Citations

7006 Background: Measurable residual disease (MRD) prior to allogeneic hematopoietic cell transplantation (alloHCT) is associated with increased relapse and death in patients with acute myeloid leukemia (AML) in cytomorphological complete remission (CR). We recently demonstrated AML MRD detected in pre-alloHCT blood by DNA-sequencing was associated with increased relapse and decreased overall survival in patients randomized to reduced intensity conditioning (RIC) versus myeloablative conditioning (MAC). The clinical utility of such ultra-deep next-generation sequencing (NGS-MRD) had not yet been reported in a large multi-center cohort. Methods: Patients aged 18 or older who underwent first alloHCT between 2013-2017 for AML in first CR (CR1), reported to be FLT3, NPM1, IDH1, IDH2 and/or Kit mutated at diagnosis, with a pre-conditioning remission blood sample available in the CIBMTR biobank were eligible for this study. Ultra-deep anchored multiplex PCR-based NGS-MRD for the above mutations was performed on 500ng gDNA with error-corrected variant calling as previously described. The pre-specified statistical analysis plan was registered on OSF. Results: Of 457 patients with a sample available, 448 had sufficient clinical annotation and DNA for analysis. 147 of these 448 patients (33%) experienced relapse at a median of 5.6 months post-alloHCT. NGS-MRD was positive in 129 pre-alloHCT patient samples (29%), averaging 1.35 mutation(s)/patient (range: 1-4). 173 mutations were detected with a median VAF of 0.18% (range: 0.0054-62%), most frequently FLT3-ITD (n = 43 patients), NPM1 (n = 48), and IDH2 (n = 46). Testing positive by NGS-MRD prior to alloHCT was associated with a 3yr RFS of 36% (95% CI: 28-45%) compared with 56% (51-62%) in those testing negative (p < 0.001). Detection of NPM1 and/or FLT3-ITD mutations prior to alloHCT was associated with a 3yr relapse probability of 55% (43-67%) and RFS of 26% (16-37%). NGS-MRD impact was modified by conditioning intensity: positive patients receiving RIC/NMA had the highest relapse of 57% at 3yr, testing negative followed by RIC/NMA had the same relapse rate at 3yr (35%) as those who tested positive but received MAC (p < 0.001). At three years, those positive for FLT3-ITD and/or NPM1 mutations prior to RIC/NMA alloHCT had a relapse probability of 67% (50-83%) with a RFS of 19% (8-33%). HR for relapse if NGS-MRD positive pre-alloHCT in CR1 was 2.3 (p < 0.001, 95% CI 1.6-3.1) when adjusting for conditioning intensity and age group. Conclusions: In this largest cohort of NGS-MRD testing prior to alloHCT for AML reported to date, we confirm the ability to identify patients in CR1 but at high-risk of subsequent relapse. This evidence provides the foundation for future precision medicine approaches to reduce post-transplant AML relapse.

763 Background: Non-invasive biomarkers with high sensitivity and specificity would be of great value for patients with Pancreatic Ductal Adenocarcinoma (PDAC). This would aid in early detection and serve other purposes that 'liquid biopsies' are being explored in. Besides circulating tumor DNA (ctDNA) and methylation markers, glycosylation markers hold great potential promise. We developed a novel workflow using high-resolution quantification of site-specific protein glycosylation by liquid chromatography and tandem mass spectrometry to evaluate the clinical utility of glycoprotemics signature for patients with PDAC. Methods: Serum samples from newly diagnosed PDAC patients and controls were obtained from a commercial biobank (Indivumed, Hamburg, Germany), and a panel of 504 glycan motifs, representing 73 previously reported proteomic markers, was determined. Age-adjusted generalized linear regression models were used to evaluate the differential abundance of each marker, and stepwise variable selection was used for model construction. Results: We analyzed 45 PDAC and 136 control samples. PDAC patients (60% male) had a mean age of 67 (±11) years. with 4.4%, 71.1%, 4.4%, and 20% at stage 1, 2, 3,4, respectively. Controls were women with benign histology after pelvic mass surgery; with a mean age of 61 (±11) years. Twenty-six glycoproteomic markers showed statistically highly significant differential abundance among cases and controls (p<1e-4 each) and were highly reproducible(Pearson’s r > 0.85), which were glycoforms in proteins that have previously been found to be associated with PDAC. Fourteen of these markers displayed >0.8 area under the curve of the receiver operating characteristic (AUC). Multivariate logistic regression modeling with backward selection yielded a classification model with an AUC of 0.94 (95% CI: 0.89-0.99), sensitivity of 91% (95% CI: 75-97%) and specificity of 86% (95% CI: 81-92%). Conclusions: Circulating glycoproteomic biomarkers may be useful in the early detection and clinical management of PDAC patients; offering a new platform to explore and validate.