Abstract Background With the advent of the first targeted therapy for Rett Syndrome (RTT), a comprehensive assessment of the journey of RTT is needed to elucidate on present unmet needs in this ...population. This study characterized females with RTT in the United States and their disease journey with respect to longitudinal treatment patterns, RTT-related outcomes, and changes in disease severity. Methods This retrospective cohort study used registry data of females with RTT from the 5211 RTT Natural History Study (RNHS) (November 2015–July 2021). Pharmacological and supportive therapy use, RTT-related outcomes, and RTT severity, as measured by the Clinical Severity Scale and Motor Behavioral Assessment scale, were evaluated following the first RNHS visit. Analyses were conducted overall and in subgroups by RTT type (classic and atypical RTT) and age at first visit (pediatric and adult). Results A total of 455 females with RTT were included in the study, of whom 90.5% had classic RTT and 79.8% were pediatric individuals. Over a median follow-up of 4 years, use of pharmacological therapies, including prokinetic agents (42.7% vs. 28.3%), and supportive therapies, including physical therapy (87.3% vs. 40.2%) and speech-language therapy (86.8% vs. 23.9%), were more common in pediatric than adult individuals (all p < 0.05). Nearly half (44.6%) of all individuals had a hospital or emergency room visit, with a higher proportion of visits in individuals with classic RTT than atypical RTT and pediatric than adult individuals (both p = 0.001). An increasing trend in clinical severity was observed in pediatric individuals (mean change per year: 0.24; 95% confidence interval CI: 0.03, 0.44), while an increasing trend in motor-behavioral dysfunction was observed in pediatric individuals (mean change per year: 1.12; 95% CI: 0.63, 1.60) and those with classic RTT (mean change per year: 0.97; 95% CI: 0.53, 1.41). Conclusions Findings from this study highlight the considerable burden of RTT across disease subtype and age. Despite reliance on supportive therapies and healthcare encounters, individuals with RTT experience increasing disease severity and motor-behavioral dysfunction in childhood and adolescence, underscoring the unmet needs of this population and the value of early intervention to manage RTT in the long-term.
Introduction: Venetoclax has demonstrated consistent efficacy and manageable toxicity in patients with previously untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic ...leukemia (CLL/SLL). However, evidence on venetoclax use in patients previously treated with Bruton tyrosine kinase inhibitors (BTKi) is limited. This real-world evidence (RWE) study assessed clinical outcomes of patients who received venetoclax after covalent BTKi (cBTKi) therapy, i.e., response rates, time to next treatment or death (TTNT-D), and progression-free survival (PFS), overall and stratified by line of therapy. Methods: The CLL Collaborative Study of Real-World Evidence (CORE), a retrospective, international, observational study (23 centers) provided data for this analysis. Adult patients diagnosed with CLL/SLL were included if they received a venetoclax-based regimen after discontinuation of a cBTKi-based regimen. Baseline characteristics at venetoclax initiation were summarized using descriptive statistics. Overall response rate (ORR) was calculated as the proportion of patients with complete response (CR) or partial response (PR) among patients with documented responses as recorded in the patients' medical charts based on physician assessment. TTNT-D was measured from date of venetoclax initiation to change of treatment/death (event) or end of follow-up, while PFS was measured from date of venetoclax initiation to disease progression/death (event) or end of follow-up. Outcomes were reported for the overall population and stratified by line of therapy (1L→2L and 2L→3L) and also by with and without CT/CIT exposure prior to cBTKi for 2L→3L. Results: Of the 2,020 patients included in CORE, 1,287 (63.7%) received a cBTKi-based regimen in ≥1 line of therapy; 184 patients (14.3%) discontinued cBTKi (intolerance: 83 45.1%, progression: 78 42.4%) and initiated venetoclax-based therapy (115 venetoclax monotherapy; 69 venetoclax combined with rituximab or obinutuzumab). Mean age at venetoclax initiation was 68.6 (median: 68.2) years old, 69.0% were male, and 31.0% had Medicare. Among tested patients, 41/61 (67.2%) had unmutated IGHV, and 28/109 (25.7%) had 17p deletion or TP53 mutation at venetoclax initiation. Average follow-up time from initiation of venetoclax therapy was 19.6 months (median: 16.6). Of the 127 patients (69.0%) with a documented response, the ORR was 78.0% (CR: 43.3%, PR: 34.6%). The median TTNT-D for these patients was 39.5 months (95% CI: 30.4, not reached NR) with 12- and 18-month rates of 82.3% and 72.4%, respectively. The median PFS was 43.2 months (95% CI: 31.9, NR), with 12- and 18- month PFS rates of 82.8% and 75.1%, respectively. Among patients who started venetoclax-based therapy post-cBTKi as 1L→2L (n=65), the ORR was 84.1% (CR: 54.5%, PR: 29.5%, out of 44 documented). The median TTNT-D for these patients was NR (95% CI: 31.9, NR) but the 12- and 18-month rates were 85.0% and 73.9%, respectively. The median PFS was 43.2 months (95% CI: 39.5, NR) with 12- and 18- month rates of 86.4% and 81.8%, respectively. Among patients who started venetoclax-based therapy post-cBTKi as 2L→3L (n=67), the ORR was 78.3% (CR: 41.3%, PR: 37.0%, out of 46 documented). The median TTNT-D for these patients was 44.2 months (95% CI: 37.0, NR) with 12- and 18-month rates were 83.1% and 76.5%, respectively. The median PFS for these patients was 44.1 months (95% CI: 31.8, NR) with 12- and 18- months rates were 85.2% and 80.4%, respectively. The results for ORR, TTNT-D, and PFS were also similar for those with and without CT/CIT exposure prior to cBTKi. Conclusions: In this multicenter real-world study, results demonstrate that venetoclax is effective overall and also when used either in 2L or 3L following cBTKi therapy. Additionally, even with prior CT/CIT exposure, results support that venetoclax-based therapy remains effective as a therapeutic option. Thus, this study demonstrates that venetoclax-based therapy post-cBTKi is associated with durable remission. These results are especially timely as the CLL treatment paradigm continues to evolve with multiple treatment options available, providing clinicians with valuable evidence to inform modern clinical practice. Further analysis of this study with larger cohorts and longer follow-up time will be undertaken as part of future work to grow this body of evidence.
