (HRMDS) receiving Ven combinations in frontline and R/R settings to provide real-world insight into their use in UK clinical practice. Methods: A retrospective analysis was performed of all patients with AML or HR-MDS who received Ven combination therapy at University College London Hospital between April 2020 and September 2021. Patient demographics, treatment history and bone marrow results were obtained from electronic health care and laboratory records. Disease stratification and response assessments were made as per European LeukemiaNet (ELN) criteria (Döhner et al., 2017). Results: At the time of analysis, 95 patients received Ven combinations (61 as frontline treatment and 34 for R/R AML), with a median follow up of 14 months. The majority of patients in both groups had adverse risk ELN classification (70.5% of frontline patients, 64.7% of R/R) and received Ven-Aza (100% frontline and 91.1% R/R) (Table 1). The median ages were 72 and 59 years respectively. The incidence of composite CR/CRi was 70.5% in the frontline setting, with median duration of response (DoR) of 8.3 months and overall survival (OS) of 7.1 months. In R/R AML, the CR/CRi rate was 64.7%, median DoR 10.5 months and median OS 9.8 months. Four out of the 43 patients who achieved CR/CRi (9.3%) following frontline treatment and 9 of the 22 R/R (40.9%) patients proceeded to allogeneic stem cell transplant (alloSCT) post induction. The median survival for all patients who underwent alloSCT is not reached in this analysis. The highest CR/CRi rates were observed in intermediate risk patients (90.9% in frontline treatment, 71.4% in R/R), with lower rates in both favourable (80% and 66.7%) and adverse risk patients (65.1% and 59.1% respectively). The presence of NPM1 and IDH1/2 mutations were associated with high CR/CRi rates in both the frontline (85.7% and 84.6% respectively) and R/R groups (100% and 81.8%), with below average response rates seen in TP53 mutated AML (62% in frontline, 40% in R/R). Notable responses were seen in patients with RUNX1 mutations in both settings (77.8% frontline, 66.6% R/R). Summary/Conclusion: Our data describes real world effectiveness for venetoclax combinations as both frontline and salvage therapy in UK clinical practice, similar to that seen in clinical trials. This further contributes to our understanding of these therapies, in particular their use as a viable treatment option in R/R patients and as a bridge to alloSCT, and highlights the importance of further characterisation of genetic predictors of response to inform treatment decisions in real-world practice.