Advances in Therapy最新文献

Introduction: This study aimed to identify potential concepts of interest (COIs) and clinical outcome assessments (COAs) for late-onset and infantile-onset Pompe disease (LOPD and IOPD) and to assess whether the current COAs are reliable and valid to capture patients' experiences.

Methods: Two literature reviews were conducted to identify, describe, and document key signs, symptoms, and impacts relevant to patients and to identify COAs used in Pompe disease. The COAs identified were mapped against the potential COIs to determine which instruments provided the best concept coverage from a patient perspective. Shortlisted COAs were further examined to assess their content validity and psychometric properties.

Results: Sixteen articles for LOPD and 9 for IOPD were identified for concept extraction. Patients with Pompe disease experience a range of signs, symptoms, and impacts. Most COAs currently used in Pompe disease are generic; only 3 LOPD COAs and 1 IOPD COA were disease-specific. Following mapping, 14 instruments for LOPD and 4 for IOPD were identified as providing the greatest coverage, with notable evidence gaps supporting content validity and/or psychometric properties of all shortlisted COAs.

Conclusion: Several COIs were identified from the literature that may be of importance to patients with Pompe disease. Individual COAs frequently used in assessing these concepts were found to have gaps with regards to content validity and psychometric properties. Additional research with patients with Pompe disease could be considered to address issues of content validity. Furthermore, the use of several COAs could be considered in future studies to capture what matters most to patients with Pompe disease.

Introduction: Pulmonary arterial hypertension (PAH) is a progressive, often fatal disease characterized by an elevation in pulmonary arterial pressure and pulmonary vascular resistance (PVR). Oral treprostinil is indicated for the treatment of PAH and has been shown to delay disease progression and to improve exercise capacity.

Methods: The purpose of this report is to examine and summarize the data on the use of oral treprostinil in patients already on dual therapy with an endothelin receptor antagonist (ERA) and phosphodiesterase type-5 inhibitor (PDE-5i), using data from the FREEDOM-C study, FREEDOM-C2 study, and a retrospective chart review.

Results: In this analysis, background monotherapy versus dual therapy did not have an impact on clinical parameters (6-min walk distance). Additionally, the number of background therapies did not have an impact on the dose of oral treprostinil achieved at week 16 or measures typically used to assess clinical efficacy in patients with PAH (change in 6MWD at week 16 and NT-proBNP).

Conclusion: Oral treprostinil is a safe and efficacious treatment option and has been shown to further improve clinical parameters and risk status in patients with PAH on background dual therapy.

Trial registry: ClinicalTrials.gov identifier, NCT00325442 and NCT00887978.

The prevalence of obesity continues to rise, with notable increase in stage III obesity in North America. The accumulation of excess adipose tissue can impair health with cardiovascular disease being the leading cause for increased mortality in people with obesity. The chronicity of the condition makes sustainable weight loss and improved health difficult for many with lifestyle changes alone, often necessitating the need for pharmacotherapy and bariatric surgery. Bariatric surgery remains the most efficacious treatment for obesity, despite improved pharmacotherapies. However, its low acceptability and accessibility render it an underutilized treatment. Meanwhile, the use of obesity pharmacotherapy, especially glucagon-like peptide 1 receptor agonists (GLP1RA) has become widespread with significant weight loss and improved health outcomes in randomised control trials. The real-world effectiveness of GLP1RA is hindered by issues including cost and tolerability. This narrative review discusses strategies to improve the effectiveness of pharmacotherapy and bariatric surgery and posits that bariatric surgery will continue to play an important role in obesity treatment in the GLP1RA era.

Introduction: Treatment for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has shifted from chemoimmunotherapy (CIT) to targeted therapies, administered as continuous treatment until progression or in fixed-duration regimens. Fixed-duration regimens with targeted therapies (usually in combination regimens with venetoclax and a Bruton tyrosine kinase inhibitor [BTKi] and/or an anti-CD20 monoclonal antibody) are of increasing interest, and recent phase 3 trial results support this approach. Fixed-duration treatment offers a pre-defined treatment stopping point and may provide patients with a treatment-free interval, potentially reducing the burden of long-term therapy while minimizing cumulative toxicity and costs.

Methods: Here, we review the currently approved fixed-duration regimens and some investigational combinations in ongoing registrational clinical trials.

Results: The registrational fixed-duration studies CLL14 (venetoclax plus obinutuzumab), GLOW (ibrutinib plus venetoclax), CAPTIVATE (ibrutinib plus venetoclax), AMPLIFY (acalabrutinib plus venetoclax with or without obinutuzumab), and MURANO (venetoclax plus rituximab) along with the investigator-initiated CLL17 study, which may impact treatment guidelines, demonstrated extended treatment-free intervals. Generally, targeted fixed-duration regimens in patients with unmutated immunoglobulin heavy chain variable region or TP53 and/or del(17p) demonstrated greater efficacy than CIT, but outcomes were typically poorer than in patients without these high-risk features. Cardiovascular toxicity and death remain a significant concern with ibrutinib plus venetoclax, which was also associated with high rates of diarrhea and atrial fibrillation.

Conclusion: Successful fixed-duration regimens in CLL should achieve deep remission (i.e., undetectable minimal residual disease), sustain long-term progression-free survival, decrease the burden of treatment-related adverse events, and allow for re-treatment with minimal risk of drug resistance. Although fixed-duration treatment represents a positive step forward for most patients with CLL/SLL, the currently approved regimens often fall short in patients at high risk of progression. Continued research and development of next-generation drugs is essential to enhance efficacy and safety, ultimately improving outcomes in all patients with CLL/SLL.

Introduction: Gestational trophoblastic neoplasia (GTN) is a highly curable malignancy arising from placental trophoblasts, yet a small subset of patients develops multidrug resistance with limited therapeutic options. The discovery of high programmed death-ligand 1 (PD-L1) expression across trophoblastic tumors has provided a compelling biological rationale for immunotherapy, particularly immune checkpoint blockade targeting the PD-1/PD-L1 axis.

Objective: To summarize current evidence on immunotherapy in GTN, integrating biological foundations, clinical experiences, and ongoing clinical trials, and to discuss future perspectives toward individualized, fertility-preserving management.

Methods: A narrative review was conducted according to structured PRISMA-based principles. Literature was retrieved from PubMed, Scopus, and Web of Science from 2000 to 2025 using predefined descriptors related to GTN and immunotherapy. Eligible studies included clinical trials, case series, case reports, and translational research addressing immune checkpoint inhibitors in GTN.

Results: GTN exhibits high PD-L1 expression, mirroring the immune-privileged nature of the placenta. Checkpoint inhibitors alone, such as pembrolizumab, avelumab, or the combination of camrelizumab plus apatinib (that potently suppresses the kinase activity of vascular endothelial growth factor 2), have demonstrated complete and durable responses in approximately 70-80% of patients with multidrug-resistant GTN, with acceptable safety and preserved fertility.

Conclusions: Immunotherapy has expanded therapeutic GTN, transforming refractory disease as a result of its immune responsiveness. Checkpoint inhibition not only achieves high remission rates but also offers fertility preservation and long-term survivorship. The future challenge lies in optimizing combination strategies, refining biomarkers, and ensuring equitable global access to these emerging treatments.

Introduction: The relative efficacy of ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) in relapsed/refractory multiple myeloma (RRMM) was assessed via unanchored matching-adjusted indirect comparison (MAIC) using data from the CARTITUDE-4 and CARTITUDE-1 (cilta-cel) and KarMMa-3 (ide-cel) trials. This updated MAIC includes longer follow-up and overall survival (OS).

Methods: An unanchored MAIC was performed utilizing individual patient-level data (IPD) from CARTITUDE-4 [1-3 prior lines of therapy (LOT); n = 208] and CARTITUDE-1 (3-4 prior LOT; n = 37). Patients fulfilling KarMMa-3 inclusion criteria (2-4 prior LOT, triple-class exposed) were selected, and outcomes were compared against published aggregate KarMMa-3 data. Cilta-cel IPD were weighted to match reported baseline characteristics of KarMMa-3 on key prognostic factors identified a priori. Comparative efficacy was estimated for progression-free survival (PFS), OS, overall response rate, very good partial response (VGPR) or better rate, and complete response (CR) or better rate.

Results: Eighty-five patients from CARTITUDE-4 and CARTITUDE-1 were included. After adjustment, patients in the cilta-cel group (effective sample size = 39) had a 58% reduction in PFS risk [hazard ratio (HR) 0.42 (95% CI 0.26-0.68); p = 0.0004] and a 42% reduction in OS risk [HR 0.58 (0.34-0.99); p = 0.0452] versus ide-cel. Patients in the cilta-cel group were significantly more likely to achieve an overall response [relative response ratio (RR) 1.22 (95% CI 1.08-1.38); p = 0.0126] and deeper levels of response [≥ VGPR: RR 1.37 (1.19-1.59); p = 0.0009; ≥ CR: RR 1.80 (1.49-2.18); p < 0.0001] versus ide-cel.

Conclusion: This updated MAIC with longer follow-up time demonstrated significant superiority of cilta-cel over ide-cel in PFS, OS, and response outcomes in patients with triple-class exposed RRMM treated with 2-4 prior LOT. The OS results reinforce the added value of cilta-cel in this population.

Trial registration: ClinicalTrials.gov ID: CARTITUDE-1: NCT03548207; CARTITUDE-4: NCT04181827; KarMMa-3: NCT03651128.

Introduction: Malignant pleural mesothelioma (MPM) is a rare malignancy typically attributed to occupational asbestos exposure and associated with dismal survival outcomes. The standard of care for unresectable MPM was platinum-based chemotherapy until the approval of immunotherapy in 2020. We examined treatment patterns, clinical outcomes, health care resource use (HCRU), and costs in patients with MPM to understand disease burden before the first immunotherapy approval.

Methods: This retrospective study used the Surveillance, Epidemiology, and End Results (SEER)-Medicare deidentified database in the US to select patients aged ≥ 65 years who initiated first-line therapy (1L, index event) for advanced MPM (regional extension or distant) diagnosed between 2007 and 2019. Eligible patients had continuous Medicare enrollment from the diagnosis date to ≥ 3 months post-index date, with ≥ 6-month follow-up after 1L initiation. Kaplan-Meier methods were used to estimate real-world time to treatment discontinuation (rwTTD) and overall survival (OS). Data cutoff was December 31, 2020.

Results: Among 554 patients with MPM who initiated 1L, median age was 74 years; most were white (95.0%) and male (73.7%). The most common 1L regimens were platinum-pemetrexed (75.6%), pemetrexed monotherapy (8.5%), and bevacizumab-platinum-pemetrexed therapy (8.1%); the median rwTTD of 1L therapy was 5.3 (95% CI, 4.2-6.3) months. Of 554 patients, 300 (54.2%) initiated second-line therapy (2L), and 120 (21.7%) initiated third-line therapy (3L). Platinum-pemetrexed (25.0%) and gemcitabine (25.0%) were the most common 2L and 3L, respectively. Median OS was 16.3 (95% CI, 15.4-17.8) months, with 5-year survival of 7.9% (95% CI, 5.5-10.9). Mean per-patient-per-month all-cause inpatient admissions, outpatient visits, emergency department visits, and total costs were 0.04, 1.74, 0.18, and $11,432, respectively.

Conclusion: The study highlights a substantial clinical and economic burden among patients with advanced MPM who received 1L chemotherapy in the years preceding immunotherapy approvals, underscoring the need for more effective therapies to improve outcomes.

Introduction: Sickle cell pain crises (SCPCs) are debilitating pain events that significantly impact quality of life in patients with sickle cell disease (SCD), but no fit-for-purpose tool exists to capture patients' experiences of them. We developed a patient-reported outcome (PRO) tool to capture patients' SCPC experiences and ensured its content validity through cognitive debriefing (CD) interviews with adolescents and adults with SCD.

Methods: In this non-interventional, qualitative research study, a targeted literature review (TLR) was conducted to create preliminary items and a preliminary conceptual model (CM) of SCPCs in patients with SCD. Next, an item-generation session was held with clinical experts, followed by hybrid concept elicitation (CE) and CD interviews with patients over three waves; the preliminary items and CM were refined iteratively after each wave. SCPC and impact disturbance ratings were summarised using descriptive statistics. CD responses were analysed on the basis of a semi-structured discussion guide.

Results: The TLR identified 12 articles describing 47 concepts related to pain, anatomical sites, duration, frequency, and impacts of SCPCs. In CE interviews, patients described various aspects of their SCPC experience, including anatomical sites affected, pain characteristics, and duration. CD interviews confirmed the content validity of the eDiary, with patients finding most questions and response options clear and useful. The diary was modified on the basis of patient feedback per wave.

Conclusion: The SCPC eDiary is a novel PRO instrument that captures the frequency, severity, and impact of home-managed pain crises. Future studies should assess its real-world use and performance in clinical settings.