Median Persistence Research Articles

Abstract 4126158: Persistence to once weekly GLP-1 RAs is associated with lower risk of MI, stroke, and 2-point MACE among patients with T2D and ASCVD in the real world.

Introduction: Studies have shown the reduction of CV events in patients with T2D treated with GLP-1 RAs. However, little is known about how persistent use of GLP-1 RA therapy affects CV outcomes in patients with T2D and ASCVD. The objective of this study was to estimate the association between persistent use of once weekly (OW) GLP-1 RAs and 2-point MACE and its components (MI, stroke) in patients with T2D and ASCVD in a real-world setting. Methods: Adult patients with T2D and ASCVD with ≥1 pharmacy claim for OW GLP-1 RAs during Jan 2018-Nov 2022 were identified in the Optum Research Database. The date of the first OW GLP-1 RA claim was defined as the index date. Patients were followed until a CV event occurred or censored. Discontinuation was defined as a ≥60-day gap in supply of OW GLP-1 RAs. All patients were required to be persistent for ≥3 months of follow-up to allow titration of the therapy. CV events of interest include 2-point MACE, MI and stroke. Kaplan-Meier analyses were used to examine risk of CV events by persistent status within 6, 12, or 18 months of follow-up. Cox proportional hazards models with time-varying exposures were used to assess associations between persistent status and MACE, with persistent status of patients updated for each day of follow-up, adjusting for demographic and baseline clinical characteristics. Results: Among a total of 29516 patients, the median follow up duration was 412 days, median persistence was 254 days, and 63.9% of patients (n=18849) were persistent throughout their variable follow up period. Kaplan-Meier analyses indicated risk of 2-point MACE, MI, and stroke was significantly lower in patients who were persistent within 6, 12 or 18 months of follow-up compared to patients who discontinued within 6, 12 or 18 months of follow-up (all p<0.05); longer persistence led to a qualitatively greater risk reduction. Adjusted hazard ratio (95% confidence interval) from Cox regression with time-varying persistence status during the full variable follow up in all patients for risk of 2-point MACE, MI, and stroke associated with persistent use of OW GLP-1 RAs was 0.70 (0.63-0.77), 0.71 (0.62-0.81), and 0.67 (0.57-0.78), respectively. Conclusions: Patients with T2D and ASCVD who were persistent with OW GLP-1 RAs had a lower risk of 2-point MACE, MI, and stroke than those who discontinued the therapy in real-world clinical practice. Longer persistence of OW GLP-1 RAs appeared to provide greater CV benefits.

Long-Term Safety and Efficacy of the Fully Human CAR-T Therapy CT103A in Relapsed/Refractory Multiple Myeloma

CT103A is a fully human chimeric antigen receptor T-cell (CAR-T) product for targeting B-cell maturation antigen (BCMA). This study presents the updated safety and efficacy profiles of CT103A in patients with relapsed/refractory multiple myeloma (RRMM) after long-term follow-up. As of July 31, 2023, the median follow-up time after CAR-T-cell infusion was 45.0 months (range, 0.7-58.3 months). During long-term follow-up, the incidence of adverse events gradually decreased over time. One patient had a maximum duration of response of nearly five years. All 18 patients (100%) achieved partial remission or better; 77.8% (14 of 18) of patients eventually exhibited complete response (CR) or stringent complete response (sCR), with response increasing over time. At the time of data cut-off, nine patients were still alive, and seven patients had an sCR status with negative minimal residual disease (MRD). The median progression-free survival (PFS) was 22.6 months, and the median overall survival (OS) was 50.2 months for all 18 patients. The median CAR transgene persistence was 14.0 months (range, 0.7-57.3 months). Long-term follow-up demonstrated that CT103A confers durable clinical benefit for RRMM patients based on the sustained presence of fully human CAR-T cells.

Real-world utilisation and switching between Janus kinase inhibitors in Australian patients with rheumatoid arthritis in the OPAL dataset.

To describe use and treatment persistence for Janus kinase inhibitors (JAKi) in rheumatoid arthritis (RA) by line of therapy, and the mechanism of action for the drug switched to after JAKi discontinuation. This was a retrospective, observational analysis using the OPAL dataset, a large collection of deidentified electronic medical records from 112 rheumatologists around Australia. Adult patients with RA were included if they initiated tofacitinib (TOF), baricitinib (BARI) or upadacitinib (UPA) between 1 October 2015 and 30 September 2021. Data were summarised using descriptive statistics. Kaplan-Meier survival was used to analyse treatment persistence. 5,900 patients initiated JAKi within the study window (TOF n=3,662, BARI n=1,875, UPA n=1,814). Median persistence was similar across JAKi within each line of therapy where there was sufficient follow-up, and almost 3 years for first-line: 34.9 months (95% CI 30.8, 40.7; n=1,408) for TOF, 33.6 months (95% CI 25.7, not reached; n=545) for BARI. While JAKi to JAKi switching occurred across all lines of therapy, switches to a tumour necrosis factor inhibitor (TNFi) were more frequent after first- or second-line JAKi. JAKi monotherapy use at baseline increased with line of therapy, and was highest at follow-up after switching to another JAKi. 'Lack of efficacy' was the most common reason for discontinuing JAKi. In this large analysis of Australian real-world practice separated by line of therapy, treatment persistence for JAKi was high overall subject to differential follow-up, but declined in later lines. JAKi to JAKi switching was observed across all lines of therapy.

Imatinib Adherence and Persistence in Patients with Chronic Myeloid Leukemia in Belgium: Evidence from Real-World Data.

Imatinib adherence and persistence are key components of the successful treatment of Chronic Myeloid Leukemia (CML). In Belgium, there is no study assessing these behaviors at a national level. Our study aimed to provide the first nationwide measure and to identify associated pharmacy-based predictors (age, gender, comorbidities). We also assessed mortality and transplantation incidence according to adherence status. Based on medico-administrative database linkage, we identified a retrospective Belgian cohort of 1194 patients diagnosed with CML between 2004 and 2016 and treated with imatinib. Adherence was measured over 24 months, considering the proportion of days covered (PDC). Persistence was measured as the time until discontinuation (gap of ≥90 days). Multivariable Poisson regression models with robust standard error were conducted to identify predictors associated with adherence (≥90% PDC). To identify factors associated with persistence, a multivariable Cox regression was performed. At six months, 60.3% of patients were adherent, declining to 41.5% at 12 months, and to 30.1% at two-year follow-up (n=998). Adherence was greater at a younger age (eg 31-40 years vs ≥75 years, adjusted prevalence ratio (aPR) 1.73; 95% confidence interval (CI): 1.09-2.77) and among patients with no comorbidity (0 vs ≥2 comorbidities (aPR 1.56; 95% CI: 1.11-2.19). The median persistence was 334.5 days (Q1:200-Q3:505.5); persistence at 24 months was 83.6% (n=998). Only age was associated with higher risk of discontinuation, with adjusted hazard ratio (aHR) of 6.05 for patients ≥75 years (95% CI: 5.52-6.58). Transplants and deaths mainly occurred in patients defined as non-adherent at 24 months. This Belgian nationwide representative study revealed a critical low level of imatinib adherence, which decreased over time even though persistence was high at six months. We pinpointed pharmacy-based predictors that were easily identifiable by health care stakeholders in order to undertake interventions to improve adherence.

STRIvE-02 Arm C: Phase 1 study of concurrent PD-1 inhibition with B7-H3 CAR T cell immunotherapy for recurrent/refractory pediatric solid tumors.

e14626 Background: B7-H3 expression by a broad range of pediatric solid tumors has led to development of B7-H3-directed chimeric antigen receptor (B7-H3-CAR) T cells. However, early phase clinical trials of B7-H3-CAR T cells in recurrent/refractory solid tumors demonstrated inconsistent CAR T cell expansion and limited anti-tumor activity. We subsequently developed a dual transduced CAR product expressing B7-H3-CAR and CD19-CAR (CARB7H3x19) to enhance CAR T cell expansion with antigenic stimulation by normal B cells (STRIvE-02 Arm B). Augmented expansion was observed but CAR T cell persistence was variable, leading to a hypothesis that concurrent use of pembrolizumab (pembro), a PD1-inhibitor, would help prolong persistence, leading to improved anti-tumor activity. Methods: Patients up to age 26 years with recurrent/refractory solid tumors (excluding primary CNS) enrolled onto Arm C of STRIvE-02 to examine safety and feasibility of CARB7H3x19 at a dose of 0.5 x 106 CD19-CAR T/kg followed by pembro 2 mg/kg (max 200 mg) either 7- (Dose regimen (DR) 1) or 21-days (DR 2) post-CAR T cell using a 3+3 statistical design. All subjects received lymphodepletion with fludarabine and cyclophosphamide prior to CAR T cells. CTCAEv5 was used for toxicity grading. Results: Of six patients (pts) enrolled (age range 11–25 yrs, median 20 yrs, four received CAR T cell+pembro; three received DR1 pembro (day (D)+7), and one received DR2 (D+21). A pt on DR2 with nonseminomatous germ cell tumor developed grade (gr) 5 immune effector cell-associated hyperinflammatory syndrome (IEC-HS) on D+17 prior to pembro, resulting in trial suspension. One pt did not receive CAR T cells and is unevaluable. Adverse effects occurring in pts who received pembro included gr 3 fever in setting of neutropenia (n=1), and gr 2 hyperthyroidism (n=1), with no dose limiting toxicity attributed to CAR T cell+pembro. Maximum circulating CAR T expansion for Arm C was 192.18 cells/uL (range 6.86 – 192.18 cells/uL) with median persistence of 28 days (range 28 - 84), compared to a maximum circulating CAR T expansion of 740.95 cells/uL (range 8.29 – 740.95 cells/uL) and median persistence of 65 days (range 21 - 274) in pts treated on Arm B receiving the same CAR dose level (n=8). D+28 disease restaging in the four Arm C pts who received CAR T cells+pembro demonstrated stable disease (n=1) and disease progression (n=3). Conclusions: Although we observed tolerable toxicity among patients who received CAR T cell+pembro, the small number of patients limit full toxicity assessment. T cell expansion and persistence was observed, but the effects of pembro on CAR T cell fitness are unclear. Phenotypic characterization of circulating CAR T cells is underway to further assess impact of pembro. Of note, this is the first reported death attributed to IEC-HS in a patient after receiving B7-H3-CAR T cells. Investigations into etiology are ongoing. Clinical trial information: NCT04483778 .

Real-world study of the use of azacitidine in myelodysplasia in Australia.

Hypomethylating agents are the most widely used upfront therapy for patients with myelodysplastic syndrome (MDS) who are not suitable for hematopoietic stem cell transplantation. In Australia, azacitidine was, until recently, the only approved and subsidized treatment for patients with intermediate-2 and high-risk MDS, chronic myelomonocytic leukemia, and low blast acute myeloid leukemia. We analyzed prescription data to evaluate the real-world persistence and overall survival (OS) of patients prescribed azacitidine for the first time in Australia. A retrospective cohort analysis of patients who had been prescribed Pharmaceutical Benefits Scheme (PBS)-listed azacitidine for the first time, between January 2016 and April 2021, was conducted using the PBS 10% dataset. Treatment persistence and OS were estimated using Kaplan-Meier methods. The impact of the number of treatment cycles and treatment adherence on OS was also estimated. There were 351 patients in the PBS 10% dataset who initiated treatment with azacitidine. The average age (standard deviation [SD]) at azacitidine initiation was 71.9 (11.1) years and the average number (SD) of azacitidine prescriptions was 5.6 (0.2). The median persistence on azacitidine was 15.6 months, and the OS was 13.4 months. The median OS for patients who had six or more cycles of azacitidine treatment was greater compared to patients who had five or less cycles of treatment. The data from this real-world study illustrate the unmet medical needs of patients with MDS treated with azacitidine in Australia. The majority of patients are not treated with the optimal number of cycles of azacitidine, which is negatively correlated with patient outcomes.

The Real-World Effectiveness, Persistence, Adherence, and Safety of Janus Kinase Inhibitor Baricitinib in Rheumatoid Arthritis: A Long-Term Study.

Background/Aim: Baricitinib (BAR) is the first oral selective Janus kinase inhibitor approved in Europe for rheumatoid arthritis (RA). Real-world data are still needed to clarify its long-term benefits/risk profile. This study aimed to evaluate the effectiveness, persistence, adherence, and safety of BAR in a real-world setting. Methods: An ambispective study was conducted between October 2017 and December 2021 in RA patients starting BAR. The effectiveness was evaluated, assessing changes from the baseline of the Disease Activity Score using 28-joint counts-C reactive protein (DAS28CRP), and the achievement of low disease activity/remission. Drug persistence was evaluated using Kaplan-Meier analysis. Adherence was estimated using the medication possession ratio (MPR) and the 5-item Compliance Questionnaire for Rheumatology. Safety was assessed determining global incidence proportion and adverse event adjusted incidence rates. Results: In total, 61/64 recruited patients were finally analyzed, 83.6% were female, 78.7% were seropositive, the mean age was 58.1 (15.4) years, and the disease duration was 13.9 (8.3) years. A total of 32.8% of patients were naïve to biologics and 16.4% received BAR as monotherapy. The median exposure to BAR was 12.4 (6.6-31.2) months (range 3.1-51.4). A significant change in DAS28CRP was observed after treatment (difference -1.2, p = 0.000). 70.5% and 60.7% of patients achieved low disease activity or remission, respectively, and 50.8% (31/61) remained on BAR throughout the follow-up, with a median persistence of 31.2 (9.3-53.1) months. The average MPR was 0.96 (0.08) and all patients exhibited "good adherence" according to the questionnaire. In total, 21.3% of patients discontinued baricitinib due to toxicity. Conclusions: In our real-world practice, BAR demonstrated effectiveness, large persistence, high adherence to treatment, and an acceptable safety profile.

Real-World Adherence to and Persistence with Vibegron in Patients with Overactive Bladder: A Retrospective Claims Analysis.

Vibegron is a β3-adrenergic receptor agonist approved for overactive bladder (OAB). This analysis assessed real-world adherence and persistence with vibegron in patients with OAB, along with demographics and clinical characteristics associated with adherence and persistence. This retrospective study used the Optum Research Database to identify patients treated with vibegron from April 2021 to August 2022 (identification period). Patients had ≥ 60days of continuous pharmacy coverage in a commercial or Medicare Advantage plan following the index fill (follow-up). Adherence was assessed as proportion of days covered (PDC) from index to end of follow-up and was defined as PDC ≥ 80%. Persistence was measured as days to discontinuation of therapy (30-day gap) or end of follow-up. Data for adherence and persistence are presented descriptively. Characteristics associated with adherence and persistence were analyzed using multivariable models among patients with medical and pharmacy benefits during the 90days before index (baseline). Overall, 9992 patients had a vibegron claim during the identification period; 9712had ≥ 2months of follow-up. Mean (SD) age was 74.2 (10.7) years; 68.2% were female. Mean (SD) PDC was 0.64 (0.34). Median (95% confidence interval) persistence was 142 (132-153) days. Of the 5073 patients who were ≥ 18years old with continuous baseline pharmacy and medical benefits ≥ 90days before index, 2497 (49.2%) were adherent. Patients were more likely to be adherent and persistent if they received a greater days' supply for the index fill and had baseline medication count ≥ 6. Patients were more likely to discontinue if their index copay was > $45. Nearly half of the patients initiating vibegron were adherent. Factors associated with adherence and persistence were more likely to be related to prescribing practices than patient characteristics. These results suggest it may be best to follow up with patients approximately 4to5months after initiating treatment with vibegron.

Real-world evaluation of persistence, effectiveness and usage patterns of tofacitinib in treatment of psoriatic arthritis in Australia

ObjectivesTo describe treatment patterns and persistence of tofacitinib, interleukin 17 inhibitors (IL-17Ai) and tumour necrosis factor inhibitors (TNFi), in patients with psoriatic arthritis (PsA).MethodsData from adult patients with PsA and who had received at least one prescription of tofacitinib, IL-17Ai or TNFi between May 2019 and September 2021 were sourced from the Australian OPAL dataset. Persistence, analysed via Kaplan–Meier methods, and propensity score matching between tofacitinib and bDMARD (IL-17Ai and TNFi) groups were conducted.ResultsOf 16,692 patients with PsA, 1486 (n = 406 tofacitinib, n = 416 IL-17Ai and n = 664 TNFi) were included. More females were in the tofacitinib group (75.4%) than in the IL-17Ai (61.1%) and TNFi (64.8%) groups. Overall, 19.2% of tofacitinib patients were first line, compared with 41.8% of IL-17Ai and 62.8% of TNFi patients. In the overall population, the median persistence was 16.5 months (95% CI 13.8 to 19.5 months), 17.7 months (95% CI 15.8 to 19.6 months) and 17.2 months (95% CI 14.9 to 20.5 months) in the tofacitinib, IL-17Ai and TNFi groups, respectively. Persistence was similar in the tofacitinib/IL-17Ai matched population; however, in the tofacitinib/TNFi matched population, persistence was longer in the tofacitinib group (18.7 months, 95% CI 15.6 to 21.4 months) compared with the TNFi group (12.2 months, 95% CI 19.9 to 14.9 months).ConclusionsIn this Australian real-world dataset, tofacitinib was more frequently used in later lines and among a slightly higher proportion of female patients than IL-17Ai or TNFi. Overall, treatment persistence was similar for tofacitinib, IL-17Ai and TNFi, but tofacitinib exhibited longer persistence than TNFi in a matched population.Key Points• This is the first, large real-world study from Australia investigating the demographics, treatment patterns and comparative treatment persistence of patients with psoriatic arthritis (PsA) treated with tofacitinib and biologic disease-modifying drugs (bDMARDs).• The study suggests that tofacitinib is an effective intervention in PsA with at least comparable persistence to bDMARDs: tumour necrosis factor inhibitors (TNFi) and interleukin-17 A inhibitors (IL-17Ai).

Treatment Persistence and Switching Patterns of Adalimumab Biosimilar ABP 501 in European Patients with Rheumatologic Diseases.

ABP 501 was an adalimumab (ADA) biosimilar approved for treating immune-mediated inflammatory diseases (IMIDs) including rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). In this retrospective study, we aimed to examine the treatment patterns of ABP 501 among patients with these IMIDs using German and French pharmacy claims databases. Patients with RA, PsA, or AS who initiated ABP 501 between October 2018 and March 2020 and were observed continuously for ≥ 365days both before and after ABP 501 initiation were included. Descriptive analyses of persistence and switch after ABP 501 discontinuation were conducted and reported for each disease cohort by prior use of ADA products (patients naïve to ADA or patients experienced with ADA). Median (95% confidence interval) persistence on ABP 501 was 9.4 (8.6-10.3), 10.2 (9.0-11.7), and 12.1 (11.0-13.1) months in German patients, and 11.7 (9.9-13.3), 7.1 (5.8-8.4), and 10.8 (9.6-11.9) months in French patients for RA, PsA, and AS, respectively. For patients who switched from ABP 501 to another targeted therapy during the first 12months of follow-up, switching patterns varied between patients naïve to ADA and patients experienced with ADA in both Germany and France, with patients naïve to ADA switching most frequently to other targeted therapies including non-ADA tumor necrosis factor inhibitor (TNFi), non-TNFi biologic, or Janus Kinase inhibitor (JAKi) and patients experienced with ADA switching most frequently back to ADA reference product (RP). Across three rheumatologic diseases, about half of patients persisted on ABP 501 at the end of 12months after treatment initiation in both Germany and France. Patients experienced with ADA were more likely to switch back to ADA RP, regardless of indication and country, suggesting a possible nocebo effect. Future studies are warranted to understand reasons of discontinuation and switching.

Treatment persistence and switching patterns of ABP 501 in European patients with inflammatory bowel disease.

Approval of the adalimumab (ADA) biosimilar ABP 501 for inflammatory bowel disease (IBD) indications was based on the principle of extrapolation, without indication-specific clinical trial data. To evaluate the real-world treatment patterns of ABP 501 in patients with IBD. Retrospective analysis of pharmacy claims data from Germany and France. Continuously insured adult IBD patients who initiated ABP 501 between October 2018 and March 2020 were included. Treatment persistence, adherence, and post-ABP 501 switching patterns were evaluated for two mutually exclusive groups: ADA-naïve patients (i.e. no baseline use of ADA products) and ADA-experienced patients (i.e. previously treated with ADA products). A total of 3362 German patients and 733 French patients were included, with 54.4% and 65.3% being ADA-naïve patients, respectively. Median persistence (95% CI) on ABP 501 was 10.9 months (9.8-11.6) in ADA-naïve patients and 14.2 months (12.7-15.2) in ADA-experienced patients in Germany; for the French cohort, ADA-naïve and -experienced patients had median persistence of 12.8 months (10.2-14.7) and 11.5 months (8.8-14.4), respectively. During the first 12 months of ABP 501 initiation, 53.7% of German patients and 51.0% of French patients were adherent to the therapy. About 20% of patients in both countries switched from ABP 501 to another targeted therapy. In the German cohort, ADA-naïve patients most frequently switched to non-tumor necrosis factor inhibitor biologics, but ADA-experienced patients most commonly switched to reference product (RP); in the French cohort, patients most often switched to RP regardless of prior exposure to ADA products. About 50% of patients persisted on and were adherent to ABP 501 therapy during the first 12 months after treatment initiation in two large European countries. Post-ABP 501, switching patterns varied between countries, indicating diversified treatment practices warranting further research on reason(s) for switching and potential overall treatment outcomes.

Effect of implementation strategies on pre-exposure prophylaxis persistence among female sex workers in South Africa: an interrupted time series study

A disproportionate number of new HIV infections in South Africa are among female sex workers; pre-exposure prophylaxis (PrEP) for HIV prevention is freely available to female sex workers in the country, but unique barriers challenge PrEP persistence. TB HIV Care, a large South African non-profit organisation that provides daily oral PrEP (tenofovir disoproxil fumarate and emtricitabine), has implemented multiple strategies to improve PrEP persistence. We aimed to evaluate the effect of different implementation strategies on PrEP persistence in a large-scale real-world setting. In this interrupted time series study, we estimated level changes in 1-month oral PrEP persistence associated with roll-out of various implementation strategies among female sex workers across nine districts in South Africa. We used routinely collected data from TB HIV Care programme files from June 7, 2016, to April 30, 2021. Poisson regression of 1-month persistence was used to assess the effect of these strategies. In secondary analyses, we tested the association between each of the strategies and 4-month persistence. The median 1-month PrEP persistence for female sex workers was 33% (IQR 27-40). SMS support and refill reminders were associated with an 11% relative increase in 1-month persistence (risk ratio [RR] 1·11, 95% CI 1·02-1·26) and clinical mentoring for PrEP providers was associated with a 127% relative increase (RR 2·27, 95% CI 1·94-2·66) among female sex workers. The loyalty rewards programme was negatively associated with 1-month persistence (RR 0·71, 95% CI 0·67-0·83). Although clinical mentoring improved 4-month persistence, SMS support text messages had no significant effect. Identification and subsequent use of clinical mentoring for PrEP providers and SMS support and refill reminders might improve the usefulness of PrEP overall to prevent new HIV infections among female sex workers. PrEP persistence remains an important issue, and strategies to build on our findings are needed. National Institute of Mental Health and National Institute of Allergy and Infectious Diseases.

A Phase 2 Trial of SCRI-CAR19 Demonstrates Favorable Leukemia-Free Survival (LFS), with a Pilot Study of CD19-Expressing T-Cell Antigen Presenting Cells (CD19t T-APCs) Demonstrating Safety and Tolerability

The value of CD19 directed CAR T cell therapy for relapsed, refractory B-ALL has been well established. Iterative and complementary clinical trials have identified subgroups with improved outcomes, including those with low disease burden at the time of treatment as well as those with prolonged CAR T cell in vivo persistence. PLAT-02 was a phase 1/2 study of SCRI-CAR19, a 2 nd generation murine CAR with 41BB co-stimulation. Phase 1 previously reported 1 year LFS, event-free (EFS) and overall survival (OS) of 55%, 51.2%, and 69.5%. Subjects with low CD19 antigen burden in the bone marrow (<15%) prior to lymphodepletion (LD) and those with a rapid contraction of CAR T cells between Day 10 and 14 (ratio ≥1.5) were at higher risk of early loss of persistence. Phase 2 of PLAT-02 was a multisite trial along with a single site pilot study, PLAT-03, to explore administration of exogenous CD19 antigen designed to boost CAR T cell engraftment in subjects at high risk of early loss of persistence. PLAT-02 (NCT02028455) enrolled subjects 1-26 years of age with relapsed, refractory CD19+ B-ALL. The primary efficacy cohort was defined as those who received fludarabine/cyclophosphamide (flu/cy) LD and were infused with CAR19. PLAT-03 (NCT03186118) was a pilot study of CD19t T-APCs (manufactured T cells with CD19 tag) administered at doses of 10x10 6/kg or flat dosing of 5x10 8 for subjects >25kg every 4 weeks up to 6 total doses. Cohort A included subjects with low CD19 antigen burden, and cohort B included those with rapid early contraction of CAR19. 88 subjects with B-ALL were enrolled on PLAT-02 with plans for treatment at the recommended phase 2 dose (RP2D) of 1x10 6 CAR+ T cells/kg. Eighty-six percent had at least one prior relapse and 42% had undergone prior hematopoietic cell transplant (HCT). The feasibility of manufacturing was 98%. 71 subjects were in the primary efficacy cohort with an 89% minimal residual disease negative complete remission (MRDneg CR) rate. EFS and OS probability estimates with 95% CI at 1 year following CAR19 were 0.65 (0.53, 0.75) and 0.76 (0.64, 0.84). LFS at 1 year from entering MRDneg CR was 0.71 (0.58, 0.81). Cytokine release syndrome (CRS) was grade (Gr) 1 (53%), Gr 2 (26%), Gr 3 (10%), and Gr 4 (3%). Neurotoxicity occurred in 53%: Gr 1 (24%), Gr 2 (13%), Gr 3 (15%), and Gr 5 (1%). 25 subjects were treated on PLAT-03, 10 as cohort A (10 received CAR19 on PLAT-03, 9 received T-APCs), and 11 as cohort B (5 received CAR19 on PLAT-02, 6 received CAR19 on PLAT-03, and 9 total received T-APCs). One was cohort C (retreatment) and 3 were cohort D (no T-APCs). A total of 72 infusions of T-APCs were administered, with no occurrence of CRS or neurotoxicity. Two subjects had grade 3 toxicities related to T-APCs, 1 febrile neutropenia and 1 infusion related reaction. EFS and OS probability estimates at 1 year following CAR19 were 0.67 (0.43, 0.83) and 0.95 (0.71, 0.99). Overall LFS at 1 year was 0.63 (0.38, 0.80); by cohort: cohort A, 0.44 (0.13, 0.72) and cohort B, 0.80 (0.41, 0.95). Median duration of persistence, as determined by cumulative incidence using B cell aplasia (BCA) as a surrogate, among all subjects who received RP2D of CAR19 with flu/cy LD across PLAT-02 and PLAT-03, engrafted and achieved MRDneg CR, was 12.9 months (m). For subjects who did not receive T-APCs, the median persistence was 12.1m. Impact of antigen burden prior to LD was again observed; those with >15% CD19 antigen burden had persistence of >12.1m vs. 3.9m in the low antigen burden group. For subjects treated with T-APCs, the median persistence was 16m; 9.9m in cohort A and >16m in cohort B. The improvement in LFS after SCRI-CAR19 in phase 2 compared to phase 1 is likely multi-factorial, with contributing factors including earlier treatment, uniform use of LD, enhanced persistence, and better allocation of patients who benefit from consolidative HCT. The use of T-APCs was well tolerated without recurrent CAR T cell mediated toxicity. Although not directly comparable, there did appear to be enhancement of CAR T cell persistence with the use of T-APCs in populations predicted to have inferior persistence, including those with low antigen burden. There was not a clear improvement of LFS in those who received T-APCs. However, subjects were not randomized to receive T-APCs and those enrolled on PLAT-03 were more heavily treated and more likely to have received a prior HCT. Further exploration of T-APCs is warranted to define and evaluate their impact on persistence and durable responses.

Dendritic Cell Vaccines Extend CD19 CAR-T Cell Persistence and Improve the Outcomes in Refractory/Relapsed Adult B-ALL

Introduction: The long-term efficacy of anti-CD19 chimeric antigen receptor (CAR)-T cell in refractory or relapsed (r/r) adult B-cell acute lymphoblastic (B-ALL) patients is limited, and the recurrence rate is high. CAR-T cell depletion and limited CAR-T cell persistence are some of the most common reasons for relapse. Our previous in vitro studies confirmed that dendritic cell (DC) vaccines targeting tumor antigens could induce CAR-T cell rejuvenation and increase the killing function of CAR-T cells. So, we designed a clinical trial to study CD19 CAR-T cell combined with DC vaccination for adult r/r B-ALL to explore whether this therapy improves LFS. (clinicaltrials.gov, no: NCT03291444). Methods: Adult r/r B-ALL patients who expressed HLA-A1101, A2402, or A0201 and had high expression of EPS8 or WT1 were eligible. An EPS8 peptide-derived DC (EPS8-DCs) vaccine was used in EPS8-high patients, while a WT1 peptide-derived DC (WT1-DC) vaccine was used in EPS8-negative patients with WT1 positivity. Lymphodepleting chemotherapy comprising fludarabine (30 mg/m²) and cyclophosphamide (300 mg/m²) was administered intravenously daily for 3 days before CD19 CAR-T cells infusion. After 4 weeks of CAR-T infusion, if bone marrow morphologic remission had been achieved, DC vaccination was administered intradermally every 2 weeks for 4 doses. Results: Eight adult patients with r/r B-ALL were enrolled and successfully received CAR-T cells and DC cells, of which 4 (50%) relapsed after allogeneic hematopoietic stem cell transplantation. They were successfully administered one dose of CD19 CAR-T with a median dose of 2.26×10 6/kg (range 6.4×10 5/kg to 4.46×10 6/kg) on day 0 and four doses of DC vaccination with a median dose of 5.44×10 6 (range 2.97×10 6/dose to 2.68×10 7/dose) every 2 weeks after 4 weeks of CAR-T infusion. All eight evaluable patients achieved complete response (CR) after receiving CD19 CAR-T. With a median follow-up of 608 days, the median LFS time was 489 days, and the median OS was not reached. Seven of the eight evaluable patients were still alive. Four (50%) were in continuous MRD-negative remission at the cutoff time, and two of them (pt 02 and pt 03) maintained MRD-negative CR for more than 4 years. The median peak of CAR-T cell expansion in the PB was detected on day 7 after infusion of CD19 CAR-T. The median persistence time of CAR-T was 336 days (range 84 to 1549 days). CAR-T cells were reamplified after infusion of the DC vaccine. For patients with an LFS of more than 2 years (pt 02, pt 03, and pt 05), CD19 CAR-T cells were still detectable for more than 1 year, with a maximum of 4.2 years in pt 03. The activity of the CTLs measured by IFN-γ ELIspot showed that IFN-γ-secreting CTLs were significantly increased after DC vaccination. These assays showed that antigen-specific cellular immune activity was enhanced after vaccination. No grade ≥3 cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) occurred after infusion of 4sCAR19. No grade ≥3 events occurred during the infusion of the DC vaccine. Only 1 of 8 patients experienced local skin reactions after infusion of the DC vaccine. Conclusions: This study reports a novel combination therapy strategy (CAR-T cell combining with individualized DC vaccination) for adult r/r B-ALL. DC vaccination has higher safety, may prolong the persistence of CAR-T cells, and may prolong the survival time and quality of life. CAR-T cell therapy combining with DC vaccination is a potential therapy strategy for adult r/r ALL patients who are not eligible for transplantation or who relapse after transplantation.

Varnimcabtagene Autoleucel (IMN-003A): Pharmacokinetic Profile with Predominant Naïve and Central Memory Phenotype Demonstrates Sustained In Vivo Persistence and Durable Responses in a First-in-India Industry Phase-2 Study (IMAGINE)

Background: Varnimcabtagene autoleucel (IMN-003A) is an autologous CD19 directed CAR-T cell product with a 4-1BB co-stimulatory domain and a non-FMC63 murine single chain variable fragment (A3B1 binder), manufactured in India, tested in the IMAGINE study (CTRI/2022/03/041162), a phase-2 clinical trial for patients (pts) with relapsed and/or refractory B cell malignancies (RR BCM). A fractionated infusion of 1 x 10 6 CAR+ cells (IMN-003A)/kg for B-ALL cohort and 5 x 10 6 CAR+ cells (IMN-003A)/kg for B-NHL cohort was administered over 3 days as 10%, 30% and 60% fractions after Fludarabine-Cyclophosphamide lymphodepletion regimen (LR). Here we present var-cel pharmacokinetic data and correlation with efficacy. Methods: Varnimcabtagene autoleucel was manufactured using a cGMP compliant closed system (CliniMACS Prodigy ®). The manufacturing data were obtained and analyzed, including % CAR transduction in the final product (FP) by flow cytometry (FC). Peripheral blood (PB) samples were obtained after consent at screening and as per patient schedule after infusion. Persistence of IMN-003A was evaluated in PB after infusion by ddPCR. Safety and efficacy data were collected for analysis. Bone marrow (BM) MRD (B-ALL) and PET-CT (B-NHL) was assessed at screening, D+28 and D+90 for efficacy. Minimal residual disease (MRD) was performed by FC with 10 -4 sensitivity. Apheresis, FP, and PB/BM samples on D+28 were analyzed for T-cell subpopulations and surface markers by FC. Statistical analysis was calculated using appropriate tests. Results: Of 25 patients (pts) enrolled and apheresed, 24 pts received var-cel (1 withdrawal) with majority of infusions on Days 0, +3, +7. Median product doubling time and manufacturing time was 1.04d (range 0.74-2.12) and 14 days (range 10 - 27) with 100% success with T cell purity median 99.4% (range 96.3-99.9). The mean % transduction of var-cel was 33.12% (range 8.50 - 58.35) with median transgene copies / genome of 2.57 (range 0.76 - 4.16). The mean CD4/CD8 ratio at apheresis and final product was 0.47 and 2.58 respectively. There was reversal of CD4/CD8 ratio from apheresis to final product (CAR+ T cells) which was statistically significant (p<0.01). There was statistically significant increase (p<0.01) in the number of naïve (CCR7+ RA+) and central memory (CCR7+ RA-) T cell subsets between apheresis and final product (CAR+ T cells). There was predominance of naïve and central memory CAR+ T cell subsets in the FP (58.19%; Figure 1A). Median Apheresis to Infusion time was 25d (range 16 - 95). There was a statistically significant trend (p<0.01) towards reversal of CD4/CD8 ratio in the PB from D0 to D+90. Var-cel showed maximum PB expansion (T max) at D+10 (range 7 - 28 days) with median C max 125,242 CAR copies / µg gDNA (range 18256 - 413,968). Among pts with 28-day and 90-day and last follow-up, 79.2%, 29.2% and 20.8% respectively had evidence of var-cel in PB, with median persistence of 28 days (range 10 - NR). Post-infusion, peak interleukin-6 level was median 42.3 pg/mL (range 6.71 - 17,481). B cell aplasia was observed in all pts concurrent with CAR-T expansion (Figure 1B). Median loss of B cell aplasia was not reached (range 42 - NR), with no apparent association with response at D+28 and D+90. Hypogammaglobulinemia was noted in 11 pts and 16 pts received IVIg. Of evaluable patients with CD4+ T-cell counts below 200/μL, recovery (>200/μL) was seen at median of 12 days (range 2 - NR) after var-cel infusion. Overall response rate (ORR) was 91.7% (22/24) at D+28 (B-ALL 91.7%, MRD neg 83.3% (n=10/12); B-NHL 91.7%, CR 66.7%) and 80.9% (17/21) at D+90 [B-ALL 80%, MRD neg 80% (n=8/10); B-NHL 81.8% (9/11), CR 63.6%]. One B-NHL pt in PR at D+28 achieved CR at D+90. Three pts relapsed by D+90. Updated results will be presented at the meeting. Conclusion: Varnimcabtagene autoleucel manufacturing process results in a drug product characterized by highly pure T cells, with high proportion of naïve and central memory polyfunctional cells. In this industry-led first-in-India phase-2 study, var-cel resulted in a cytokine response with sustained in vivo proliferation and persistence resulting in robust and durable responses.

ADA_ETA_BIO2021: real-world evaluation of adherence, persistence, and cost-effectiveness of originator and biosimilar biologic drugs in the treatment of rheumatoid arthritis: a multicenter study in Italy

Objectives The objective was to assess the adherence, persistence, and costs of bDMARDs through a multicentre study of nine Italian hospital pharmacies. Methods The drugs analysed were Abatacept, Adalimumab, Certolizumab, Etanercept, Golimumab and Tocilizumab. Adult subjects with Rheumatoid Arthritis were considered in the analysis. In this study, we calculated the following metrics: Adherence to treatment was evaluated as dose-intensity, which is the ratio between the amount of medication received and probably taken by the patient at home (Received Daily Dose, RDD) and the amount prescribed by the clinician (Prescribed Daily Dose, PDD). Persistence was calculated as the number of days between the first and last dispensing of the same drug. Lastly, costs were assessed based on persistence to treatment and normalized for adherence. Results Adherence to treatment was found to be above 0.8 for all drugs studied. The median persistence for a 5-year treatment period was 1.4 years for Abatacept, 1.7 years for Adalimumab, 1.8 years for Certolizumab, 1.4 years for Etanercept, 1.3 years for Golimumab, and 1.6 years for Tocilizumab. Conclusions This multicentre retrospective observational study of bDMARDs used in the treatment of RA showed that, for all the drugs studied, there was no problem with adherence to treatment but rather a difficulty in maintaining treatment with the same drug over time.

Comparative Treatment Persistence and Adherence to Endothelin Receptor Antagonists Among Patients with Pulmonary Arterial Hypertension in Japan: A Real-World Administrative Claims Database Study.

Real-world data on the comparative effectiveness of endothelin receptor antagonists (ERAs; macitentan, bosentan, ambrisentan) for pulmonary arterial hypertension (PAH), particularly in Asian countries, are scarce. We evaluated the persistence of these ERAs before and after macitentan approval in Japan (2015). We used real-world data from the Japanese Medical Data Vision administrative claims database between April 2008 and November 2020. Patients with PAH were identified from the dataset. Persistence to ERA treatment before and after approval of macitentan in Japan was defined as the time between start of the index ERA and treatment discontinuation or death. Propensity score adjustment was applied to minimize confounding effects among treatment groups. In the pre-macitentan approval cohort, 153 and 51 patients received bosentan and ambrisentan, respectively. In the post-macitentan approval cohort, 331, 284, and 91 patients received macitentan, bosentan, and ambrisentan, respectively. Unadjusted median persistence for ambrisentan- and bosentan-treated patients was 19 and 10months, respectively (adjusted HR 0.87 [95%CI 0.61-1.24]; P = 0.434 [bosentan as reference]). In the post-macitentan approval cohort, unadjusted median persistence was 18months for macitentan-treated patients versus 6 and 8months for ambrisentan- and bosentan-treated patients, respectively. Adjusted HRs for ambrisentan and bosentan were 1.48 (95%CI 1.12-1.95; P = 0.006) and 1.63 (95%CI 1.30-2.04; P < 0.001 [macitentan as reference]), respectively. Real-world data for Japanese patients with PAH showed that persistence was significantly higher for macitentan, versus ambrisentan and bosentan, since its approval.

Long-Term Follow-up of Fully Human BCMA-Targeting CAR (CT103A) in Patients with Relapsed/Refractory Multiple Myeloma

Background: CT103A is a fully human chimeric antigen receptor T cell product targeting B cell maturation antigen (BCMA). Our previous reports showed a remarkable efficacy and safety of CT103A in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 394 days. Here, we report the updated safety and efficacy profile in the long-term follow-up. Methods: This trial was a phase 1, single-arm, open-label study conducted in Tongji hospital in China. Eighteen consecutive patients with RRMM were enrolled, who received at least three lines of prior therapies that contain a proteasome inhibitor and an immunomodulatory agent. Lymphodepletion was performed using Fludarabine (30 mg/m 2) and cyclophosphamide (500 mg/m 2) for three consecutive days. CT103A was administered at 1, 3 and 6×10 6 CAR-positive T cells/kg in the dose-escalation phase, and 1×10 6 CAR-positive T cells/kg in the expansion cohort. From one-year post infusion, the response was evaluated every six months according to the IMWG 2016 consensus criteria. Minimal residual disease (MRD) was evaluated in the visits that bone marrow aspiration was performed. The minimum sensitivity of MRD was 10 -5 nucleated cells by standardized flow cytometry. All the adverse events (AEs) during the long-term follow-up were recorded and graded by CTCAE v5.0. Results: As of December 31, 2022, the median follow-up time after CAR T-cell infusion was 41.47 months (range, 0.63-51.33 months). Of the 18 patients assessable for efficacy, all patients (100%) achieved an overall response (partial remission or better) to CT103A. Among them, a total of 77.8% (14 of 18) of the patients finally achieved a CR or sCR, with enhanced responses over time. At the time of data-cutoff, nine patients (50%) were still alive, and seven patients (38.9%) remained sCR status with negative MRD. The median progression free survival (PFS) was 22.64 months and the median overall survival (OS) was 41.97 months. The rate of PFS and OS at 2 year was 50.0% and 72.2%, respectively. The patients with EMM had shorter survival than those without EMM. The median PFS was 12.02 months and the median OS was 28.52 months in patients with EMM, whereas the median PFS was 27.92 months and the median OS was 41.97 months in patients without EMM. During the long-term follow-up, the occurrence of AEs gradually reduced over time. The most common late adverse events occurring 8 weeks after CAR T-cell infusion were hematologic toxicities. Leukopenia and neutropenia could be observed in 11 patients (61.1%). After 8 weeks, the adverse events were mainly infections. 26 infectious events were recorded in 11 patients (61.1%) beyond 8 weeks, including nine events judged as severe AE (sAE) in 6 patients (33.3%). Five infectious events in five patients (27.8%) occurred after one year. Severe infections led to the death of 4 patients. The recovery of B cells and globulin were observed in 5 and 15 patients, respectively. But for the seven alive patients with sCR, only two of them had B cell recovered. The median CAR transgene persistence was 419 days. To the cutoff date, CAR transgenes were detectable in seven (38.9%) patients, six of these patients were in sCR state. Conclusion: The updated data from the long-term follow-up of CT103A demonstrated a durable clinical benefit for RRMM patients, based on the sustained existence of fully human CAR-T cells. In addition, the favorable safety profile strengthens the prospect of clinical application of CT103A.

Maintenance Therapy with Chidamide Plus Azacitidine after Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Acute Myeloid Leukemia Patients

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is theoretically the only curative option for high-risk acute myeloid leukemia (AML) patients. However, many patients relapse after allo-HSCT, and treatment options are very limited. Azacitidine, a DNA methyltransferase inhibitor exhibits anti-leukemia activity in myeloid diseases. Chidamide, a selective histone deacetylase inhibitor, effectively induces apoptosis of AML cells. They have synergistic inhibitory effect on AML cells when combined together. Therefore, we conducted a multicentre, prospective study (ChiCTR2300067593) to examine the tolerability and efficacy of a combination of both chidamide and azacitidine as a maintenance therapy for high-risk AML patients after allo-HSCT. Patients and methods： Patients ≤ 60 years of age with high-risk AML post- allo-HSCT were enrolled. The high-risk characteristics of AML were defined as one or more of the following criteria: a) Patients with poor prognosis according to the genetic risk stratification assessment of European Leukmia Net (ELN) in 2022; b) Primary refractory or recurrent AML; c) Secondary AML (secondary to MDS or treatment-related AML). All patients received Chidamide 5 mg/d combined with azacitidine 75 mg/m2/d for 5 days. The cycle interval was 6-8 weeks. A total of 6 cycles was recommended. Treatment started as early as 3 months after transplantation. The primary endpoint of this study was cumulative incidence of relapse (CIR). The secondary endpoints included rates of overall survival (OS) and event-free survival (EFS). Survival outcomes were estimated using Kaplan-Meier analysis. Results： Thirty-six patients have been recruited. The median age was 42 years (range, 16-59). Baseline characteristics are shown in Table 1. With a median follow-up time of 412（185-762）days, the 1-year CIR was 12.3 (6.5-18.1) %, the 1-year OS and EFS rates were 100.0% and 87.7 (81.9-93.5) %, respectively. The median OS and EFS time were not reached. Four patients relapsed, two died, and two are still alive and ready for the second transplantation. The most common adverse events (AEs) were thrombocytopenia reaction and gastrointestinal tract reaction. Grade 2 or 3 AEs were observed in 16.7% (6/36) and 25.0% (9/36) of the patients, respectively. No grade &amp;gt;3 AEs were noted. 9 patients (6/36,16.7%) developed grade 3-4 thrombocytopenia, without active hemorrhage. All of them received blood transfusion and thrombopoietin receptor agonist. The median persistence of thrombocytopenia was 3 (2-5) d. Chronic graft-versus-host-disease (cGVHD) occurred in 25.0% (9/36) of patients. Four cases (4/36, 11.1%) were complicated with infection. They were one case of intestinal infection, one case of pulmonary and EBV infections, one case of hepatitis B virus activation and one case of herpes zoster. And all infected patients recovered safely after anti-infection and symptom-oriented treatment. CMV activation was not observed. Non relapse mortality (NRM) was zero. Conclusions： We conclude that chidamide plus azacitidine can be administered safely after allo- HSCT with no evidence of an increased incidence of GVHD, and this combination may decrease the relapse rate in high-risk AML patients. This novel maintenance therapy may be a promising way to prevent relapse in high-risk AML patients.

A New Year-Round Weather Regime Classification for North America

Abstract Weather regimes defined through cluster analysis concisely categorize the anomalous regional circulation pattern on any given day. Owing to their persistence and low dimensionality, regimes are increasingly used in subseasonal-to-seasonal prediction and in analysis of climate variability and change. However, a limitation of existing regime classifications for North America is their seasonal dependence, with most existing studies defining regimes for winter only. Here, we normalize the seasonal cycle in daily geopotential height variance and use empirical orthogonal function analysis combined with k-means clustering to define a new set of year-round North American weather regimes: the Pacific Trough, Pacific Ridge, Alaskan Ridge, and Greenland High regimes. We additionally define a “No Regime” state to represent conditions close to climatology. To demonstrate the robustness of the classification, a thorough assessment of the sensitivity of the clustering solution to various methodological choices is provided. The median persistence of all four regimes, obtained without imposing a persistence criterion, is found to be one week, approximately 3 times longer than the median persistence of the No Regime state. Regime-associated temperature and precipitation anomalies are reported, together with the relationship between the regimes and modes of climate variability. We also quantify historical trends in the frequency of the regimes since 1979, finding a decrease in the annual frequency of the Pacific Trough regime and an increase in the summertime frequency of the Greenland High regime. This study serves as a foundation for the future use of these regimes in a variety of weather and climate applications. Significance Statement Weather regimes provide a simple way of classifying daily large-scale regional weather patterns into a few predefined types. Existing methods usually define regimes for a specific season (typically winter), which limits their use, or provides only a minimal assessment of their robustness. In this study, we objectively quantify four weather regimes for use year-round over North America, while we classify near-normal conditions as No Regime. The four regimes represent persistent large-scale weather types that last for about a week and occasionally much longer. Our new classification can be applied to subseasonal-to-seasonal forecasts and climate model output to diagnose recurrent weather types across the North American continent.