Treatment Switch Research Articles

S46 Remission Status and Reasons for Treatment Switching in Patients With Crohn’s Disease by Treatment Line: A Real-World Study in Europe and the United States of America

S46 Remission Status and Reasons for Treatment Switching in Patients With Crohn’s Disease by Treatment Line: A Real-World Study in Europe and the United States of America

Real-World Discontinuation and Switching Patterns for Interleukin-Inhibitor Treatments in Patients with Moderate-to-Severe Psoriasis in Japan.

Patients with moderate-to-severe psoriasis (PsO) treated with interleukin (IL)-inhibitors may require treatment modification to achieve disease control. This study evaluated discontinuation and switching of IL-inhibitors for PsO patients in Japan. Japan Medical Data Center claims (1/2005-5/2022) were used to identify patients with PsO diagnosis preceding a first IL-inhibitor claim (index date) with ≥ 6months of eligibility prior. Treatment switch (claim for another biologic) and discontinuation (gap in care ≥ 150% of the days' supply of the preceding prescription) were assessed up to 24months following initiation. Censored Kaplan-Meier time-to-event analyses calculated rates, and Cox proportional hazards models estimated hazard ratios (HRs) adjusting for baseline characteristics. The study included 1481 unique patients treated with brodalumab (BRO; n = 159), guselkumab (GUS; n = 360), ixekizumab (IXE; n = 279), risankizumab (RIS; n = 327), secukinumab (SEC; n = 366), tildrakizumab (n = 40; excluded due to limited data), and ustekinumab (UST; n = 262). At 12/24months, 25.9%/38.6% of patients overall had discontinued their index IL-inhibitor and 13.5%/21.2% had switched to another biologic. Discontinuation at 12/24months was lowest for RIS (11.2%/17.4%), followed by UST (17.9%/32.2%), IXE (27.0%/37.0%), GUS (29.8%/43.0%), SEC (35.6%/53.8%), and BRO (37.2%/47.2%). Switching showed a similar trend: RIS (5.7%/10.7%), UST (11.2%/19.9%), SEC (14.7%/25.7%), IXE (14.8%/21.5%), GUS (16.9%/23.2%), and BRO (19.7%/26.8%). HRs of discontinuation relative to RIS were 2.07 for UST, 2.59 for IXE, 2.70 for GUS, 3.65 for BRO, and 3.69 for SEC (all P ≤ 0.001). HRs of switching relative to RIS were 2.05 for IXE, 2.45 for GUS, 2.67 for SEC, 2.73 for UST, and 2.77 for BRO (all P ≤ 0.01). Treatment modification of IL-inhibitors for PsO was commonly observed and could indicate insufficient disease control and/or incremental economic burden. Discontinuation and switching rates were lowest for RIS regardless of time point and adjustment for patient characteristics.

Recent Patterns of Care with BTK Inhibitors and Distribution of Social Determinants of Health Among Patients with CLL/SLL in the US Community Setting

BACKGROUND: The treatment landscape for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) has shifted with the introduction of second-generation Bruton tyrosine kinase (BTK) inhibitors. Few real-world studies, however, have examined sequencing patterns among BTK inhibitors for CLL/SLL and the patient characteristics across different sequences, including social determinants of health (SDOH). The aim of this study is to examine the characteristics, treatment patterns, and SDOH among patients with CLL/SLL who received BTK inhibitors in a large network of community oncology practices. METHODS: This was a retrospective study of adult patients diagnosed with CLL/SLL who were prescribed a BTK inhibitor between 1/1/2020-4/30/2023 in The US Oncology Network. Study data were captured from structured fields in the iKnowMed electronic health record (EHR), with linkage to external sources to evaluate patients' Area Deprivation Index (ADI) scores and rural/urban status. ADI scores were determined by mapping patients' home addresses to a census block group (CBG), which was then linked to the ADI. ADI rankings are based on CBG and determined by the domains of income, education, employment, and housing quality, where high scores indicate increased disadvantage. Low socioeconomic status (SES) was defined as the top 20% of ADI scores on a national and state level (cut-off based on literature review). Rural/urban status was based on the RUCA codes published by the US Department of Agriculture. Insurance coverage was reported “as is” in the claims system with Medicaid an indicator of low SES. Results were assessed by treatment sequence, and SDOH measures results were reported as counts, frequency, and 95% confidence intervals (CI). Chi Square p-values were reported for selected SDOH measures and are shown in text. Data are presented for treatment subgroups with at least 30 eligible patients. RESULTS: In total, 2,082 patients were included in the analysis (median age 73 years; 61.9% male; 73.5% white; 35.0% Rai stage 0-I; median follow-up 14.1 months). The highest proportion of patients received acalabrutinib or ibrutinib without an observed subsequent BTK inhibitor (n=1,159 and n=628, respectively). Patient characteristics by the top 6 treatment sequences are provided in Table 1. Demographic and clinical characteristics across the treatment sequences were similar, including sex, race, and ethnicity distributions, along with Rai stage and ECOG performance status at baseline. Across the subgroups, 8.7% (n=182) were observed to receive a subsequent BTK inhibitor. Among patients who received a BTK inhibitor in 2020 (n=597), 62.3% (n=372) received ibrutinib and a single patient received zanubrutinib. Among the 206 patients who received a BTK inhibitor in 2023, 6.8% (n=14) and 28.6% (n=59) received ibrutinib and zanubrutinib, respectively. In total, 137 patients (6.6%; 95% CI 5.6-7.7) were classified as living in rural locations. Low SES status based on state and national indicators was observed among 361 (17.3%; 95% CI 15.7-19.0) and 125 (6.0%; 95% CI 5.0-7.1) patients, respectively, and was also similar across the subgroups. The highest proportion of patients had Medicare insurance coverage (42.1%; n=877; 95% CI 40-44.3), followed by managed Medicare (24.4%; n=508; 95% CI 22.6-26.3). A statistical difference was found between the treatment regimens for rural/urban ( P<0.01), but not for state ADI ( P=0.52), national ADI ( P=0.36), or Medicaid insurance coverage vs. all others ( P=0.18). The actual values for each regimen are in the Table 1. CONCLUSIONS: The results of this study provide insight into the shifting treatment landscape of BTK inhibitor use among patients with CLL/SLL. During the observation period, the use of ibrutinib decreased while acalabrutinib and zanubrutinib increased. When evaluating measures of SDOH, similarities across the treatment sequence subgroups suggest that patients' SES and Medicaid do not influence prescribing patterns, but rural/urban status show differences. Further real-world research and longitudinal follow-up are needed to examine the impact of SDOH on treatment choice, treatment switching, reasons for switching, and outcomes among users of BTK inhibitors. Additionally, a better understanding of the specific treatment regimen(s) and reasons driving rural/urban differences is needed.

Pharmacogenetics and Pharmacokinetics of Posaconazole in Patients with Acute Myeloid Leukemia: Useful Tools for Antifungal Stewardship

DISCUSSION INTRODUCTION Antifungal prophylaxis with posaconazole in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy is usually recommended [1]. Few studies described the clinical impact of suboptimal posaconazole plasma concentrations during prophylaxis, which may be associated with a higher risk of invasive fungal infections (IFI) and a strong impact on clinical outcome [2]. ENDPOINT: The primary endpoint of this study was to evaluate weekly posaconazole Cthrough plasma concentration in AML patients treated with induction chemotherapy. Since polymorphisms of genes encoding enzymes, transporters and transcription factors were also analyzed a possible association amongst plasma exposure, genetic polymorphisms, risk of breakthrough infection and clinical outcam was evaluated . MATERIALS AND METODS: This was a prospective, single center study at “City of Health and Science”, Molinette Hospital in Turin, Italy. Adult Patients with AML undergoing induction chemotherapy admitted to Haematological wards, were enrolled between March 2023 and July 2023. Antifungal prophylaxis with oral posaconazole, 300mg bid the first day and 300 mg qd thereafter was given. Biological samples (plasma for posaconazole quantificatication and whole blood for genetics) were obtained for each patient after loading dose and then posaconazole C trough were evaluated weekly (at 7, 14, 21 and 28 days). The Following genes were evaluated: UGT1A1, UGT1A3, ABCB1, ABCG2, ABCC2, ABCB11, SLCO1B1, SLCO1B3, SLC22A6, PXR, CAR, VDR, CYP27B1, CYP24A1, GC. The mortality was assessed at day 28 from hospital admission. Invasive fungal disease (IFD) was defined as the occurence of a proven or probable IFD according to the European Organization for Research and Treatment of Cancer/National insitute of Allergy and Infection Diseases Micoses Study Group Criteria (EORTC/MSG) revised definitions [3]. Furthermore, according to the clinical suspicion of breakthrough infection, the switch from prophylaxis to antifungal therapy was also recorded as well as antifungal restaging before treatment change. RESULTS: Twenty patients were included: 9 were women (45%) with a median age of 67 years old (±10.5) and a median Charlson Comorbidity Index of 5 (±1.3). Mean posaconazole C through plasma concentrations are reported in Table 1 and were in range for all the different timepoints. According to EORTC criteria, two patients (10%) had a probable IFI on day 14, and antifungal therapy with liposomal amphotericin B was started [3]. One of those patients had low C trough value at time of suspected breaktrough infection (T 14; 0.2 microg/L 9). The 28 day mortality was 10%, due to the haematological underlying disease. Regarding pharmacogenetic analysis, posaconazole C trough at day 7 and 14 was associated with ABCB1 1236 polymorphism with p=0.022 and p=0.038, respectively. Furthermore, VDR ApaI (p=0.010), VDR TaqI (p=0.023), VDR BsmI (p=0.042), ABCB11 (p=0.023) and UGT1A3 023 (p=0.023) genetic variants were reported in patients with probable IFI. There is a potential impact of the use of posaconazole plasma levels monitoring and associated pharmacogenetics to evaluate the risk of underexposure during antifungal prophylaxis, but also at antifungal restaging before treatment switch. These useful tools may help clinicians to identify patients with a higher risk for under-effective plasma concentrations of posaconazole and can be used to improve antifungal stewardship approach in this setting. The utility of such approaches should also be evaluated in azole-to-azole strategies BIBLIOGRAPHY Olivia White et al. Isavuconazonium or posaconazole for antifungal prophylaxis in patients with acute myeloid leukemia. J Oncol Pharm Pract 2023 May 15;10781552231175825. doi: 10.1177/10781552231175825.Tang LA et al. Risk factors for subtherapeutic levels of posaconazole tablet. J Antimicrob Chemother. 2017 Oct 1;72(10):2902-2905. doi: 10.1093/jac/dkx228. PMID: 29091205Peter Donnelly et al. Revision and update of the Consensus definition of Invasive Fungal Disease from the European Organization for Research adn Treatment of Cancer and the Mycoses study Group Education and Research Consortium. Clin Infect Dis 2020 Sep 12;71(6):1367-1376. doi: 10.1093/cid/ciz1008.

Treatment-Free Remission Era: BCR-ABL1 mRNA Transcript Level

Background: Early acquisition of a deeper molecular response (DMR) and maintenance of a sustained DMR are prerequisites for implementing treatment-free remission (TFR) in CML patients. Earlier identification of patients who have not reached 24-month DMR and timely intervention is particularly important for patients with a strong desire for TFR. Early molecular response (EMR) of BCR-ABL1 mRNA <10% at 3 months after the initiation of TKI therapy is strongly predictive of a 12-month major molecular response (MMR). Whether the EMR <10% is also a good predictor of the 24-month DMR is unknown. Exploring early predictors of 24-month DMR could help guide clinical treatment decisions and advance the implementation of the TFR plan. Aim: Exploring early predictors of 24-month DMR. Methods: We performed a retrospective analysis of all adult patients with newly diagnosed CML-CP in the Department of Hematology at Guangdong Provincial People's Hospital (Guangzhou, China) between Mar 2009 and May 2019. Patients were monitored with BCR-ABL1 mRNA quantitative RT-PCR monthly for the first 3 months of TKI treatment, then every 3 months for a minimum of 2 years, and then every 3 to 6 months. Results: A total of 314 patients with complete medical recorders and routinely monitoring BCR-ABL1 mRNA transcript data of each molecular response milestone were enrolled. Patients' characteristics are summarized in Table 1. The median follow-up time was 54 months (14 to 146 months). The 5-year cumulative rate of MMR, MR 4 and MR 4.5 with TKI treatment were 80%, 48.1%, and 38.4%, respectively. The results of the ROC analysis showed that a 3-month BCR-ABL1 mRNA transcript level of 4.94% correlated well with the 24-month DMR. The sensitivity and specificity of its predictive function were 82.8% (95% CI, 73.6-89.8) and 66.97% (95% CI, 60.3-73.1), respectively. So, we adopted BCR-ABL1 mRNA transcript level ≤4.94% at 3 months as the optimal threshold for predicting 24-month DMR. To reveal the cumulative incidence (CI) of 12-month MMR, 24-month MR 4 and MR 4.5 at different thresholds of BCR-ABL1 mRNA transcript levels at 3 months. Patients were divided into 3 groups according to the BCR-ABL1 mRNA transcript levels, group I <5% (n=150, 47.7%), group II 5% to 10% (n=36, 11.5%), group III >10% (n=128, 40.8%). Patients with BCR-ABL1 mRNA transcript levels <5% at 3 months after TKI initiation are more likely to achieve DMR than the other two groups and take less time to achieve DMR. Patients of Group I with 12-month MMR and 24-month MR 4 were significantly higher than the other two groups, with 66.7% vs 30.6% or 8.6% and 50% vs 16.1% or 7% (P<0.001), respectively. And group II was compared with group III. The cumulative incidence of MMR, MR 4 and MR 4.5 was also significantly higher in Group I than in the other two groups (Fig.1). The survival outcome of patients with BCR-ABL1 transcript levels <5% at 3 months had significantly superior compared with those with BCR-ABL1 transcript levels ≥5%: the 5-year EFS， PFS and OS were 88.6% vs 86.4% (P=0.037), 100% vs 95.7% (P=0.011) and 100% vs 95% (P=0.014)， respectively (Fig. 1). Conclusion: BCR-ABL1 mRNA transcript levels <5% at 3 months is a new landmark EMR (EMR <5%) which can predict 24-month DMR for patients with TKI treatment. EMR <5% may be used to guide the clinical timely switching of TKI or treatment and facilitate the implementation of TFR.

Real-World Switching Pattern, Persistence, and Associated Healthcare Resource Utilization of Bruton Tyrosine Kinase Inhibitors for the Treatment of Mantle Cell Lymphoma in the United States

Introduction: Mantle cell lymphoma (MCL) is an aggressive form of B-cell non-Hodgkin's lymphoma. While incurable, MCL can be controlled for a prolonged period of time, but typically becomes refractory or relapsed and requires additional treatment. Bruton tyrosine kinase inhibitors (BTKi) are approved for relapse/refractory MCL and recommended by the National Comprehensive Cancer Network (NCCN ®); However, it is unclear how BTKi are being utilized and switched in the real-world patient populations. This study aimed to examine treatment patterns, persistence, and associated healthcare resource utilization of BTKi use in patients with MCL in the US. Methods: A retrospective observational study was conducted using Symphony Integrated Dataverse (IDV ®), a comprehensive, longitudinal, open-claims database and integrated Electronic Medical Record (EMR) data. Patients aged ≥18 years with ≥1 diagnosis for MCL and initiated a BTKi between 1/1/20 and 12/31/22 were included in the study. Patients were required to be continuously enrolled for 365 days leading up to the index date and ≥90 days following the index date (date of BTKi initiation). The full patient history in the database was used to identify previous BTKi use and analyze switching patterns for each patient. Three mutually exclusive cohorts (ibrutinib, acalabrutinib, zanubrutinib) were developed based on first-initiated BTKi. Patients were followed until the end of the study period (3/31/23) or lost to follow-up. Treatment switching pattern, duration, persistence, time to discontinuation (TTD), and healthcare resource utilization (HCRU) were examined by each BTKi cohort. Treatment duration was defined as time from BTKi initiation to the end date of last BTKi prescription. TTD was defined as time from BTKi initiation to the end date of the BTKi prescription that had a gap of >60 days with a subsequent BTKi prescription. Treatment persistence was evaluated as the proportion of patients that were continually prescribed BTKi (≥80% proportion of days covered) across 30-day intervals. HCRU was measured by number of outpatient visits and inpatient services, per patient per month (PPPM), during the treatment regimen. Results: BTKi switching patterns were analyzed for the 1,674 patients that initiated any BTKi therapy during study period (acalabrutinib [n= 697]; ibrutinib [n=693]; zanubrutinib [n=284]). Switching rates were 23.8% for ibrutinib, 5.6% for acalabrutinib, and 2.8% for the zanubrutinib cohort. In the ibrutinib cohort, the majority of patients switched to acalabrutinib (72.7%). Of those who switched from acalabrutinib, more than half (59.9%) switched to zanubrutinib. Of those who switched in zanubrutinib cohort, they were equally switched to ibrutinib and acalabrutinib (Table 1). Mean outpatient visits PPPM were 1.39 for patients who initiated with ibrutinib then switched to zanubrutinib, and 1.49 for those who switched to acalabrutinib. Mean inpatient services PPPM were 0.39 for patients who switched from ibrutinib to zanubrutinib, and 0.59 for those who switched to acalabrutinib. The 3 BTKi cohorts were similar across sociodemographic characteristics. The zanubrutinib cohort had higher median TTD (days) (188.5) compared to ibrutinib (161.5) and acalabrutinib (179), as well as higher median treatment duration (200) compared to ibrutinib (171) and acalabrutinib (194). Among MCL patients continuously enrolled for ≥ 360 days, zanubrutinib patients consistently had higher persistence rates (p=0.0079. Figure 1). Persistence at 90-days was 66.9% for zanubrutinib compared to 56.3% for ibrutinib and 62.7% for acalabrutinib. After 360 days, zanubrutinib continued to have the highest persistence (16.9%) compared to ibrutinib (10.8%) or acalabrutinib (13.2%). Zanubrutinib had the least number of mean inpatient services PPPM (0.56) compared to ibrutinib (0.83) and acalabrutinib (0.71) and mean outpatient visits-zanubrutinib (1.53), ibrutinib (1.81), acalabrutinib (1.59). Conclusions: This real-world study suggested that US patients with MCL receiving zanubrutinib showed longer treatment persistence, treatment duration and TTD, as well as lower switching rates and HCRU compared to those receiving acalabrutinib and ibrutinib.

First-Time Users of Advanced Therapies Among Adult Patients with Persistent or Chronic Primary Immune Thrombocytopenia: Patient Characteristics, Treatment Switching Patterns, and Clinical Outcomes

Background Primary immune thrombocytopenia (ITP) is a rare acquired autoimmune disorder characterized by low platelet count, with an overall age/sex-standardized annual incidence of 6.1 per 100,000 persons in the US in 2016. Patients who fail to respond or maintain a response to initial therapy (e.g., corticosteroids, intravenous immunoglobulins), move to advanced therapies with robust evidence such as thrombopoietin receptor agonists (TPO-RAs [eltrombopag/ romiplostim/ avatrombopag]), rituximab, and fostamatinib, as per the international consensus guidelines. Among patients with primary ITP lasting ≥3 months who are first-time users of advanced therapies, there is limited real-world evidence on patient characteristics, treatment patterns, and clinical outcomes. Objectives The key objectives were to assess patient characteristics, treatment patterns, and clinical outcomes of first-time users of advanced therapy in patients with primary ITP lasting ≥3 months. Methods This retrospective, cohort study included patients identified from Optum de-identified Clinformatics ® Data Mart database, aged ≥18 years with primary ITP lasting 3 months or more, who initiated advanced therapy for the first time between October 1, 2015, and August 31, 2020. Patients were required to have ≥365 days of available data prior to index date, without evidence of conditions associated with secondary ITP. Patients were indexed on the date of initiation of advanced therapies. Baseline characteristics, including demographics, comorbidities, use of medication, and bleeding events requiring medical attention (e.g., intracranial bleeding, gastrointestinal bleeding, hematuria) were assessed 365 days prior to index and reported using descriptive statistics. Treatment patterns and rates of bleeding events, thromboembolic events (TEs), bacterial infections, and hospitalizations were assessed during follow-up, which began one-day after index date and until discontinuation of the index therapy. Patients were censored on death, end of data accrual, disenrollment, or switch to another advanced therapy. Outcomes were reported as the number of events per 1000 person-years and time to first event. Results Total 375 patients with primary ITP lasting ≥3 months, who were first-time users of advanced therapies were included, with 51% (n=192) initiating TPO-RAs, 49% (n=182) initiating rituximab, and <1% (n=2) initiating fostamatinib. Mean (SD) age of overall population was 62 (19) years, and 55.7% were female. About 9% of patients were Black, 4% Asian, and 11% Hispanic ( Table 1). In year prior to index date, previous bleeding events were most common clinical symptoms in patients with ITP initiating advanced therapies (any bleeding, 39.7%). Other frequently reported comorbidities were diabetes (28.5%), coronary artery disease (18.9%), and asthma (17.3%); 13.1% of patients had a TE. About 5% patients reported bacterial infections ( Table 1). Patients initiating TPO-RA and those starting rituximab were observed for a median (interquartile range, IQR) duration of 22.2 (14.5-34.9) months and 27.1 (13.5-43.2) months, respectively. Almost 9% of TPO-RAs initiators switched to rituximab (median [IQR] time to switch: 3.2 [1.7-6.9] months), while 23.6% of rituximab initiators switched to TPO-RAs (median [IQR] time to switch: 3.1 [1.7-7.6] months) during follow-up. After initiating advanced therapies, the rates of any bleeding event and TEs were 288 per 1000 person-years (95% CI: 240-336) and 129 per 1000 person-years (95% CI: 99-158), respectively. Mean (SD) time to first bleeding event was 299 (351) days and that of TE was 257 (325) days. Infection rate was 70 per 1000 person-years ( Table 2). In follow-up, 31% of patients had ≥1 ITP-related hospitalization and 38% had an all-cause hospitalization, resulting in rates of 215 [95% CI: 176-255] and 299 [95% CI: 250-349] per 1000 person-years, respectively. Approximately 5% of patients underwent splenectomy (incidence rate: 27 per 1000 person-years [95% CI: 15-40]) with mean (SD) time of 245 (186) days post initiation of advanced ITP therapy ( Table 2). Conclusion This study demonstrated high clinical burden and need for subsequent additional therapies among patients with primary ITP lasting ≥3 months, which is evident from high rates of switching between advanced therapies, bleeding events requiring medical attention, TEs, and ITP-related hospitalizations.

Evaluating Physician-AI Interaction for Multiple Myeloma Management: Paving the Path Towards Precision Oncology

Introduction The gap between clinical trials and real-world care continues to grow in the field of multiple myeloma (MM). Randomized controlled trials (RCTs) cannot account for every patient scenario. Modern clinical decision support systems (CDSSs) that leverage machine learning (ML) models offer an alternate path to precision oncology. However, little work has been done to understand how clinicians reconcile RCT with ML data, particularly when results are discordant. Aim We designed a CDSS that displays simulated survival and adverse event data from an RCT and ML model and conducted a survey study to evaluate how clinicians incorporate the available data to make treatment decisions for 12 patients with MM. Methods Participants were presented with varying combinations of RCT and ML results in increasing “tiers” of information for 12 patients (A-L) with MM (Table 1). In tier 1, participants were provided RCT data only. In tier 2, participants were given outcomes of an ML model and in tier 3, they were provided with information about how the model was trained and validated. At each tier, participants were asked to select a treatment (“red pill” or “blue pill”), rate their confidence in treatment on a Likert scale from 1-10, and when ML data was available, rate their perceived reliability of the model on a Likert scale from 1-10. Participants were recruited from internal medicine and hematology/oncology departments via email between January and April 2023, and were offered a $50 Amazon gift card as incentive. We used descriptive statistics to analyze respondent characteristics. For each scenario, we ran two-sample paired t-tests to compare the change in confidence and reliability between tier 2 and tier 1 (ML versus RCT data) and tier 3 versus tier 2 (ML data with information about training and validation versus without). We utilized a Bonferroni correction to adjust the alpha level for significance. We also ran McNemar's tests with a Bonferroni correction to assess the difference in proportions of blue pill selection at different tiers to characterize the extent of treatment switching. Results A total of 284 physicians were invited to participate in the study and 32 participated, for a response rate of 11.3%. Half were internal medicine residents and half were hematology/oncology fellows and attendings. A majority were male (72.0%), white (69.0%) and all were less than 40 years of age. For scenarios A-D, the patient met inclusion criteria for the RCT and was well represented in training data for the ML model. Confidence was highest for scenario A where survival results between the RCT and ML model were concordant (Figure 1). Across scenarios B, C, and D, confidence dropped after seeing the ML results (B: p=0.05, C: p=0.05, D: p=0.36) but increased after participants learned the ML model was trained on patients like theirs (B: p=.002, C: p=0.17, D: p=0.06). In scenarios C and D, a majority of participants switched treatment after learning the ML model showed no benefit with the red pill (C: p=5.1x10 -4, D: p=1.5x10 -5). In scenarios E-H, the patient did not meet inclusion criteria for the RCT but was well represented in the training data for the ML model. When the ML model showed worse adverse events (F) or no benefit with the red pill (G, H) the majority of participants switched treatment choice (F: p=0.27, G: p=0.002, H: p=1.9x10 -4). There was an increase in confidence when participants learned the ML model had been trained on representative patients (E: p=0.008, F: p=0.01, G: p=0.18, H: p=2.0x10 -3). In scenarios I-L, the patient did not meet inclusion criteria for the RCT and was not well represented in the training data for the ML model. There was a decrease in confidence when participants learned this in tier 3 (I: p=0.18, J: p=3.0x10 -4, K: p=0.05, L: p=0.009). However, the majority of participants still switched to the blue pill when the ML model showed no benefit with the red pill (K: p=1.9x10 -4). Conclusions Confidence in treatment was highest when RCT and ML findings were concordant. Participants chose treatments based on ML model estimates even before assessing how the ML model was trained or validated. Participants preferred the treatment that demonstrated a survival benefit, regardless of whether it was supported by RCT data or an ML model.

Comparison of the General Characteristics of Patients with Severe Asthma Who Switched from Omalizumab to Mepolizumab versus Patients Who Responded to Omalizumab Treatment: A Real-Life Study

Introduction: Severe asthma is characterized by frequent recurrent airway symptoms and exacerbations, and these affect the quality of life. Biological agents can be used in the treatment of patients with severe asthma if the disease cannot be controlled with standard controller treatment. The aim of this study was to compare the clinical characteristics and laboratory data of patients with severe asthma who were switched from omalizumab to mepolizumab and patients with severe asthma who responded to omalizumab. Methods: The clinical characteristics and laboratory data of patients with severe asthma who responded to omalizumab and switched from omalizumab to mepolizumab were compared retrospectively. Results: Evaluation was made of a total of 79 patients, including 64 omalizumab responders and 15 who switched to mepolizumab from omalizumab. After omalizumab and mepolizumab treatment, the annual number of asthma attacks, the use of oral corticosteroid (OCS), the annual number of hospitalizations, and the eosinophil count significantly decreased (omalizumab: p < 0.001, p < 0.001, p < 0.001, p < 0.001, respectively; mepolizumab: p = 0.001, p = 0.001, p = 0.002, p = 0.001, respectively). After omalizumab treatment, the increase in forced expiratory volume in 1 s (FEV1) (%) and asthma control test (ACT) score were determined to be statistically significant (p < 0.001, p < 0.001, respectively). After mepolizumab treatment, the increase in ACT score was significant (p = 0.003). Drug allergy, chronic sinusitis with nasal polyps (CRSwNP), regular use of OCS, and high baseline eosinophil count (cells/µL) were associated with poor response to omalizumab treatment (odds ratio [OR] = 7.86, p = 0.003; OR = 52.92, p < 0.001; OR = 10.16, p = 0.004; OR = 0.99, p = 0.004, respectively). House dust mite sensitivity and high baseline FEV1 (%) were associated with good response to omalizumab treatment (OR = 0.29, p = 0.041; OR = 1.06, p = 0.03, respectively). The blood eosinophil count had diagnostic value in predicting the nonresponsiveness to omalizumab treatment (area under the curve [AUC]: 0.967, p < 0.001, cut-off: 510). Conclusion: A high pretreatment eosinophil count, concomitant CRSwNP, a history of drug allergy, and regular OCS use may be associated with poor response to omalizumab treatment in patients with severe asthma. Depending on the treatment response, treatment switching can be applied between biological agents. The results of the current study should be supported by multicenter studies.

Treatment Patterns and Modifications of Tyrosine Kinase Inhibitors (TKI) Therapy in Early Lines in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP): Real-World Analysis from a Large Commercial Claims Database in the United States (US)

Introduction: Although current TKI options are often successful in managing CML-CP in early lines of therapy, patients may experience issues related to tolerability or resistance to TKIs. Physicians often have to proceed with treatment modifications including discontinuation, switching, temporary interruptions, or dose modifications when the patient's current treatment is not working as expected. This retrospective cohort study assessed these TKI therapy management patterns in patients with CML in first-line (1L) or second-line (2L) treatment in the US. Methods: A large administrative claims database of commercially insured patients, the OptumInsight Clinformatics database (January 2007-June 2022), was used to select adult patients with CML who received 1L TKI therapy (imatinib, dasatinib, nilotinib, or bosutinib; 1L cohort) and those who received 2L TKI therapy (imatinib, dasatinib, nilotinib, bosutinib, or ponatinib; 2L cohort), with treatment initiation (index date) on or after 2012. Patients were required to have ≥6 months of continuous health plan enrollment pre-index, with no hematopoietic stem cell transplantation (HSCT) or CML-related chemotherapy treatments for accelerated phase (AP) or blast crisis (BC) pre-index. Treatment modifications assessed post-index included 1) treatment discontinuation, defined as the earliest of HSCT/treatment switch (defined below)/initiation of a CML-related chemotherapy for AP or BC, 2) treatment switch defined as initiation of another TKI/omacetaxine mepesuccinate, 3) temporary treatment interruption defined as gap of ≥ 14 days followed by resuming the index TKI, and 4) dose reduction (as compared to the initial dose) were assessed. Time to first event post-index were conducted using Kaplan Meier analyses for each of these treatment modifications, in 1L and 2L cohorts, separately. Results: A total of 2,043 patients were included in the 1L cohort with 47.8% of them receiving imatinib, 31.0% dasatinib, 19.2% nilotinib, and 2.0% bosutinib (median age: 64 years; 44.9% female; 69.7% White; 49.5% with Medicare advantage plan operated by commercial insurance [Part C]). Patients in the 1L cohort were observed for a mean (SD) period of 29.1 (27.3) months from index date to earliest of loss of follow-up/end of data. Overall, more than a quarter of patients (27.3%) experienced treatment discontinuation, with rates of discontinuation of 16.1% at 6 months, 25.0% at 12 months, and 33.5% at 24 months post-index ( Figure 1). Treatment switch was observed in 26.0% of the patients, with rates of 15.5% at 6 months and 24.4% at 12 months post-index. The proportion of patients with temporary treatment interruption was 18.6%, with rates of 20.6% at 6 months and 22.2% at 12 months post-index. Dose reduction (as compared to initial dose) occurred in 21.9% of patients, with rates of 18.8% at 6 months and 23.3% at 12 months post-index. A total of 586 patients were included in the 2L cohort with 23.0% of them receiving imatinib, 36.9% dasatinib, 26.6% nilotinib, 10.9% bosutinib and 2.6% ponatinib (median age: 65 years; 47.3% female; 72.5% White; 48.3% with Medicare advantage plan operated by commercial insurance [Part C]). Patients in the 2L cohort were observed for a mean (SD) period of 28.4 (25.4) months from index date to earliest of loss of follow-up/end of data. Almost a third of patients (32.8%) experienced treatment discontinuation, with rates of discontinuation of 22.1% at 6 months, 29.9% at 12 months, and 43.1% at 24 months post-index ( Figure 1). Treatment switch was observed in 30.5% of patients, with rates of 20.5% at 6 months and 28.3% at 12 months post-index. The proportion of patients with temporary treatment interruption was 21.3%, with rates of 24.8% at 6 months and 25.4% at 12 months post-index. Dose reduction as compared to initial dose occurred in 20.6% of patients, with rates of 17.5% at 6 months and 27.2% at 12 months post-index. Conclusions: Findings from this real-world study demonstrate that almost a quarter of patients with CML treated with current TKI treatment options in 1L or 2L experienced treatment discontinuation/switch in the first year from TKI initiation suggesting lack of optimal response/tolerability to currently available TKIs, with more pronounced rates in 2L. This suggests that unmet clinical needs still persist in this population, warranting optimal 1L and 2L treatment options with better tolerability profile for CML management.

Active Vitamin D Use and Fractures in Hemodialysis Patients: Results from the International DOPPS.

Active vitamin D is commonly used to control secondary hyperparathyroidism in dialysis patients, but it is unknown whether active vitamin D directly improves bone strength, independently of its ability to suppress parathyroid hormone (PTH). We analyzed the association between the prescription of active vitamin D and incidence of any fracture and hip fracture in 41,677 in-center hemodialysis patients from 21 countries in phases 3 to 6 (2005 to 2018) of the Dialysis Outcomes and Practice Patterns Study (DOPPS). We used Cox regression, adjusted for PTH and other potential confounders, and used a per-protocol approach to censor patients at treatment switch during follow-up. We also used a facility preference approach to minimize confounding by indication. Overall, 55% of patients were prescribed active vitamin D at study enrollment. Event rates (per patient-year) were 0.024 for any fracture and 0.010 for hip fracture. The adjusted hazard ratio (95% confidence interval) comparing patients prescribed versus not prescribed active vitamin D was 1.02 (0.90 to 1.17) for any fracture and 1.00 (0.81 to 1.23) for hip fracture. In the facility preference approach, there was no difference in fracture rate between facilities with higher versus lower active vitamin D prescriptions. Thus, our results do not suggest a PTH-independent benefit of active vitamin D in fracture prevention and support the current KDIGO guideline suggesting the use of active vitamin D only in subjects with elevated or rising PTH. Further research is needed to determine the role of active vitamin D beyond PTH control. © 2023 American Society for Bone and Mineral Research (ASBMR).

Sequenced treatment alternatives to relieve adolescent depression (STAR-AD): a multicentre open-label randomized controlled trial protocol

BackgroundAdolescent major depressive disorder (MDD) is a prevalent mental health problem with low treatment success rates. Whether fluoxetine or fluoxetine combined with cognitive-behavioural therapy (CBT) is the more effective initial treatment for adolescent MDD remains controversial, and few studies have investigated whether treatment switching or augmentation is preferred when the initial treatment is not working well.MethodsWe developed a multicentre open-label Sequential Multiple Assignment Randomized Trial (SMART) design, consisting of two phases lasting 8 weeks each. In phase 1 (at baseline), patients will be recruited and grouped in fluoxetine group or fluoxetine combined with CBT group by patient self-selection. In phase 2 (after 8 weeks of treatment), the nonresponders will be randomly assigned to six groups, in which participants will switch to sertraline, vortioxetine, or duloxetine or added aripiprazole, olanzapine, or lithium carbonate to fluoxetine. After the full 16 weeks of treatment, we will assess the long-term sustainability of the treatment effects by evaluating participants during their subsequent naturalistic treatment. The primary outcome will be the response rate, determined by the Children’s Depression Rating Scale-Revised (CDRS-R). Secondary outcomes include the change in scores on the Beck Depression Inventory (BDI), the Screen for Child Anxiety-Related Emotional Disorders (SCARED) and the Safe Assessment.DiscussionThe results from this study will aid clinicians in making informed treatment selection decisions for adolescents with MDD.Trial registrationThis protocol was registered at ClinicalTrials.gov with Identifier: NCT05814640.

Fabry disease biomarkers in patients switched from enzyme-replacement therapy to migalastat oral chaperone therapy.

Background: A biomarker profile was evaluated longitudinally in patients with Fabry disease switched from enzyme-replacement therapy (ERT) to migalastat. Methods: 16 Gb3 isoforms and eight lyso-Gb3 analogues were analyzed in plasma and urine by LC-MS/MS at baseline and at three different time points in naive participants and participants switching from either agalsidase α or β to migalastat. Results: 29 adult participants were recruited internationally (seven centers). The Mainz Severity Score Index and mean biomarker levels remained stable (p≥0.05) over a minimum of 12months compared with baseline following the treatment switch. Conclusion: In this cohort of patients withFabry diseasewith amenable mutations, in the short term, a switch from ERT to migalastat did not have a marked effect on the average biomarker profile.

Optimizing the "Time to pregnancy" in women with multiple sclerosis: the OPTIMUS Delphi survey.

The debate on how to manage women affected by multiple sclerosis (MS) during reproductive age is still open, as is the issue of fertility in such patients. Main issue regard the identification of the optimal window for pregnancy and how to deal with medical therapy before and during conception. The aim of this Delphi consensus was to collect the opinions of a multidisciplinary group, involving reproductive medicine specialists and neurologists with experience in the management of multiple sclerosis women with reproductive desire. Four experts plus scientific coordinators developed a questionnaire distributed online to 10 neurologists and later discussed the responses and amended a list of statements. The statements were then distributed via an online survey to 23 neurologists (comprising the first 10), who voted on their level of agreement/disagreement with each statement. Consensus was achieved if agreement or disagreement with a statement exceeded 66%. Twenty-one statements reached consensus after two rounds of voting, leading to the following main recommendations: (1) Fertility evaluation should be suggested to wMS, in case of the need to shorten time to pregnancy and before treatment switch in women on DMTs contraindicated in pregnancy, particularly in case of highly active disease and age > 35 years. (2) ART should not be discouraged in wMS, but the use of DMTs until pregnancy confirmation should be suggested; ART may be considered in order to reduce time to pregnancy in MS women with a reduced ovarian reserve and/or age > 35 years, but in case of an expected poor ART prognosis and the need for more than one ART cycle, a switch to a high-efficacy DMD before ART should be offered. (3) Oocyte cryopreservation may be considered in women with reduced ovarian reserve, with unpredictable time to complete diagnostic workup and achieve disease control; a risk/cost-benefit analysis must be performed in women >35 years, considering the diminished ovarian reserve. This consensus will help MS neurologists to support family planning in wMS, respecting MS therapeutic needs while also taking into account the safety and impact of advancing age on fertility.

Statistical considerations in long-term efficacy evaluation of anti-cancer therapies.

Anti-cancer therapy has been a significant focus of research. Developing and marketing various types and mechanisms of anti-cancer therapies benefit a variety of patients significantly. The long-term benefit to patients in evaluating the risk-benefit ratio of anti-cancer therapy has become a significant concern. This paper discusses the evaluation of long-term efficacy within the estimand framework and summarizes the various strategies for addressing potential intercurrent events. Non-proportional hazards of survival data may arise with novel anti-cancer therapies, leading to potential bias in conventional evaluation methods. This paper reviews statistical methods for addressing this issue, including novel endpoints, hypothesis testing, and efficacy estimation methods. We also discuss the influences of treatment switching. Although advanced methods have been developed to address the non-proportional hazard, they still have limitations that require continued collaborative efforts to resolve issues.

Barakat syndrome diagnosed decades after initial presentation.

Barakat syndrome, also called HDR syndrome, is a rare genetic disorder encompassing hypoparathyroidism (H), sensorineural deafness (D) and renal disease (R). A 64-year-old woman was referred to our endocrinology clinic for a switch in treatment (from dihydrotachysterol to calcitriol). She had progressive sensorineural deafness since the age of 18 and idiopathic hypoparathyroidism diagnosed at age of 36. Her medical history included osteoporosis with hip/spine fractures, nephrolithiasis and a family history of hearing loss, osteoporosis and kidney disease. The patient's clinical presentation indicated Barakat syndrome. Genetic analysis found a GATA3:c.916C>T nonsense variant. Further tests such as audiometry, labs and renal imaging supported the diagnosis. Due to rarity and manifold symptoms, diagnosis can be challenging. Optional GATA3 testing was suggested in 2018, except in cases of isolated sensorineural deafness or renal disease with pertinent family history. In isolated 'H' cases without 'D' and 'R', GATA3 studies are not required, as no haploinsufficiency cases were reported. Given the rise in genetic disorders, physicians should consistently consider rare genetic disorders in patients with suggestive symptoms, even decades after onset. Although diagnosis might not always impact management directly, it aids patients in accepting their condition and has broader family implications. There is currently an important increase in genetic and clinical characterization of new orphan diseases and their causative agents. Unbiased re-evaluation for possible genetic disorders is necessary at every consultation. It is essential to recognize the differential diagnosis of idiopathic hypoparathyroidism. The patient's clinical presentation and family history can be important to establish the correct diagnosis. Physicians should not hesitate to search a patient's signs and symptoms online.

Suboptimal management of rheumatoid arthritis in France: a real-world study based on data from the French National Health Data System

ObjectivesThe emergence of targeted therapy is changing rheumatoid arthritis (RA) management, but real-world data remain limited. This study aimed to describe real-world RA treatment patterns using data from a French...

P374 COMET: effects of avalglucosidase alfa and treatment switch from alglucosidase alfa on week 145 QMFT individual item responses

P374 COMET: effects of avalglucosidase alfa and treatment switch from alglucosidase alfa on week 145 QMFT individual item responses

Real-Life Data on the Use of Omalizumab in Patients with Severe Asthma and Chronic Urticaria and Mepolizumab in Patients with Severe Asthma: A Retrospective Study

This study aimed to assess the real-life effectiveness of omalizumab and mepolizumab in patients with severe asthma and chronic spontaneous urticaria (CSU), explicitly examining changes in IgE levels and eosinophil counts during treatment. This retrospective study involved patients with severe asthma or CSU treated with biologic agents, including omalizumab and mepolizumab. The primary outcome measures were serum IgE levels, eosinophil counts, urticaria activity scores (UAS), and asthma control test scores (ACT). We studied 61 patients with severe asthma or chronic urticaria treated with biological agents. Patients with asthma exhibited a significant reduction in the median annual attack rate from 4 to 0 with omalizumab (p&amp;lt;0.001) and from 6 to 1 with mepolizumab (p&amp;lt;0.001). Eosinophil counts, and ACT scores significantly decreased with mepolizumab (p&amp;lt;0.001). Six patients who transitioned from omalizumab to mepolizumab did not experience severe asthma attacks in the first six months following the treatment switch. Patients with CSU showed a significant response to omalizumab (p&amp;lt;0.001). We observed significant improvements in various markers, including total IgE levels, eosinophil counts, UAS, and ACT scores, indicating that these treatments can effectively manage the symptoms of both conditions. These findings underscore the potential benefits of using these treatments as effective therapeutic options.

Effectiveness and safety of oral anticoagulants for non-valvular atrial fibrillation: a population-based cohort study in primary healthcare in Catalonia.

Objectives: Our objective was to analyse effectiveness and safety of oral anticoagulants (OAC) for stroke prevention in non-valvular atrial fibrillation. Material and methods: Population-based cohort study including adults initiating oral anticoagulants, either direct oral anticoagulants (DOAC) or vitamin K antagonists (VKA), during 2011-2020. Data source: SIDIAP, capturing information from the electronic health records of Primary Health Care in Catalonia, Spain. Study outcomes: stroke, cerebral and gastrointestinal (GI) haemorrhage, assessed by patients' subgroups according to different clinical characteristics. Results: We included 90,773 patients. Male sex, older than 75, previous event, peripheral artery disease, deep vein thrombosis, or receiving antiplatelets, antidiabetics or proton pump inhibitors (PPI) was associated with higher stroke risk. For DOAC-treated, treatment switch increased stroke risk, while being adherent had a protective effect. Men, antidiabetic treatment or a previous event increased the risk of cerebral bleeding. Receiving direct oral anticoagulants had a protective effect in comparison to vitamin K antagonists. For DOAC-treated, treatment switch increased, and adherence decreased the bleeding risk. Men, people with chronic kidney disease or a previous event posed an increased risk of gastrointestinal bleeding, whereas receiving PPI had a protective effect. For DOAC-treated, switch was associated with a higher bleeding risk. Conclusion: Being men, a previous event and DOAC-switch posed a higher risk for all study outcomes. direct oral anticoagulants had a protective effect against cerebral bleeding in comparison to vitamin K antagonists. Adherence to direct oral anticoagulants resulted in lower risk of stroke and cerebral bleeding. We found no differences in the risk of stroke and gastrointestinal bleeding when we compared direct oral anticoagulants vs. vitamin K antagonists.