Citations

Abstract Background and study aims Limited comparative data exist to guide optimal through-the-scope (TTS) clip selection. The aim of this study was to compare the efficacy, retention, and safety of three industry-leading TTS clips on tissue that mimics common clinical scenarios. Methods A survival study involving six domestic pigs was undertaken. Three commonly used clip models were selected: Assurance (STERIS, Mentor, Ohio, United States), Resolution (Boston Scientific, Boston, Massachusetts, United States), and SureClip (Micro-Tech, Ann Arbor, Michigan, United States). To mimic clinical practice, the following scenarios were assessed: (1) normal mucosa; (2) cold snare resection; and (3) hot mucosal resection simulating fibrotic ulcers. Deployment of clips was randomized to target sites. Repeat endoscopy was performed 2 weeks following placement. Endoscopists rated the ease of use of clip placement on a Likert scale of 1 to 5. Results Fifty-four clips (18 Assurance, 18 Resolution, and 18 SureClip) were placed in six pigs. Mucosal healing was noted at all sites on follow up. Overall retention was nine of 18 (50.0%) SureClip, 10 of 18 (55.6%) Assurance, and 13 of 18 (72.2%) Resolution (P=0.369). There was no difference in clip retention on normal and cold snare resection sites; however, clip retention was significantly higher for Resolution clips on fibrotic ulcers (50.0% versus 0% for Assurance and 0% SureClip, P=0.03). No adverse events were reported. Ease of use was equivalent across all models. Conclusions All clips were equivalent in efficacy and safety with successful clip deployment and mucosal healing. Overall retention rate was low for fibrotic tissue, with an improved retention rate observed with Resolution clips.

Introduction: Next-generation sequencing (NGS) represents a promising modality for measurable residual disease (MRD) testing in patients with acute myeloid leukemia (AML), but systematic efforts are required to define the appropriate targets, test characteristics, and clinical implications. We recently reported that detection of persistent NPM1 or FLT3 internal tandem duplication (ITD) mutations in adults with AML in first complete remission (CR1) prior to allogeneic hematopoietic cell transplantation (alloHCT) is associated with increased relapse and death compared with those testing negative (JAMA 2023, PMID: 36881031). FLT3 tyrosine kinase domain (TKD) variants are present in 7-10% of adult patients with AML but the utility of this target for AML MRD testing in CR1 prior to alloHCT was previously unknown. Methods: Patients aged 18 or older who underwent alloHCT for AML in CR1 between 2013 and 2019 reported to have a FLT3-TKD variant at diagnosis and a pre-conditioning remission blood sample available in the CIBMTR biorepository were eligible for this study. Single-amplicon NGS (SA-NGS) library generation utilizing UMI-tagged primers targeting the D835 and I836 codons of FLT3 was performed on 400ng genomic DNA sequenced with unique dual indices, with error-corrected variant calling. Primary outcomes were overall survival (OS) and cumulative incidence of relapse (CIR). Secondary outcomes were relapse-free survival (RFS) and non-relapse mortality (NRM), with NRM being considered as a competing risk. Results: A total of351 patients met inclusion criteria for this study, and 342 (97.4%) had sufficient DNA for SA-NGS and were analyzed for clinical outcomes. Of these patients, 81 (23.7%) experienced relapse at a median of 5 months post-alloHCT. Using the current ELN-recommended variant allele fraction (VAF) threshold of 0.1% for NGS-based AML MRD, 14 patients (4.1%) tested positive. Patients with FLT3-TKD MRD VAF≥0.1% experienced higher rates of relapse (73.8% vs. 20.5%, p < 0.0001) and decreased OS (11.4% vs. 66.8%, p < 0.001) compared to VAF<0.1%. The highly sensitive SA-NGS method allowed for exploration to determine if a deeper VAF threshold of 0.01% (previously validated for NPM1 and FLT3-ITD in the Pre-MEASURE study) was prognostic for FLT3-TKD as an MRD target. This led to an additional 20 patients being reclassified as positive (n = 34 with VAF above 0.01%, =9.9%). However, there was no significant difference in CIR (33.6% vs. 19.7%, p = 0.089) or OS (65.2% vs. 66.9%, p = 0.267) between patients with 0.01%≤VAF<0.1% and VAF<0.01% ( Figure). Out of 28 SA-NGS positive calls, 6 could not be validated by orthogonal digital droplet PCR testing, and interestingly, none of those 6 patients experienced relapse. Site-reported pre-transplant remission multiparametric flow cytometry (MFC) was available for 335 patients (98%). Results of MFC were not associated with differences in CIR (HR 1.2, 95% CI 0.52 - 2.76, p = 0.67) or OS (HR 0.78, 95% CI 0.34 - 1.77, p = 0.551).In multivariable analysis, FLT3-TKD NGS-MRD VAF≥0.1% remained prognostic for CIR (HR 6.1, 95% CI 3.1 - 12.0, p < 0.001) and OS (HR 3.2, 95% CI 1.7 - 5.9, p < 0.001). Conclusions: Detectable persistence of FLT3-TKD variants in blood from AML patients in first remission prior to first alloHCT is rare, but at a VAF level of 0.1% was strongly associated with increased relapse and death after transplant compared to those testing negative. In contrast to FLT3-ITD NGS-MRD, no evidence was found to support lowering the NGS-MRD VAF threshold from 0.1% to 0.01% for FLT3-TKD. Alternative methodology may further improve NGS-MRD test performance. Site-reported MFC prior to alloHCT did not stratify for post-transplant relapse or survival. Optimal NGS-MRD testing for patients with AML will likely require a multi-target approach and testing for persistence of FLT3-TKD MRD is shown here to represent an important component of this strategy.

Introduction: Detection of measurable residual disease (MRD) prior to allogeneic hematopoietic cell transplant (alloHCT) in patients with acute myeloid leukemia (AML) in remission is associated with increased relapse and inferior survival after transplant. We recently reported that next-generation sequencing (NGS) detection of mutated NPM1 or FLT3-ITD in first complete remission (CR1) blood prior to alloHCT is strongly associated with increased relapse and death (PMID: 36881031). However, the prognostic implications of detecting persistence of other common AML-associated mutations at this treatment landmark remain incompletely defined. Around 20% of patients diagnosed with AML have variants in isocitrate dehydrogenase ( IDH) genes (~7% for IDH1) and clinical outcomes are known to differ due to co-occurrence of other mutations, IDH subtypes, treatment strategies, and patient factors. Studies have examined the relationship between residual IDH1 variants ( IDH1m) in CR and subsequent clinical outcomes, but definitive standardized evidence to inform decision-making for the clinical utility of IDH1m as a target for AML MRD testing was not previously available. Methods: Adult patients undergoing alloHCT for IDH1 mutated AML in CR1 at CIBMTR sites in the USA between 2013-2019 were eligible for the study if remission blood sample collected within 100 days before alloHCT and outcome data were available. Ultrasensitive error-corrected NGS (NGS-MRD) targeting IDH1, NPM1, and FLT3 genes was performed on DNA from pre-conditioning blood to identify residual variants. Detected IDH1m were validated by digital droplet PCR (ddPCR). The day of transplant was considered as day 0. Median follow-up time was calculated for censored patients. Overall survival (OS) was estimated using Kaplan-Meier (log-rank tests) and Cox proportional hazards models (forward selection); cumulative incidence of relapse was examined using Fine-Gray regression models with non-relapse mortality as a competing risk. Results: A total of 148 patients were included in the study, with a median follow-up time of 24 months. Relapse was observed in 37 (25%) patients, with the majority occurring within 1 year after alloHCT (n = 28, 76%). Pre-transplant flow cytometry results were reported by the transplant centers for 97% of patients (n = 144), but no statistically significant differences in clinical outcomes were observed between the positive and negative groups (OS: p = 0.3; relapse: p = 0.07). 53 patients (36%) tested positive for IDH1m persistence in CR1, with a 100% validation rate by ddPCR for variants with an orthogonal assay available. Logistic regression indicated that IDH1m persistence in remission was more likely to occur in patients older than 40 years (OR: 1.02 with every 1-year increase after 40, p = 0.04). Clinical outcomes showed no statistically significant difference between the pre-alloHCT IDH1m positive and negative groups (Figure 1A), and this remained true after further subgroup analysis by age. The variant allele fraction (VAF) of the residual IDH1m ranged from 0.09% to 48.5% (median: 1.5%), and no differences in clinical outcomes were observed when stratifying by high (≥2.5%) or low VAF (<2.5%). Among patients with co-mutated NPM1 and/or FLT3-ITD at baseline (n=69), those with residual mutated NPM1 and/or FLT3-ITD in pre-transplant remission had significantly higher rates of relapse compared to those with residual IDH1m only or NGS-negative groups (p = 0.01, Figure 1B). The cohort excluding patients with co-mutated NPM1 and/or FLT3-ITD did not show any significant clinical outcome differences based on IDH1m persistence. Conditioning intensity did not show an association with clinical outcomes, and multivariable analysis for overall survival and relapse did not identify residual IDH1m as an important marker. Conclusion: Detection of persistent IDH1 variants in the blood of adult patients with AML in CR1 prior to first alloHCT is common, but not associated with increased relapse or death after transplant compared with those testing negative. For those patients with IDH1 mutated AML co-mutated with either NPM1 and/or FLT3-ITD, detection of persistent NPM1 and/or FLT3-ITD was associated with higher rates of relapse. These findings, from the largest study to date, do not support the detection of isolated IDH1 variants in CR1 blood prior to alloHCT as evidence of AML MRD or increased post-transplant relapse risk.

Introduction: Detection of measurable residual disease (MRD) in AML patients during remission is associated with adverse clinical outcomes after allogeneic hematopoietic cell transplant (alloHCT), including recent strong evidence from our group regarding residual NPM1 and/or FLT3-ITD variants (PMID: 36881031). Large studies examining the significance of other potential MRD targets, including isocitrate dehydrogenase isoform 2 ( IDH2), are needed. IDH2, which is mutated in approximately 12% of AML patients, is of particular interest due to the possibility of targeted clinical intervention. Methods: Patients over the age of 18 in first complete remission (CR1) with IDH2 mutated AML undergoing alloHCT transplant at a CIBMTR site between 2013-2019 with remission blood samples within 100 days of alloHCT and available clinical data were included in this study. Residual variants in IDH2, NPM1, and FLT3genes were detected by ultrasensitive error-corrected next-generation sequencing (NGS-MRD) on genomic DNA from pre-conditioning blood and validated by digital droplet PCR (ddPCR). The primary outcomes were overall survival (OS) and cumulative incidence of relapse with non-relapse mortality as a competing risk. The day of transplant was considered as time 0, and the median follow-up time was calculated for censored patients. Kaplan-Meier estimation (log-rank tests), Cox proportional hazards models, and Fine-Gray regression models were fitted to examine the clinical outcomes. Results: Among the 257 IDH2-mutated AML patients in this study, 57 (23%) experienced relapse, with 41 events occurring within 12 months after alloHCT. The median follow-up time was 25 months. Among 247 patients with pre-transplant remission flow cytometry results reported, 25% were positive, but no difference in rates of relapse or OS was observed between positive and negative patients. NGS MRD analysis detected residual IDH2 variants in remission samples of 130 patients (51%) with variant allele fraction (VAF) ranging from 0.05-56% (median: 3%), and 100% validation by ddPCR. NGS MRD IDH2 positive patients had increased rates of relapse (p = 0.03; 3yr: +11%, 95% CI: 0.2% to 22%) and decreased OS (p < 0.001; 3yr: -25%, 95% CI: -13% to -38%) compared to those who tested negative (Figure 1A). These OS differences were still observed between NGS MRD IDH2 positive and negative patients, regardless of age stratification (under 60yr p < 0.001, 3yr: -28%, 95% CI: -12% to -43%; over 60yr p = 0.04, 3yr: -19%, 95% CI: -1% to -40%); however, only patients over 60yrs had increased rates of relapse (p = 0.007; 3yr: +21, 95% CI: 6% to 36%). The impact of co-mutation status was examined by subdividing the cohort based on the presence of NPM1 or FLT3-ITD mutations at baseline. Residual IDH2 variants in patients without baseline NPM1 or FLT3-ITD co-mutations (n = 151) were associated with decreased OS and increased relapse ( IDH2+ vs IDH2-; OS p = 0.005, 3yr: -23%, 95% CI: -6% to -40%; Relapse p = 0.01, 3yr: +19, 95% CI: 6% to 32%; Figure 1B). In contrast, residual IDH2 variants were not predictive of relapse in co-mutated patients (n=106, p = 0.5). In these patients, the only prognostic marker for relapse was NPM1 and/or FLT3-ITD MRD, with similar relapse risk between IDH2 only positive and MRD negative groups (p < 0.001; 3yr: 83% vs. 11% vs. 15%; Figure 1B). In multivariable analysis, IDH2 MRD positivity was associated with decreased OS (HR 2.5, 95% CI: 1.5-4.2, p < 0.001) and increased rates of relapse (HR 2.1, 95% CI: 1.4-5.7, p = 0.003) after adjusting for other characteristics. Conclusion: In this study, we demonstrate that adult patients with IDH2-mutated AML who have IDH2 variants detected in CR1 prior to first alloHCT experienced increased relapse rates and decreased overall survival. However, this association is significant only in patients without baseline NPM1 and FLT3-ITD mutations. In co-mutated patients, NPM1 and/or FLT3-ITD MRD serve as superior prognostic markers. Subgroup analyses show the potential influence of factors such as conditioning intensity and age on clinical outcomes. Nevertheless, larger studies with balanced subgroups and more comprehensive baseline mutational information, including IDH2 mutation subtype, are needed to better define the clinical relevance of IDH2 MRD in this context.

Background: In the past year, multiple studies have demonstrated the drastically increased risk of relapse and death in patients with Acute Myeloid Leukemia (AML) who have persistent FLT3 internal tandem duplication (ITD) mutations detectable in clinical remission by next generation sequencing (NGS). Translating this evidence into a change in clinical practice requires both widely available testing and a clear understanding of the clinical implications of FLT3-ITD detection at defined threshold levels. In the largest of the recent studies (Pre-MEASURE, PMID: 36881031), we performed FLT3-ITD MRD detection in blood DNA collected from 608 patients at the time of first remission (CR1) prior to allogeneic hematopoietic cell transplant (alloHCT). To evaluate cross-assay comparability and the impact of residual disease burden levels, we performed analysis on this cohort using a commercially available FLT3-ITD MRD NGS assay. Methods: Of the 608 patients aged 18 or older from the Pre-MEASURE study who received an alloHCT for FLT3-ITD mutated AML during CR1 at a CIBMTR reporting site in the USA between the years of 2013-2019, patients not experiencing non-relapse mortality and with sufficient DNA from pretransplant blood available were included in this analysis. A commercially available testing kit (IVS, Invivoscribe, San Diego, CA), which can detect FLT3-ITD MRD by NGS for up to 21 patients on one Illumina MiSeq flow cell, was used to establish a workflow following clinical testing standards and validated to detect ITDs down to a variant allele fraction (VAF) of at least 0.005%. Results were compared to those previously reported using an anchored multiplex PCR-based (AMP) targeted NGS assay. Overall survival (OS) and cumulative incidence of relapse were estimated with the day of transplant as time 0 using Kaplan-Meier estimation (log-rank tests) and Cox proportional hazards models. Results: A total of 451 patients were included in this study, of which 173 (38%) experienced relapse (median: 5.2 months; range 0.7-52.1) and 133 (29%) died (median: 10.7 months; range 2-53.8) post-alloHCT. The IVS assay identified 232 FLT3-ITD variants with a median VAF of 0.005% (range 0.0002-44%) and length of 51bp (range 5-228). IVS positive patients had a median of 1 FLT3-ITD variant (range 1-15) and median maximum VAF of 0.01% (range 0.0003-44%). Utilizing the same VAF cutoff of 0.01% for MRD positivity for the IVS test as used in the Pre-MEASURE study, patients testing positive prior to alloHCT exhibited higher rates of relapse (79% vs 31%, p<0.0001) and decreased survival (29% vs 77%, p<0.0001) at 3 years compared to testing negative. These results closely align with those previously reported using the AMP assay (Figure A). The IVS test has a superior limit of detection compared with the AMP test, allowing investigation of alternative VAF thresholds. In total, 151 patients (33.5%) were FLT3-ITD MRD positive by IVS of which only 75 (17%) had VAF ≥0.01%. A threshold-free approach for the IVS test improved the ability to identify patients at risk of relapse, predicting 63% of relapses within 6 months of transplant compared to 43% with the 0.01% cutoff, but resulted in decreased specificity as 42% of all positive patients relapsed within 6 months vs. 57% with the 0.01% VAF cutoff. In multivariable analysis, IVS FLT3-ITD MRD status was associated with both relapse and overall survival (Figure B). Additionally, stratifying patients by their level of residual FLT3-ITD disease burden prior to alloHCT revealed a dose-dependent increase in risk for death (Figure B) and relapse. Any detectable level of residual FLT3-ITD over 0.001% VAF exhibited increased risk, with VAFs ≥0.01% being the highest. Conclusions: In this analysis of patients with AML from the Pre-MEASURE study, we show cross-assay evidence that the detection of residual FLT3-ITD variants in pre-transplant blood during CR1 is associated with significantly increased risk of relapse and death after alloHCT. The highly sensitive assay used in this study could identify ~2/3 of patients who relapsed within 6 months and demonstrated that a dose-dependent correlation between residual FLT3-ITD level and adverse clinical outcomes exists, with VAF ≥0.01% representing the highest risk. This evidence provides strong justification for NGS-based AML MRD clinical testing for persistent FLT3-ITD prior to alloHCT to identify patients at high risk of post-transplant relapse and death.

Background Innovative restructuring of cardiac rehabilitation (CR) delivery remains critical to reduce barriers and improve access to diverse populations. Destination Cardiac Rehab is a novel virtual world technology‐based CR program delivered through the virtual world platform, Second Life, which previously demonstrated high acceptability as an extension of traditional center‐based CR. This study aims to evaluate efficacy and adherence of the virtual world–based CR program compared with center‐based CR within a community‐informed, implementation science framework. Methods Using a noninferiority, hybrid type 1 effectiveness‐implementation, randomized controlled trial, 150 patients with an eligible cardiovascular event will be recruited from 6 geographically diverse CR centers across the United States. Participants will be randomized 1:1 to either the 12‐week Destination Cardiac Rehab or the center‐based CR control groups. The primary efficacy outcome is a composite cardiovascular health score based on the American Heart Association Life's Essential 8 at 3 and 6 months. Adherence outcomes include CR session attendance and participation in exercise sessions. A diverse patient/caregiver/stakeholder advisory board was assembled to guide recruitment, implementation, and dissemination plans and to contextualize study findings. The institutional review board–approved randomized controlled trial will enroll and randomize patients to the intervention (or control group) in 3 consecutive waves/year over 3 years. The results will be published at data collection and analyses completion. Conclusions The Destination Cardiac Rehab randomized controlled trial tests an innovative and potentially scalable model to enhance CR participation and advance health equity. Our findings will inform the use of effective virtual CR programs to expand equitable access to diverse patient populations. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05897710.

Abstract Glioblastoma (GBM) is the most common primary brain malignancy in adults. Standard of care (SOC) for suspected GBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed GBM (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM, including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been initiated to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949). After surgical resection, patients will be treated with IGV-001 or placebo followed by SOC. 25 US sites have been selected with a target enrollment of 93 patients (2:1 randomization) and the study is open to enrollment. Key inclusion criteria are 18 to 70 years of age, Karnofsky performance status score ≥ 70, diagnosis of GBM based on the treating neurosurgeon's best clinical judgement, confirmed measurable disease pre-operatively, tumor located in the supratentorial compartment, and adequate bone marrow and organ function. Key exclusion criteria include bihemispheric disease, multicentric disease, or treatment with Tumor Treating Fields prior to documented progression. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include overall survival, defined as the time from randomization to death due to any cause, and safety.