Initial Non-responders Research Articles

Emergent role of dynamic optimization in cardiac resynchronization therapy: Systematic review and network meta-analysis.

Suboptimal device programming is frequent in non-responders to cardiac resynchronization therapy (CRT). However, the role of device optimization and the most appropriate technique are still unknown. The aim of our study was to analyse the effect of different CRT optimization techniques within a network meta-analysis. A systematic search was conducted on MEDLINE, Embase and CENTRAL for studies comparing outcomes with empirical device settings or optimization using echocardiography, static algorithms or dynamic algorithms. Studies investigating the effect of optimization in non-responders were also analysed. A total of 17 studies with 4346 patients were included in the quantitative analysis. Of the treatments and outcomes examined, a significant difference was found only between dynamic algorithms and echocardiography, with the former leading to a higher echocardiographic response rate [odds ratio (OR): 2.02, 95% confidence interval (CI) 1.21-3.35], lower heart failure hospitalization rate (OR: 0.75, 95% CI 0.57-0.99) and greater improvement in 6-minute walk test [mean difference (MD): 45.52m, 95% credible interval (CrI) 3.91-82.44m]. We found no significant difference between empirical settings, static algorithms and dynamic algorithms. Seven studies with 228 patients reported response rates after optimization in non-responders. Altogether, 34.3%-66.7% of initial non-responders showed improvement after optimization, depending on response criteria. At the time of CRT implantation, dynamic algorithms may serve as a resource-friendly alternative to echocardiographic optimization, with similar or better mid-term outcomes. However, their superiority over empirical device settings needs to be investigated in further trials. For non-responders, CRT optimization should be considered, as the majority of patients experience improvement.

Sequential Acute Courses of Transcranial Magnetic Stimulation in Major Depressive Disorder: A Retrospective Analysis in a Veteran Cohort

BackgroundRepetitive transcranial magnetic stimulation (TMS) is now widely accepted as an effective non-pharmacologic treatment for treatment-resistant depression. However, whether repeated acute TMS courses can recapture the antidepressant effects of the initial acute course is still an open question, especially in the Veteran population. We present here a retrospective analysis of a specialty clinic within the Veteran Affairs Hospital System to help address this question. AimsFollowing an acute treatment course of TMS, we sought to determine the treatment response of a subsequent TMS course. We hypothesized that those who responded to an initial acute TMS course would respond in a similar manner to a subsequent treatment course. Methods116 cases referred for evaluation for TMS between September 2017 to April 2021 were reviewed. 63 Veterans completed at least one acute course of TMS and 12 completed at least two courses and met inclusion criteria for this review. 6 met criteria for treatment response in the first course, while the other 6 were initial treatment nonresponders. Symptoms were evaluated via self-reported scales at baseline and weekly throughout treatment. Clinical response to subsequent treatment (>50% symptom reduction as measured by the PHQ-9) was compared to initial treatment response. ResultsOf the initial treatment responders (n = 6), all six responded to a second acute course, with an 85.3% symptom reduction. Of the initial treatment nonresponders (n = 6), three responded to a second acute course. No adverse events were reported in those who completed a second course, and the Veterans tolerated the treatment well. ConclusionsOur findings support the growing understanding that a second acute TMS treatment course for treatment-resistant depression is safe, well-tolerated, and effective in initial responders and some non-responders. Despite multiple confounders in a naturalistic setting, robust initial treatment response was sustained in a second acute course. Low power limits generalizability, and larger powered, prospective studies are needed.

Treatment of chronic COVID-19 with convalescent/postvaccination plasma in patients with hematologic malignancies.

Immunocompromised patients are at high risk to fail clearance of SARS-CoV-2. Prolonged COVID-19 constitutes a health risk and a management problem as cancer treatments often have to be disrupted. As SARS-CoV-2 evolves, new variants of concern have emerged that evade available monoclonal antibodies. Moreover, antiviral therapy promotes SARS-CoV-2 escape mutations, particularly in immunocompromised patients. These patients frequently suffer from prolonged infection. No successful treatment has been established for persistent COVID-19 infection. Here, we report on a series of 21 immunocompromised patients with COVID-19-most of them hematologic malignancies-treated with plasma obtained from recently convalescent or vaccinated donors or a combination thereof. Repeated dosing of SARS-CoV-2-antibody-containing plasma could clear SARS-CoV-2 infection in 16 out of 21 immunocompromised patients even if COVID-19-specific treatments failed to induce sustained viral clearance or to improve clinical course of SARS-CoV-2 infection. Ten patients were major responders defined as an increase delta(d)Ct of > = 5 after the first administration of convalescent and/or vaccinated plasma (C/VP). On average, SARS-CoV-2 PCR Ct values increased from a median value of 22.55 (IQR = 19.10-24.25) to a median value of 29.57 (IQR = 27.55-34.63; p = <.0001) in the major response subgroup. Furthermore, when treated a second time with C/VP, even 4 out of 5 of the initial nonresponders showed an increase in Ct-values from a median value of 23.13 (IQR = 17.75-28.05) to a median value of 32.79 (IQR = 31.75-33.75; p = .013). Our results suggest that C/VP could be a feasible treatment of COVID-19 infection in patients with hematologic malignancies who did not respond to antiviral treatment.

Missingness mechanisms and generalizability of patient reported outcome measures in colorectal cancer survivors – assessing the reasonableness of the “missing completely at random” assumption

BackgroundPatient-Reported Outcome Measures (PROM) provide important information, however, missing PROM data threaten the interpretability and generalizability of findings by introducing potential bias. This study aims to provide insight into missingness mechanisms and inform future researchers on generalizability and possible methodological solutions to overcome missing PROM data problems during data collection and statistical analyses.MethodsWe identified 10,236 colorectal cancer survivors (CRCs) above 18y, diagnosed between 2014 and 2018 through the Danish Clinical Registries. We invited a random 20% (2,097) to participate in a national survey in May 2023. We distributed reminder e-mails at day 10 and day 20, and compared Initial Responders (response day 0–9), Subsequent Responders (response day 10–28) and Non-responders (no response after 28 days) in demographic and cancer-related characteristics and PROM-scores using linear regression.ResultsOf the 2,097 CRCs, 1,188 responded (57%). Of these, 142 (7%) were excluded leaving 1,955 eligible CRCs. 628 (32%) were categorized as initial responders, 418 (21%) as subsequent responders, and 909 (47%) as non-responders. Differences in demographic and cancer-related characteristics between the three groups were minor and PROM-scores only marginally differed between initial and subsequent responders.ConclusionIn this study of long-term colorectal cancer survivors, we showed that initial responders, subsequent responders, and non-responders exhibit comparable demographic and cancer-related characteristics. Among respondents, Patient-Reported Outcome Measures were also similar, indicating generalizability. Assuming Patient-Reported Outcome Measures of subsequent responders represent answers by the non-responders (would they be available), it may be reasonable to judge the missingness mechanism as Missing Completely At Random.

Abstract 2826: Examples of translational preclinical models to mimic cancer drug resistance

Abstract Drug resistance is becoming a major obstacle when treating patients with cancer. Cancer is characterized by an uncontrolled growth of abnormal cells with permanent genome alterations, which lead to severe mutations including resistance mechanisms. Mutations can occur in different resistance pathways, such as inhibition of drug transport, DNA damage repair, drug efflux, EMT (epithelial-mesenchymal transition), drug target alteration and cell death inhibition. Resistance mechanisms are now well studied in vitro, based on mutated cell lines for specific resistance pathways. There is however a gap in our knowledge of resistance mechanisms observed in patient tumor cells. We are challenged to discover cancer resistance treatments in patients and need predictive models of clinical situations. Animal tumor models are the best translational tools to study cancer drug resistance, especially when they closely mimic human pathologies. Such models can bridge the gap between our understanding of cancer resistance in vitro and in tumor patients. In this poster we show different pre-clinical experiments, simulating clinical translational approaches, that led to novel and unique tumor resistant models. Patient Derived Xenograft (PDX) models: Using our breast cancer PDX collection we showed that after repeated treatment with a spindle poison, tumor-bearing mice started to develop resistance and continued tumor growth under drug pressure. Following this successful approach, we initiated the development of a novel ER2-expressing PDX breast tumor model, resistant to hormone therapy by repeated Fulvestrant treatment. Using our colon cancer PDX collection we were able to recapitulate clinical situations by correlating PDX molecular profiles and drug sensitivity. We confirmed the key role of a KRAS mutation in cetuximab resistance. Syngeneic model: In this model, animals were dosed with anti-PDL1 as first line of treatment. All animals were then defined as initial responders or non-responders at the end of the dosing schedule. Following this, a new treatment protocol was initiated with a Tyrosine Kinase inhibitor to study the effect of second line drug treatment in responder and non-responder arms. Human model: In this experiment, we performed a first line Avastin treatment on human colon carcinoma tumor-bearing mice. A tumor resistance to Avastin was observed. During the second line of treatment with a tyrosine kinase inhibitor, we observed an antitumor activity on Avastin resistant animals. In each of these case studies, we developed a novel tumor-resistant mechanism model. In some tumor models, we showed the added value of treating animals with new drugs as second line treatment, after establishing resistance to the first line standard of care treatment. Citation Format: Marc Hillairet de Boisferon, Nicolas Hoffmann, Elodie Rajon, Ismahène Benzaid. Examples of translational preclinical models to mimic cancer drug resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2826.

Long-term Efficacy and Safety Following Switch Between Upadacitinib and Adalimumab in Patients with Rheumatoid Arthritis: 5-Year Data from SELECT-COMPARE.

This study aimed to describe the long-term efficacy and safety of upadacitinib and adalimumab through 228weeks following immediate switch to the alternate therapy with a different mechanism of action (MoA) in patients with rheumatoid arthritis (RA) not achieving treatment goals with their initial randomized therapy in the ongoing phase3 SELECT-COMPARE study. Patients with non-response or incomplete response to initially prescribed upadacitinib 15mg once daily or adalimumab 40mg every other week were switched to the alternate therapy by week26. Efficacy was evaluated through 228weeks post-switch using validated outcome measures, including Clinical Disease Activity Index (CDAI) low disease activity (LDA; ≤ 10)/remission (≤ 2.8); 28-joint Disease Activity Score based on C-reactive protein ≤ 3.2/< 2.6; ≥ 20%/50%/70% improvement in American College of Rheumatology (ACR) response criteria; and change from baseline in ACR core components. Data are reported as observed. Safety was assessed by treatment-emergent adverse events (TEAEs) through week264. Of patients initially randomized to upadacitinib and adalimumab, 38.7% and 48.6%, respectively, switched to the alternate therapy by week26. Clinically relevant improvements in all efficacy measures were observed through 228weeks post-switch and were generally similar between groups, with small numeric differences mostly in favor of switching to upadacitinib. CDAI remission was achieved by 32.7% and 28.6% of initial non-responders, and 27.5% and 27.3% of incomplete responders, while CDAI LDA was achieved by 76.9% and 72.9% of non-responders, and 72.5% and 72.7% of incomplete responders switching to upadacitinib and to adalimumab, respectively. TEAE rates were similar between groups, although herpes zoster infection, lymphopenia, and creatine phosphokinase elevation were more frequent when switching to upadacitinib. No new safety signals were identified. Switching to a different MoA may provide long-term benefit to patients with RA not achieving treatment goals with their initial therapy, with acceptable safety profiles. NCT02629159.

Contingency management plus acceptance and commitment therapy for initial cocaine abstinence: Results of a sequential multiple assignment randomized trial (SMART)

BackgroundThis study tested an adaptive intervention for optimizing abstinence outcomes over phases of treatment for cocaine use disorder using a SMART design. Phase 1 assessed whether 4 weeks of contingency management (CM) improved response with the addition of Acceptance and Commitment Therapy (ACT). Phase 2 assessed pharmacological augmentation with modafinil (MOD) vs. placebo (PLA) for individuals not achieving abstinence during Phase 1. MethodFor Phase 1 of treatment, participants (N=118) were randomly allocated to ACT+CM or Drug Counseling (DC+CM), the comparison condition. At week 4, treatment response was defined as the submission of six consecutive cocaine-negative urine drug screens (UDS). Phase 1 non-responders were re-randomized to MOD or PLA as adjunct to their initial treatment. Phase 1 responders continued receiving their initial treatment. Primary outcomes included response rate and proportion of cocaine-negative UDS for Phase 1 and 2. Analyses used Bayesian inference with 80% pre-specified as the posterior probability (PP) threshold constituting moderate evidence that an effect exists. ResultsPhase 1 response was higher in the ACT+CM group (24.5%) compared to the DC+CM group (17.5%; PP = 84.5%). In Phase 2, the proportion of cocaine-negative UDS among Phase 1 responders did not differ by initial treatment (PP = 61.8%) but remained higher overall compared to Phase 1 non-responders (PPs > 99%). No evidence of an effect favoring augmentation with MOD was observed. DiscussionAdding ACT to CM increased abstinence initiation. Initial responders were more likely to remain abstinent compared to initial non-responders, for whom modafinil was not an effective pharmacotherapy augmentation strategy.

A Single-Center Retrospective Study of Pediatric Vitiligo in a Tertiary Hospital.

Vitiligo is a common disorder; however, its management is unknown by many primary-care doctors and pediatricians. Most articles focus on adults; we analyze the characteristics and impact on children. A single-center retrospective study was conducted over 10 years on 254 children diagnosed with vitiligo. About 50.4% were male with a mean age of 8.24 years. There was a slight predominance of nonsegmented vitiligo. About 12.59% had family history of vitiligo and 11.4% of autoimmune diseases. Around 15.7% patients presented other dermatological diseases and 9.05%, autoimmune diseases. No significant statistical differences were found when comparing age, sex, and type of vitiligo with other variables. Almost 96.06% received treatment with calcineurin inhibitors and 66.53% topical steroids. Around 77% obtained repigmentation, and out of the initial nonresponders, 16% responded to phototherapy. In general, our results concur with the scarce literature. A long-term follow-up of children with vitiligo is needed to identify treatment side effects and diseases associated.

Clinical presentation and prognosis in children over 10-year-old with primary nephrotic syndrome

Objective: To summary the clinical presentation and prognosis of primary nephrotic syndrome (PNS) in teenagers. Methods: The clinical data, renal pathological types and prognosis of 118 children over 10-year-old with PNS treated in the Department of Nephrology of the Children's Hospital Affiliated to Capital Institute of Pediatrics from January 2010 to December 2020 were retrospectively analyzed, with 408 children ≤10-year-old as control group synchronously. Chi-square test was used to compare the difference of clinical types, pathologic types, response to steroids and tubulointerstitial changes between the groups. The teenagers with steroid resistant nephrotic syndrome (SRNS) were divided into initial non-responder group and late non-responder group. Kaplan-Meier method was used to compare the difference of persistent proteinuria, and Fisher's exact test for the histological types. Results: There were 118 children >10-year-old, including 74 males and 44 females, with the onset age of 12.1 (10.8, 13.4) years; and 408 children ≤10-year-old with the onset age of 4.5 (3.2, 6.8) years. The proportion of SRNS was significantly higher in patients >10-year-old than those ≤10-year-old (24.6% (29/118) vs. 15.9% (65/408), χ2=4.66, P=0.031). There was no statistical difference in the pathological types between >10-year-old and ≤10-year-old (P>0.05), with minimal change disease the most common type (56.0% (14/25) vs. 60.5% (26/43)). The percentage of cases with renal tubulointerstitial lesions was significantly higher in children >10-year-old compared to those ≤10-year-old (60.0% (15/25) vs. 23.3% (10/43), χ2=9.18, P=0.002). There were 29 cases presented with SRNS in PNS over 10-year-old, including 19 initial non-responders and 10 late non-responders. Analyzed by Kaplan-Meier curve, it was shown that the percentage of persistent proteinuria after 6 months of immunosuppressive treatments was significantly higher in initial non-responders than those of the late non-responders ((22±10)% vs. 0, χ2=14.68, P<0.001); the percentage of minimal change disease was significantly higher in patients of late non-responders than those of the initial non-responders (5/6 vs. 3/13, P=0.041). Of the 63 >10-year-old with steroid-sensitive nephrotic syndrome followed up more than one year, 38 cases (60.3%) had relapse, and 14 cases (22.2%) were frequent relapse nephrotic syndrome and steroid dependent nephrotic syndrome. Among the 45 patients followed up over 18-year-old, 22 cases (48.9%) had recurrent proteinuria continued to adulthood, 3 cases of SRNS progressed to kidney insufficiency, and one of them developed into end stage kidney disease and was administrated with hemodialysis. Conclusions: Cases over 10-year-old with PNS tend to present with SRNS and renal tubulointerstitial lesions. They have a favorable prognosis, but are liable to relapse in adulthood.

Binge-Eating Disorder Interventions: Review, Current Status, and Implications.

Binge-eating disorder (BED) is a serious psychiatric problem associated with substantial morbidity that, unfortunately, frequently goes unrecognized and untreated. This review summarizes the current status of behavioral, psychological, pharmacological, and combined treatments for BED in adults with a particular focus on recent findings and advances. Certain specific psychological treatments, notably CBT and IPT, and to some extent DBT, have demonstrated efficacy and are associated with durable benefits after treatment. Certain specific lower-cost scalable interventions, notably CBTgsh, have demonstrated efficacy and have potential for broader uptake. An important advance is the emerging RCT data indicating that BWL, a generalist and available behavioral lifestyle intervention, has effectiveness that approximates that of CBT for reducing binge eating and eating-disorder psychopathology but with the advantage of also producing modest weight loss. There exists only one pharmacological agent (LDX) with approval by the FDA for "moderate-to-severe" BED. Research with other "off label" medications has yielded modest and mixed outcomes with a few medications statistically superior to placebo over the short-term and almost no longer-term data. Nearly all research combining medications and psychological treatments has failed to enhance outcomes (combined appears superior to pharmacotherapy-only but not to psychotherapy-only). Many people with BED suffer in silence and shame, go untreated, and rarely receive evidence-based treatments. Patients and practitioners need to recognize that research has identified several effective interventions for BED, and these can work quickly for many patients. Future research should identify treatments for those who do not derive benefit from initial interventions, identify additional pharmacological options, test agents with relevant mechanisms of action, and utilize innovative adaptative "SMART" designs to identify treatments to enhance outcomes among initial responders and to test alternative treatments to assist initial non-responders.

Risk factors and characteristics influencing humoral response to COVID-19 vaccination in patients after allogeneic stem cell transplantation.

Vaccination against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is approved and recommended for immunocompromised patients such as patients after allogeneic stem cell transplantation (allo-SCT). Since infections represent a relevant cause of transplant related mortality we analyzed the advent of immunization to SARS-CoV-2 vaccination in a bicentric population of allogeneic transplanted patients. We retrospectively analyzed data of allo-SCT recipients in two German transplantation centers for safety and serologic response after two and three SARS-CoV-2 vaccinations. Patients received mRNA vaccines or vector-based vaccines. All patients were monitored for antibodies against SARS-CoV2-spike protein (anti-S-IgG) with an IgG ELISA assay or an EIA Assay after two and three doses of vaccination. A total of 243 allo-SCT patients underwent SARS-CoV-2 vaccination. The median age was 59 years (range 22-81). While 85% of patients received two doses of mRNA vaccines, 10% had vector-based vaccines and 5% received a mixed vaccination. The two vaccine doses were well tolerated with only 3% patients developing a reactivation of graft versus host disease (GvHD). Overall, 72% of patients showed a humoral response after two vaccinations. In the multivariate analysis age at time of allo-SCT (p=0.0065), ongoing immunosuppressive therapy (p= 0.029) and lack of immune reconstitution (CD4-T-cell counts <200/μl, p< 0.001) were associated with no response. Sex, intensity of conditioning and the use of ATG showed no influence on seroconversion. Finally, 44 out of 69 patients that did not respond after the second dose received a booster and 57% (25/44) showed a seroconversion. We showed in our bicentric allo-SCT patient cohort, that a humoral response could be achieve after the regular approved schedule, especially for those patients who underwent immune reconstitution and were free from immunosuppressive drugs. In over 50% of the initial non-responders after 2-dose vaccination, a seroconversion can be achieved by boostering with a third dose.

Responder Rates With Eptinezumab Over 24 Weeks in Patients With Prior Migraine Preventive Treatment Failures (S47.007)

Responder Rates With Eptinezumab Over 24 Weeks in Patients With Prior Migraine Preventive Treatment Failures (S47.007)

Revaccination of patients with systemic lupus erythematosus or rheumatoid arthritis without an initial COVID-19 vaccine response elicits seroconversion in half of the patients.

To investigate the effect of COVID-19 mRNA revaccination (two doses) on the antibody response in patients with rheumatic diseases (RD) who were initial vaccine non-responders. Further, to examine if B-cell levels or T-cell responses before revaccination predicted seroconversion. From a RD cohort vaccinated with the standard two-dose COVID-19 vaccinations, we enrolled cases without detectable antibody responses (n=17) and controls with detectable antibody response (n=29). Blood donors (n=32) were included as additional controls. Samples were collected before and six weeks after completed revaccination. Total antibodies and specific IgG, IgA, and IgM against SARS-CoV-2 spike protein, SARS-CoV-2 neutralising antibodies, and SARS-CoV-2 reacting CD4+ and CD8+ T-cells were measured before and after revaccination. B-cells (CD19+CD45+) were quantified before revaccination. Forty-seven percent of cases had detectable neutralising antibodies after revaccination. However, antibody levels were significantly lower than in controls and blood donors. Revaccination induced an antibody class switch in cases with a decrease in IgM and increase in IgG. No significant difference was observed in T-cell responses before and after revaccination between the three groups. Only 29% of cases had measurable B-cells compared to 100% of controls and blood donors. Fifty percent of revaccinated cases who seroconverted had measurable B-cells before revaccination. Forty-seven percent of initial non-responders seroconverted after two-dose revaccination but still had lower levels of SARS-CoV-2 antibodies compared with controls and blood donors. RD patients without a detectable serological response after the initial COVID-19 mRNA vaccine had a T-cell response similar to immunocompetent controls and blood donors.

Abstract 909: Single-cell multi-omics reveals type-2 function and metabolic fitness in maintaining CAR T cell longevity associated with 8-year leukemia remission

Abstract Despite high response rate in chimeric antigen receptor (CAR) T therapy for acute lymphocytic leukemia (ALL), approximately half of the patients relapse within the first year, representing an urgent question to address in the next stage of cellular immunotherapy. To interrogate the molecular determinants of ultra-long CAR T persistence, we sequenced one million pre-infusion CAR T cells from 82 pediatric ALL patients and 6 healthy donors and obtained high quality multi-omics data from ~700k single cells at the basal level or upon antigen specific stimulation. We identified that elevated type-2 functionality in both CD4+ and CD8+ subsets was associated with five patients maintaining a median B-cell aplasia duration of 8.4 years (BCA-L group), which was independently validated using both intracellular flow cytometry and multiplexed secretomic assay. Further network analysis revealed several pathways promoting the activation of the Th2 master regulator GATA3 in BCA-L cells. Through ligand-receptor interaction analysis, type-2 cytokines were found to regulate a specific cluster of Tim-3+ terminal effector cells showing overactivation of cytotoxicity, impaired immune function, elevated exhaustion signature and diminished proliferative potentiality, and CAR T cells from BCA-L patients showed reduced dysfunctional hallmarks. In addition, activated BCA-L cells maintained a significantly higher level of oxidative phosphorylation metabolism that is likely associated with their observed central memory phenotype, whereas CAR T cells from patients who developed primary resistance or relapse exhibited imbalanced functional and metabolic programs. Specifically, CAR T products from initial non-responders showed hyperactive glycolysis metabolism, and the CD19-negative relapsed patients (RL- group) had significantly attenuated gene module expression of a broad spectrum of metabolic categories, including major energy-producing metabolisms. By direct comparison with BCA-L cells, our analysis identified a strikingly impaired mTOR signaling in RL- CAR T cells, along with reduced proliferation activities and a systematic deficiency of pathways orchestrating immune response. Although the mechanism is still unclear, our hypothesis is that the impaired mTOR signaling could only endow blunted functional and metabolic response in RL- cells, thereby conferring more opportunities to leukemic cells to escape the attack. In summary, our large-scale single-cell multi-omics dataset provides valuable insights for dissecting mechanistic basis of CAR T cell longevity in mediating 8-year leukemia remission, highlighting several therapeutic strategies to edit specific CAR T functionality to ameliorate clinical outcome, particularly boosting the type-2 immunity to mitigate dysfunction thereby extending persistence. Citation Format: Zhiliang Bai, J. Joseph Melenhorst, Stephan A. Grupp, Rong Fan. Single-cell multi-omics reveals type-2 function and metabolic fitness in maintaining CAR T cell longevity associated with 8-year leukemia remission [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 909.

Deep TMS H1 Coil treatment for depression: Results from a large post marketing data analysis

Phase IV study evaluated Deep TMS for major depression in community settings. Data were aggregated from 1753 patients at 21 sites, who received Deep TMS (high frequency or iTBS) using the H1 coil. Outcome measures varied across subjects and included clinician-based scales (HDRS-21) and self-assessment questionnaires (PHQ-9, BDI-II). 1351 patients were included in the analysis, 202 received iTBS. For participants with data from at least 1 scale, 30 sessions of Deep TMS led to 81.6% response and 65.3% remission rate. 20 sessions led to 73.6% response and 58.1% remission rate. iTBS led to 72.4% response and 69.2% remission. Remission rates were highest when assessed with HDRS (72%). In 84% of responders and 80% of remitters, response and remission was sustained in the subsequent assessment. Median number of sessions (days) for onset of sustained response was 16 (21 days) and for sustained remission 17 (23 days). Higher stimulation intensity was associated with superior clinical outcomes. This study shows that beyond its proven efficacy in RCTs, Deep TMS with the H1 coil is effective for treating depression under naturalistic conditions, and the onset of improvement is usually within 20 sessions. However, initial non-responders and non-remitters benefit from extended treatment.

P462 Delayed Responders with Ustekinumab in Ulcerative Colitis Have Increased Inflammatory Burden but Similar Long-term Outcomes as Early Responders

Abstract Background Differences in one-year outcomes among early compared to delayed responders to vedolizumab have been demonstrated in ulcerative colitis. However, it is unclear whether differences exist with ustekinumab, and what factors differentiate delayed responders from non-responders. Methods This was a post-hoc analysis of patient-level data from the UNIFI clinical trial. Ustekinumab-treated patients with clinical response, defined as reduction in total Mayo score ≥30% and ≥3 points from baseline with reduction in rectal bleeding subscore (RBS)≥1 or RBS≤1, at week 8 were deemed early responders and their outcomes were compared with delayed responders (week 8 non-responders who subsequently responded at week 16). The primary outcome assessed was one-year clinical remission (CR), defined as total Mayo score ≤2 and no subscore &amp;gt;1. Other one-year clinical, endoscopic, and histologic outcomes were also assessed. Outcomes were compared using t-tests and biomarkers compared using one-way repeated measures analysis of variance. Results We included 642 ustekinumab-treated patients, including 321 (50%) early responders, 115 (17.9%) delayed responders, and 205 (32.1%) non-responders (Table 1). No differences were observed for one-year CR among early vs. delayed responders [132/321 (41.1%) vs. 40/115 (34.8%), p=0.233], nor for any other outcome assessed (Table 2). Similar findings were observed among delayed responders regardless of weight-based vs. fixed ustekinumab induction dose (Table 3). Compared to early responders, delayed responders had more severe endoscopic disease at baseline as measured by the MES [88/115 (76.5%) vs. 206/321 (64.2%), p=0.015] and were more likely to have abnormal CRP at baseline based on a threshold &amp;gt; 3mg/L [83/115 (72.2%) vs. 183/321 (57%), p=0.004]. Compared to non-responders, delayed responders had a significant decline in CRP (F(4, 844), p&amp;lt;0.0001) and fecal calprotectin (F(4, 818), p&amp;lt;0.0001) through week 16 (Figure 1). Conclusion Compared with early ustekinumab responders, delayed responders had greater inflammatory burden at baseline. Early and delayed responders have similar one-year outcomes. Biomarker decline can be observed in delayed responders and help differentiate them from non-responders. The decision to prolong ustekinumab among initial non-responders should be informed with biomarkers and weighing the overall risk to benefit.

Improved benefit of continuing luspatercept therapy: sub-analysis of patients with lower-risk MDS in the MEDALIST study

Red blood cell transfusion independence (RBC-TI) is an important goal in treating lower-risk myelodysplastic syndromes with ring sideroblasts. In the phase 3 MEDALIST study, RBC-TI of ≥ 8 weeks was achieved by significantly more luspatercept- versus placebo-treated patients in the first 24 weeks of treatment. In this post hoc analysis, we evaluated RBC transfusion units and visits based on patients’ baseline transfusion burden level and the clinical benefit of luspatercept treatment beyond week 25 in initial luspatercept nonresponders (patients who did not achieve RBC-TI ≥ 8 weeks by week 25) but continued luspatercept up to 144 weeks. RBC transfusion burden, erythroid response, serum ferritin levels, and hemoglobin levels relative to baseline were evaluated. Through week 25, fewer RBC transfusion units and visits were observed in luspatercept-treated patients versus placebo, regardless of baseline transfusion burden. This continued through 144 weeks of luspatercept treatment, particularly in patients with low baseline transfusion burden. Sixty-eight patients were initial nonresponders at week 25 but continued treatment; most (81%) received the maximum dose of luspatercept (1.75 mg/kg). Sixteen percent achieved RBC-TI for ≥ 8 weeks during weeks 25–48, 26% had reduced RBC transfusion burden, 10% achieved an erythroid response, 44% had reduced serum ferritin, and hemoglobin levels increased an average of 1.3 g/dL from baseline. These data have implications for clinical practice, as transfusion units and visits are less in luspatercept-treated patients through week 25 regardless of baseline transfusion burden, and continuing luspatercept beyond week 25 can potentially provide additional clinical benefits for initial nonresponders. Trial registration: NCT02631070.

Rituximab-treated rheumatic patients: B cells predict seroconversion after COVID-19 boost or revaccination in initial vaccine non-responders.

To investigate the effect of either a booster vaccine (one dose) or revaccination (two doses 3 weeks apart) on the antibody response to the COVID-19 mRNA vaccines in patients with rheumatic disease (RD) treated with rituximab (RTX) who had not produced vaccine-reactive antibodies after the initial two vaccine doses. Further, to examine if B cell levels in peripheral blood predicted seroconversion. We included 91 RTX-treated RD patients previously vaccinated against COVID-19. Patients were offered revaccination or a single booster vaccination with an mRNA vaccine. Serum total antibodies against SARS-CoV-2 spike protein were measured before and 6 weeks after the last vaccine dose. B cells (CD19+CD45+) were measured by flow cytometry at inclusion. Of RD patients with undetectable SARS-CoV-2 antibody levels before inclusion, seroconversion was seen in 38% 6 weeks after the booster dose and 32% after revaccination. Patients receiving revaccination had significantly higher antibody levels than patients receiving a booster dose (P < 0.001). In both univariate and multivariate logistic regression analysis, only B cells higher than 10/µl before boost or revaccination were associated with seroconversion (P = 0.009 and P = 0.01, respectively). Seroconversion was independent of age, gender, diagnosis, cumulative RTX dose, RTX treatment time and time since last RTX treatment. Continuously impaired humoral response to mRNA vaccines was found in most RTX-treated patients after a booster dose or revaccination. Seroconversion was observed in approximately one-third of the patients. Measurable B cells before boosting or revaccination was the strongest predictor of antibody response after boost or revaccination.

Fourth dose of the SARS-CoV-2 vaccine in kidney transplant recipients with previously impaired humoral antibody response

Fourth dose of the SARS-CoV-2 vaccine in kidney transplant recipients with previously impaired humoral antibody response

Full seroconversion in initial non-responders with higher antibody levels after heterologous COVID-19 vaccination schedule.

Antibody testing after COVID-19 vaccination is generally not recommended. Here, we present the results of a retrospective study, in which we analyzed antibody levels before and after the first dose of the ChAdOx1 vector vaccine. We identified 5% non-responders (43.6 ± 10.6 years; females: 41%) and 3.4% low-responders (44.2 ± 10.1 years; females: 64%) after the first dose. Of these, 61 individuals received a timely second dose either with a homologous (ChAdOx1/ChAdOx1) or heterologous (ChAdOx1/mRNA-1273) schedule. All vaccinees achieved positive S1-specific IgG titers to the ancestral SARS-CoV-2 strain after the second dose, but antibody levels as well as neutralization titers against the ancestral SARS-CoV-2 strain were higher after the heterologous schedule. However, Omicron-specific neutralizing antibodies were not detectable after two doses in either group, indicating that a third vaccine dose is needed to enhance cross-reactive antibodies against currently circulating and emerging variants of concern.