Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic cancers. Cytokines play an important role in the regulation of normal and pathologic hematopoiesis. A pro-inflammatory state, described in hematopoietic malignancies, may participate in clonal selection. To identify recurrent cytokine patterns according to AML ontogenic subtypes, we quantified the concentration of 49 cytokines in the bone marrow (BM) plasma from 124 patients with AML or myelodysplastic syndrome (MDS), and from 94 healthy volunteers. We confirmed a pro-inflammatory profile in MDS and AML, with increased concentrations of CXCL8, CXCL10 and IL-6. Only a few cytokines varied when comparing AML to MDS. De novo AML subtypes carry a specific cytokine pattern dominated by the increase in CLEC11A concentrations and the decrease in FLT3 ligand concentrations. These cytokines could participate in clonal selection in this subtype of AML while being less critical in the other AMLs - i.e. secondary-like or TP53-mutated subtypes.
825 Background: Pembrolizumab (Pb) is a treatment (trt) for advanced urothelial carcinoma (aUC). In this study, we analyzed the fecal metaproteome of aUC patients (pts) to investigate the differences in the taxonomic and functional composition of the gut microbiome in responders (R) vs non-responders (NR) to pembrolizumab monotherapy as second-line trt. Methods: We designed a prospective multicenter study in France. Stool samples were collected before and nine weeks after the start of Pb, with a maximum follow-up of 36 weeks. Trt efficacy was evaluated using the Response Evaluation Criteria in Solid Tumors v1.1. Proteins were extracted from each sample and analyzed using high-resolution tandem mass spectrometry combined with liquid reverse phase chromatography. Raw data were interpreted without a priori assumptions. The R package Metacoder was used to analyze taxonomic diversity, while the mixOmics package was used to perform partial least squares discriminant analysis (sPLSDA) to reveal microbiota changes between R and NR pts. A Benjamini-Hochberg (BH)-corrected Wilcoxon test identified microbial functions with different frequencies in R and NR pts. A multivariate logistic regression analysis with Bonferroni correction was conducted to create a response-prediction classifier based on clinical variables and identified relevant microbial genera. The significance threshold was set at 5%. Results: From 2019 to 2022, 53 samples were taken from 34 different pts. Of these, 3 (8.8%) pts with complete response, 5 (14.7%) with partial response and 2 (5.9%) with stable disease were classified as R. Four (11.8%) deceased pts before response evaluation were excluded from the analysis. NR corresponded to disease progression in 20 pts (58.8%). No dysbiosis was detected. There were no statistically significant differences in alpha diversity over time or between R and NR. Beta diversity index showed microbiome stability at individual level during follow-up. sPLSDA at the genus level pooling all samples (before and after trt) showed a distinctive separation between R and NR (p ≤ 0.05). Of the genera contributing most to this separation, 4 genera were identified using logistic regression: Anaerostipes, Sutterella, Escherichia, Evtepia (adj. p ≤ 0.05). Functional composition analysis identified 31 signaling pathways that differ between R and NR. These signaling pathways were clustered highlighting 7 functions that differed between R and NR when modulated by Pb. Host function analysis identified the “response to external biotic stimuli” signaling pathway significantly associated to R (BH adj p-value ≤0.05). Conclusions: The composition of the gut microbiome and metabolic functions differed between R and NR pts with aUC under Pb. The genera Anaerostipes , Sutterella, Escherichia and Evtepia could be biomarkers for the efficacy of pembrolizumab. Clinical trial information: NCT03584659 .
514 Background: Locoregional management of early stage breast cancer (BC) has evolved from maximal tolerable to minimal effective therapies. Significant advancements in radiation therapy (RT), such as limited target volumes and hypofractionation, have led to accelerated partial breast irradiation (APBI). This study reports on toxicity and cosmetic outcomes of APBI in post-menopausal women with unifocal pT1-N0-M0 invasive BC. Methods: The SHARE trial (NCT01247233) is a non-inferiority, multicenter, randomized trial comparing local control of APBI versus Whole Breast Irradiation (WBI). Eligible patients were postmenopausal women over 50 years who had lumpectomy with surgical margins > 2mm. Only patients who had at least 4-5 clips placed in the tumor bed during surgery were eligible. Patients were randomized to receive either WBI (50Gy in 25 fractions (fr) with optional 16Gy-boost or 40Gy in 15 fr, or 42.5Gy in 16fr) or APBI (38.5Gy or 40Gy in 10fr twice daily). Primary endpoint was local recurrence. Secondary endpoints included grade >2 toxicity (NCI-CTCAE-v4) and cosmetic outcomes (good/excellent versus intermediate/poor) evaluated by both patients and doctors, over the follow-up time. We estimated the cumulative incidences (CI) using the Kalbfleisch-Prentice method due to competing events, and cause-specific Hazard Ratios (cs-HR APBI/WBI ) from Cox models adjusted on stratification factors. Results: Among 1006 patients (503 per arm) enrolled between December-2010 and July-2015, with a median follow-up of 5.8 years, 28 deaths and 11 local recurrences were reported. The risk of severe toxicity appeared significantly reduced in the APBI-arm when considering all type of toxicity (cs-HR APBI/WBI =0.74, [95%-CI: 0.61-0.89], p=0.001; 3-year CI=45% [41-49] in WBI vs 36% [32-40] in APBI), or only breast skin toxicity (cs-HR=0.55 [0.44-0.70], p<0.001; 3-year CI=36% [32-40] vs 21% [18-25], respectively). Conversely, for non skin breast toxicities, WBI was less toxic: cs-HR APBI/WBI =2.06 (1.49-2.86), p<0.001). We observed no significant difference of patient-reported cosmetic results: cs-HR APBI/WBI =1.08 (0.85-1.37), p=0.54. Findings were similar for doctor-evaluated results. Rib fractures incidence was nearly double in APBI compared to WBI. Conclusions: The SHARE trial showed that APBI is associated with reduced severe and skin-related toxicities compared to WBI, with no significant difference in cosmetic outcomes. Conversely, WBI was less toxic concerning non-skin breast toxicity, mainly breast fibrosis. The question that currently remains open on a practical level is how to consider APBI in the context of the widespread adoption of the “Fast Forward” regimen for patients at low risk of recurrence. Clinical trial information: 2010-A00243-36 .
Abstract Background Risankizumab (RZB) is an anti-IL23 monoclonal antibody blocking the p19 subunit, whose recent Phase 3 trial demonstrated its efficacy in CD. Compassionate use has been possible since December 2019. The aim of this study was to investigate whether RZB and IL22 levels correlated with deep remission. Methods Any CD patient receiving RZB (compassionate use) was eligible for the study. All patients were treated with a regimen of RZB (600mg W0, W4 and W8) followed by 360 mg/sc every 8 weeks from W12. Patients with other dosing regimens were excluded. Before each infusion or SC injection, fecal calprotectin, CRP, RZB levels (ELISA ; Theradiag) and IL-22 levels (ELLA automated system; Biotechne). Clinical and biochemical remission was defined by a clinical score (CDAI) < 150 with fecal calprotectin < 250 µg/ml and CRP < 5 mg/l. Results 28 patients on failure to anti TNF, vedolizumab and ustekinumab (mean age: 44 years, sex ratio M/F: 1.3) with 95 RZB maintenance samples (360mg/sc every 8 weeks) were eligible. For 44 RZB samples (46%), patients were in clinical and biochemical remission . Patients with clinical and biochemical remission had higher mean RZB levels than patients without clinical and biochemical remission (21.6 +/-13.3 versus 7.4+/-6.4 µg/ml; p=0.001). Biochemical and clinical remission rates were significantly higher in the highest RZB quartiles (p=0.01) (Figure 1). Area under the curve analysis (AUC: 0.93; p<0.001) isolated a RZB threshold significantly associated with clinical and biochemical remission: 11.5 µg/mL (sensitivity: 81.8%, specificity: 80.3%, PPV: 78.2%, NPV: 83.6%, accuracy: 81%.) . The progression-free survival curves towards loss of clinical and biochemical remission were significantly more favorable in the group of patients with RZB levels > 11.5µg/mL (p=0.03) . In univariate and multivariate analysis, only RZB level was isolated as a factor associated with clinical and biochemical remission: HR: 1.36 (CI95: 1.05-1.35), p=0.001). Conversely, albumin, CRP, albumin and other patient variables were not significantly associated with deep remission. The IL22 levels are not statistically significantly different between clinical and biochemical remission or not (respectively, 10.4 pg/mL (4.2-17.2) vs 8.6 pg/mL (4.3-16.2); p = 0.73) Conclusion RZB levels are significantly higher in clinical and biochemical remission CD. A threshold of 11.5µg/mL predicts clinical and biochemical remission in CD and is associated with significantly better progression-free survival. Conversely, IL22 levels are not associated with clinical and biochemical remission. However, these results are in a limited patient population of those receiving compassionate use therapy.
