Autoantibodies neutralizing type I interferons (IFN-Is) can underlie infection severity. Here, we trace the development of these autoantibodies at high-resolution using longitudinal samples from 1,876 well-treated individuals living with HIV over a 35-year period. Similar to general populations, ∼1.9% of individuals acquired anti-IFN-I autoantibodies as they aged (median onset ∼63 years). Once detected, anti-IFN-I autoantibodies persisted lifelong, and titers increased over decades. Individuals developed distinct neutralizing and non-neutralizing autoantibody repertoires at discrete times that selectively targeted combinations of IFNα, IFNβ, and IFNω. Emergence of neutralizing anti-IFNα autoantibodies correlated with reduced baseline IFN-stimulated gene levels and was associated with subsequent susceptibility to severe COVID-19 several years later. Retrospective measurements revealed enrichment of pre-existing autoreactivity against other autoantigens in individuals who later developed anti-IFN-I autoantibodies, and there was evidence for prior viral infections or increased IFN at the time of anti-IFN-I autoantibody triggering. These analyses suggest that age-related loss of self-tolerance prior to IFN-I immune-triggering poses a risk of developing lifelong functional IFN-I deficiency.
Introduction: Non-transplant eligible newly diagnosed multiple myeloma (NTE-NDMM) patients have a heterogeneous clinical outcome, depending of frailty level. The aim of this study was to prospectively investigate the efficacy and tolerability of Ixazomib-Daratumumab-low dose dexamethasone (IDd) in intermediate-fit NTE-NDMM patients. Methods: In this phase II multicenter HOVON-143 study, IWMG-frailty index based intermediate-fit patients were treated with nine induction cycles of IDd, followed by maintenance with IDd for a maximum of two years. Health related quality of life (HRQoL) was investigated at baseline, after 3 and 9 induction cycles and after 6, 12 and 24 months of maintenance treatment. Results: Sixty-five patients were included. The overall response rate during induction was 71% (95% confidence interval (CI) 63-73%). After a median follow-up of 41 months (range 28.9-53.8), median PFS was 18.2 months. Median PFS2 and OS were not reached, PFS2 at 2 years was 80% (95% CI 68-88%), OS at 3 years was 83% (95% CI 71-90%). (Figure 1) Thirty-five patients (54%) completed induction treatment and started maintenance therapy. During maintenance, 12/35 (34%) patients had an improvement of response. Reasons for discontinuation of induction treatment were progressive disease (PD) (19/30; 63%), toxicity (4/30; 13%), incompliance (3/30; 10%), sudden death (1/30; 3%) and other (3/30; 10%). Of the 35 patients who started maintenance therapy, 15 (43%) patients completed the protocol and 20 patients discontinued treatment due to PD (13/20; 65%), refusal (2/20; 10%), toxicity (2/20; 10%), death (1/20; 5%) or other reasons (2/20; 10%). Hematologic adverse events (AE) grade ≥3 during induction occurred in 12% of patients, of which neutropenia was most commonly reported (6%). During maintenance only 1 patients (1/35; 3%) experienced a grade 3 hematologic AE (thrombocytopenia). Non-hematologic AEs grade ≥3 during induction occurred in 51% of patients, of which most commonly gastro-intestinal AEs (14%) and central nervous system AEs (14%). All grade polyneuropathy (PNP) occurred in 42% of patients, including 5% grade 3 PNP. During the maintenance phase non-hematologic AEs grade ≥3 occurred in 46% of patients, which were most commonly gastro-intestinal AEs (11%) and infections (9%). There was no new onset of grade ≥3 PNP. Dose modifications of ixazomib occurred in 24/65 (37%) patients during induction treatment and in 19/35 (54%) patients during maintenance. Eight/35 (23%) patients discontinued ixazomib treatment during the maintenance phase, while continuing with daratumumab once every eight weeks. The global health status/quality of life improvement significantly during treatment and was clinically significant from the 9th induction cycle onwards. Of the patients who experienced PD, second line treatment was started in 40 out of 42 patients (95%). The remaining 23 patients were still free of progression (18) or died before the occurrence of PD (5). Second line therapy was most commonly lenalidomide based (35/40; 88%). Conclusion: IDd treatment in intermediate-fit patients with NDMM is safe and improves global quality of life. However, PFS is limited, partly explained by limited efficacy due to frequent dose modifications of ixazomib, mainly due to neurotoxicity. This underscores the need for more efficacious and tolerable regimens improving the outcome in non-fit patients.
Background: Frail patients with newly diagnosed multiple myeloma (NDMM) have an inferior PFS and OS, a higher treatment discontinuation rate and more grade ≥3 non-hematologic toxicity, compared to fit patients. In order to improve their outcome we investigated a three-drug regimen with a presumed low-toxicity profile; ixazomib, daratumumab and low-dose-dexamethasone (Ixa-Dara-dex). This trial is registered at www.trialregister.nl as NTR6297. Aims: To present the long term follow up outcome, with an emphasis on the maintenance phase. Methods: NDDM patients, who were frail according to the IMWG-Frailty Index, were included. Patients defined frail based on age only (frail-age) were compared to frail patients based on other reasons (impairments (i)ADL and/or CCI≥2; frail-other) and patients frail based on age as well as other reasons (frail-both). After nine cycles of Ixazomib (4mg; days 1, 8, 15), daratumumab (16mg/kg iv; cycles 1-2: days 1, 8, 15, 22; cycles 3-6: days 1, 15; cycles 7-9: day 1) and low dose dexamethasone (on the days daratumumab was administered; cycle 1-2: 20mg; subsequent cycles 10mg), patients without progressive disease or excessive toxicity continued with maintenance treatment, consisting of 8-week cycles with ixazomib (4mg orally on days 1, 8, 15, 29, 36, 43), daratumumab (16mg/kg iv or 1800mg subcutaneously on day 1) with dexamethasone (10mg intravenously on day 1), until progression, for a maximum of two years. Results: Sixty-five frail patients were included. After a median follow-up of 39 months, the median progression free survival was 13.8m (95%CI: 9.2-17.7). The median PFS2 for all patients was 30.7m (22.2-39.1), 39.1 months in patients classified as frail-age, 24.5 months in frail-other patients and 26.6 months in frail-both patient (log-rank p=0.30). Median OS for all patients was 34.0m (24.0-41.2), not reached (frail age), 28.1m (frail-other) and 30.7 months (frail-both) (log-rank p=0.29) (Table 1). Thirty-two patients (49%) proceeded to the maintenance phase. During maintenance treatment, 6 patients (19%) had improvement of response: 1 SD to MR, 3 PR to VGPR, 1 VGPR to CR and 1 VGPR to sCR. The rate of VGPR or better improved from 41% to 50% during maintenance. During maintenance, 21/32 (66%) patients discontinued therapy, because of progressive disease (14/21; 67%), toxicity (2/21; 10%; infection and intracranial hemorrhage), non-compliance (1/21; 5%), intercurrent death (1/21; 5%) and other reasons (3/21; 14%; physician’s choice, dementia and patient condition). Hematologic ≥3 grade adverse events (AEs) during maintenance were limited: neutropenia 0%, anemia 3% and thrombocytopenia 9%. Non-hematologic ≥3 grade AEs occurred in 18 (56%) patients. Most common AEs were infections (9%), nervous system disorders (9%; cognitive disturbance, stroke and syncope) and gastro-intestinal complaints (6%). There were 2 (6%) second primary malignancies and one patient (3%) experienced grade 3 neuropathy. Image:Summary/Conclusion: Ixa-dara-dex maintenance treatment in frail patients was safe, and resulted in an improvement in response rate in 19% of patients. Patients frail based on age, had higher PFS, PFS2 and OS, as compared to other frail subgroups.
Background: Frailty in non-transplant eligible (NTE) newly diagnosed multiple myeloma (NDMM) patients is associated with toxicity which can negatively affect physical functioning and quality of life (QoL). Older patients may prefer QoL and physical independence over length of life, highlighting the importance of taking health-related (HR) QoL assessment into account for treatment guidance. Methods: The HOVON123 study (NTR4244) was a phase II trial in which 238 NTE-NDMM patients ≥75 years were treated with 9 dose-adjusted cycles MPV. Nine (3 functional; 6 symptom) subscales of two HRQoL instruments (EORTC QLQ-C30 and MY20) were obtained at baseline (T0), after 3 (T1) and 9 (T2) cycles of therapy, and 6 (T3) and 12 (T4) months after discontinuation of therapy in patients without progression. The presence of “tingling hands/feet” was used as a proxy for neuropathy. Differences in baseline HRQoL were analysed with independent t-tests and changes over time with linear mixed models. HRQoL changes and/or differences were reported only when both statistically significant (p<0.005, adjusted for multiple testing) and clinically relevant (>MID). Results: A total of 137 frail and 71 intermediate-fit patients were included in the HRQoL analysis, after exclusion of fit patients and patients whose frailty status or baseline HRQoL questionnaire was missing. Compliance was not materially different in both groups. Frail patients had an inferior HRQoL at baseline in the subscales global health status, physical functioning, fatigue and pain, compared with intermediate-fit patients. Both groups reported improvements in global health status and future perspective. In contrast to intermediate fit patients, frail patients improved in physical functioning, fatigue and pain over time. The improvements in global health status were reached earlier in frail patients (T1) compared with intermediate fit patients (T2), Figure 1. In both intermediate fit and frail patients there was an increase in neuropathy. All other subscales remained within MID ranges and/or were not statistically significant different from baseline. The improvement in global health status sustained after treatment completion (T3-T4) both for frail and intermediate fit patients. This also accounted for future perspective at T3, however, at T4 for intermediate fit patients only. In contrast, the improvement in all other HRQoL domains during treatment, lost clinical relevance and/or statistical significant difference during the TFI. The deterioration in neuropathy remained until T4 in frail patients, but not for intermediate fit patients, reversing at T4, Figure 1. Conclusion: HRQoL in frail patients is inferior as compared to intermediate fit patients at diagnosis. Importantly, treatment improved HRQoL, irrespective of frailty level, being more pronounced and occurring even faster in frail patients. Therefore, physicians should not withhold therapy in these patients because of their frailty status only.
The latent HIV-1 reservoir in treated patients primarily consists of resting memory CD4+ T cells. Stimulating the T-cell receptor (TCR), which facilitates transition of resting into effector T cells, is the most effective strategy to purge these latently infected cells. Here we demonstrate that TCR-stimulated effector T cells still frequently harbor latent HIV-1. Renewed TCR-stimulation or subsequent activation with latency reversing agents (LRAs) did not overcome latency. However, interaction of infected effector cells with dendritic cells (DCs) triggered further activation of latent HIV-1. When compared to TCR-stimulation only, CD4+ T cells from aviremic patients receiving TCR+DC-stimulation reversed latency more frequently. Such a “one-two punch” strategy seems ideal for purging the reservoir. We determined that DC contact activates the PI3K-Akt-mTOR pathway in CD4+ T cells. This insight could facilitate the development of a novel class of potent LRAs that purge latent HIV beyond levels reached by T-cell activation.
Background: In the HOVON 126/NMSG 21.13 trial non-transplant eligible newly diagnosed multiple myeloma (NTE-NDMM) patients were treated with 9 induction cycles of ixazomib, thalidomide and dexamethasone (ITd), followed by randomization between either ixazomib or placebo until progression or unacceptable toxicity. The overall response rate and PFS data have been previously published. Aims: We here present the long-term PFS2 and overall survival data. Methods: Patients were treated with 9 induction cycles (28 days) of ixazomib (4mg on day 1, 8 and 15), thalidomide (100mg on day 1-28) and dexamethasone (40mg on day 1, 8, 15 and 22), followed by maintenance with either ixazomib or placebo (4mg, both on day 1, 8 and 15, every 28 days). Patients were classified as fit, intermediate fit or frail, based on a modified IMWG frailty index which incorporated age, the Charlson Comorbidity Index (CCI) and the WHO performance as a proxy for (instrumental) Activities of Daily Living (iADL) (scoring WHO 0 as 0 points, WHO 1 as 1 point, and WHO 2-3 as 2 points). Results:From registration: 143 eligible patients were included in the study. After a median follow-up (FU) of 67.4 months (m), the median PFS was 14.3m (95% CI 11.5-16.8), median PFS2 was 34.6m (30.7-41.5) and median OS was 58.3m (50.5-65.0). There was no difference in PFS between frailty subgroups. In contrast, median PFS2 and OS were longer in fit patients (PFS2: 49.1m (34.6-74.1), OS: NR (66.6-NR)) versus intermediate-fit (30.1m (25.1-39.0); 51.2m (32.3-63.9) resp.) and frail patients (30.9m (24.0-42.3); 50.5m (32.9-59.4) resp.). From randomization: 78 (55%) patients were randomized, 39 patients in each arm. After a median FU of 60 months from randomization, there was no difference in PFS between the ixazomib-arm (median 9.5m; 95% CI 5.5-14.8) and the placebo-arm (8.4m; 3.0-13.8). Median PFS2 was 39.8m (28.8-60.0) for patients on ixazomib, as compared to 28.7m (22.8-43.2) for patients in the placebo arm, although this difference was not statistically significant. Median OS was not reached for the ixazomib arm and was 50.7m (41.3-58.1) for the placebo arm (HR 0.39; 95% CI 0.19-0.78, p=0.008). In both arms 32 (82%) patients received 2nd line treatment. With the caveat of low numbers and heterogeneous treatment regimens, more patients in the ixazomib arm received daratumumab-lenalidomide-dexamethasone (4 patients, 13%) and panobinostat-bortezomib-dexamethasone (6 patients, 19%), compared to the placebo arm (2 patients (6%) and 3 patients (9%) respectively). In order to explain the difference in OS, subsequent lines of therapy are currently being investigated. Image:Summary/Conclusion: With longer FU, we here confirm that ixazomib maintenance therapy did not improve PFS, compared to placebo. However, PFS2 tends to be longer and OS was superior in patients treated with ITd followed by maintenance with ixazomib versus placebo.
Abstract: Although the prognosis of multiple myeloma (MM) patients has dramatically improved during recent years, virtually all patients eventually develop relapsed refractory disease. Several new therapeutics have been developed in the last few years, including carfilzomib, a second-generation proteasome inhibitor (PI) that has been approved by the US Food and Drug Administration (FDA) in the setting of relapsed and/or refractory MM, as a single agent with or without dexamethasone, and in combination with lenalidomide in 2012 and 2015, respectively. Other promising combinations with carfilzomib are being investigated. Carfilzomib has shown superiority over the first-generation PI bortezomib on both efficacy and toxicity. In particular, profoundly lower incidence in polyneuropathy compared to bortezomib has been described. However, carfilzomib has a different toxicity profile, with more cardiovascular adverse events. Therefore, caution should be taken with the use of carfilzomib for elderly and cardiovascularly compromised patients. The once-weekly administration of carfilzomib, recently approved by the FDA in combination with dexamethasone, will lead to a lower burden for the patient and caregivers compared to the twice-weekly schemes that were routinely used until recently. This review has a focus on clinical trial data that has led to drug approval, as well as new promising combination studies, and provides advice for treating physicians who are now prescribing this drug to patients. Keywords: carfilzomib, relapsed, refractory multiple myeloma, proteasome inhibitor
ABSTRACT Betacoronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV), are important pathogens causing potentially lethal infections in humans and animals. Coronavirus RNA synthesis is thought to be associated with replication organelles (ROs) consisting of modified endoplasmic reticulum (ER) membranes. These are transformed into double-membrane vesicles (DMVs) containing viral double-stranded RNA and into other membranous elements such as convoluted membranes, together forming a reticulovesicular network. Previous evidence suggested that the nonstructural proteins (nsp’s) 3, 4, and 6 of the severe acute respiratory syndrome coronavirus (SARS-CoV), which contain transmembrane domains, would all be required for DMV formation. We have now expressed MERS-CoV replicase self-cleaving polyprotein fragments encompassing nsp3-4 or nsp3-6, as well as coexpressed nsp3 and nsp4 of either MERS-CoV or SARS-CoV, to characterize the membrane structures induced. Using electron tomography, we demonstrate that for both MERS-CoV and SARS-CoV coexpression of nsp3 and nsp4 is required and sufficient to induce DMVs. Coexpression of MERS-CoV nsp3 and nsp4 either as individual proteins or as a self-cleaving nsp3-4 precursor resulted in very similar DMVs, and in both setups we observed proliferation of zippered ER that appeared to wrap into nascent DMVs. Moreover, when inactivating nsp3-4 polyprotein cleavage by mutagenesis, we established that cleavage of the nsp3/nsp4 junction is essential for MERS-CoV DMV formation. Addition of the third MERS-CoV transmembrane protein, nsp6, did not noticeably affect DMV formation. These findings provide important insight into the biogenesis of coronavirus DMVs, establish strong similarities with other nidoviruses (specifically, the arteriviruses), and highlight possible general principles in viral DMV formation. IMPORTANCE The RNA replication of positive stranded RNA viruses of eukaryotes is thought to take place at cytoplasmic membranous replication organelles (ROs). Double-membrane vesicles are a prominent type of viral ROs. They are induced by coronaviruses, such as SARS-CoV and MERS-CoV, as well as by a number of other important pathogens, yet little is known about their biogenesis. In this study, we explored the viral protein requirements for the formation of MERS-CoV- and SARS-CoV-induced DMVs and established that coexpression of two of the three transmembrane subunits of the coronavirus replicase polyprotein, nonstructural proteins (nsp’s) 3 and 4, is required and sufficient to induce DMV formation. Moreover, release of nsp3 and nsp4 from the polyprotein by proteolytic maturation is essential for this process. These findings provide a strong basis for further research on the biogenesis and functionality of coronavirus ROs and may point to more general principles of viral DMV formation.
