Interruption Rate Research Articles

Abstract PS14-01: Immune related adverse events in patients ≥65 years vs. <65 years with breast cancer treated with immunotherapy

Abstract Background: Pembrolizumab is approved for early/advanced triple negative breast cancer (TNBC), and atezolizumab was previously approved for advanced TNBC. Toxicity of immunotherapy (IO) and immune related adverse events (irAEs) in patients ≥65 years with TNBC is not described in detail in results from registration trials (KEYNOTE 522, KEYNOTE 355, and IMPassion130), where patients ≥65 years were a minority. Understanding real-world IO toxicity and irAEs in patients with breast cancer ≥65 years may inform clinical decision making. Methods: We studied IO toxicity and irAEs in patients with breast cancer ≥65 years vs. < 65 years (at IO start) who received IO at an academic institution. A retrospective review was conducted to identify IO toxicity and irAEs (classified by CTCAE v 5.0). Cohorts were compared with Pearson's chi-squared test (categorical variables) and Wilcoxon rank-sum test (continuous variables). Results: Cohorts had 25 patients ≥65 years (median age 73 years, interquartile range (IQR) 69-74 years) and 104 patients < 65 years (median age 48 years, IQR 39-56 years). Stage I-III/IV breast cancer distribution was 36%/64% for ≥65 years and 68%/32% for < 65 years. Baseline ECOG performance status was mainly 0-1 in both cohorts. IO was mainly pembrolizumab (≥65 years: 96%; < 65 years: 83% for first IO regimen) vs. atezolizumab. Table 1 depicts characteristics of IO toxicity. IO duration was longer in patients < 65 years. While rates of IO interruption for toxicity and discontinuation for toxicity were numerically higher in patients ≥65 years, these findings did not reach statisticial significance, possibly due to the sample size. Similar overall rates of irAEs were seen (≥65 years: 72%; < 65 years: 65%, p=0.47) but there were differences in the types of irAEs. Patients < 65 years had more transaminitis (≥65 years: 12%; < 65 years: 33%, p=0.04), and grade 2-3 hypothyroidism (among patients developing hypothyroidism, ≥65 years: grade 1- 75%, grade 2- 25%, grade 3- 0%; < 65 years: grade 1- 11%, grade 2- 79%, grade 3- 11%, p=0.017). Conversely, patients ≥65 years had higher rates of irAE nephritis (≥65 years: 12%; < 65 years: 1%, p=0.004); notably, none of the patients had baseline chronic kidney disease. Rates of full resolution of irAEs were similar between cohorts (≥65 years: 67%; < 65 years: 57%, p=0.47), but patients ≥65 years had more steroid use for management of first irAE while patients < 65 years required more thyroid hormone supplementation (first irAE management distribution, ≥65 years: steroids- 71%, thyroid hormone- 7%, supportive care- 21%; < 65 years: steroids- 31%, thyroid hormone- 25%, supportive care- 44%, p=0.025). Late onset irAEs and deaths from irAEs were rare in both cohorts, with 1 irAE related death in the cohort ≥65 years. Conclusions: In this real-world cohort, similar overall rates of irAEs were observed in patients ≥65 years and < 65 years. However, patients ≥65 years had higher rates of irAE nephritis and steroid use for irAEs, while patients < 65 years had more transaminitis and higher grade hypothyroidism, requiring more thyroid hormone supplementation. Given these age specific differences, validation in a larger cohort is merited. Table 1. Characteristics of IO toxicity. Citation Format: Neelima Vidula, Jennifer Hutchinson, Abigail McLaren, Lianne Ryan, Andrzej Niemierko, Aditya Bardia. Immune related adverse events in patients ≥65 years vs. <65 years with breast cancer treated with immunotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS14-01.

Future HIV epidemic trajectories in South Africa and projected long-term consequences of reductions in general population HIV testing: a mathematical modelling study

After successful intensive interventions to rapidly increase HIV awareness, coverage of antiretroviral therapy (ART), and viral suppression, HIV programmes in eastern and southern Africa are considering scaling back of some interventions, such as widespread general population HIV testing. We aimed to model whether scaling back of general population HIV testing in South Africa could result in a resurgence of the HIV epidemic or substantial slowing of declines in HIV incidence, resulting in increased long-term ART. In this modelling study, we used the Thembisa 4.5 model (a deterministic compartmental model of HIV transmission in South Africa) to project the South African HIV epidemic to 2100 assuming the continuation of 2022 epidemiological conditions and HIV programme implementation. We assessed how implementing reductions in general population HIV testing services in 2025 (while maintaining antenatal, symptom-based, and risk-based testing modalities and other HIV prevention services at 2022 levels) would affect HIV incidence and prevalence among people aged 15-49 years, the year in which incidence would reach one per 1000 people aged 15-49 years (the threshold for virtual elimination of HIV), and associated costs, as well as numbers of additional new HIV infections and AIDS-related deaths. We also modelled the effects of delaying reductions in general population testing services by 5-year increments. Additionally, we modelled the potential effects of reductions in general population testing services in combination with increases or decreases in ART interruption rates (ie, the annual rate at which people who are on ART discontinue ART) and condom usage in 2025-35. If general population HIV testing services and the HIV risk environment of 2022 were maintained, we projected that HIV incidence would steadily decline from 4·95 (95% CI 4·40-5·34) per 1000 population in 2025 to 0·14 (0·05-0·31) per 1000 in 2100, and that the so-called virtual elimination threshold of less than one new infection per 1000 population per year would be reached in 2055 (95% CI 2051-2060). Scaling back of general population HIV testing services by 25%, 50%, or 75% in 2025 delayed time to reaching the virtual elimination threshold by 5, 13, or 35 years, respectively, whereas complete cessation of general population testing would result in the threshold not being attained by 2100. Although the incidence of HIV continued to fall when general HIV testing services were reduced, our modelling suggested that, with reductions of between 25% and 100%, between 396 000 (95% CI 299 000-474 000) and 2·50 million (1·97 million-2·98 million) additional HIV infections and between 115 000 (94 000-135 000) and 795 000 (670 000-926 000) additional AIDS-related deaths would occur between 2025 and 2075, depending on the extent of reduction in testing. Delaying reductions in general population HIV testing services for 5-25 years mitigated some of these effects. HIV testing accounted for only 5% of total programmatic costs at baseline; reducing testing moderately reduced short-term total annual costs, but increased annual costs after 25 years. Increases in ART interruption and reductions in condom usage were projected to slow the decline in incidence and increase the coverage of general HIV testing services required to control transmission but did not cause rapid resurgence in HIV infections. Our modelling suggests that scaling back of general population HIV testing would not result in a resurgence of HIV infections, but would delay attainment of incidence-reduction targets and result in long-term increases in HIV infections, AIDS-related deaths, and costs (via increased need for ART provision). HIV programmes need to balance short-term potential resource savings with long-term epidemic control objectives. Bill & Melinda Gates Foundation.

Gender, Race, and Interruptions at Supreme Court Confirmation Hearings

In this research letter, we examine whether gender and racial bias affect interruption rates at one of the most visible events in American politics: US Supreme Court confirmation hearings. Using original data from 1939 to 2022, we find that male and white participants are more likely to interrupt women and person of color speakers, respectively, relative to male and white speakers. This finding holds for both senators and nominees as interrupters. Our results provide evidence that biased interruptive behavior occurs in even the most public and salient of political settings and that it can be mitigated (or intensified) by shared (or opposite) partisanship among speaking pairs. We also find interruption inequalities are not isolated to women as the interrupted, revealing that people of color in political and legal settings are subject to heightened rates of interruptions as well.

Stable matching with evolving preference for adaptive handover in cellular-connected UAV networks

Unmanned Aerial Vehicles (UAVs) can effectively and reliably complete aerial tasks in various fields. However, the high-speed mobility of UAVs and the 6G ultra-dense heterogeneous network architecture in future will lead to frequent handover of UAVs during aerial tasks in cellular networks, increasing the potential service interruption rate. Therefore, there is an urgent requirement to address the lack of service adaptability in the overall time-space dimension. To achieve the seamless handover in highly dynamic and stochastic scenarios, we firstly transform the handover problem into a stable matching model. We then extend the stable matching of single time slot to the overall time-space dimension, and transform the dynamically changing time-space information into the preference relations evolution. By flexibly adapting the evolution of the preference lists to current network topology, we propose a Dynamic Stable Matching based Adaptive Handover (DSMAH) algorithm to find stable matching efficiently in a dynamic environment. Simulation results show that the proposed algorithm can achieve a better trade-off between communication quality, handover frequency, and convergence speed and significantly improves the stability of the cellular-connected network as compared to benchmark schemes. The proposed scheme not only effectively addresses the challenges posed by frequent handovers and ping-pong effect, but also shows its notable advantages in dynamic environments.

First-line dual immune checkpoint inhibitor therapies versus combination therapies comprising immune checkpoint inhibitors and tyrosine kinase inhibitors for advanced renal cell carcinoma: a comparative analysis of the effectiveness using real-world data.

There are few comparative studies on dual immune checkpoint inhibitors (ICIs) (i.e., IO-IO) and combination therapies comprising ICIs plus tyrosine kinase inhibitors (TKIs) (i.e., IO-TKI) for advanced renal cell carcinoma (RCC), especially in real-world settings. We retrospectively evaluated data of 175 patients with IMDC intermediate-risk or poor-risk RCC; as first-line therapy, 103 received IO-IO, and 72 received IO-TKI. An inverse probability of treatment weighting (IPTW) analysis was conducted to balance patients' backgrounds in the IO-IO and IO-TKI groups. Based on the IPTW analysis, progression-free survival (PFS) was longer in the IO-TKI group than in the IO-IO group (median: 15.6 vs. 8.3months; p = 0.0386). In contrast, overall survival was not different between groups (median: 46.7 vs. 49.0months; p = 0.465). Although the IPTW-adjusted objective response rate was not significantly different (51.2% vs. 43.9%; p = 0.359), the progressive disease rate as the best overall response was lower in the IO-TKI group than in the IO-IO group (3.3% vs. 27.4%; p < 0.0001). Regarding the safety profile, the treatment interruption rate was higher in the IO-TKI group than in the IO-IO group (70.3% vs. 49.2%; p = 0.005). In contrast, the IO-IO group had a higher corticosteroid administration rate (43.3% vs. 20.3%; p = 0.001). IO-TKI therapy exhibited superior effectiveness over IO-IO therapy in terms of PFS improvement and immediate disease progression prevention and was associated with a higher risk of treatment interruption and a lower risk of needing corticosteroids.

Association Between Kidney Function and Outcomes Following Immune Checkpoint Inhibitor-Based Combination Therapy in Patients With Advanced Renal Cell Carcinoma

BackgroundIt remains unclear whether kidney function affects outcomes following immune checkpoint inhibitor (ICI)-based combination therapy for advanced renal cell carcinoma (RCC). MethodsWe retrospectively evaluated data of 167 patients with advanced RCC, including 98 who received ICI dual combination therapy (ie, immunotherapy [IO]-IO) and 69 who received ICI combined with tyrosine kinase inhibitor (TKI) (ie, IO-TKI). In each regimen, treatment profiles were assessed according to the grade of chronic kidney disease (CKD) as defined by the KDIGO 2012 criteria. ResultsOf the 98 patients who received IO-IO, 31 (32%), 30 (31%), 15 (15%), and 22 (22%) had CKD G1/2, G3a, G3b, and G4/5, respectively. Of the 69 patients who received IO-TKI, 18 (26%), 25 (36%), and 26 (38%) had G1/2, G3a, and G3b/4/5, respectively. Regarding efficacy, progression-free survival, overall survival, or objective response rate was not different according to the CKD grade in both treatment groups (P > .05). Regarding safety, the rate of adverse events, treatment interruption, or corticosteroid administration was not different according to the CKD grade in the IO-IO group (P > .05), whereas in the IO-TKI group, the incidence of grade ≥ 3 adverse events were significantly higher (P = .0292), and the rates of ICI interruption (P = .0353) and corticosteroid administration (P = .0685) increased, according to the CKD grade. ConclusionThere is a differential safety but comparable efficacy profile between the IO-IO and IO-TKI regimens in patients with CKD. Further prospective studies are required to confirm these findings.

Effect of Cost-Exemption Policy on Treatment Interruption in Patients With Newly Diagnosed Pulmonary Tuberculosis in South Korea.

In 2021, South Korea had the highest incidence rate (49 per 100 000 population) and the third highest mortality rate (3.8 per 100 000 population) due to pulmonary tuberculosis (TB) among Organization for Economic Co-operation and Development countries. Notably, premature interruption of TB treatment interferes with TB control efforts. Therefore, we examined the effect of the co-payment waiver on treatment interruption and mortality among patients with pulmonary TB in South Korea. Patients who had newly treated TB in South Korea from 2013 to 2019 were selected from the nationwide data of the entire Korean National Health Insurance Service (NHIS) population. The effects of policy implementation on treatment adherence and mortality rates depending on treatment interruption history were evaluated. In total, 73 116 and 1673 patients with drug-susceptible (DS) and multidrug-resistant (MDR) pulmonary TB, respectively, were included in the final study population. After implementing the cost-exemption policy, the treatment interruption rate tended to decrease in the continuation phase in the DS-TB group (slope change: -0.097, P=.011). However, it increased in the intensive phase in the MDR-TB group (slope change: 0.733, P=.001). MDR-TB patients were likely to experience an interruption of TB treatment (adjusted odds ratio [aOR], 6.04; 95% CI, 5.43-6.71), and treatment interruption history was a significant risk factor for 1-year and overall mortality rates (adjusted hazard ratios [aHRs]: 2.01, 95% CI, 1.86-2.18 and 1.77, 95% CI, 1.70-1.84, respectively) in the DS-TB group. Implementing the cost-exemption policy effectively reduced the treatment interruption rate among patients with DS pulmonary TB.

Effect analysis of information-guided enteral nutrition-associated diarrhea treatment process in patients with chronic obstructive pulmonary disease undergoing continuous non-invasive assisted ventilation: a mixed cohort study of pre- and post-control

To clarify the application effect of information-guided enteral nutrition-associated diarrhea (ENAD) management process in patients with chronic obstructive pulmonary disease (COPD) undergoing non-invasive assisted ventilation. A mixed cohort study of pre- and post-control was conducted. Thirty-nine patients with COPD who were admitted to the emergency intensive care unit (ICU) of Huzhou First People's Hospital from July 1, 2021 to July 31, 2022 were enrolled. Taking the completion of the software development of ENAD management software for critically ill patients on January 28, 2022 as the time node, 20 patients admitted from July 1, 2021 to January 28, 2022 were set as the control group, and 19 patients admitted from January 29 to July 31, 2022 were set as the observation group. The two groups of patients received the same enteral nutrition support treatment, and the control group implemented the conventional ENAD treatment process with enteral nutrition intolerance disposal process as the core. On the basis of the control group, the observation group implemented the information-guided ENAD treatment process, and the system software actively captured the information of ENAD patients and reminded the medical team to improve the patient's diarrhea-related examination and provide alternative treatment plans. The duration of antidiarrhea, feeding interruption rate, and energy and protein intake, blood biochemical indexes, incidence of abnormal blood electrolyte metabolism, daily continuous non-invasive assisted ventilation and endotracheal intubation after 7 days of targeted diarrhea intervention were compared between the two groups. Except for the basal pulse rate, there were no significant differences in gender distribution, age, and vital signs, basic nutritional status, arterial blood gas analysis and blood biochemistry at admission between the two groups, indicating comparability between the two groups. When ENAD occurred, the patients in the observation group obtained earlier cessation of diarrhea than those in the control group [days: 3.00 (2.00, 3.25) vs. 4.00 (3.00, 5.00), P < 0.01], and the feeding interruption rate was significantly lower than that in the control group [10.53% (2/19) vs. 65.00% (13/20), P < 0.01]. After 7 days of diarrhea intervention, the energy intake of the observation group was significantly higher than that of the control group [kJ×kg-1×d-1: 66.28 (43.34, 70.36) vs. 47.88 (34.60, 52.32), P < 0.01], the levels of hemoglobin (Hb), albumin (Alb) and serum prealbumin (PAB) were significantly higher than those in the control group [Hb (g/L): 119.79±10.04 vs. 110.20±7.75, Alb (g/L): 36.00 (33.75, 37.25) vs. 31.00 (30.00, 33.00), PAB (mg/L): 155.79±25.78 vs. 140.95±14.97, all P < 0.05], the daily continuous non-invasive assisted ventilation duration was significantly shorter than that of the control group [hours: 14 (12, 16) vs. 16 (14, 18), P < 0.01], and the arterial partial pressure of carbon dioxide (PaCO2) was significantly lower than that of the control group [mmHg (1 mmHg ≈ 0.133 kPa): 66.00 (62.00, 70.00) vs. 68.00 (67.50, 70.05), P < 0.05]. However, there were no significant differences in protein intake, incidence of abnormal electrolyte metabolism, and incidence of endotracheal intubation due to acute respiratory failure between the two groups. The information-guided ENAD treatment process can enable the COPD patients undergoing continuous non-invasive assisted ventilation who experience ENAD to receive earlier cessation of diarrhea, and improve the protein energy metabolism and respiratory function of the patients.

Increase in creatinine levels associated with niraparib maintenance therapy in ovarian cancer.

In Japan, Niraparib maintenance therapy for primary and recurrent ovarian cancer was approved in September 2020 and is expected to improve the prognosis of ovarian cancer. However, the safety of niraparib maintenance therapy in Japanese patients has not been fully evaluated. Patients with ovarian cancer (including fallopian tube and peritoneal cancer) treated with niraparib at Jichi Medical University Hospital from September 2020 to August 2022 were enrolled in this study. Patient background, starting dose, rates of interruption, reduction, or discontinuation, adverse events (AEs) during treatment, and estimated glomerular filtration rate (eGFR) trends were retrospectively analyzed. Twenty-nine patients received niraparib maintenance therapy during the study period, including 21 with primary cancer and 8 patients with recurrent cancer. Seventeen patients (58.6%) required dose interruptions and 16 patients (55.2%) required dose reductions. Only two patients (6.9%) discontinued treatment due to fatigue and nausea. The most frequent AE was creatinine increases in 18 patients (62.1%, all grades). Although eGFR levels decreased significantly after niraparib therapy compared to before niraparib therapy (59.3 vs. 50.3 mL/min/1.73 m2 , p < 0.001), the levels returned to pre-niraparib initiation levels after discontinuation of niraparib (64.6 vs. 64.6 mL/min/1.73 m2 , p = 0.96). Multivariate regression analysis showed that diabetes was independently associated with decreased eGFR (p = 0.013). Niraparib maintenance therapy frequently increased serum creatinine, but the change was reversible. Further studies are needed to determine the effects of niraparib on renal function in Japanese patients.

Incidence and predictors of treatment interruption among patients on anti-tuberculosis treatment in Nekemte public healthcare facilities, Oromia, Western Ethiopia.

Tuberculosis treatment interruption increases the risk of poor treatment outcomes and the occurrence of drug resistant Tuberculosis. However, data on the incidence and predictors of tuberculosis treatment interruption are still scarce in Ethiopia, as well as in the study area. Therefore, this study aimed to assess the incidence and predictors of treatment interruption among patients on tuberculosis treatment in Nekemte public healthcare facilities, Oromia region, Western Ethiopia, from July 1, 2017, to June 30, 2021. A retrospective cohort study design was conducted among 800 patients enrolled in anti-tuberculosis treatment during the study period. Data were collected from patient cards who were enrolled in treatment from July 1, 2017 to June 30, 2021. Epidata version 3.2 was used for data entry, and STATA version 14 was used for analysis. A multivariable Cox regression model with a 95% confidence interval (CI) and adjusted hazard ratio (AHR) was used to identify the significant predictors at a p value < 0.05. Finally, the log likelihood ratio, and a Cox-Snell residual graph was used to check the adequacy of the model. A total of 800 patients were followed for a median time of 2.3 (95% CI: 2.20-2.36) months, and with a maximum follow-up time of 11.7 months. The overall incidence rate of treatment interruption was 27.4 per 1000 (95% CI: 22.8-32.8) person-month observations. Age 18-34 years (AHR = 1.8, 95% CI: 1.02-3.18), male (AHR = 1.63, 95% CI: 1.1-2.42), rural residence (AHR = 3, 95% CI: 1.98-4.64), presence of comorbidity (AHR = 10, 95% CI: 5.47-18.27) and lack of treatment supporters on the treatment follow-up (AHR = 2.82, 95% CI: 1.9-4.41) were found to be significant predictors of treatment interruption. A high incidence rate of interruption was observed among TB patients in public health facilities in Nekemte town. Health facilities should provide supportive care for patients with co-morbidities and consider interventions that target middle-aged patients from rural areas that reduce treatment interruptions.

Efficacy and Tolerability of Luspatercept in Patients with Lower Risk Myelodysplastic Syndrome and Anemia: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction: Erythropoietin Stimulating Agents (ESAs) are the standard-of-care treatment for most patients with lower risk myelodysplastic syndrome (MDS) and anaemia. However, there has been unmet need for those who failed ESAs other than regular blood transfusion. Luspatercept is a recombinant fusion protein which binds TGF beta ligands resulting in reduction of erythroid maturation through reduction of SMAD2 and SMAD3 signaling. In recent years, studies have shown that luspatercept has significantly improved efficacy in patients with lower risk MDS who failed ESAs with some notable adverse events. The purpose of our meta-analysis is to determine efficacy by observing the rate of transfusion independence for 12 weeks or longer and haematological improvement in erythroid (HIE), and tolerability by rate of treatment emergent serious adverse events (SAE), treatment discontinuation (TD) and treatment interruption (TI) or dose reduction and treatment related mortality in patients with lower risk MDS treated with luspatercept. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing luspatercept in patients with lower risk MDS that mention efficacy i.e. transfusion independence 12 weeks or longer and HIE and tolerability i.e. rate of treatment discontinuation and interruption, dose reduction, treatment emergent serious adverse events, treatment related mortality were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results: 2 phase III RCTs (MEDALIST and COMMANDS) including total 583 patients were eligible in our meta-analysis. MEDALIST trial compared luspatercept vs placebo and COMMANDS trial compared luspatercept vs erythropoietin stimulating agent. The randomization ratios were 2:1 in MEDALIST and 1:1 in COMMANDS trials. Transfusion independence for 12 weeks or longer was noted in 141 (47%) in study arm vs 77 (33.5%) in control arm at RR of 1.67 (95% CI: 1.35 -2.06; P &amp;lt;0.00001). 190 (63.3%) patients in study arm achieved HIE response compared to 88 (38.3%) in control arm at RR of 1.85 (95% CI: 1.53 -2.24; P&amp;lt;0.00001). TD due to TEAE was reported in 21 (6.3%) of luspatercept group vs 10 (4%) in control group with RR of 1.38 (95% CI: 0.67 -2.84; P = 0.39). The incidence for TI or dose reduction due to TEAE was similar between the two groups at 18% with RR of 1.23 (95% CI: 0.88 -1.72; P = 0.22). Treatment emergent SAEs were observed in 116 (35%) in the luspatercept group vs 83 (32.9%) in control group (RR, 1.09; 95% CI: 0.87-1.38; P=0.45). Treatment related mortality was noted in 13 (3.9%) of patients in the study group compared to 16 (6.3%) in the control group with RR of 0.65 (95% CI: 0.31 -1.33; P = 0.24). Conclusions: According to our meta-analysis, luspatercept significantly improved transfusion independent rate and HIE response in patients with lower risk MDS and anaemia compared to control arm. Furthermore, there was no statistically significant difference in the treatment emergent SAEs, treatment discontinuation, treatment interruption or dose reduction and treatment related mortality between the two groups.

Lower-Initiating Dose of Bosutinib for Resistant or Intolerant to Prior Therapy Chronic Myeloid Leukemia Patients (BOGI trial): A Single-Arm, Multicenter, Phase II Trial

Introduction: The introduction of ABL1 tyrosine kinase inhibitors (TKIs) has markedly improved the survival outcomes in patients with chronic phase chronic myeloid leukemia (CML-CP). Second-generation TKIs are highly active for patients with newly diagnosed and resistant/intolerant CML-CP. Although bosutinib is generally safe, drug-related toxicities (DRTs) such as diarrhea or increased transaminase leading to treatment discontinuation, are often observed. The standard initial daily dosage of bosutinib is 400 mg for newly diagnosed or 500 mg for resistant/intolerant patients with CML-CP, whereas some experts suggest lower dose (200-300 mg) initiation is recommended to reduce adverse events (AEs). However, the safety and efficacy of lower dose initiation of bosutinib are unknown. Hence, we conducted a phase 2 study of BOsutinib Gradual Increase as a second/third-line treatment for CML-CP (BOGI trial, UMIN 000032282) to clarify whether a lower initiating dose of bosutinib (200 mg daily) would reduce discontinuation or interruption of treatment due to DRTs. Patients and methods We included CML patients who developed at least one line of treatment failure (resistant or intolerant), aged &amp;gt;18 years with an ECOG performance status of 0-2 and adequate organ function. After enrollment, the patients initiated 200 mg of bosutinib daily; subsequently, dose escalation was performed by 100 mg daily (up to 500 mg daily) every 2 weeks if no grade 3 or higher AEs occurred. BCR::ABL1 mRNA levels were measured by the standardized international scale at a central laboratory at 3, 6, 9, and 12 month since treatment initiation. The primary endpoint was the treatment discontinuation rate due to DRTs at 12 months. Secondary endpoints included the treatment interruption rate, mean bosutinib dosage, dosing days and relative dose intensity until 12 months, achievement of cytogenetic response (CCyR), cumulative rates of major molecular response (MMR) or deep molecular response (DMR). Sample size calculation was performed by research and biostatistics SWOG statistical tools (at null proportion = 0.32, alternative proportion = 0.14, one-sided α error = 5% and β error = 20%, power 80%) with the discontinuation rate of the previous Japanese phase 1/2 study of bosutinib as a reference (Nakaseko C, et al. Int J Hematol. 2015). Considering protocol deviations, sample size was 35 participants. Results Between Feb 4, 2019, and May 24, 2022, 35 patients enrolled from four Japanese hospitals. The median age was 61 years (range, 26 - 81 years); 19 patients were male and 16 were female and 16, 12, and 7 patients had low,intermediate, and high Sokal scores, respectively. Ten patients had hypertension, five had diabetes millitus, three had chronic heart disease, two had solid tumor, and one had cerebrovascular disease, respectively. Numbers of patients with previous TKIs were one for 19 (54%), two for 12 (34%) and three for 4 (11%), respectively and prior TKIs are imatinib (8, 23%), dasatinib (27, 77%), nilotinib (16, 46%) and bosutinib (1, 3%), respectively. In the intention to treat population, the bosutinib discontinuation rate at 12 months was 25.7% (95% CI, 15.6-39.3%) which is significantly lower than that of the previous report (v.s. 43.0%, p=0.019). Similarly, bosutinib discontinuation rate due to DRTs was 11.4% (95% CI, 5.2 - 23.2%), which is also significantly lower (v.s. 32%, p = 0.005). These results suggest lower initiating dose of bosutinib reduced bosutinib discontinuation rate due to DRTs, thus the primary endpoint was met. A total of 22 patients (62.9%) interrupted bosutinib at least once. Median bosutinib dosage, bosutinib dosing days and relative dose intensity until 12 months were 391.7 (204.9-477.3) mg/day, 351.0 (20-365) days and 78% (41-95), respectively. 28 patients (80.0%) achieved cytogenetic response (CCyR) at 6 months; cumulative incidence of MMR and DMR at 12 months were 23 (65.7%; 95%CI, 49.2-79.2%) and 15 (42.9%; 95%CI, 28.0-59.1%), indicating these secondary endpoints were comparable with the previous report. Grade 3 to 4 transaminase elevation was 20% which is comparable with the previous report (v.s. 29%, p=0.427), while a lower rate of diarrhea (3%; v.s. 25%, p=0.009) was notable. Conclusion The lower initiating dose followed by a gradual dose increase of bosutinib reduced the drug discontinuation rate due to severe DRTs, especially diarrhea, while efficacy was assured.

Disparities in dosing, drug reduction, and drug discontinuation among US FDA approved tyrosine kinase inhibitors

Background: Tyrosine kinase inhibitors (TKIs) have altered the therapeutic landscape of multiple hematological and solid malignancies. FDA approved starting doses of TKIs are based on the recommended phase 2 dose (RP2D) in clinical trials. However, patients are started on lower doses in practice. We assessed the dosing, drug reduction rates, and drug discontinuation rates among FDA approved TKIs and observed the disparity among study populations to understand if there was adequate representation of diversity in race. Methods: We established a database of all FDA approved TKIs from the FDA online label repository. We extracted descriptive data for indications and usage, type of approval, approval dosage, dose reduction recommendation, median age, race, dose reduction rates, drug discontinuation rates, dose modification, warnings, adverse reactions, clinical trial experience, and geriatric use above 65 yrs and 75 yrs. Results: Among all TKIs, median dose was 200 mg and average dose was 307.7 mg; 36 (24%) were approved bid vs 107 (72%) qd. Among approved indications, median rates of dose reduction rate (DRR), drug interruption rate (DIR), drug discontinuations rate (DDR) were 31%, 52%, and 10% respectively. Reasons for DRR, DIR, and DDR were diarrhea, fatigue, nausea, vomiting, hepatotoxicity, rash, and hypertension. Black and Hispanic races are consistently underrepresented among the TKI studies. Conclusions: TKIs have a variable dose reduction and drug discontinuation rate but these studies were done mostly in White individuals. Clinical trials should evaluate multiple dosing regimens and schedules to lessen the toxicity burden and improve QOL in patients while broadening the study population so that the studies will be generalizable to patients in clinical practice. Future studies are warranted to increase representation in the studies to address the disparities.

Abstract 15234: Greater Statin Interruption Rates and Lower Adherence for Women versus Men With HIV in the United States

Introduction: People with HIV, particularly women, have an elevated CVD risk, and a recent trial showed they can benefit from statin initiation even at low/moderate predicted CVD risk. Yet &lt;50% of patients with HIV on statins experience adequate lipid reductions. To inform efforts to reduce CVD risk and gender disparities in this population, we examined statin persistence and adherence by gender in a nationwide sample of privately insured people with HIV. Methods: Among people with HIV ≥18 in MarketScan Commercial Claims who initiated a statin in 2015-2020, we used outpatient pharmacy claims to estimate 1) time to statin interruption (first gap &gt;30 days) and 2) monthly proportion of days covered (PDC) by a statin. PDC analyses censored people if they were off statins ≥6 months. We estimated gender differences in interruption rates using hazard ratios (HR) and in having low adherence (PDC&lt;80%) using risk ratios (RR) adjusted for age, calendar year, US census region, and employment status. Results: There were 7809 statin initiators (17% women; 60% in the South; median age 52 years, IQR 47-57). Two years after statin initiation, 81.0% (95% CI 78.1%-83.8%) of women and 69.8% (68.4%-71.3%) of men had ≥1 statin interruption (adjusted HR women vs. men 1.35 [1.25-1.46]) (Fig. 1A). Monthly PDC decreased in the first 6 months of statin use to 61% for women and 68% for men, then increased to 73% and 80%, respectively, after 2 years (Fig. 1B). Over all months, women more commonly had PDC&lt;80%, with an adjusted RR of 1.27 (1.20-1.34). Conclusions: People with HIV had high statin interruption rates and adherence &lt;80% at most time points, with disparities for women versus men. It is possible that, despite having insurance, women with HIV in this sample are more affected than men with HIV by socioeconomic and other barriers to statin adherence. Gender-specific efforts in people with HIV should address these barriers to promote adherence to CVD preventative pharmacotherapy in this population at high risk.

Tolerability in Transplant-Ineligible Patients with Newly Diagnosed Acute Myeloid Leukemia Treated with Venetoclax Based Combination Therapy: A Systematic Review and Meta-Analysis of Phase III Randomized Controlled Trials

Introduction Therapeutic challenge remains in older patients with acute myeloid leukemia (AML) with significant comorbidities who are not fit for induction chemotherapy and haemopoietic stem cell transplantation. Leukemic cells depend on BCL-2 protein (anti-apoptotic protein) for their survival. Venetoclax is a selective small-molecule BCL-2 inhibitor which binds to BCL-2 resulting in apoptosis of leukemic cells. In recent years, venetoclax has been approved in combination with azacitidine or low dose cytarabine in transplant-ineligible patients with newly diagnosed AML (ND AML). However, there are notable toxicities. The purpose of our meta-analysis is to determine tolerability, rates of treatment emergent serious adverse events (SAE), treatment discontinuation (TD) and treatment interruption (TI), dose reduction and 30-day mortality in transplant-ineligible patients with ND AML treated with venetoclax based combination therapy. Methods We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 30 th, 2023. Phase III RCTs utilizing venetoclax in transplant-ineligible patients with ND AML that mention tolerability, rate of treatment discontinuation and interruption, dose reduction, treatment emergent serious adverse events, 30-day mortality were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results A total of 637 transplant-ineligible patients with ND AML from 2 phase III RCTs (VIALE-A and VIALE-V) were eligible. VIALE-A and VIALE-V compared azacitidine + venetoclax vs azacitidine + placebo, and venetoclax + low dose cytarabine vs placebo + low dose cytarabine respectively. The randomization ratio was 2:1 in both studies.TD due to treatment emergent adverse events (TEAE) was noted in 104 (24.5%) of venetoclax group vs 45 (21.2%) in control group with RR of 1.15 (95% CI: 0.85 -1.57; P = 0.37).TI due to TEAE was higher in the venetoclax group (68.9%) compared to control group (55.6%) with RR of 1.24 (95% CI: 1.08 -1.42; P = 0.002). 21 (4.9%) of patients in venetoclax group and 10 (4.7%) in the control group required dose reduction of treatment due to TEAE, RR 1.03 (95% CI: 0.50 -2.16; P = 0.93).Treatment emergent SAEs were reported in 77.4% in the venetoclax group vs 60% in control group (RR, 1.30; 95% CI: 1.15-1.46; P &amp;lt;0.0001). 30-day mortality was reported in 39 (9.1%) of patients in the venetoclax group and 20 (9.4%) in the control group with RR of 0.96 (95% CI: 0.58 -1.60; P = 0.89). Conclusions Our meta-analysis showed that there was no significant difference in the rate of treatment discontinuation and dose reduction due to adverse events in transplant-ineligible patients with ND AML treated with venetoclax combination regimens, compared to control arm although rates of treatment emergent SAEs and treatment interruption were considerably higher in the venetoclax-treated arm. However, the 30-day mortality rate was similar between the two groups. Longer follow up and timely supportive care are required to improve treatment emergent SAEs and treatment interruption.

Long-term outcomes of highly experienced people with HIV undergoing salvage therapy with raltegravir.

Raltegravir and other third-line drugs have shown promise in improving outcomes in treatment-experienced patients. However, the efficacy and tolerability of these agents vary. This study assessed real-life virologic success, long-term survival, and adverse events in patients receiving raltegravir or other third-line drugs as salvage regimens. This retrospective cohort study included adults who experienced treatment failure (human immunodeficiency syndrome-1 RNA plasma viral load >1000 copies/mL) and subsequently initiated raltegravir or other third-line drugs (darunavir/ritonavir, maraviroc, or etravirine). Propensity score matching methods were employed to account for differences at the time of switching from failing antiretroviral therapy regimens. The matched subset was analyzed using the Kaplan-Meier method and Generalized Wilcoxon tests to evaluate the probability of achieving virologic suppression (plasma viral load <50 copies/mL). Mortality rates, toxicity, treatment interruption, virologic failure, and loss to follow-up were determined using Poisson regression. One hundred and sixty-eight patients initiating salvage regimens were included, with 123 receiving raltegravir and 45 other third-line drugs. Propensity score matching resulted in a subset of 90 patients, 45 in each group. During the follow-up period, there were no significant differences observed between the groups in terms of virologic suppression (77.8% vs 82.2%, P = .73), mortality rates (4.04 vs 6.18 persons per 100 person-years [p-y]; P = .67), drug toxicity (0.00 vs 2.06 persons per 100 p-y; P = .49), treatment interruption (8.07 vs 0.00 persons per 100 p-y; P = .06), virologic failure (2.02 vs 4.12 persons per 100 p-y; P = .61), and loss of follow-up (6.05 vs 4.12 persons per 100 p-y; P = .70). Our findings indicate comparable survival and virological success rates between raltegravir and other drugs used in salvage regimens. Similar rates of drug toxicity, treatment interruption, virologic failure, and loss of follow-up were also observed. These results suggest that raltegravir may be a viable option for salvage therapy, demonstrating outcomes comparable to other third-line drugs in real life.

A context-based approach to predict intelligibility of meaningful and nonsense words in interrupted noise: Model evaluation.

The context-based Extended Speech Transmission Index (cESTI) by Van Schoonhoven et al. (2022) was successfully used to predict the intelligibility of meaningful, monosyllabic words in interrupted noise. However, it is not clear how the model behaves when using different degrees of context. In the current paper, intelligibility of meaningful and nonsense CVC words in stationary and interrupted noise was measured in fourteen normally hearing adults. Intelligibility of nonsense words in interrupted noise at -18 dB SNR was relatively poor, possibly because listeners did not profit from coarticulatory cues as they did in stationary noise. With 75% of the total variance explained, the cESTI model performed better than the original ESTI model (R2 = 27%), especially due to better predictions at low interruption rates. However, predictions for meaningful word scores were relatively poor (R2 = 38%), mainly due to remaining inaccuracies at interruption rates below 4 Hz and a large effect of forward masking. Adjusting parameters of the forward masking function improved the accuracy of the model to a total explained variance of 83%, while the predicted power of previously published cESTI data remained similar.

Interim Analysis of a Non-Randomized Prospective Trial Comparing Hypofractionated Post-Mastectomy Radiotherapy (HF-PMRT) to Conventional Post-Mastectomy Radiotherapy (CF-PMRT) for Breast Cancer (BC) Patients

The standard of care for treatment for LABC patients who have undergone modified radical mastectomy (MRM) is PMRT. Post-mastectomy RT (PMRT) for LABC patients has been established in three trials to improve locoregional control and overall survival (OS). A published trial from China showed that HF-PMRT was non-inferior to CF-PMRT. This study was conducted to determine if HF-PMRT can provide similar efficacy and toxicity. A non-randomized prospective trial design was employed to compare HF-PMRT and CF-PMRT in post-MRM BC patients. Patients with pathologically proven BC who underwent MRM without positive margins and with less than 8 positive nodes were included. Informed consent was obtained. Patients decided which treatment they will receive. They received either HF-PMRT of 43.2 Gy in 16 fractions (fx) [2.7 Gy/fx] or CF-PMRT of 50-50.4 Gy in 1.8-2.0 Gy/fx to both chest wall and regional nodes (axillary and supraclavicular) in both regimens. Primary endpoints were 2-year OS and 2-year local recurrence free survival (LRFS). Secondary endpoints include acute and late toxicities. Analysis was done as intention-to treat. An interim analysis of 2-year results is presented. A total of 37 patients were enrolled in two separate cohorts: a single-arm cohort that recruited 10 HF-PMRT patients from 2014-2015 and a two-arm prospective trial that started recruitment last 2019 and included 12 HF-PMRT and 15 CF-PMRT patients. Median follow-up was 35 months. There were more Stage IIB and Stage III for the CF-PMRT arm [p = 0.040]. Treatment interruptions were more frequent in the CF-PMRT arm (100% vs 68%, p = 0.028). The duration of interruption was also longer in CF-PMRT (median 8 vs 3 days) [p < 0.003]. Acute and late toxicities were not statistically different. There was one patient each with RTOG Grade 2 acute skin toxicity in the HF-PMRT (4.55%) and CF-PMRT arms (6.67%) [p = 0.703]. For late toxicities, the HF-PMRT arm had 6 Grade 1 late skin toxicities and 1 Grade 3 late skin toxicity vs 1 Grade 1 late skin toxicity for CF-PMRT arm [p = 0.196]. 2-year OS rate (86.3% vs 100%, p = 0.403) 2-year DFS rate (68.18% and 73.33%, p = 0.126) were both not statistically different. There were no reported locoregional recurrences (LCR). In terms of local control, both arms have showed no LCRs. 2-year OS and DFS rate were no different. As the study has not yet reached the adequate sample size, the non-inferiority of HF-PMRT cannot be definitively concluded. Acute and late toxicities were no different. There was a significantly higher rate of treatment interruptions in the CF-PMRT compared to the HF-PMRT arm. The results of this interim analysis prove to be promising and patients will continue to be accrued. The final results of this study might have tremendous implications in local practice.

Comorbidities and Their Impact on Treatment Tolerance and Outcome in Elderly NSCLC Patients Treated with Concurrent Chemoradiation Using Proton or Photon Followed by Immunotherapy

To investigate comorbidities and their impact on treatment tolerance and survival for elderly NSCLC patients treated with concurrent chemoradiation using proton beam therapy (PBT) or intensity modulated radiation therapy (IMRT) followed by immunotherapy (IO). This is a retrospective study in senior patients (≥ 65 years) with inoperable locally advanced- NSCLC (LA-NSCLC) who received concurrent chemoradiation (CRT) therapy followed by adjuvant IO. Comorbidities are listed in table 1 and scored according to hazard ratios (HRs) of death. Treatment tolerance and comorbidities were compared between modalities using Fisher's exact test. Association between comorbidities and treatment tolerance was analyzed using logistic regression; association between comorbidities and survival was analyzed by Cox proportional hazards regression. Total 218 patients were included with median age of 72 (range 65-86) years. Fifty-three (24.3%) were PBT and 165 (75.7%) were IMRT. Majority patients were white ethnics, had stage III adenocarcinoma disease and good performance score, and received RT dose 60-66 Gy. The median follow-up time for the whole group was 23 months. A 97% of patients had ≥1, and 62% had ≥4 comorbidities. The combined comorbidity scores ranged from 0 to 25. No significant difference in comorbidities between modalities except IMRT had more patients with COPD (36% vs. 51%, p = 0.047). Rates of hospitalization and ER visit during CRT+IO were 28% and 5%, respectively. Rates of IO discontinuation and interruption were 55% and 8%, respectively. Patients received >6 months IO had significantly lower risk of death (HR: 0.25, p<0.001). No significant difference in treatment tolerance between modalities. In multivariable analysis, atrial fibrillation, pulmonary disease, and depression were the comorbidities associated with hospitalization during CRT+IO (p<0.05); dementia was the comorbidity associated with IO interruption (p = 0.042); heart failure, COPD, asthma, osteoporosis and HIV were the comorbidities associated with poor OS (p<0.05). Combined comorbidity score was associated with OS with HR of 1.13 (p<0.001) with adjustment of race, GTV and induction chemotherapy. Comorbidities were associated with hospitalization and IO interruption during the whole course of CRT and IO therapy, with increased IO discontinuation which negatively impacted survival. Evaluating and scoring comorbidities at diagnosis could be a useful method to predict risk of death before treatment start.

A nomogram based on clinical characteristics and nutritional indicators for relative and absolute weight loss during radiotherapy in initially inoperable patients with locally advanced esophageal squamous cell carcinoma

ObjectiveRadiation for locally advanced esophageal squamous cell carcinoma often is accompanied by radiation esophagitis, which interferes with oral intake. We aimed to develop a nomogram model to identify initially inoperable patients with relative and absolute weight loss who need prophylactic nutritional supplementation. MethodsA total of 365 initially inoperable patients with locally advanced esophageal squamous cell carcinoma receiving radiotherapy between January 2018 and December 2022 were included in the study, which was divided into discovery and validation cohorts. Receiver operating characteristic and Kaplan-Meier curve analyses were performed to compare the areas under the curve and survival benefits. ResultsA total of 42.2% (154 of 365) of the patients had been diagnosed with cancer cachexia. The malnourished group had a higher interruption rate of radiotherapy and number of complication diseases (P < 0.05). Meanwhile, patients with malnutrition had lower lymphocytes and prognostic nutritional index (P < 0.05). The combined index showed a higher area under the curve value (0.67; P < 0.001) than number of complication diseases (area under the curve = 0.52) and prognostic nutritional index (area under the curve = 0.49) for relative weight loss (≥ 5%). Similarly, the combined index had a higher area under the curve value (0.79; P < 0.001) than number of complication diseases (area under the curve = 0.56), treatment regimens (area under the curve = 0.56), subcutaneous fat thickness (area under the curve = 0.60), pretreatment body weight (area under the curve = 0.61), neutrophils (area under the curve = 0.56), and prognostic nutritional index (area under the curve = 0.50) for absolute weight loss (≥ 5 kg). Absolute and relative weight loss remained independent prognostic factors, with short overall survival rates compared with the normal group (P < 0.05). Patients with high nomogram scores supported by nutritional intervention had less weight loss, better nutrition scores, and increased plasma CD8+ T cells, and interferon gamma. ConclusionsWe developed a nomogram model that was intended to estimate relative and absolute weight loss in initially inoperable patients with locally advanced esophageal squamous cell carcinoma during radiotherapy, which might help facilitate an objective decision on prophylactic nutritional supplementation.