143 Background: In ARASENS, darolutamide (DARO) + ADT + docetaxel (DOC) significantly reduced the risk of death by 32.5% (HR 0.68; 95% CI 0.57–0.80; P <0.0001) vs placebo (PBO) + ADT + DOC with similar incidence of treatment-emergent adverse events (TEAEs) between groups in patients (pts) with mHSPC. DARO + ADT + DOC has become one of the standards of care in mHSPC. We report post-hoc efficacy and safety in pts by age subgroups (<75 y, ≥75 y) in ARASENS. Methods: Pts were randomized to receive DARO 600 mg orally twice daily or PBO, with ADT + DOC. Age subgroups were analyzed for baseline characteristics including ongoing comorbidities, treatment duration, completion of DOC therapy, use of first subsequent therapy, key efficacy outcomes, and safety. Results: Of 1305 pts analyzed in ARASENS, ages ranged from 41–89 y, with 1086 pts <75 y (83%; DARO n=546; PBO, n=540) and 219 pts ≥75 y (17%; DARO n=105; PBO n=114). Baseline characteristics were generally similar in the DARO and PBO groups by age subgroup. The most common comorbidities by system organ class in pts <75 y and ≥75 y were vascular (55%, 67%), musculoskeletal/connective tissue (42%, 42%), and metabolism/nutrition (35%, 43%) disorders. Treatment duration was consistently longer with DARO vs PBO (<75 y: 41.2 vs 16.8 mo; ≥75 y: 38.5 vs 15.0 mo). Most patients completed 6 cycles of DOC (<75 y: 89%, 88%; ≥75 y: 80%, 76%). Among pts who entered follow-up, fewer DARO vs PBO pts initiated subsequent therapy independent of age (<75 y: 57% vs 76%; ≥75 y: 54% vs 73%). The overall survival (OS) benefit of DARO vs PBO was consistent across age subgroups (<75 y: HR 0.70, 95% CI 0.58–0.84; ≥75 y: HR 0.61, 95% CI 0.41–0.91). Time to metastatic castration-resistant prostate cancer (mCRPC) was longer with DARO vs PBO across age subgroups (<75 y: HR 0.35, 95% CI 0.30–0.43; ≥75 y: HR 0.42, 95% CI 0.28–0.64) as was time to initiation of subsequent therapy (<75 y: HR 0.40, 95% CI 0.34–0.48; ≥75 y: HR 0.35, 95% CI 0.22–0.54). TEAEs were generally similar between DARO and PBO, with slightly higher incidence rates in older pts. Few patients discontinued DARO or PBO due to TEAEs in both age subgroups (<75 y: 13.2%, 9.1%; ≥75 y: 15.1%, 17.7%). The most common grade 3/4 TEAEs were generally similar between DARO and PBO across age subgroups and occurred most frequently during overlapping DOC treatment. TEAEs commonly associated with androgen receptor pathway inhibitors occurred at similar incidences between treatment groups in both age subgroups. Conclusions: Pts with mHSPC benefited from DARO + ADT + DOC irrespective of age (<75 y and ≥75 y), with consistent improvements in OS, time to mCRPC, and time to initiation of subsequent therapy. DARO was well tolerated in both age subgroups, with similar incidences of TEAEs vs PBO. Clinical trial information: NCT02799602 .
In a large multicenter real-world cohort, we aimed to evaluate outcomes of FLAG-Ida salvage therapy for relapsed/refractory (R/R) acute myeloid leukemia (AML) and validated the SALFLAGE prognostic score. We analyzed 1079 adults with R/R AML treated across 112 PETHEMA institutions over 26 years (1998-2024), including patients with primary refractory disease (36.9%) and first relapse episode (63.1%), with a median age of 52 years. Complete remission composite (CRc) was achieved 56.8%, including complete remission (CR) in 51.0%, CR with incomplete recovery in 4.0%, and morphological-free-state in 1.8%, enabling 35.2% of patients and 62% of responders to proceed to allogeneic transplantation without morphological disease. With median follow-up of 50.9 months, median overall survival (OS) was 10.2 months, with 5-year OS rate of 21.6%. Prior allogeneic transplantation (HR 0.54; p < 0.001) and relapse-free interval ≥ 1 year (HR 0.75; p = 0.024) independently predicted improved OS, whereas modified high-risk cytogenetics including t(8; 21) (HR 3.58; p < 0.001), FLT3-ITD mutation at primary diagnosis (HR 1.61; p < 0.001), and age ≥ 60 (HR 1.43; p < 0.001) conferred inferior OS. Validation of the SALFLAGE score demonstrated moderate discrimination (C-index 0.67), with 5-year survival of 38.4%, 27.2%, and 12.7% across risk categories (p < 0.001). Outcomes improved over periods (1998-2005 vs. 2006-2016 vs. 2017-2024): 30-day mortality was 6.9% vs. 9.3% vs. 5.0%, respectively (p = 0.030), and median OS was 7.8 versus 9.4 versus 11.1 months, respectively (p = 0.16). We confirm FLAG-Ida as a reference salvage regimen in fit R/R AML and validate the SALFLAGE score in this setting.
Mutations in FLT3 are present in approximately 30% of patients with AML. The addition of midostaurin (MIDO) to intensive chemotherapy (IC) became standard of care following the RATIFY trial, but comprehensive real-world data spanning the full adult age spectrum and including both FLT3-ITD and FLT3-TKD mutations remain limited. We retrospectively analyzed 1658 adults aged 14-85 years with newly diagnosed FLT3-mutated AML from 129 PETHEMA registry centers: 469 received IC + MIDO and 1189 IC alone. Composite complete remission was higher with IC + MIDO than IC (81.4% vs. 71.7%; p < 0.001) and Day 30 mortality was substantially lower (2.1% vs. 7.1%; p < 0.001). Median overall survival was 47.2 versus 19.3 months (HR 0.64; 95% CI, 0.53-0.76; p < 0.001), and the benefit was sustained after multivariable adjustment (HR 0.73; p = 0.017). In 261 propensity score-matched pairs, the effect was attenuated, remaining significant for event-free survival (HR 0.77; p = 0.029) and showing a nonsignificant trend for OS (HR 0.77; p = 0.06). Allogeneic hematopoietic stem cell transplantation in first remission was more frequent in the IC + MIDO cohort (48.9% vs. 41.3%; p = 0.023). Time-dependent analyses showed the largest MIDO effect among autologous and non-transplanted patients (OS HR 0.45; p = 0.138, and HR 0.69; p = 0.014, respectively). The benefit of MIDO was consistent irrespective of FLT3 mutation type, FLT3-ITD allelic burden, cytogenetic risk, and gender, while less improvement occurred among NPM1 wild type and secondary AML patients. This large real-world cohort confirms the survival benefit of MIDO plus IC across the full adult age spectrum, supporting its standard-of-care status in FLT3-mutated AML.
INTRODUCTION:Therapeutic apheresis (TA) is an extracorporeal technique used to treat various renal and non-renal pathologies, for which the ASFA guidelines provide recommendations. In Spain, nephrology services have progressively adopted various forms of TA, and since 2018, the Spanish Society of Nephrology (S.E.N.) has maintained a national TA registry to monitor its use. OBJECTIVE:To describe the activity of nephrology services participating in the TA registry of the S.E.N (AFT-S.E.N.) between 2019 and 2023. MATERIAL AND METHODS:A descriptive observational study was conducted that included all treatments consecutively recorded in the AFT-S.E.N. registry between 2019 and 2023. A total of 4331 procedures performed on 525 patients across 19 nephrology services were analysed. RESULTS:The median age was 43.7 years, and 49.6% of patients were female. The main indications were neurological diseases (33%), renal diseases (22%), and metabolic diseases (19.6%). Sixty percent of the procedures were performed for acute episodes and 40% in chronic programmes. The most commonly used technique was plasma exchange (72.2%), followed by double filtration (19.7%). Adverse effects occurred in 7% of sessions, primarily hypotension and vascular access issues. CONCLUSIONS:The AFT-S.E.N. registry represents the first multicentre initiative in Spanish nephrology. The data demonstrate the expansion and diversification of TA techniques and the implementation of chronic programmes. They also show that TA is being integrated into clinical nephrology practice, with an acceptable safety profile.
Epigenetic clocks have been widely used to estimate biological age across various tissues, but their accuracy in breast tissue remains suboptimal. Classical models such as Horvath's and Hannum's clocks perform poorly in predicting chronological age in breast tissue, underscoring the need for a tissue-specific approach. In this study, we introduce a Breast Tissue-specific Epigenetic Clock (BTEC), developed using DNA methylation data from 553 healthy breast tissue samples across seven different studies. BTEC significantly outperformed existing clocks, demonstrating superior correlation with chronological age (r = 0.91) and lower prediction errors (MAE = 3.0 y) without requiring dataset-specific regressions adjustments. Notably, BTEC showed consistent performance across ancestry groups, in contrast to existing clocks which exhibited variable ancestry-related biases. We also found that residual-based epigenetic age acceleration, commonly used to correct for prediction bias, is highly dependent on the choice of reference dataset and does not provide a generalizable correction. BTEC's chronological age predictions for tumor-adjacent samples showed distortions, with an average deviation of -2.3 y, which was even more pronounced in tumor samples, where the average difference between predicted and chronological age was -14 to -15 y. When analyzed by molecular subtype, the distortion was greater in the more aggressive HER2+ and TNBC tumors compared to HR+ tumors. Overall, our findings indicate that breast tumors do not generally exhibit accelerated epigenetic aging. The probes used by BTEC were associated with known oncogenes such as JAK1, TP73, PDGFRA, CCND1 and STAT5B, as well as genes involved in cancer-related pathways, including Wnt, Hedgehog and ErbB signaling. Importantly, extreme deviations in epigenetic age, as measured by BTEC-derived epigenetic age acceleration (EAA), were associated with patient survival in HR+ breast cancer patients in an exploratory analysis, highlighting the prognostic value of tissue-specific epigenetic aging measures. These findings demonstrate that BTECs not only improve age prediction in breast tissue but also capture biologically meaningful alterations in tumor epigenetic aging with potential clinical implications.
