Predict Disease Relapse Research Articles

Impact of positive CD4 cells on event-free survival in follicular lymphoma patients.

Previous results about prognostic value of CD4+ T cells in follicular lymphoma (FL) remain controversial. Immunohistochemistry was used to examine expression of positive CD4 cells in 103 patients with FL 1-3A. Early failure was described as failing to achieve event-free survival (EFS) at 12 or 24 months. There were 49 (47.6%) male and 54 (52.4%) females, with a median age of 54 years. Compared to patients with <20% of positive CD4 cells, patients with ≥20% of positive CD4 cells exhibited a significant lower risk of early failure (2-year EFS rate: 56.7% vs 73.5%, p = 0.047). When patients were stratified based on positive CD4 cell combined with FLIPI, the median EFS (p = 0.002) and median OS (p = 0.007) were significantly different. This study demonstrated that higher expression of positive CD4 cells predicts lower risk of early failure in follicular lymphoma, and combination analysis of CD4 and FLIPI could better predict disease relapse and survival outcome.

Revealing the distinct clinical patterns and relapse risk factors in seronegative IgG4-RD patients: A retrospective cohort study over a decade.

Our study aimed to investigate the distinct clinical patterns of seronegative IgG4-related disease (IgG4-RD) patients. We retrospectively enrolled 698 treatment-naïve IgG4-RD patients in this study. Patients were divided into four different subgroups according to their baseline serum IgG4 levels. The distinct clinical patterns of seronegative IgG4-RD patients were revealed through the comparison of baseline clinical data and disease prognosis among the different subgroups. COX regression analyses were used to investigate the risk factors for disease relapse and to construct the nomogram model. Seronegative IgG4-RD patients account for a minority of IgG4-RD patients (49/698, 7.02%). The proportions of seronegative IgG-RD patients in our study and several Asian cohorts were significantly lower than those of the European and American cohorts. Seronegative IgG4-RD patients got lower serum IgG levels (p<0.0001), lower eosinophil count (p<0.0001), lower serum IgE levels (p<0.0001)), lower IgG4-RD responder index (RI) scores (p<0.0001), and fewer affected organ numbers (p<0.0001) compared with other subgroups, whereas they were more likely to manifest fibrotic type with some special organ involvement. Younger age at onset, GCs monotherapy, elevated C-reactive protein level, and elevated erythrocyte sedimentation rate level are the risk factors for the disease relapse of seronegative IgG4-RD patients. An effective nomogram model predicting disease relapse of seronegative IgG4-RD patients was constructed. Seronegative IgG4-RD patients with scores >84.65 at baseline were susceptible to suffering from disease relapse. Distinct clinical features and multiple risk factors for disease relapse of seronegative IgG4-RD patients have been revealed in this study. A nomogram model was constructed to effectively predict disease relapse during the follow-up period.

Abstract PO4-03-03: Conditional Use of Serial Serum Tumor Markers CA 15.3 and CEA as Predictors of Disease Relapse in Patients with High-Risk Early-Stage Breast Cancer

Abstract Background: Because of the diagnosis at an earlier stage, and the wider availability of more effective therapies, treatment outcomes of patients with breast cancer are getting much better resulting in an increasing proportion of patients surviving their disease, however, a significant percentage of patients with early-stage disease at initial diagnosis may eventually relapse. Residual tumor cells can remain dormant for many years before causing tumor recurrence. Physical examination and mammography are strongly recommended in surveillance guidelines, but data on routine blood tests or imaging is lacking. The revolution made in recent years, following the approval of novel targeted and immunotherapy agents, may have better outcome if started earlier in the disease course with the lowest tumor burden and in patients with good performance status and adequate organs’ function. Additionally, early detection of oligometastatic disease can give a chance for cure for a subset of these patients. Levels of CA15.3 and CEA are used in decision making in the metastatic setting but their role in surveillance is still controversial. We aim to investigate whether serial measurement of tumor markers, when it correlates with tumor bulk (conditional), can detect early asymptomatic recurrence among subset of patients with high-risk early-stage breast cancer. Methods: Patients with high-risk early-stage breast cancer were invited to participate. High-risk features include any of the following: large tumor size (T3/4), grade-3, node-positive, triple-negative, HER2-positive or hormone receptor (HR)-negative disease. Patients were considered eligible if they have elevated CA15.3 and/or CEA at baseline, that subsequently normalize 6 weeks after surgical resection; upfront or following neoadjuvant chemotherapy. Serial testing of the elevated CA15.3 and/or CEA is done every 2 months thereafter, samples are cryopreserved and will not be processed until disease relapse. As such results will not be used for clinical decisions. The study is still ongoing, we here present an interim analysis evaluating the correlation between certain tumor characteristics and elevated serum marker(s) levels. Results: Since the launch of the study, 367 patients deemed high-risk by the above criteria, accepted to participate. Abnormal baseline CA15.3 and/or CEA was found in 110 (30%); 65 (18%) patients had elevated CA 15.3 while elevated CEA was found in 45 (12%) patients. Abnormal CA 15.3 was found in 27% of cases with T3/4 disease compared with 13% in T1/2 disease (p=0.001), and in 21% of node positive disease versus 7% in node negative disease (p=0.002), in 9% of HR negative disease versus 20% in HR-positive (P=0.038). Tumor grade and HER2 status were not associated with significant difference. Regarding CEA, abnormal levels were detected in 24% of HER2-positive disease compared to 5% of HER2-negative disease (P&amp;lt; 0.0001). Other tumor features were not associated with significant difference. Conclusions: Only a third of patients with high-risk early-stage breast cancer had high level of serum tumor markers at initial diagnosis and thus such markers may correlate with tumor presence. Large tumors (T3/4) and node positive disease were associated with high CA15.3 but not CEA. HER2-stutus and tumor grade had no effect on CA15.3 level, while HER2 positive disease correlated well with high CEA. Citation Format: Sarah Edaily, Baha' Sharaf, Maher Sughayer, Lina Yousef, Hala Abu-Fares, Sarah Abdel-Razeq, Hala Abu-Jaish, Mahmoud Abunasser, Suhaib Khater, Anas Zayed, Osama El Khatib, Rahaf Rahal, Hazem Abdulelah, Maria Shraim, Hikmat Abdel-Razeq. Conditional Use of Serial Serum Tumor Markers CA 15.3 and CEA as Predictors of Disease Relapse in Patients with High-Risk Early-Stage Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-03-03.

Effects of Thiopurine Withdrawal on Vedolizumab-Treated Patients With Ulcerative Colitis: A Randomized Controlled Trial

Background and aimsThe impact of thiopurine de-escalation whilst on vedolizumab versus continuing thiopurine therapy in ulcerative colitis (UC) is unclear. We aimed to determine the effect of thiopurine withdrawal for patients with UC in remission on vedolizumab. MethodsThis multi-centre randomized controlled trial recruited UC patients on vedolizumab 300mg IV every 8 weeks and a thiopurine. Patients in steroid-free clinical remission for ≥6 months and endoscopic remission/improvement (Mayo endoscopic subscore[MES]≤1) were randomized 2:1 to withdraw or continue thiopurine. Primary outcome was comparing week 48 vedolizumab trough concentrations. Secondary outcomes were clinical relapse (partial Mayo score≥3 and fecal calprotectin>150μg/g or increase in MES≥1 from baseline), fecal calprotectin remission (<150μg/g), C-reactive protein remission (<5mg/L), centrally-read endoscopic remission (MES=0), histologic remission (Nancy index=0), histo-endoscopic remission and adverse events. ResultsIn total, 62 patients were randomized to continue (n=20) or withdraw (n=42) thiopurine. At week 48, vedolizumab trough concentrations were not significantly different between continue and withdrawal groups (14.7μg/mL [IQR:12.3-18.5μg/mL] versus 15.9μg/mL [IQR:10.1-22.7μg/mL] respectively, P=0.36). The continue group had significantly higher fecal calprotectin remission (95.0% [19/20] versus 71.4% [30/42], P=0.03), histologic remission (80.0% [16/20] versus 48.6% [18/37], P=0.02) and histo-endoscopic remission (75.0% [15/20] versus 32.4% [12/37], P=0.002) than the withdrawal group. Histological activity (HR:15.5 [95%CI:1.6-146.5],P=0.02) and prior anti-TNF exposure (HR:6.5 [95%CI:1.3-33.8],P=0.03) predicted clinical relapse after thiopurine withdrawal. ConclusionThiopurine withdrawal did not affect vedolizumab trough concentrations. However, it may increase fecal calprotectin, histologic and histo-endoscopic activity. Histological activity and prior anti-TNF exposure may predict disease relapse upon thiopurine withdrawal for patients using vedolizumab for UC; Australian and New Zealand Trial Registry, number ACTRN12618000812291.

Abstract LB346: Dynamic changes in the tumor microenvironment from initial diagnosis through sequential therapies in patients with large B cell lymphoma undergoing axicabtagene ciloleucel (axi-cel) treatment

Abstract Axicabtagene ciloleucel (axi-cel), marketed as YESCARTA®, is an approved autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory large B cell lymphoma patients following one prior therapeutic intervention. The pivotal ZUMA-1 trial (NCT02348216), a Phase 1/2 multicenter study, reported an impressive 83% objective response rate and a robust 58% complete response rate at 5 years (Locke et al., Lancet Oncol. 2019). Subsequently, ZUMA-7 (NCT03391466), a Phase 3 multicenter trial focusing on patients with one prior systemic therapy, demonstrated comparable outcomes with an 83% objective response rate and a remarkable 65% complete response rate at 2 years (Locke et al., Lancet Oncol. 2022). Previous studies have highlighted the crucial connection between the tumor microenvironment (TME) and CAR T-cell therapy outcomes. Notably, the pre-treatment tumor immune contexture has been proposed as a major determinant of clinical outcomes in ZUMA-1 and ZUMA-7 patients (Scholler et al., Nature Medicine 2022; Locke et al., Nature Medicine, in press; ASH2023 oral presentation #226). This study aims to provide novel insights into the dynamic changes in the TME from initial diagnosis through sequential therapeutic interventions in large B-cell lymphoma patients treated with axi-cel. Utilizing multiplex immunohistochemistry (Brightplex®), we analyzed 165 commercial tumor biopsies (at diagnosis), 100 ZUMA-7 samples (40 at diagnosis, 60 after 1 prior therapeutic line), and 35 ZUMA-1 samples (20 pre- and 15 post-CAR T infusion). Three Brightplex® assays were developed to assess T-cell (CD3 CD8 FOXP3 TIM3 PD1 LAG3 GZMB) and macrophages infiltration (CD68 CD64 CD163 CD204 CD206 PDL1), along with single staining for the NK cell marker, NKP46. Our findings revealed significant changes and evolution from diagnosis through post-axi-cel infusion: a significant decrease in lymphocyte levels (cytotoxic, helper, and regulatory, with p-values of 0.042, 1.3e-05, 0.024, respectively), a notable decrease in M1 macrophages proportion (p-value=5.8e-06), and a substantial increase in M2 macrophages proportion (p-value=4.5e-10) across different lines of standard care therapy. Importantly, high baseline proportions of protumor M2 macrophages may serve as predictors of disease relapse post-axi-cel treatment, while low baseline M2 proportions could be associated with a complete response. This comprehensive characterization of the immune contexture provides crucial insights to better highlight TME modification depending on the line of therapy, and further correlative analysis of cell subsets will be presented, contributing to a deeper understanding of treatment impact on the TME in large B cell lymphoma. Citation Format: Michael Mattie, Regis Perbost, Aurelie Auguste, Sarah Turcan, Jenny J. Kim, Christina To, Jenny Nater, Simone Filosto, Rhine R. Shen, Jérôme Galon. Dynamic changes in the tumor microenvironment from initial diagnosis through sequential therapies in patients with large B cell lymphoma undergoing axicabtagene ciloleucel (axi-cel) treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB346.

Abstract 4136: Tracking metastatic dissemination and tumor growth using longitudinal imaging and ctDNA

Abstract Metastatic lung cancer is a heterogeneous disease, characterized by different patterns of clinical progression and therapy response. The scale of this heterogeneity on a lesion specific level has yet to be quantified but is of clinical importance because it may provide an indication of molecular mechanisms underpinning metastasis growth. Currently, whether metastasis growth patterns can be predicted by the primary tumor or governed by metastasis specific characteristics is not known. Furthermore, circulating tumor DNA (ctDNA) has proven useful to predict disease relapse, but how closely it reflects metastatic growth post relapse is unclear. In 104 patients enrolled in the TRACERx study with disease relapse post-surgical resection of the primary tumor, lesion volumetric dynamics were tracked in 460 metastases. Total volume growth rate (TVGR) was calculated using CT imaging performed between disease relapse and death. All patients had whole exome sequencing (WES) of the primary tumor. For 19 patients enrolled in the PEACE autopsy study WES and RNAseq from 60 metastases visible on imaging prior to death and subsequently sampled at autopsy were analyses. In 29 patients, ctDNA was used to track 200 tumor-specific mutations to assess tumor burden and detect metastatic subclones. High TVGR correlated with poor survival (hazard ratio for death 1st vs 2nd tertile was 0.21, p&amp;lt;0.001; 2nd vs 3rd tertile was 0.51, p=0.04). Primary tumor subclonal whole genome doubling was predictive of high TVGR. There was considerable heterogeneity in the growth rate of metastases within patients. The anatomical location of metastases contributed to this, extrathoracic soft tissue and pleura had the highest growth rates, whilst lymph node and adrenal the lowest (p&amp;lt;0.001). Molecular attributes differed between metastases, with fast growing metastases being enriched for proliferation pathway gene expression. It was observed that the most prevalent population of cells, or clone, in the fastest growing metastasis within a patient was exclusive to that metastasis, suggesting that genomic features that characterize the clone might support rapid growth. ctDNA tracked with tumor burden post relapse and patients with extrathoracic relapse had higher levels of ctDNA. In 9 patients, metastasis specific mutations identified at autopsy and in ctDNA, were used to determine the proportion of ctDNA shed by different metastatic sites. ctDNA subclonal fraction was found to track with changes in lesion volumes during disease progression. This work highlights significant heterogeneity in metastatic growth rates which can potentially be attributed to the presence of distinct genomic features which may dictate tumor growth rate. ctDNA accurately reproduces patterns of radiological disease progression and when combined with longitudinal imaging and tumor DNA sequencing, can accurately reconstruct the natural history of cancer evolution. Citation Format: Wing Kin Liu, Boyue Ding, Hessey Sonya, Carlos Martinez-Ruiz, Cristina Naceur-Lombardelli, Corentin Richard, Hyothaek Lee, Catarina Veiga, Kishen Patel, Ariana Huebner, Allan Hackshaw, Christopher Abbosh, Alexander M. Frankell, Gary Royle, Charles Swanton, Mariam Jamal-Hanjani. Tracking metastatic dissemination and tumor growth using longitudinal imaging and ctDNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4136.

P066 Serum amyloid A – A Novel Biomarker of Ulcerative Colitis Disease Activity

Abstract Background Despite recent advancements in the treatment of ulcerative colitis (UC), a substantial number of patients fail to achieve long-term remission. Persistent histological activity has been linked with poorer treatment outcomes. Histological remission is now an accepted treatment target; however there remains significant variability in the interpretation of UC histology. As such, there is a need for novel biomarker identification to aid assessment and ultimately predict disease relapse. Serum amyloid A (SAA) is an acute-phase protein, of which serum levels have shown promise as a biomarker in IBD1. This study aims to explore the utility of SAA levels in UC colonic tissue as a diagnostic biomarker for disease activity and progression. Methods Two cohorts were prospectively recruited, including healthy controls and UC patients. Sigmoid biopsies were collected and tissue explants generated. Tissue-conditioned media from these explants was collected and secreted SAA quantified using 54 V-plex ELISA. Demographic information, disease characteristics, endoscopic Mayo scores and disease progression were documented. Endoscopic remission was defined as a Mayo endoscopic sub-score ≤1. Disease progression was defined as the requirement for corticosteroid therapy, UC-related hospitalisation, UC-related surgery or the introduction of a new immunomodulatory agent in follow-up period. P values &amp;lt;0.05 were considered significant in analyses. Results The two cohorts included 11 healthy controls and 16 UC patients (endoscopic remission n=6). Active UC patients demonstrated significantly higher SAA concentrations than healthy controls (p=0.0013) and those in endoscopic remission (p=0.02). There was no significant difference in SAA concentrations between healthy controls and UC patients in remission (p=NS). UC patients in the lowest SAA concentration quartile had a significantly longer time to disease progression (p=0.0462) (Figure 1). Conclusion Quantification of SAA secretion in IBD ex-plants has potential as a biomarker of UC activity and progression. Further investigation of SAA as a biomarker in IBD is warranted.

Macrophage migration inhibitory factor: A noval biomarker upregulates in myasthenia gravis and correlates with disease severity and relapse

ObjectiveTo explore the relationship between macrophage migration inhibitory factor (MIF) and disease severity and relapse in patients with myasthenia gravis (MG). Methods145 MG patients including 79 new-onset patients, 30 remission patients and 36 relapse patients were enrolled in this study. The detailed characteristics of all enrolled MG patients were routinely recorded, including gender, age, type, MGFA classification, antibody, thymic status, clinical score, treatment, MGFA-PIS and B cell subsets (memory B cells, plasmablast cells and plasma cells) detected by flow cytometry. Serum MIF levels were measured by enzyme-linked immunosorbent assay (ELISA) kit. The correlation of MIF levels with clinical subtypes, disease severity and B cell subsets were investigated. Moreover, logistic regression analysis was applied to assess the factors affecting relapse of generalized MG (GMG). ResultsSerum MIF levels were higher in new-onset MG patients than those in controls and were positively associated with QMG score, MGFA classification and memory B cells. Subgroup analysis revealed that MIF levels were increased in GMG patients than in ocular MG (OMG), as well as elevated in MGFA III/IV compared with MGFA I/II. With the remission of the disease, the expression of serum MIF decreased. The multivariate logistic regression models indicated that high MIF and thymoma was a risk factor for relapse of GMG, and rituximab could prevent disease relapse. ConclusionsMIF can be used as a novel biomarker to reflect disease severity and predict disease relapse in MG patients.

Pre- and Post-Treatment Immune Contexture Correlates with Long Term Response in Large B Cell Lymphoma Patients Treated with Axicabtagene Ciloleucel (axi-cel)

Background: Axi-cel is a US and EU-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for pts with relapsed/refractory large B cell lymphoma after 1 prior therapy as a result of ZUMA-7 (NCT. In ZUMA-1 (NCT02348216), the pivotal study which initially led to the approval of axi-cel in the 3L+ setting, the objective response rate was 83% (58% complete response rate; Locke et al. Lancet Oncol. 2019) and at 5 years follow up an OS rate of 42.6%, 5 years durable response and 5 years disease specific survival at 51% ( Neelapu et al. Blood 2023). T cell-related biology (Immunosign 21; Immunoscore®IC) measured pretreatment in the tumor microenvironment (TME) was associated with response to axi-cel ( Scholler et al., 2022). Increased density of activated PD-1+LAG-3+/−TIM-3−CD8+ T cells, measurable pretreatment, facilitates clinical response in pts post-axi-cel. This expanded analysis characterized the impact of axi-cel treatment on the TME immune contexture and examined associations between immune cell subsets and relapse. Methods: Baseline and post-infusion tumor biopsy samples were analyzed by multiplex immunohistochemistry ( Brightplex®). Four panels were developed and applied to assess T cell infiltration (CD3 CD8 FOXP3 TIM3 PD1 LAG3 TOX), regulatory T cell subtyping (CD3 CD8 GATA3 TBET RORg BCL6), T cell activation &amp; exhaustion (CD3 CD8 TIM3 LAG3 PD1 GZMB KI67), macrophage (CD68 CD64 CD163 CD204 CD206 PDL1) and MDSC (CD3 CD11B CD68 CD14 CD15 LOX1 S100A9) subsets. Transcriptomic analysis was performed using nCounter® Pan Cancer panel. The association between T cell subtypes and macrophages cell subset density, and probability to relapse was evaluated. T test values were based on Brightplex analysis. Results: 34 tumor biopsies (16 at baseline, 18 post-infusion) from 26 pts were analyzed including 11 relapsed (6 CR/5 PR) and 15 durable response (15 CR). The baseline and post-infusion TME comprised all major macrophages, MDSC and T cell subsets, with diverse distribution across samples analyzed. Low proinflammatory M1 macrophage density was observed at baseline and post-infusion across patients. In relapsed patients, baseline tumors were enriched with a significantly higher proportion of protumoral M2 macrophage (p&amp;lt;0.0001). A shift of M1-M2 polarization was observed between baseline and post-infusion (Baseline 33%M1M2 / 65%M2, post infusion 76%M1M2 / 21%M2, p&amp;lt;0,0001) across the cohort. In contrast, in relapsed patients, M-MDSC cell density was significantly increased post treatment (p=0.0420). In addition, Innate lymphocyte cells subtype 2 (ILC2) cell density, previously described to be positively correlated with improved overall survival in CRC ( Huang et al. 2021 Cancers), was significantly decreased in relapsed patients post infusion (p=0.019).Post-infusion, durable response was associated with a significant increase in pan-Macrophages (p=0.0360) and cytotoxic T cell subset densities: CD8 naïve T cells (p=0.016); Activated Cytotoxic T cell (GZMB+)(p=0.0203); PD1+TIM3+LAG3- cytotoxic T cell (p=0.0117); CD8 regulatory T cell (FOXP3+)(p=0.012). Regarding T helper lineage, ongoing response was associated with a significant increase of: CD4 naïve T cells (p=0.021); T helper Th2 (p=0.020); cytotoxic T lymphocyte TC2 and TC1/TC2 cell densities (respectively p=0.0052 and 0.011).Additional characterization of the immune contexture and correlative analysis of cell subsets will be presented. Conclusion: These results suggest that baseline proportions of protumor M2 macrophages may predict disease relapse after axi-cel treatment. Following infusion, relapse is also associated with spatial enrichment of M-MDSC, whereas durable response is related to increases in T cell subpopulation densities inclusive of cytotoxic T cells, T helper, TC1/TC2 ratios and innate T-subpopulations. These findings suggest that axi-cel treatment drastically impacts tumor immune mobilization, infiltration and contexture, which correlates with long term response.

Factors Associated with Refractoriness or Relapse after Varnimcabtagene Autoleucel (IMN-003A) in Patients with Relapsed Refractory B Cell Malignancies: Phase 2 First-in-India Industry (IMAGINE) Study

Background: Varnimcabtagene autoleucel (IMN-003A) is an anti-CD19 CAR-T cell immunotherapy for patients with relapsed refractory B cell malignancies (RR BCM) in the Phase 2 IMAGINE study. Some patients (pts) do not respond or relapse early after CD19 directed CAR-T cell therapy. This abstract reviews the factors associated with disease relapse to help improve patient outcomes and development of novel strategies. Methods: Patients (pts) aged 3 to 45 years (B-ALL) and ≥ 18 years (B-NHL) with RR BCM were eligible for IMAGINE study if they had measurable disease, as assessed by lymphoid blasts (B-ALL) or metabolic tumour bulk (B-NHL), received ≥1 prior regimen, refractory to the last line of treatment with good performance status (ECOG 0 to 1). Multiple characteristics for disease progression were reviewed (n=36) and risk stratified as: 1) Baseline parameters (age, lines of treatment, bridging therapy, cytogenetics, blasts, total metabolic tumour volume (TMTV), sum of perpendicular diameter (SPD), refractory, relapse within 6 months, laboratory parameters - haemoglobin, neutrophil count, lymphocyte count, platelet count, CRP, LDH, ferritin, baseline interleukin-6 (IL-6), baseline total T cells, CD4, and CD8 subsets in peripheral blood); 2) Apheresis parameters (total T cells, naïve / central memory in CD4 and CD8 subsets); 3) Final Product characteristics [total CAR+ cells, naïve / central memory in CD4 and CD8 subsets, CD8 (naïve &amp; central memory subsets / tumour burden (TMTV and SPD), product doubling time] and 4) Post Infusion factors (CAR peak &amp; persistence, B cell aplasia, hypogammaglobulinema, infections and intravenous immunoglobulin (IVIg) replacement). These parameters were analyzed using chi-square and appropriate multivariant odds ratio (OR) to examine the association with disease relapse. Results: At data cut-off, of 25 pts enrolled (median age 31 yrs, range 3 - 66) with RR BCM (n=13 B-ALL; n=12 B-NHL), 24 pts received var-cel (1 withdrawal). Median follow-up after IMN-003A administration was 205 days (range 12 - 434). Overall response rate (ORR) was 91.7% (22/24) at D+28 (B-ALL 91.7%; B-NHL 91.7%) and 80.9% (17/21) at D+90 (B-ALL 80%; B-NHL 81.8%). Median progression free survival (PFS, range 12-NR), duration of response (DOR, range 0-NR) and overall survival (OS) were not reached (range 12-NR). Treatment related mortality was 4.2% (n=1/24); 3 pts died of disease progression. Nine pts had relapsed disease (B-ALL 4; B-NHL 5; overall 37.5%; CD19+ 7 pts; CD19- 2 pts; B-ALL: CD20 variable; CD22+ n=4/4; B-NHL PDL1 n=1/5) with median PFS of 178 days (range 28-319). For relapsed pts, median duration of B cell aplasia after primary infusion was 270 days (range 70-NR); var-cel was detected in 1 pt (n=1/4) at relapse and hypogammaglobulinema (IgG &amp;lt;4g/L) was seen in 4 pts. For the 36 multiple parameters studied, age, high risk cytogenetics / genomic aberrations, refractoriness / early relapse &amp;lt;6m, blasts burden in B-ALL, absolute lymphocyte count, inflammatory markers (LDH, ferritin) and baseline T cell subsets did not show association with disease relapse. Ten variables showing some association with disease progression on univariant analysis were: SPD, baseline haemoglobin, platelets, CRP, Apheresis CD8+ T N+CM, Final Product doubling time, CAR-T dosage (B-NHL), CD8 CAR+ T N+CM (weight &amp; dose adjusted), Post Infusion Cmax and IVIg replacement. Multivariant analysis of these parameters showed some statistical significance for following variables: Baseline Platelet count &amp;lt;200 x 10 9/L (overall); Final Product doubling time ≥1 day (B-ALL); baseline SPD ≥2000 mm 2, Hb &amp;lt;12 g/dL, Platelet count &amp;lt;200 x 10 9/L and post infusion IVIg replacement (B-NHL), Table1 &amp; Figure 1. Of these variables, statistically significant association was seen with Final Product doubling time ≥1 day (B-ALL) and baseline SPD ≥2000 mm 2 with Hb &amp;lt;12 g/dL and Platelet count &amp;lt;200 x 10 9/L (B-NHL). The impact of IVIg replacement on efficacy needs further study. Conclusions: In the IMAGINE study, with ORR 80.9% at primary endpoint and median PFS not reached, relapse was seen in 37.5% pts with median PFS of 178 days. Multivariant analysis has identified factors which may predict disease relapse. Further research is needed to identify strategies such as reinfusion or CAR-T targeting a different antigen to achieve cure.

The Role of miRNA in Testicular Cancer: Current Insights and Future Perspectives.

Background and Objectives: Despite advancements in the diagnosis and treatment of testicular germ cell tumours (TGTCs), challenges persist in identifying reliable biomarkers for early detection and precise disease management. This narrative review addresses the role of microRNAs (miRNAs) as potential diagnostic tools and therapeutic targets in the treatment of TGCTs. Materials and Methods: Three databases (PubMed®, Web of Science™, and Scopus®) were queried for studies investigating the utility of miRNA as diagnostic tools, assessing their prognostic significance, and evaluating their potential to guide TGCT treatment. Different combinations of the following keywords were used, according to a free-text protocol: "miRNA", "non-coding RNA", "small RNA", "Testicular Cancer", "seminomatous testicular germ cell", "non-seminomatous testicular germ cell". Results: The potential of miRNAs as possible biomarkers for a non-invasive diagnosis of TGCT is appealing. Their integration into the diagnostic pathway for TGCT patients holds the potential to enhance the discriminative power of conventional serum tumour markers (STMs) and could expedite early diagnosis, given that miRNA overexpression was observed in 50% of GCNIS cases. Among miRNAs, miR-371a-3p stands out with the most promising evidence, suggesting its relevance in the primary diagnosis of TGCT, particularly when conventional STMs offer limited value. Indeed, it demonstrated high specificity (90-99%) and sensitivity (84-89%), with good positive predictive value (97.2%) and negative predictive value (82.7%). Furthermore, a direct relationship between miRNA concentration, disease burden, and treatment response exists, regardless of disease stages. The initial evidence of miRNA decrease in response to surgical treatment and systemic chemotherapy has been further supported by more recent results suggesting the potential utility of this tool not only in evaluating treatment response but also in monitoring residual disease and predicting disease relapse. Conclusions: MiRNAs could represent a reliable tool for accurate diagnosis and disease monitoring in the treatment of TGCT, providing more precise tools for early detection and treatment stratification. Nevertheless, well-designed clinical trials and comprehensive long-term data are needed to ensure their translation into effective clinical tools.

858O Minimal residual disease (MRD) diagnosed by a plasma tumor-agnostic circulating tumor DNA (ctDNA) assay after curative therapy in locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) predicts disease relapse and survival

858O Minimal residual disease (MRD) diagnosed by a plasma tumor-agnostic circulating tumor DNA (ctDNA) assay after curative therapy in locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) predicts disease relapse and survival

Preoperative urine sediment chromosomal instability level predicts urothelial cancer prognosis

PurposeUrothelial carcinomas (UCs) are often characterized by frequent recurrences after surgery, making UC one of the costliest cancers. Chromosomal instability (CIN) has been proven to be a hallmark of UCs and is related to the prognosis of many cancer types. In this study, we evaluated CIN of urine sediments as a prognostic indicator for UCs. MethodsPatients with UC were prospectively recruited. Preoperative urine samples were collected for whole genome sequencing and urine cytology tests. Patients underwent standard-of-care treatment and were followed up until disease relapse or study ended. Concordance and accuracy of CIN alone or in combination with cytology in predicting disease relapse were assessed. The value of CIN combined with European Organization for Research and Treatment of Cancer (EORTC) model were also analyzed. ResultsA total of 137 patients with UCs were included in this study. Median follow-up was 44.2 months and 41.61% patients suffered from cancer relapse. Patients with CIN-high indicated higher relapse rate, and this distinction was significant for patients underwent transurethral resection of bladder tumor (57.89% vs. 34.29%, P = 0.016). Combination of cytology and CIN result could further classified patients into subgroups with distinct relapse risks. Meanwhile, the combination of CIN and EORTC model significantly improved the prediction accuracy compared with EORTC alone (Harrel's C-index: 0.71 vs. 0.65). ConclusionCIN level of preoperative urine exfoliated cells had robust prognostic value for bladder cancer patients underwent TURBT. The prognostic model by combining CIN and EORTC may help in stratifying patients to optimize follow-up regimen.

Clinical Features and Risk Factors of Relapse and Mortality in Thrombotic Thrombocytopenic Purpura Patients: A Seven-Year Experience.

Background: Thrombotic thrombocytopenic purpura (TTP) is associated with microangiopathic hemolytic anemia, thrombocytopenia, and microvascular thrombosis. No comprehensive report exists on clinical characteristics and risk factors of relapse and mortality in Iranian TTP patients. In this study, we aimed to report clinical features of Iranian TTP patients, to evaluate disease relapse and mortality rate and their associated risk factors. Materials and Methods: This study was a cohort study of patients diagnosed with microangiopathic hemolytic anemia admitted to the Shariati Hospital, Tehran, a referral center for TTP patients, from 2010 to 2017. Demographic, clinical, and laboratory data were recorded and patients were followed for 3 years regarding disease relapse and mortality. Results: 114 patients (80 females, 34 males) with a mean age of 39.3 ± 14.99 years were included. Hematologic and neurologic symptoms were the most common manifestations. Abnormal laboratory findings at the presentation included thrombocytopenia, anemia, and elevated LDH. All patients were treated with plasma exchange, and 75.5% of them had a response to treatment, while the 3-year relapse and mortality rate was 23.6 and 26.3%. Lower platelet count was a predictor of disease relapse. Age, hematological, or neurological initial presentation were associated with TTP mortality. Conclusion: Based on the largest study of TTP patients ever in Iran, the demographic and clinical characteristics of Iranian TTP patients are similar to other existing reports. Knowledge of the risk factors for TTP relapse and mortality could be useful to alert hematologists for prompt therapeutic actions when necessary.

Muscle glycome in idiopathic inflammatory myopathies: Impact in IL-6 production and disease prognosis

Idiopathic inflammatory myopathies (IIM) are a group of chronic autoimmune diseases mainly affecting proximal muscles. Absence of meaningful prognostic factors in IIM has hindered new therapies development. Glycans are essential molecules that regulate immunological tolerance and consequently the onset of autoreactive immune response. We showed that muscle biopsies from patients with IIM revealed a deficiency in the glycosylation pathway resulting in loss of branched N-glycans. At diagnosis, this glycosignature predicted disease relapse and treatment refractoriness. Peripheral CD4+ Tcells from active-disease patients shown a deficiency in branched N-glycans, linked to increased IL-6 production. Glycan supplementation, restoring homeostatic glycosylation profile, led to a decrease in IL-6 levels. This study highlights the biological and clinical importance of glycosylation in IIM immunopathogenesis, providing a potential mechanism for IL-6 production. This pinpoints muscle glycome as promising biomarker for personalized follow-up and a potential target for new therapies in a patients' subgroup with an ominous evolution.

Prediction of the Duration to Next Admission for an Acute Affective Episode in Patients with Bipolar I Disorder

Predicting disease relapse and early intervention could reduce symptom severity. We attempted to identify potential indicators that predict the duration to next admission for an acute affective episode in patients with bipolar I disorder. We mathematically defined the duration to next psychiatric admission and performed single-variate regressions using historical data of 101 patients with bipolar I disorder to screen for potential variables for further multivariate regressions. Age of onset, total psychiatric admissions, length of lithium use, and carbamazepine use during the psychiatric hospitalization contributed to the next psychiatric admission duration positively. The all-in-one found that hyperlipidemia during the psychiatric hospitalization demonstrated a negative contribution to the duration to next psychiatric admission; the last duration to psychiatric admission, lithium and carbamazepine uses during the psychiatric hospitalization, and heart rate on the discharge day positively contributed to the duration to next admission. We identified essential variables that may predict the duration of bipolar I patients' next psychiatric admission. The correlation of a faster heartbeat and a normal lipid profile in delaying the next onset highlights the importance of managing these parameters when treating bipolar I disorder.

Acute Myeloid Leukemia Stem Cells in Minimal/Measurable Residual Disease Detection.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by an abundance of incompletely matured or immature clonally derived hematopoietic precursors called leukemic blasts. Rare leukemia stem cells (LSCs) that can self-renew as well as give rise to leukemic progenitors comprising the bulk of leukemic blasts are considered the cellular reservoir of disease initiation and maintenance. LSCs are widely thought to be relatively resistant as well as adaptive to chemotherapy and can cause disease relapse. Therefore, it is imperative to understand the molecular bases of LSC forms and functions during different stages of disease progression, so we can more accurately identify these cells and design therapies to target them. Irrespective of the morphological, cytogenetic, and cellular heterogeneity of AML, the uniform, singularly important and independently significant prognosticator of disease response to therapy and patient outcome is measurable or minimal residual disease (MRD) detection, defined by residual disease detection below the morphology-based 5% blast threshold. The importance of LSC identification and frequency estimation during MRD detection, in order to make MRD more effective in predicting disease relapse and modifying therapeutic regimen is becoming increasingly apparent. This review focuses on summarizing functional and cellular composition-based LSC identification and linking those studies to current techniques of MRD detection to suggest LSC-inclusive MRD detection as well as outline outstanding questions that need to be addressed to improve the future of AML clinical management and treatment outcomes.

Minimal residual disease in acute leukemia based on the insight of molecular genetics monitoring

Patients with acute leukemia port 10 malignant cells at presentation. Following chemotherapy or stem cell transplant, patients in complete remission by conventional analyses may still harbor 106/108 malignant cells below the detection limit of standard clinical assessment. Minimal residual disease (MRD) monitoring is one of the most powerful predictors of disease-free and overall survival, particularly for children with acute lymphoblastic leukemia (cALL), the percent annual of cALL increase in the incidence of cALL in Saudi Arabia. Breakpoint fusion regions of chromosomal aberrations can be used as tumor-specific targets for MRD detection by polymerase chain reaction. Levels of MRD, measured at critical time points, significantly correlate with clinical outcomes. Previous works investigated the prognostic significance of leukemia-associated immunophenotypes (LAIPs) as an assessment of the index of MRD in 125 adult B-ALL patients by eight-colour flow cytometry. More advanced molecular and genetics studies are so necessary to identify the mechanisms and cellular structure of the minimal-level disease. Selecting molecular methods for minimal residual disease detection have a much higher sensitivity and precision (100-fold or more) than others. This review highlights the minimal residual disease molecular detection to demonstrate the characterization of the lymphoblastic leukemia gene. Precise MRD monitoring predicts disease relapse after chemotherapy or SCT, provides early intervention, and may result in the rescue of many patients and improvement in the probability of long-term disease-free survival.

Perioperative ctDNA-Based MRD Detection in NSCLC—Response

We appreciate Yu and colleagues for their interest in our study and we would like to give our reply to their concerns.In LUNGCA-1 study, a total of 330 patients with resected tumor tissues and preoperative blood samples available were included in prognostic analysis, and all but one of these 330 patients had at least one available plasma sample at postoperative 3 days and/or 1 month (1). Thus, preoperative circulating tumor DNA (ctDNA) and postoperative ctDNA-based molecular residual disease (MRD) analysis was done for 330 and 329 patients respectively, as reflected in the number of patients in both Fig. 1 and detailed sample information listed in Supplementary Table S5. LUNGCA-1 study was aimed at evaluating the potential of ctDNA-based MRD during perioperative period for predicting disease relapse and identifying patients who may potentially benefit from adjuvant therapy, and throughout the entire article, there was no mentioning of ctDNA testing after adjuvant therapy.We designed two postoperative blood collection timepoints for ctDNA-based MRD detection. We found that the amount of cell-free DNA increased significantly at 3 days after surgery, and then dropped at postoperative 1 month. ctDNA status at postoperative 3 days was significantly associated with recurrence-free survival (P < 0.001), although with lower prognostic value than ctDNA status at postoperative 1 month (HR: 8.6 vs. 14.3). Among 5 patients whose ctDNA was positive at postoperative 3 days but negative at the other two perioperative timepoints, 4 (80.0%) experienced disease relapse, and the only one who remained disease free had received adjuvant therapy and had a relatively short follow-up (437 days) at the time of data lockdown. Therefore, ctDNA at 3 days after surgery proved to be useful in complementing MRD analysis at postoperative 1 month by increasing detection sensitivity without sacrificing specificity.The current LUNGCA-1 study focused on the association of postoperative MRD detection with disease relapse. The clinical relevance of preoperative ctDNA concentration was not a concern of the published paper and therefore not reported. The criteria for determining ctDNA status had been clearly described in the paragraph “Next-generation sequencing and ctDNA analysis” of the Materials and Methods section, as well as the Supplementary Methods. Disease relapse included locoregional recurrence and distant metastases after surgery, which was determined by radiological methods and/or biopsy.See the original Letter to the Editor, p. 1155W. Chen reports other support from Genecast outside the submitted work. No disclosures were reported by the other authors.

P144 Impact of major medication discontinuation during the first wave of COVID-19 pandemic on the risk of early relapse in patients with inflammatory bowel disease: a French observational retrospective study

Abstract Background The prevalence of nonadherence to major treatments and the subsequent adverse outcomes in IBD patients during the first wave of COVID-19 pandemic remain scarce. Aim to investigate the risk of early disease relapse in a cohort of IBD patients under immunosuppressants and/or biologics who decided themselves to discontinue their IBD-related major treatments without previous medical advice during the first wave of COVID-19 pandemic. Methods All consecutive patients with inactive IBD under immunosuppressants and/or biologics who acknowledged having withdrawn their major therapy for IBD without previous medical advice during the first wave of COVID-19 (from March 2020 to December 2020) were enrolled. The primary endpoint was the survival rate without disease relapse. Kaplan-Meier curves were plotted for time from inclusion to IBD relapse and a logistic regression model with uni- and multivariate analyses was performed to identify predictors of relapse after drug discontinuation. Results During the study period, among the 862 IBD patients followed as outpatients either treated with infliximab or vedolizumab (outpatient clinics n= 368) or treated with oral azathioprine, adalimumab, golimumab or ustekinumab alone or in combination (n= 494), 54 patients (6.2 %) (42 CD, 12 UC, 28 F, median age 36 years) who had discontinued themselves their IBD-related major therapy without previous medical advice were included. The median duration of drug withdrawal was 7.0 weeks (range 2-24) and the median time to relapse was 9.0 weeks (range 4-20). The most treatments withdrawn were adalimumab (n=19), ustekinumab (n=19), azathioprine (n= 12), golimumab (n=1) and a lesser degree infliximab (n=7) eand vedolizumab (n=6). During the median follow-up period of 24 weeks (range 5-42), 22 out of 54 patients (40.7 %) who discontinued their IBD treatment experienced a relapse in whom 6 requiring administration of oral steroids, 4 hospitalization and 2 IBD-related surgery. By univariate analysis, past IBD related surgery was identified as the only predictor of disease relapse after drug withdrawal (OR=3.3 CI 95 % [1.08-10.38]. Conclusion In IBD patients, major treatment discontinuation by the patients themselves without medical advices during the first wave of pandemic Covid-19 including the lockdown was associated with a substantial risk of disease relapse occurring in around 4 out of 10 patients and subsequent further risk of need for steroids, hospitalization and surgery. Strategies targeting the adherence to therapy and patient’s informations about the real risks leading to drug discontinuation are of paramount interest, especially during health crisis to minimize such issues.