Standard Of Care For Treatment Research Articles

Model-based meta-analysis using latent variable modeling to set benchmarks for new treatments of systemic lupus erythematosus.

Several investigational agents are under evaluation in systemic lupus erythematosus (SLE) clinical trials but quantitative frameworks to enable comparison of their efficacy to reference benchmark treatments are lacking. To benchmark SLE treatment effects and identify clinically important covariates, we developed a model-based meta-analysis (MBMA) within a latent variable model framework for efficacy end points and SLE composite end point scores (BILAG-based Composite Lupus Assessment and Systemic Lupus Erythematosus Responder Index) using aggregate-level data on approved and investigational therapeutics. SLE trials were searched using PubMed and www.clinicaltrials.gov for treatment name, SLE and clinical trial as search criteria that resulted in four data structures: (1) study and investigational agent, (2) dose and regimen, (3) baseline descriptors, and (4) outcomes. The final dataset consisted of 25 studies and 81 treatment arms evaluating 16 different agents. A previously developed (K Goteti etal. 2022) SLE latent variable model of data from placebo arms (placebo + standard of care treatments) was used to describe aggregate SLE end points over time for the various SLE placebo and treatment arms in a Bayesian MBMA framework. Continuous dose-effect relationships using a maximum effect model were included for anifrolumab, belimumab, CC-220 (iberdomide), epratuzumab, lulizumab pegol, and sifalimumab, whereas the remaining treatments were modeled as discrete dose effects. The final MBMA model was then used to benchmark these compounds with respect to the maximal efficacy on the latent variable compared to the placebo. This MBMA illustrates the application of latent variable models in understanding the trajectories of composite end points in chronic diseases and should enable model-informed development of new investigational agents in SLE.

Pediatric Patients with High-Risk B-Cell ALL in First Complete Remission May Benefit from Less Toxic Immunotherapy with Blinatumomab - Results from Randomized Controlled Phase 3 Trial AIEOP-BFM ALL 2017

Background: One of the key questions in trial AIEOP-BFM ALL 2017 focused on the reduction of treatment-related complications by replacing parts of the highly intensive consolidation phase by two courses of Blinatumomab (Blina) in a prospective randomized trial. Herein, we report the toxicity profile of B-cell acute lymphoblastic leukemia (B-ALL) patients (pts) with high-risk (HR) characteristics pending final outcome data. Patients and Methods: 728 pts with HR B-ALL were enrolled from July 15, 2018 to October 31, 2022 in this multicenter trial run in 8 different countries. Patients were included in the HR group in view of the presence of at least one of the following criteria: induction failure; high levels of minimal residual disease (MRD) at day 15 of induction, or at the end of induction (EOI), or at the end of consolidation (EOC); presence of KMT2A::AFF1, of IKZF1+ and positive MRD at EOI (Stanulla et al, JCO 2018), TCF3::HLF, or hypodiploidy. B-ALL pts with one or several of these characteristics represented 20.8% of all pts aged 0-18 years of age with B-ALL. After a 4-drug induction phase, and two weeks of consolidation treatment, patients were randomized to receive Bortezomib in addition to standard consolidation (not part of this report). Before treatment continued with intensive consolidation block HR-1', MRD was analyzed in order to identify patients eligible for subsequent hematopoietic stem cell transplantation (HSCT) based on MRD results. After block HR-1', all B-ALL HR pts were randomized to receive either two courses of consolidation (blocks HR-2', and HR-3'), or two 28-day courses of Blina at 15µg/m 2/d administered by continuous IV infusion (with a 2-week treatment-free interval). Two intrathecal injections of methotrexate (MTX) for CNS prophylaxis were given on days 1 and 29 of each Blina course, respectively. Out of 728 HR B-ALL pts, 619 pts were eligible for randomization [reasons for non-eligibility were: Event (death or relapse) before randomization was due (26), Down syndrome (25; scheduled for a non-randomized intervention with Blina), presence of TCF3::HLF (3; could receive any alternative therapy including Blina), discontinuation/substantial change of preceding therapy (23) or other protocol exclusion criteria (32)]. 572 pts were randomized (92.4% of those eligible). One pt assigned to the experimental arm (EA) and 4 pts assigned to the control arm (CA) received the other arms, respectively. Results: Toxicity was evaluated in randomized pts according to treatment administered during the randomized phase, respectively, until next element started: 268 pts were treated in the control and 281 in the EA (see Table). 16 of them switched in/after the first Blina cycle to the HR blocks due to toxicity or poor response to Blina (due to increasing MRD, >=1x10 -4). Medically relevant adverse reactions of special interest (ARSI) according to MedDRA (specified in the protocol) were evaluated in the randomized treatment phases (CA: HR-2‘/HR-3‘ block, EA: 2 Blina cycles). ARSI were recorded in 61 of 268 pts in the CA (22.8%, 71 ARSI) and in 29 of 281 pts in the EA (10.3% [p<0.001], 33 ARSI); 3 of the 33 ARSI in the EA were related to HR blocks and were observed in 3 of the 16 pts that switched to HR blocks. Life-threatening SAR were seen in 14 pts of the control group (5.2%) and in no patient in the EA (p<0.001). Conclusions: Taken together, these results show for the first time in newly diagnosed pts with HR B ALL, the favorable toxicity profile previously reported with Blinatumomab in pediatric relapsed ALL (Locatelli F et al, JAMA 2021; Brown P et al, JAMA 2021). We have demonstrated that the toxicity profile of Blinatumomab is much more favorable as compared to the intensive chemotherapy approach using HR-blocks. If upcoming analyses of outcome data will show no inferiority of the EA, blinatumomab replacement of some of the intensive chemotherapy blocks will become the new standard of care for treatment if newly diagnosed patients with HR B-ALL.

Management and Evolution after VTE Recurrence and/or Bleeding in Cancer Patients Receiving Anticoagulant Therapy for VTE: A Nationwide Cohort Study in France

CONCLUSION Until recently, the standard of care for treatment of venous thromboembolism ( VTE) in cancer patients was low molecular weight heparins (LMWH). Despite anticoagulation therapy (AC), patients remain at high risk of treatment failure (VTE recurrence and/or bleeding). To determine the characteristics, management and the course of treatment after experiencing a recurrent VTE and/or bleeding event in VTE cancer patients receiving LMWH. A nationwide retrospective cohort study of all adult patients (identified via the French national health data system: SNDS) with VTE and active cancer prescribed LMWH from 2013 to 2018. Of 31,771 patients administered LMWH, 1,256 patients (mean age 64.1 years) experienced a recurrent VTE (median time to the first recurrent VTE event: 1.2 months) and 1,129 patients (mean age 67.5 years) experienced a bleeding event leading to hospitalization (median time to the first bleeding event: 1.5 months) during the first six months, and among them 46.7% and 40.9% patients experienced the event within the first month. The proportion of patients with recurrent VTE and bleeding varied according to cancer sites (7.3%, 6.5% and 5.1% for recurrent VTE and 5.0%, 6.1% and 4.1% for bleeding, respectively in lung, colorectal and breast cancer) (Figure 1). The management of patients with recurrent VTE consisted of a switch to another AC treatment in 370 patients, in whom 262 switched to an oral AC (179 to a DOAC and 83 to a VKA), the remaining continuing LMWH. The management of patients with bleeding consisted of a switch to another AC treatment in 159 patients. Among the 159 switched patients, 94 switched to an oral AC (73 to a DOAC and 21 to a VKA), <10 stopped AC (Figure 2). Our results indicate that recurrent VTE and bleeding events lead to a heterogenous switch of AC therapy. Further research is needed to optimize secondary AC management in VTE cancer patients. This study was sponsored by Pfizer and Bristol Myers Squibb Keywords : venous thromboembolism; cancer; anticoagulants; bleeding; low molecular weight heparin; treatment pattern

Oncogenetic-Driven Targeted Therapy for Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia : A French ALL-Target Observatory Report

Introduction T-cell acute lymphoblastic leukemia (T-ALL) is an orphan disease diagnosed mostly in adolescent and young adults. In adult population, 5-10% of T-ALL patients (pts) will be primary refractory and 30-40% will relapse. In relapse/refractory (R/R) patients, standard of care treatments, including nelarabine, yield response rate of about 20-40% and responses are of short duration. On behalf of the GRAALL (Group for Research on Adult Acute Lymphoblastic Leukemia), we launched the ALL-TARGET project combining a precision medicine platform dedicated to R/R T-ALL and T-cell lymphoblastic lymphoma (T-LL), and an observatory to evaluate therapeutic proposals based on mutational profile and intracellular signaling pathways alterations. Objectives and methods Leukemic samples from pts with R/R T-ALL/LL were shipped to the GRAALL T-ALL central laboratory in France (V. Asnafi, Hôpital Necker). Biological characterization comprised oncogenetic, phenotypic and in some cases functional analysis. Clinical data from R/R T-ALL/LL pts were collected in a real-life observatory (NCT05832125). Adults pts were eligible if an oncogenetic characterization was available at diagnosis or relapse, and if they received a salvage, either with conventional therapy or with a targeted therapeutic option (TTO). For example, TTOs included Tofacitinib and Venetoclax (Tofa/Ven) in case of IL7R (CD127) expression or IL7R-pathway alterations (IL7R ALT), 5-azacytidine and Venetoclax (Aza/Ven) in case of T-ALL/LL with epigenetic regulators alterations (DNMT3A, ASXL1, PHF6, TET2, PRC2, IDH1/2, SRSF2...) or Temsirolimus, Erwinase and Venetoclax (Tem/Erw/Ven) in case of PI3K signaling pathway alterations (PI3K ALT). The ALL-TARGET Observatory primary endpoint was overall response rate (ORR) including complete remission (CR), CR with incomplete hematological recovery and partial response. We report here the results of the first pts included, with a focus on those who received TTOs as salvage therapy. Results Eighty-nine were analyzed, including 80 T-ALL and 9 T-LL. Sex ratio was 3 and median age at diagnosis was 37.5y, and 51y at the time of the first TTO. Seventy-one pts were in relapse (79.7%) and 18 primary refractory (20.2%). Relapses occurred after a median first CR duration of 16.6 months (range: 2.5-92), with 62.8% in bone marrow, 30% in CNS and 30.3% in other extramedullary sites. Phenotype at diagnosis was available for 68 pts, including 36 Early T-cell Precursor (ETP or near-ETP) (52.9%), 6 immature non-ETP (8.8%), 20 cortical (29.4%) and 6 mature phenotype (8.8%). IL7R-expression was available for 53 pts, of whom 40 were IL7R+ (75.5%) and 13 IL7R- (24.5%). Out of 50 samples with available BCL2-expression, 47 were BCL2+ (94%) and 3 BCL2- (6%). IL7R ALT were evidenced in 41 pts (48.2%), PI3K ALT in 21 pts (24.7%), RAS pathway alterations (RAS ALT) in 19 pts (22.4%) and epigenetic dysregulation in 42 pts (49.4%). Ten pts harbored TP53/ATM mutations (11.7%) . These different alterations could coexist. At relapse, 33 phenotypes were reported, showing 22 ETP (66.6%), 2 immature non-ETP (6%) and 9 cortical (27.3%). IL7R-expression was available for 26 pts, among which 21 were IL7R+ (63.6%) and 5 IL7R- (19.2%). NGS was performed in 24 patients, revealing IL7R ALT in 9 pts (37.5%), PI3K ALT in 6 pts (25%), RAS ALT in 5 pts (20.8%) and epigenetic dysregulation in 15 pts (62.5%). Nine patients had TP53 mutations (37.5%). Twenty-five patients received a TTO, including 14 Aza/Ven (56%), 8 Tofa/Ven (32%), 2 Tem/Erw/Ven (8%) and 1 Trametinib/Ven (4%). Among these, 8 were in first salvage (32%), 10 in 2 nd (40%), and 6 in 3 rd/4 th salvage (28%). Of note, 14 patients received Ven associated with chemotherapy, including 4 Nelarabine-Ven, and 3 Ven in monotherapy. By 3 months, the cumulative incidence of response under the chosen TTO was 70.7% (95%CI:51-88) (Figure). Ten of 14 patients were in response after Aza/Ven (ORR 71.4%), 4 of 8 patients after Tofa/Ven (50%) and 2 of 2 patients treated with Tem/Erw/Ven (100%). Five patients were bridged to allogeneic stem cell transplantation. Conclusion Our results demonstrate the feasibility of the ALL-TARGET project. A better knowledge of the oncogenetic landscape of T-ALL, and a close collaboration between clinicians and biologists, resulted in individualized treatment strategies. With a 3 months cumulative incidence of response of 70%, TTOs appear to be a promising approach in R/R T-ALL.

Treatment Patterns and Healthcare Resource Utilization Among Patients with Triple Class Exposed Multiple Myeloma: A Population-Based Cohort Study

Introduction: Outcomes of patients with relapsed or refractory multiple myeloma (MM) have improved substantially with access to novel therapeutic agents. However, patients with triple class exposed (TCE) MM continue to have poor outcomes. Though newer bispecific antibody and chimeric antigen receptor T-cell immunotherapies have improved outcomes of TCE patients, these therapies are inaccessible outside of clinical trials in many publicly funded healthcare systems, including Canada. This study aimed to describe treatment patterns, outcomes, unplanned health care utilization and quality-of-life impairments of TCE MM patients in Ontario, Canada. These data will provide a crucial benchmark to compare to as novel immunotherapies become available. Methods: This retrospective observational study utilized data from the Institute for Clinical Evaluative Sciences (IC/ES) administrative database, which contains all health records of patients treated within Ontario's publicly funded healthcare system. Drug exposure was determined using the Cancer Activity Level Reporting (ALR) and Ontario Drug Benefit Claims Registry (ODB) databases, housed within IC/ES, which contain data on intravenous and oral MM treatment exposure for standard of care and clinical trial regimens. Patients were defined as TCE if they had prior or current treatment with a regimen containing an immunomodulatory drug (lenalidomide or pomalidomide), a proteasome inhibitor (bortezomib, carfilzomib, or ixazomib), and an anti-CD38 monoclonal antibody (isatuximab or daratumumab). The TCE index regimen was identified as the treatment on which a patient was first identified as having met the TCE definition. Inpatient hospitalization visits did not include planned chemotherapy infusion visits. Quality of life was described using the Edmonton Symptom Assessment System Score with scores ³ 7 corresponding to severe symptoms. Overall survival (OS) was determined using the Kaplan-Meier method. Results: Of the 16,777 patients with a diagnosis of MM between 2007-2021 in Ontario, 1358 patients were classified as TCE during their treatment course. The TCE index regimen was a daratumumab-based regimen in most patients [daratumumab/velcade/dex (n=566, 42%), daratumumab/lenalidomide/dex (n=619, 46%)]. Of the TCE patients, 247 (18%) were still receiving treatment with the TCE index regimen at last follow up, 263 (19%) died without receiving any additional treatment, and 489 (36%) received a subsequent MM treatment after the TCE index regimen. Baseline characteristics of patients (n=489) treated with a subsequent MM regimen after post TCE are summarized in Table 1. The three most commonly administered therapies post TCE were carfilzomib-dexamethasone (n=111, 23%), pomalidomide-dexamethasone (n=77, 16%) and oral cyclophosphamide (n=49, 10%). The next-line treatment regimen was administered in an academic versus community treatment center in 235 (48%) versus 254 (52%) of patients, respectively. The next-line therapy was a clinical trial in only 37 (8%) patients. Regarding healthcare utilization, among TCE patients receiving subsequent therapy, 149 (30%) were evaluated in the emergency department (ED), 126 (26%) were admitted to hospital, and 48 (10%) were referred to palliative care while on treatment with the subsequent therapy. Among patients with available information, the most common severe patient-reported symptoms during the subsequent line of treatment included: tiredness (27%), pain (23%) and overall poor well-being (21%). Additionally, 35% of patients had a ECOG PS of ≥2 on next-line treatment. The median OS patients treated after the TCE index regimen was 1.05 year (95% CI 0.89-1.35) as shown in Figure 1. Of the patients that died during follow up, the majority died in hospital (n=147, 44%) and were referred to palliative care (217, 65%). Conclusion: In this real-world study, we showed that the overall outcomes of TCE MM patients remains poor in Canada, highlighting the urgent need for novel therapies. Furthermore, we demonstrated that TCE patients receiving subsequent therapy had significant unplanned health care utilization and poor quality of life. Future studies will need to assess whether the outcomes, healthcare utilization, and patient-reported quality of life improve as newer immunotherapies become accessible as standard of care treatments within our publicly funded healthcare system.

Effects of Dose Reductions of Lenalidomide Given As Maintenance Following Autologous Stem Cell Transplant in Patients with Multiple Myeloma

INTRODUCTION Lenalidomide (len) maintenance has been considered the standard of care treatment following an autologous stem cell transplantation(autoSCT) for patients (pts) with newly diagnosed multiple myeloma (MM). Len doses of up to 15 mg are used in this setting, however in clinical practice patients may experience a variety of side effects including neutropenia, infections, diarrhea, rash, or secondary malignancies, which may impact the quality of life and potentially lead to discontinuation of therapy. In this retrospective analysis, we aim to evaluate the effects of len dose reductions on progression-free survival (PFS), overall survival (OS), and other outcome measures in a post-autoSCT maintenance setting using the multiple myeloma database at our center. METHODS We reviewed patients' clinical and demographic characteristics including age and R-ISS stage at diagnosis and IMWG response after autoSCT. We included patients diagnosed with MM between 01/01/2010 to 02/28/2022. We compared pts receiving a full dose (15 mg/day) of len (control group) versus those requiring dose reductions or receiving lower doses to begin with (dose reduction group). The primary end-point was PFS, secondary end-points included OS, reasons for dose reduction, correlation with initial and follow-up disease parameters, and long-term toxicities. Demographic and clinical characteristics were summarized by cohort and compared using Mann-Whitney U and Fisher's exact tests. The PFS at (6 months and one year) and OS were summarized by cohort using Kaplan-Meier methods. Multivariate Cox regression analysis was completed adjusting for age, stage at diagnosis, prior response, full versus reduced len doses, and duration of treatment. Analyses were performed using SAS v9.4 at a significance level of 0.05. RESULTS The mean age at diagnosis was 61 and matched between groups. The median follow-up time in months was 52.9 months (range: 2.8-140.2 months). A total of 66% (134/203) of patients had lower doses than 15mg, while 34% (69/203) were maintained at 15mg of len. For the control group, 20% (n=14) had RISS I, 48% (n=33) II, and 13% (n=9) III, at the time of diagnosis, respectively; for the dose reduction group, and 38% (n=37) stage I, 39% (n=51) stage II, and 9% (n=12) stage III (remainder unknown) for the control group. These differences were not statistically significant (p=0.35). In the control group, 49% (n=33) pts had achieved CR prior to initiation of maintenance compared to 65% (n = 86) in the dose reduction group which was borderline statistically significantly different (p=0.06). Achieving CR before maintenance before maintenance was prognostically beneficial (p<0.001). The most common reason for discontinuation of len, was progression in both groups (control group 84% (n=31), dose reduction group. 41% (n=29)). This was however still statistically significantly different between the 2 groups (p<0.01). The most common reasons for dose reductions in the respective group were neutropenia (56.8%, n= 75), neuropathy (12%, n=15), and rash (9%, n=12). The duration of treatment in the control group and the dose reduction group was 24 months and 30 months respectively (p=0.113). Surprisingly, there was a statistically significant better PFS (p<0.001) and OS (p=0.003) for patients who received len at a reduced dose (figure 1 and 2). However, when adjusted for prior response using Multivariate cox regression analysis, there was no statistically significant difference in outcome between the 2 groups. CONCLUSION This retrospective analysis shows that dose reduction of len did not lead to worse PFS or OS, especially in those who achieved CR prior to maintenance. According to our data for those who fail to achieve a CR post autoSCT, increasing the dose of len to 15 mg (standard dosing practice) may lead to increased toxicities while failing to affect PFS or OS significantly. A potential bias towards long OS findings may be that patients in this investigation were limited to those who were able to get to and actually receive autoSCT. They were also not felt to require more intense maintenance with more than 1 drug. Based on real-world experience and prior studies looking at various dose schedules of len, we theorized that dose reduction may not have a large negative impact on long-term clinical outcomes.

Ex-Vivo Testing Platform to Predict Clinical Response and Resistance to Proteosome Inhibitors, IMiDs and Daratumumab in Multiple Myeloma

Treatment of Multiple Myeloma (MM) relies on Standard of Care (SoC) schemes that include immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) in combination with dexamethasone (Dexa). More recently, monoclonal antibodies such as Daratumumab (Dara) have become complementary therapeutic strategies to treat newly diagnosed and relapsed MM patients. Despite the multiple therapeutic schemes available, MM remains an incurable disease in which patients transit intermittent cycles of relapse and remission that ultimately lead to multi-drug resistance. It has therefore become clear that novel tools for personalized therapy selection are necessary to improve outcomes and reduce trial and error, particularly when selecting later lines of treatment. At OncoPrecision, we have developed a personalized ex-vivo platform that mimics the tumor microenvironment and promotes the survival of Patient-Derived Cells (PDCs), with the goal to predict the performance of the complete array of FDA-approved drugs, as well as experimental treatments, within 7 days. This technology, which we have named Patient Micro Avatars (PMAs), consists of the co-culture of PDCs with engineered neoplastic (System Control) and stromal (Tox Control) heterologous cells in combination with a multi-tagging approach coupled to high-throughput flow cytometry (Figure: Upper Panel). Our PMAs not only enable us to rank the activity of all approved treatments, but also unveil potential unspecific toxicities of novel treatments on non-tumoral cells, thus unlocking unique insights for early drug development programs. In this work, we introduce our PMA technology for MM by presenting differential response between patients in a Clinical Study performed in collaboration with two healthcare centers which, through approved IRBs, have provided MM patient samples from bone marrow aspiration. We present ex-vivo profiling results with a comprehensive MM drug matrix which includes SoC treatments used in several lines of therapy. We illustrate the potential of PMAs to identify differential activity from individual agents and synergistic drugs combinations in 13 patients (Figure: Lower Panel). By anticipating vulnerability/resistance to SoC treatments, our platform has the potential to become a first-in-class phenotypic biomarker to serve as a decision-support tool for Physicians to select optimal therapeutic regimes, as well as to elucidate valuable pre-clinical patient-derived insights for the development of innovative therapies for MM.

Complete Response As a Determinant of Survival in Plasmablastic Lymphoma Plasmablat- GELL001 Study

Introduction Plasmablastic lymphoma (LP) is a highly aggressive hematologic malignancy that has been recently described. Usually appears in immunocompromised patients, generally in the context of human immunodeficiency virus (HIV) coinfection, post-transplant status, or immunosenescence. To date, there is no standard care treatment in the first line, however, high-intensity regimens, generally EPOCH is the most described in the literature. We present the largest cohort of patients with Plasmablastic lymphoma published to date in the region, which includes patients diagnosed and treated in various medical centers in Latin America. Methods Data was collected from 11 medical centers throughout Latin America, including patients from Colombia, Argentina, Cuba, Ecuador, Mexico, and Paraguay. Data were recorded from a predetermined collection instrument, and unified in a single database. Results A total of 87 patients were diagnosed between 2008 and 2023. Twelve (n=12) were women (13.8%) and 75 men (86.2%), with an age between 18 and 76 years (median age 41 years). Most of the patients were under 50 years of age at debut (70.1%), and the majority were HIV positive (72.4%). Of the entire cohort, 82.8% presented advanced disease, only 16.1% presented early disease. Extra-nodal involvement was observed in 76 patients (87.4%), being the most frequent sites of involvement the gastrointestinal tract (33 patients - 37.9%), followed by the bone marrow and oral cavity. Among the patients who received at least one dose of therapy, the IPI was available in 72.6%, being IPI 1 6.8%, IPI 2 19.2%, IPI 3 28.8%, IPI 4: 17.8%, missing data 27.4%. Regarding the first-line treatment, most patients received EPOCH n=61 (70%). After first-line treatment, 45.9% achieved a complete response, 9 patients (10.3%) achieved a partial response, 4 patients (4.6%) stable disease, and 29.9% of patients (n= 26) had refractory disease. It is important to mention that 14 patients died without starting treatment (16%), the majority due to complications related to lymphoma. Among the patients who started therapy, with a median follow-up of 15 months, progression-free survival was 34 months (1-108), and overall survival was not reached. Median overall survival was not reached in patients who achieved complete response and was only 11 months (7.9-14.1) in patients with partial response or less (p<0.0001). In the multivariate analysis, the only independent predictor of survival was reaching a complete response with a HR of 0.007 (0.1-0.345). Conclusion To the best of our knowledge, our series is the largest in the region where we found that the most important determinant of survival is the fact of achieving a complete response after first line of treatment.

ILUVIEN® in diabetic macular edema that persists or recurs despite treatment: Results from the Retina.pt® RIVER audit.

Persistent diabetic macular edema (DME) remains a problem in clinical practice, with many patients having a suboptimal response to the standard of care (SOC). Evidence supports the long-term efficacy of intravitreal fluocinolone acetonide (FAc) implant (ILUVIEN®) in patients that have responded sub-optimally, although there is still scarce data from real-world Portuguese practices. We aimed to monitor the current SOC in selected Portuguese practices prior to FAc implantation and then assess the long-term effectiveness and safety of the FAc implant. The study included patient data from five Portuguese public hospitals. This was a non-interventional, multicenter audit of data collected from Retina.pt registry from patients with persistent or recurrent DME despite treatment. Outcome measures included changes in best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP). Results were compared at regular times over 36 months. This study included 222 eyes from 152 patients. A significant decrease in BCVA (P < 0.001) and a significant increase in CMT (P = 0.013) were observed prior to FAc. A significant increase in BCVA was registered at 6 months after FAc implant administration (P < 0.001), which was maintained during follow-up. No relevant changes in IOP were observed. Treatment burden was reduced as a result of treatment with FAc (P < 0.001 for anti-VEGF, corticosteroids, or both treatments) in the full population. In Portuguese practice, data showed that pre-FAc implantation, some patients did not respond to SOC treatment and/or they were undertreated. Following FAc implant administration, there were rapid, sustained, long-term visual and anatomical improvements, and a marked reduction in treatment burden.

Circulating Tumor DNA Dynamics as Early Outcome Predictors for Lisocabtagene Maraleucel as Second-Line Therapy for Large B-Cell Lymphoma from the Phase 3 TRANSFORM Study

Background: While the prognostic value of MRD using ultrasensitive circulating tumor DNA (ctDNA) assays after first-line immunochemotherapy for DLBCL has been shown (Roschewski M, et al. Blood 2022;140[suppl 1]:785), its relevance to outcomes after second-line (2L) treatment with CD19-directed CAR T cell therapy remains unclear. The phase 3 TRANSFORM study (NCT03575351) showed statistically significant and clinically meaningful improvements in event-free survival (EFS), CR rate, and PFS for lisocabtagene maraleucel (liso-cel) compared with standard of care (SOC) for patients (pts) with primary refractory or early relapsed large B-cell lymphoma (LBCL) eligible for autologous HSCT (Kamdar M, et al. Lancet 2022; Abramson JS, et al. Blood 2023). Here, we report longitudinally measured ctDNA levels from TRANSFORM as a prospective measure of disease burden and describe the predictive value of ctDNA after 2L liso-cel therapy for LBCL. Methods: From the original randomized population (n = 184), 551 plasma samples from 160 pts (liso-cel, n = 79; SOC, n = 81) were used for ctDNA assessment in a blinded manner by Phased Variant (PV) Enrichment and Detection Sequencing (PhasED-Seq) at Foresight Diagnostics. Tumor-derived PVs were identified directly from baseline plasma samples taken at screening without use of tumor tissue; matched DNA from peripheral blood mononuclear cells was used to censor germline variants and clonal hematopoiesis. PVs were used to longitudinally assess ctDNA on the day of liso-cel infusion; at Day 15; and Months 1, 2, 3, and 12 after infusion. For the SOC arm, only pretreatment samples were evaluated. ctDNA levels were compared with baseline characteristics, responses by Lugano 2014 criteria, and EFS. Pts/samples were reported as having detectable MRD when ctDNA levels exceeded a detection threshold (≈1:10 6 cell-free DNA molecules) corresponding to 98% specificity. Results: PVs were identified from 136 of 160 pts (85%) with evaluable pretreatment samples from the liso-cel and SOC treatment arms. The remaining samples had lower disease burden (sum of product of diameters[SPD]; 13%) or failed quality check (2%). Pretreatment ctDNA levels varied widely (median [IQR]: 136 [35‒696] haploid genome equivalents/mL) and were correlated with disease indices portraying higher-risk disease, including stage ( P = 0.02), age-adjusted International Prognostic Index ( P &amp;lt; 0.0001), disease burden (SPD; P &amp;lt; 0.0001), and LDH ( P &amp;lt; 0.0001). Serial ctDNA levels were evaluated after liso-cel infusion in 63 pts. Achieving undetectable ctDNA was associated with achieving CR and longer EFS at all time points after liso-cel infusion. ctDNA levels decreased rapidly in pts who achieved CR at Month 3, with 50% (17/34) having undetectable ctDNA by Day 15 after liso-cel infusion. Conversely, 89% of pts (16/18) with PD at Month 3 still had detectable ctDNA at Day 15 with lower levels of ctDNA clearance. These results highlight significant enrichment of undetectable ctDNA observed as early as Day 15 after infusion between pts with Month 3 CR versus PD ( P = 0.006). ctDNA clearance in pts who achieved CR at Month 3 continued to deepen further over time, with undetectable ctDNA rates of 63%, 74%, and 86% at 1, 3, and 12 months after liso-cel infusion, respectively. Furthermore, most pts in CR by PET/CT had undetectable ctDNA at paired time points (71%), confirming that pts achieving CR also achieved durable molecular remission. In the cases with discordant CR and ctDNA results, detection of residual ctDNA was significantly prognostic for shorter EFS at all respective response assessments (fraction of CR cases with residual ctDNA at 1 month and Log-rank test P value for EFS: 47% [15/32], P = 0.011; 3 months: 26% [9/34], P = 0.025; 12 months: 13% [4/31], P = 0.003). Conclusions: Achieving undetectable ctDNA in the first 3 months and as early as 15 days after liso-cel infusion was significantly associated with durable clinical benefit. Conversely, detectable ctDNA captured relapse risk unmeasured by imaging. These results demonstrate the potential clinical value of ctDNA monitoring as a biomarker for disease surveillance and as an early predictor of clinical benefit of liso-cel treatment for LBCL, which could guide and accelerate future clinical trials.

687. Zinplava Expert Retrospective Observations (ZERO) Study Findings on Clostridioides difficile Recurrence

Abstract Background Describe real world experience in the use of bezlotoxumab (BZT) for the prevention of recurrent Clostridioides difficile(CDI) infection with a 1 year follow up following administration. The original BZT studies showed approximately 16% rate of recurrence at 12 weeks with other baseline and outcome data as noted in Figure 1. Methods Retrospective study of patients administered BZT in a community based private practice infusion suite from May 2017 to October 2020. A total of 50 consecutive patients were included with background demographics, relevant medical history and CDI history obtained through chart review. In addition to the chart review, patients were contacted at least 1 year after BZT administration to see if there were any recurrences and if other treatments were required. Primary objective was to show the rate of CDI recurrence in the 1 year after BZT administration. All BZT was administered in an outpatient setting in patients who were responding to initial Standard of care (SOC) therapy. Results 50 patients were included with infusion dates from May 2017 to October 2020. Baseline patient characteristics (Figure 2) include median Age of 69 and 74% female. CDI history (Figure 3) includes an average of 2.06 episodes including the current episode at time of time treatment and median of 19.5 days to BZT administration from last positive episode (positive test or starting a new treatment course for presumed positive). SOC treatments over the course of patient’s episodes are listed in Figure 3, most patients received more than agent. In the 1 year following BZT only 4 patients had recurrence (Figure 4) with 2 going on fecal microbiota transplant. There were 3 deaths reported, all at least 3 months after BZT and none had CDI recurrence. Conclusion In our real-world use, BZT administered in an outpatient setting to patients who responded to SOC treatment resulted in only 8% recurrence after 1 year compared to 16% after 12 weeks in the trial. This supports the existing guidelines on the use of BZT in patients over 65 and with recurrent CDI to prevent further recurrence. Our data also supports administration later in the course of therapy when patients have achieved initial response. Disclosures MICAH JACOBS, Micah Jacobs, MD, FIDSA, FACP, Abbvie: Honoraria|Cumberland Pharmaceuticals: Honoraria|Merck: Grant/Research Support|Spero Pharmaceuticals: Advisor/Consultant

Time-Restricted Fasting Improves Liver Steatosis in Non-Alcoholic Fatty Liver Disease—A Single Blinded Crossover Trial

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with visceral adiposity. We assessed the effectiveness of time-restricted fasting (TRF) for 16 h daily without calorie restrictions compared to standard care (SC; diet and lifestyle advice) in improving visceral adiposity and steatosis via controlled attenuation parameter (CAP). Methods: In a prospective single-blind randomized controlled trial, 32 participants with NAFLD were randomly assigned to TRF or SC for 12 weeks. The secondary endpoints were changes in liver stiffness, anthropometry, blood pressure, and other metabolic factors. Results: Twenty-eight participants completed the first arm of the study (TRF = 14, SC = 14), with 23 completing the crossover arm (TRF = 10, SC = 13). The baseline demographics were similar between the groups. Intermittent fasting caused a significant decrease in hepatic steatosis (p = 0.038), weight (p = 0.005), waist circumference (p = 0.001), and BMI (p = 0.005) compared to standard care. Intermittent fasting also resulted in additional within-group changes that were not seen in the standard care intervention. Conclusion: TRF offers superior improvements in patients with NAFLD, improving steatosis, weight, and waist circumference despite a lack of change in overall caloric intake. Time-restricted fasting should be considered as a primary weight loss intervention in the context of NAFLD. Trial registration: ACTRN12613000935730.

Dynamic Assessment of Plasma von Willebrand Factor and ADAMTS13 Predicts Mortality in Hospitalized Patients with SARS-CoV-2 Infection.

Plasma levels of von Willebrand factor (VWF) are significantly elevated in patients with coronavirus disease 2019 (COVID-19). However, dynamic changes and prognostic value of this biomarker in hospitalized patients with COVID-19 have not been determined. A total of 124 patients infected with SARS-CoV-2 were prospectively recruited for the study. Serial blood samples were obtained at the time of admission (D1), 3-4 days following standard-care treatments (D2), and 1-2 days prior to discharge or any time collected prior to death (D3). Plasma VWF antigen, ADAMTS13 antigen, and ADAMTS13 proteolytic activity, as well as the ratio of VWF/ADAMTS13 were determined, followed by various statistical analyses. On admission, plasma levels of VWF in COVID-19 patients were significantly elevated compared with those in the healthy controls, but no statistical significance was detected among patients with different disease severity. Plasma ADAMTS13 activity but not its antigen levels were significantly lower in patients with severe or critical COVID-19 compared with that in other patient groups. Interestingly, the ratios of plasma VWF antigen to ADAMTS13 antigen were significantly higher in patients with severe or critical COVID-19 than in those with mild to moderate disease. More importantly, plasma levels of VWF and the ratios of VWF/ADAMTS13 were persistently elevated in patients with COVID-19 throughout hospitalization. Kaplan-Meier and Cox proportional hazard regression analyses demonstrated that an increased plasma level of VWF or ratio of VWF/ADAMTS13 at D2 and D3 was associated with an increased mortality rate. Persistent endotheliopathy, marked by the elevated levels of plasma VWF or VWF/ADAMTS13 ratio, is present in all hospitalized patients following SARS-CoV-2 infection, which is strongly associated with mortality.

MODL-46. RECAPITULATING CELLULAR HETEROGENEITY AND TREATMENT-SPECIFIC EFFECTS THROUGH SINGLE-CELL ANALYSIS OF PATIENT-DERIVED TUMOR SLICE CULTURE MODELS

Abstract INTRODUCTION Malignant brain tumors are almost universally fatal despite standard-of-care (SOC) therapy with radiation (XRT) and temozolomide (TMZ). Low Grade Glioma (LGG) is a subclass of malignant glioma that can harbor an R132H mutation in Isocitrate Dehydrogenase 1 (IDH1). Extensive clinical trials have explored the clinical utility of IDH1 R132H mutation small molecule inhibitors such as ivosidenib and vorasidenib; however, the direct intracellular and intercellular effects of IDH1 R132H inhibition relative to SOC remain largely unknown. Objective This study examines these issues by developing a novel patient-specific tumor slice culture model to study the effects of both SOC and IDH1 R132H inhibition on IDH1 mutant glioma. Method En-bloc tumor samples from a patient with IDH mutant LGG undergoing surgery were sectioned into 400 um thick slices using a vibratome and cultured on porous microwell inserts for up to 14 days. Tumor slices were then either left untreated or treated with SOC (XRT/TMZ) or ivosidenib and harvested at various time points. Samples were hashed, and single-cell RNA sequencing was performed and analyzed. Result: Patient-derived tumor slice cultures were able to grow and were observed to contain heterogeneous cell populations, including tumor cells, astrocytes, neurons, oligodendrocytes, and microglia. When slice cultures were treated with SOC and ivosidenib treatment, separate tumor subpopulations were shown to be sensitive to either treatment. Furthermore, scRNA analysis revealed unique subpopulations that were insensitive to either treatment. We further demonstrate that slice cultures treated with Ivosidenib enriched for gene signatures related to protein translation and antigen processing. Intriguingly, we find that tumor cultures treated with ivosidenib abrogated the Notch signaling pathways between tumor-tumor and tumor-immune clusters. CONCLUSION Herein, we demonstrate that patient-derived tumor slice cultures are a viable strategy for understanding drug effects and tumor sensitivity to different therapies.

Changes in standard of care (SOC) medication during long-term mavacamten treatment for obstructive hypertrophic cardiomyopathy (HCM): results from the EXPLORER cohort of MAVA-Long-Term Extension (LTE)

Abstract Introduction Mavacamten is efficacious and well tolerated in patients with obstructive HCM in the ongoing MAVA-LTE study (NCT03723655) as shown in previous interim analyses. Here, we present exploratory data from the EXPLORER cohort of MAVA-LTE investigating the effect of changes in SOC treatment on the efficacy and safety of mavacamten. Methods Patients who completed EXPLORER-HCM (NCT03470545) could enroll in MAVA-LTE and comprised the EXPLORER cohort. All patients in the EXPLORER cohort received mavacamten. Patients could receive beta blockers or nondihydropyridine calcium channel blockers (verapamil/diltiazem) as SOC treatment. After 24 weeks on study, SOC treatment could be adjusted. A cumulative interim analysis (data cut-off: May 31, 2022) was performed on patients who: received no SOC, discontinued SOC, had any reduction in SOC and had ≥50% reduction in SOC from baseline to data cut-off. Results In total, 231 patients (mean age, 60 years; 39% female) comprised the EXPLORER-LTE cohort (median time on study: 101 weeks at data cut-off). At baseline, 176 patients (76.2%) received beta blockers and 38 (16.5%) received nondihydropyridine calcium channel blockers. At data cut-off, 12 (5.2%) patients had received no SOC treatment from baseline, 11 (4.8%) patients had discontinued SOC, 27 (11.7%) patients had any dose reduction in SOC, 18 (7.8%) patients had a ≥50% reduction in SOC and 14 (6.1%) patients had an increase in SOC. In the no SOC subgroup, mavacamten treatment was associated with improvements from baseline to last visit in resting and Valsalva left ventricular outflow tract (LVOT) gradients, left atrial volume index (LAVI), and N-terminal pro B-type natriuretic peptide (NT-proBNP) levels (Table 1). Improvements in these parameters were also observed in the SOC discontinuation and SOC dose reduction subgroups (Table 1). In the SOC discontinuation subgroup, improvements in resting and Valsalva LVOT gradients, LAVI, and NT-proBNP levels from baseline were maintained after SOC discontinuation (Table 1). SOC medications were discontinued or reduced over a mean (range) period of 63 (9–96) and 62 (3–133) weeks, respectively. At data cut-off, left ventricular ejection fraction remained within the normal range for all patients regardless of the SOC subgroup. Patients who reduced SOC medication had small increases in heart rate (within normal range) from baseline to last visit (Table 2). Overall, blood pressure remained stable across subgroups throughout the observation period (Table 2). No patients experienced worsening of NYHA class from baseline to last visit or from withdrawal to last visit. Conclusions Beneficial and sustained effects on LVOT obstruction, NT-proBNP levels and symptoms in patients with symptomatic obstructive HCM were observed with long-term mavacamten treatment alone or after SOC discontinuation or dose reduction.

Efficacy of polyherbal formulation along with standard care of treatment in early recovery of COVID-19 patients: a randomized placebo-controlled trial

BackgroundThe coronavirus disease-2019 (COVID-19) pandemic crisis has affected millions of people worldwide. The emergence of mutant strains one after the other, breakthrough infections post-vaccination and reinfection of the virus have made it difficult to fight the pandemic and bring an end to it. Naturally available compounds with an array of phytochemicals and potent antiviral properties can provide an alternate solution in improving innate immunity, early recovery and symptomatic cure from COVID-19.ObjectiveThe present study investigates the efficacy of a polyherbal formulation, NAOQ19, on the rate of recovery and clinical improvement among COVID-19-infected patients who were not on a ventilator or in intensive care unit.MethodsA randomized placebo-controlled study design was adopted for the study. The study enrolled 124 patients with 62 patients included in the NAOQ19 arm and other 62 patients enrolled in the placebo arm along with standard care of treatment. Key outcomes of the study included improvement from COVID-19 based on RT-PCR negative test tested on day 3, 5, 7 and 10, CRP inflammatory rate and drug safety. Data analysis included intention to treat approach. Significance was accepted with a two-sided p value < 0.05 for the outcome measures.ResultsThe results of the present study demonstrated higher proportion of patients recovering in NAOQ19 arm compared to placebo arm on day 3 (33.8% vs. 8%; p < 0.001). The mean number of days required to turn RT-PCR (Real-time reverse transcriptase-polymerase chain reaction) negative was also lower in NAOQ19 arm by a day compared to placebo arm (5.4 vs. 6.2; p = 0.022). Inflammatory marker CRP (C-reactive protein) significantly reduced in the NAOQ19 arm at exit compared to placebo arm (6.25 mg/L vs. 10.26 mg/L; p = 0.048). Liver function test and kidney function test profiles were within normal limits during exit demonstrating the drug safety.ConclusionNAOQ19 along with standard care of treatment demonstrated higher percentage of population recovering from COVID-19 in comparison with those who were on standard care of treatment.Trial registration: The trial was also registered in Clinical Trial Registry India with registration number CTRI/2021/10/037423.

Abstract 18863: Clinical Assessment of Volume Status in Heart Failure is Inaccurate at Detecting Hypervolemia and Anemia as Quantified by Blood Volume Measurement

Introduction: Blood volume status is a crucial input for care decisions, especially the use of diuretics for decongestion, in acute decompensated heart failure (ADHF). In the absence of direct measurements, total blood volume (TBV) status is typically measured via clinical assessment of external fluid overload (edema, jugular venous distension, etc.), and red blood cell volume (RBCV) is assessed via hematocrit. A recent retrospective analysis showed that direct blood volume assessment (BVA) leads to better outcomes in ADHF. Hypothesis: We hypothesize that BVA-guided ADHF care can be protocolized and integrated into clinical workflow of ADHF management. Methods: The objective of this study is to prospectively compare the efficacy of standard care treatment decisions to those in a BVA-guided fluid management protocol. ADHF patients admitted to a Veterans Affairs Medical Center were randomized to either a control (n=8) or BVA-guided (n=8) arm. TBV, plasma volume (PV) and RBCV were measured at admission and prior to discharge by BVA utilizing an I-131 labeled albumin indicator-dilution technique (Daxor BVA-100). Clinician assessments of volume status were collected for all patients prior to BVA measurement. TBV status was defined relative to patient norms as: Hypovolemic (&lt; -10%), Euvolemic (-10% to +10%), Hypervolemic (&gt; +10%). RBCV status was defined as Anemic (&lt; -10%) Not Anemic (&gt; -10%). Results: Measured volume status at admission was quite heterogeneous, with 62.5% Anemic, and with 37.5% Hypovolemic, 31.25% Euvolemic, and 31.25% Hypervolemic. Clinical assessment at admission was notably inaccurate, with only 56% accuracy (sensitivity 40%, specificity 83%) on the presence of anemia, and only 31% accuracy on the presence of hypervolemia, with 94% of patients assessed by clinicians as hypervolemic. Non-hypervolemic patients in the BVA-Guided group received less diuretic treatment than non-hypervolemic controls. Conclusions: We successfully embedded a BVA guided treatment protocol into the clinical workflow of ADHF management at a large medical center. Clinical assessment of volume status was less accurate that direct BVA. Future studies will address whether BVA guided treatment leads to better outcomes in ADHF.

A Phase Ib/II Study Evaluating Navitoclax after Failure of Hypomethylating Agent and Venetoclax for Treatment of Relapsed or Refractory High-Risk Myelodysplastic Syndrome

BACKGROUND AND SIGNIFICANCE Myelodysplastic syndrome (MDS) is a heterogeneous group of blood cancers of myeloid progenitor cells. They vary widely in genetic landscape, risk of progression to acute myeloid leukemia, and risk of death, as predicted by the revised international prognostic score (IPSS-R). The hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DEC) are the standard of care for treatment of high risk (HR)-MDS, however complete response rates are &amp;lt;15% and most patients (pts) eventually progress. Outcomes after HMA failure are dismal. Defective apoptosis is a major feature of MDS. Increased expression of anti-apoptotic members of the BCL-2 family (BCL-2, BCL-X L and BCL-W) correlates with disease progression and poor outcomes. The addition of venetoclax (VEN), a selective BCL-2 inhibitor, has shown benefit when added to AZA in pts with relapsed or refractory (R/R) MDS (Zeidan, et al., AJH, 2023). However, patterns of BCL-2 family proteins are heterogeneous and response to inhibition of BCL-2 family proteins depends on the balance of pro- and anti-apoptotic proteins. Navitoclax (NAV) is a broad oral inhibitor of BCL-2, BCL-X L, and BCL-W. Increased expression of BCL-X L has been shown to make MDS cells insensitive to VEN. Further, VEN-resistant myeloid cell lines derived by prolonged VEN exposure showed up-regulation of BCL-X L, driving acquired drug resistance in these cell lines. Thus, the addition of NAV to the combination of VEN and HMA is a logical strategy to induce response in pts with R/R after HMA with or without prior VEN exposure. STUDY DESIGN AND METHODS We will perform a phase Ib/II, dose escalation and expansion study to evaluate escalating doses of NAV in combination with standard dose VEN and DEC in pts with R/R HR-MDS after failure of HMA (NCT05564650). The primary objective of the phase Ib portion of the study will be to evaluate the safety profile and determine the recommended phase II dose (RP2D) of NAV in the combination. The primary objective of the phase II portion of the study will be to evaluate the efficacy of combination therapy NAV/VEN/DEC in pts with R/R HR-MDS after failure of HMA/VEN. During cycle 1, to limit the risk of tumor lysis, pts will be treated with a short dose ramp-up with VEN 200 mg daily on day 1 and 400 mg daily on days 2-16, DEC 20 mg/m2 on days 3-7 and NAV 25 mg, 50 mg or 100 mg daily on days 3-16 during cycle 1. During cycles 2 and beyond, dosing will be similar to cycle 1 without dose ramp-up ( Figure 1). We will employ the Bayesian optimal interval (BOIN) design to identify the maximum tolerated dose and RP2D of NAV. Subsequently, the study will proceed to phase II to further evaluate the safety and efficacy of the combination. The study will enroll pts with IPSS-R ≥3 who have been previously treated with HMA/VEN. Pts in the phase I portion of the trial may be enrolled if they have not received VEN. Pts must have adequate performance status and organ function. Pts with a WBC &amp;gt;25,000 cells/µL and those taking prohibited medications will be excluded. Correlative studies will be performed to determine the impact of treatment on molecular targets and will include profiling of BCL-2 family members and single cell gene expression patterns pre- and post-treatment and at relapse. Pts who achieve a complete response (CR) or modified CR (mCR) will continue on the study until disease progression, dose limiting toxicity, availability of an alternative therapy or withdrawal of consent. Pts who have hematologic improvement but who do not attain CR or mCR can continue the study at the discretion of their treating physician in conjunction with the primary investigator.

Komet-008: A Phase 1 Study to Determine the Safety and Tolerability of Ziftomenib Combinations for the Treatment of KMT2A-Rearranged or NPM1-Mutant Relapsed/Refractory Acute Myeloid Leukemia

Background and Significance: Relapsed or refractory (R/R) acute myeloid leukemia (AML) with nucleophosmin 1-mutations ( NPM1-m) or KMT2A-rearrangment ( KMT2A-r) remain a high unmet need. Ziftomenib is a potent and selective inhibitor of the interaction between menin and mixed-lineage leukemia (MLL) lysine[K]-specific methyltransferase 2A ( KMT2A), which drives leukemogenesis in these subtypes. Preclinical data have demonstrated ziftomenib's ability to target multiple types of menin-dependent AML clones, and that the antitumor activity of ziftomenib and other menin inhibitors in cell-derived xenograft (CDX) and patient-derived xenograft (PDX) models of KMT2A-r and NPM1-m AML is enhanced by the addition of FLT3 inhibitors such as gilteritinib and quizartinib. An ongoing Phase 1/2 study (KOMET-001) in R/R AML has demonstrated that ziftomenib monotherapy is safe and well tolerated and that the clinical activity at the recommended phase 2 dose (RP2D) is robust, as the rates of response were not affected by the presence of downstream co-mutations, such as FLT3 and IDH1 or IDH2. Given the monotherapy activity seen to date, the development of ziftomenib in combination with standard-of-care (SOC) chemotherapies or FLT3 inhibitors may provide increased clinical benefit for R/R AML patients with KMT2A-r or with NPM1-m with or without concurrent FLT3-mutations ( FLT3-m) and warrants further investigation. Study Design and Methods: KOMET-008 (NCT# 05735184) is an open-label, dose escalation and expansion study to determine the safety, tolerability, and preliminary efficacy of ziftomenib when combined with SOC regimens for the treatment of either NPM1-m (Arm A) or KMT2A-r (Arm B) R/R AML. Each genetically defined arm will evaluate ziftomenib in combination with various SOC treatments in separate and independent cohorts, as outlined below: Arm A:NPM1-m R/R AML Cohort A-1: Ziftomenib plus FLAG-IDACohort A-2: Ziftomenib plus LDACCohort A-3: Ziftomenib plus gilteritinib (for NPM1-m + FLT3-m R/R AML) Arm B: KMT2A-r R/R AML Cohort B-1: Ziftomenib plus FLAG-IDACohort B-2: Ziftomenib plus LDAC The Part 1a dose escalation uses a i3+3 design, followed by dose expansion/validation in Part 1b. Key eligibility criteria include adults (≥18 years) with documented NPM1-m (±co-occurring FLT3-m) or KMT2A-r R/R AML, ECOG ≤2, prior hematopoietic stem cell transplant (HSCT) allowed, if recovered and prior gilteritinib allowed. Patients who receive an HSCT during study participation will be allowed to receive ziftomenib maintenance therapy upon recovery. The primary objectives are to establish the safety and tolerability of ziftomenib when combined with SOC therapies (ie, dose limiting toxicities, AEs per CTCAE v5.0) and to identify the RP2D of ziftomenib for each SOC combination in each genetically defined cohort. Secondary endpoints include preliminary efficacy (including MRD-negative responses and number of patients able to receive stem cell transplant) and pharmacokinetics. Exploratory end points include biomarkers for efficacy and resistance and pharmacodynamic biomarkers potentially related to the activity of ziftomenib when combined with SOC treatments in adults with R/R AML with NPM1-m or KMT2A-r.

GB261, an Fc-Function Enabled and CD3 Affinity De-Tuned CD20/CD3 Bispecific Antibody, Demonstrated a Highly Advantageous Safety/Efficacy Balance in an Ongoing First-in-Human Dose-Escalation Study in Patients with Relapsed/Refractory Non-Hodgkin Lymphoma

Introduction: GB261 is a novel and highly differentiated CD20/CD3 bispecific T cell engager antibody computationally designed to maintain Fc effector function, i.e., antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC) to broaden the mechanisms of action (MOA) for tumor cell killing. Furthermore, the “imbalanced” design of GB261 integrates de-tuned CD3 binding to reduce CRS incidence and improve safety features of the Fc effector function. Extensive pre-clinical studies have shown that GB261 has a highly advantageous safety/efficacy balance.Here, we present the preliminary clinical safety and efficacy results of an ongoing phase I/II study for GB261 (NCT04923048). Methods: This is an open-label, multicenter (China and Australia), dose-escalation/expansion phase 1/2 study of GB261 to evaluate the safety, tolerability and efficacy in patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma(B-NHL) and Chronic Lymphocytic Leukemia (CLL). Adult patients were eligible when they have CD20+ r/r B-NHL or CLL with no available standard of care treatments, adequate organ function, and no CNS involvement or other CNS disease, infections or other active/serious medical issues that may affect compliance or interpretation of results. GB261 was administered in 21-day cycles, weekly (QW) for the first 6 doses followed by every 3 weeks (Q3W) until disease progression, or other situation defined in protocol. Response assessment was based on Lugano 2014 and LYRIC 2016 criteria. Results: As of June 17, 2023, 47 r/r B-NHL patients (DLBCL:76.6%; FL:23.4%) were enrolled at flat or step-up doses of GB261 ranging from 1mg to 300 mg. Median age was 60.0 years (range: 28, 81), 55.3% of patients were male. Median prior lines of therapy were 3 (range: 1, 10). 78.7% of patients were refractory to any anti-CD20 therapy, 70.2% refractory to their last systemic therapy. Median time since last prior therapy to first study treatment was 1.9 months. In efficacy evaluable patients (n=22) from 3mg to 100mg, with at least 75% dose exposure before the first radiographic assessment, the median duration of study follow-up was 4.5 months (95%CI: 4.0, 7.4). The overall response rate (ORR) was 73% (16/22), and complete response rate (CRR) was 45.5% (10/22). ORR and CRR were 100% and 100% in 3mg, 56% and 22% in 10mg, 67% and 33% in 30mg. At 100mg dose, there were 5 evaluable patients, with ORR 100% (5/5), CRR 80% (4/5) and PR (20%, 1/5; mosunetuzumab-refractory rrDLBCL patient). Median time to response (TTR) was 1.3 months (95%CI: 1.2, 1.5), the same as median time to CR. Median duration of response (DOR) was not reached. In safety evaluable patients (n=47), the median duration of study follow-up was 4.1 months (95%CI: 2.9, 5.3). Treatment-emergent adverse events (TEAEs) were 95.7%, treatment-related adverse events were 85.1%. The most common TEAEs were COVID-19 infection (40.4%; grade 1 or 2: 27.6%; grade &amp;gt;=3: 12.8%) and neutropenia (31.9%; grade 1or 2: 14.9%; grade &amp;gt;=3: 17.0%). AE related treatment discontinuation and death were reported in 2 patients, which were all due to COVID-19 pneumonia. CRS occurred in 12.8% (6/47) patients, was mild and transient. CRS in 100mg were 14.3% (2/14). All cases of CRS were grade 1 (8.5%, 4/47) or 2 (4.3%, 2/47), no grade 3 (Lee et al., ASTCT criteria), no interruptions of treatment, and no administration of Tocilizumab. The median duration of CRS was 7 hours. No ICANS were reported. The PK profile of GB261 appeared to be linear across dose ranges tested (1mg-100mg). Effective half-life appeared to be 2-3 weeks which supports every 3-4 weeks dosing. Conclusion: GB261, a novel and highly differentiated CD20/CD3 bispecific antibody, is the first clinical stage Fc+ CD20/CD3 T cell engager. In heavily pretreated B-NHL patients, GB261 showed a highly advantageous safety/efficacy balance, consistent with the MOA. The safety profile is excellent especially for the CRS which is very mild, transient and less frequent compare with other CD20/CD3 bispecific antibodies. The response after GB261 treatment was early, deep and durable. At the 100mg dose level, 80% of patients achieved CR and with favorable safety. Additionally, clinical benefit seen in other CD20/CD3 bispecific antibody failed patients provides clinical support to the unique and differentiated MOA of GB261.