Early Relapse In Patients Research Articles

Immunohistochemistry of p53 surrogates TP53 mutation as an accurate predictor for early-relapse of surgically resected stage I-III lung adenocarcinoma

IntroductionTP53 is a strong tumor suppressor gene; its deactivation contributes to carcinogenesis and influences clinical outcomes. However, the prognostic influence of p53 deactivation on early relapse in patients with surgically resected non–small cell lung cancer remains unclear. Materials and methodsA cohort of 170 patients with primary stage I through III lung adenocarcinoma (LADC) and lung squamous cell carcinoma who underwent complete resection at Tokyo Medical and Dental University was screened for TP53 mutations using panel testing, and association studies between TP53 mutations and clinical data, including histology and postoperative recurrence, were performed. The association between TP53 mutations and postoperative recurrence was validated using data from 604 patients with MSK-IMPACT from The Cancer Genome Atlas. Additional immunohistochemistry for p53 was performed on some subsets of the Tokyo Medical and Dental University population. ResultsMutations in TP53 were recurrently observed (35.9%; 61 out of 170) in the Tokyo Medical and Dental University cohort. In the histology-stratified analysis, patients with LADC histology showed TP53 mutations that were associated with poor relapse-free survival (log-rank test; P = .020), whereas patients with lung squamous cell carcinoma histology showed TP53 mutations that were not (P = .99). The poor prognosis of TP53 mutation-positive LADCs was validated in The Cancer Genome Atlas-LADC cohort (log-rank test; P = .0065). Additional immunohistochemistry for p53 in patients with LADC histology in the Tokyo Medical and Dental University cohort showed a significant correlation between TP53 mutations and abnormal IHC pattern of p53 (Cramer's correlation coefficient V = 0.67). ConclusionsTP53 mutation is a potential marker for worse prognosis in surgically resected LADC; immunohistochemistry for p53 could be a surrogate method to identify patients with LADC with a worse prognosis.

Real-World Evidence of Relapsed/Refractory Mantle Cell Lymphoma Patients and Treatments: A Systematic Review.

Mantle cell lymphoma (MCL) is an incurable disease with an aggressive clinical course, and most patients eventually relapse after chemotherapy. Targeted therapies developed for relapsed/refractory MCL have been approved based on clinical trial data. However, real-world setting data are scarce and scattered. This systematic review aimed to collect, synthesize, and describe the characteristics and treatment outcomes of patients with relapsed/refractory MCL after receiving a second or subsequent line of therapy in the real-world setting. R/R MCL is clinically and biologically heterogeneous and still represents a therapeutic challenge, with high-risk and early relapsed patients remaining an unmet medical need. This systematic review is limited by the quality of the available data and the difficulty of comparing outcomes in R/R MCL due to the heterogeneity of the disease, but the results suggest that covalent BTKis should be positioned as second-line therapy, followed by CAR T-cells in BTK-i-relapsed patients. Chemo-free and combination therapies with established chemoimmunotherapy backbones in the relapsed and front-line settings have been recently developed, and front-line options are being improved to move targeted and cellular therapies to earlier lines, including front-line therapy, in elderly and younger fit patients. In the upcoming years, many new targeted agents will play an important role and will be incorporated to the routine practice as their sequence, and outcomes in unselected patients are determined.

Dysregulated metabolic sensing of appetite in anorexia nervosa: implications of LEAP-2 regulation

AbstractGrowing interests on the role of metabolic sensors in anorexia nervosa led to implicate metabolic sensing as consequences of anorectic sensing but also in the perpetuation of the disorder. Ghrelin is an orexigenic peptide secreted by the fundic cells of the stomach in situation of fasting and kown to initiate food intake through its activity on hypothalamic and motivation aspect of food intake. A body opf evidenc previously showed that patients suffering from anorexia nervosa display high plasma levels of ghrelin correlated with the nutritionnal status but his orexigenic signal do not seem to modify restrictive behavior. LEAP-2 (Liver Expressed Antimicrobial Peptide 2) is a recently discovered endogenous ghrelmin antagonist, increased during overnutrition and that decreases food intake in humans and animals.We explored ghanges of ghrelin and LEAP-2 in a longitudinal cohort of 30 patients suffering from anorexia nervosa during a 4 months refeeding program. We show abnormal regulation of LEAP-2 in patients with higher levels in acute stages that decrease with refeeding. This abnormal regulation was associated with early relapse in patients. This abnormal regulation could counteract with the orexigenic signal of ghrelin in patients.We discuss these results in light with recent evidence on the consequences of LEAP-2 increase of food intake and hedonic feeding relevant in understanding anorexia nervosa.Disclosure of InterestNone Declared

Predicting alcohol relapse post-detoxification: The role of cognitive impairments in alcohol use disorder patients.

Studies on early abstinence suggest that cognitive function is significantly reduced in the first year of abstinence, which raises the question of whether it is relevant to early relapse in patients with substance use disorders. This study investigates the extent to which impairments in executive function and memory predict alcohol relapse in patients with alcohol use disorder (AUD). Understanding these relationships is crucial for improving therapeutic approaches to prevent relapse in patients with AUD. We selected 116 adult patients (79 male and 37 female) diagnosed with AUD based on DSM-5 criteria, all of whom were undergoing alcohol detoxification treatment. A comprehensive array of neuropsychological tests was administered to assess global cognition, memory, and executive functions. Patients' alcohol use was monitored monthly during a 6-month follow-up period. Logistic regression and Cox regression were used to explore the relationship between cognitive function and the likelihood of alcohol relapse. Impairments in global cognition, semantic and phonemic fluency, cognitive flexibility, and learning ability during detoxification were significant predictors of relapse in AUD patients, showing similar predictive values at both 3 and 6 months post-treatment. An abnormal Montreal Cognitive Assessment (MoCA) score increased the risk of relapse by 123% (HR: 2.227), and impairments in both semantic and phonemic fluency each increased the risk by 142% (HR: 2.423). Additionally, abnormal performance on the MoCA, Trail Making Test Part B (TMT-B), and California Verbal Learning Test (CVLT) was associated with a higher number of drinking days at 3 months (IRR: 3.764; IRR: 2.237; IRR: 2.738, respectively) and abnormal MoCA and TMT-B scores at 6 months (IRR: 2.451; IRR: 1.859, respectively). The MoCA test is a valuable tool for predicting relapse risk in AUD patients undergoing detoxification treatment, with similar predictive value for relapse at 3 or 6 months. Learning ability needs to be assessed and their impairments considered in the treatment of AUD patients.Future research should explore strategies for managing patients with impairments in memory and learning ability to enhance treatment effectiveness and prevent relapse.

Real-World Data on Clinical Outcomes and Treatment Management of Advanced Melanoma Patients: Single-Center Study of a Tertiary Cancer Center in Switzerland.

Immune checkpoint inhibitors (ICIs) and BRAF/MEK inhibitors (BRAF/MEKi) have drastically changed the outcomes of advanced melanoma patients in both the resectable/adjuvant and unresectable/metastatic setting. In this follow-up analysis of real-world data, we aimed to investigate the clinical management and outcomes of advanced melanoma patients in a tertiary referral center in Switzerland approximately a decade after the introduction of ICIs and BRAF/MEKi into clinical use. Moreover, we aimed to compare the results with seminal phase 3 trials and to identify areas of high unmet clinical need. This single-center retrospective cohort study analyzed the melanoma registry of the University Hospital Zurich, a tertiary cancer center in Switzerland, and included patients treated in the resectable/adjuvant (n = 331) or unresectable/metastatic setting (n = 375). In the resectable setting, adjuvant anti-PD1 or BRAF/MEKi showed a 3-year relapse-free survival (RFS) of 53% and 67.6%, respectively, and the overall median RFS was 50 months. Patients with lymph node plus in-transit metastases or with distant metastases prior to commencing adjuvant treatment had a significantly reduced overall survival (OS). In 10.9% of patients, the treatment was stopped due to toxicity, which did not affect RFS/OS, unless the duration of the treatment was <3 months. Following a relapse of the disease during the first adjuvant treatment, the median progression-free survival (PFS2) was only 6.6 months; outcomes were particularly poor for relapses that were unresectable (median PFS2 3.9 months) or occurred within the first 2 months (median PFS2 2.7 months). A second adjuvant treatment for patients with resectable relapses still showed efficacy (median RFS2 43.7 months). Elevated LDH levels in patients with an unresectable relapse was correlated with a strong reduction in OS2 (HR 9.84, p = 0.018). In the unresectable setting, first-line anti-PD1, anti-CTLA4/PD1 combination, or BRAF/MEKi showed a 5-year OS of 46.5%, 52.4%, and 49.2%, respectively. In a multivariate analysis, elevated LDH levels or the presence of brain metastases substantially shortened OS (HR > 1.78, p < 0.035). There was a non-significant trend for the improved survival of patients treated with anti-CTLA4/PD1 compared to anti-PD1 (HR 0.64, p = 0.15). After a progression on first-line therapy, the median OS2 was reduced to below two years. Elevated LDH (HR 4.65, p < 0.001) levels and widespread disease with at least three metastatic sites, particularly bone metastases (HR 2.62, p = 0.026), affected OS2. Our study offers real-world insights into the clinical management, treatment patterns, and outcomes of advanced melanoma patients in both the adjuvant and unresectable setting. Early relapses in patients undergoing adjuvant treatment pose a particular challenge but these patients are generally excluded from first-line trials. The approved first-line metastatic treatments are highly effective in the real-world setting with 5-year OS rates around 50%. However, outcomes remain poor for patients with brain metastases or who fail first-line treatment.

Relinf Registry-Based Analysis Shows Overall Survival Improvement with New Therapies for Relapsed or Refractory Large B-Cell Lymphoma: A Study from the Geltamo Group

Introduction: Several new therapeutic agents have been approved in recent years for the treatment of relapsed/refractory (R/R) Large B cell lymphoma (LBCL) (diffuse large B cell lymphoma [DLBCL] and high-grade B cell lymphomas [HGBCL]), such as new monoclonal antibodies (MA), bispecific antibodies (BA) and CAR-T cell therapy. The objective of our study was to evaluate the epidemiology and the use of these new therapies (NT) in Spain and to analyze the impact on survival. Methods: We present a multicenter retrospective study based on the GELTAMO (Spanish lymphoma group) RELINF platform. From 60 centers actively registering on the platform, 17 university hospitals accepted to participate, and 5 of them were CAR-T therapy providers. Participating centers completed a short questionnaire on disease relapse and the use of new drugs in their registered patients. The histologies included were DLBCL, HGBCL not otherwise specified (NOS), and double hit (DH). Results: From 3270 patients with ABCL registered, 2853 patients were included in the present analysis; 738 patients experienced R/R disease, 492 (67%) were refractory or had early relapse (up to 1 year from the first line), and 246 (33%) late relapses, half of them (54%) during the second year. In both early and late relapse groups, about a third of patients were older than 80 years. Early relapses were significantly higher in double/triple hit HGL (34%) and T-cell-rich DLBCL (29%) compared to DLBCL or HGL NOS (16%) (p&amp;lt;0.001). The median number of lines among relapsed patients was 2 (1-10). 236 patients received NT, with the following distribution: CAR-T, n=144, BA, n=68, polatuzumab-based, n=92, and tafasitamab-lenalidomide, n=14. Most patients who received only 2 lines (n=376) were treated with conventional treatments, although 11 patients (3%) received CAR-T, 11 (3%) BM, 15 (4%) polatuzumab-based, and 5 (1%) tafasitamab-lenalidomide. Among 354 patients who received more than 2 lines of treatment, 130 (37%) received CAR-T cell therapy, 75 (21%) polatuzumab, 9 (2%) tafasitamab-lenalidomide, 55 (15%) BA, and 160 (45%) of these patients did not receive any NT. In the overall series, with a median follow-up of 49 months (95%CI: 47-51), median progression-free survival (PFS) was 54 months (95%CI: 48-61), and median overall survival (OS) was 82 months (95%CI: 74-90). Considering only the R/R patients, with a median follow-up of 40 months since the first relapse, the median OS2 (mOS2) was 16.8 (IC95%: 14.5-19) months. Survival analysis is shown in Table 1. The mOS2 for the early relapse group was 13.5 (95%CI: 11.5-15.5) months vs 31.1 (95%CI: 22.5-39.8) months for late relapses. Median OS2 for relapsed patients treated with NT was 31.1 months (95%CI: 22.5-39.7) compared with 11.9 months (95%CI: 9.2-14.6) for the group of standard treatment (p&amp;lt;0.001)) (Figure 1). Interestingly, OS2 was longer in patients treated in CAR-T provider centers than in non-CAR-T centers, in both early relapse group (mOS: 18.3 months [95%CI: 14.1-22.5] vs. 8.6 months [95%CI: 6.2-11]: p&amp;lt;0.001) and late relapse group (37.9 months [95%CI: 24.2-51.5] vs. 18.7 months [95%CI: 13.9-23.4], p=0.001). This difference was not found when we evaluated high complexity institutions (those that perform allogeneic transplant) vs. those that are no. In multivariate analysis, early relapse (HR 1.68, 95%CI 1.37-2.06, p&amp;lt;0.001), age over 65 years (HR 1.91, 95%CI: 1.23-2.98, p=0.004), treatment with CAR-T cell therapy (HR 0.68, 95%CI: 0.51-0.90, p=0.007) and treatment in a CAR-T cell provider center (HR 0.7, 95%CI: 0.58-0.85, p&amp;lt;0.001) independently influenced OS2. Conclusions: Our real-world analysis confirms the negative impact on OS of factors like age or early relapse in patients with R/R LBCL. According to our results, the introduction in recent years of NT has markedly improved OS, especially CAR-T cell therapy.

Identification of Clinical-Biological Features of Newly Diagnosed Early Relapse Multiple Myeloma Patients Eligible for Autologous Stem Cell Transplantation

Despite many therapeutics advances, Multiple Myeloma (MM) remains an incurable hematological malignancy with a cohort of patients who relapse early or does not respond to first-line therapy, including autologous stem cell transplantation (ASCT). The proportion of patients with early relapse is stable over time at about 30% and they have a median Overall Survival (OS) less than 3 years. Consequently, clinical and/or biological features that identify patient at high risk for early relapse at diagnosis represent a critical unmet medical need. With the aim of identify possible factors of early relapse (ER), we conducted a retrospective, observational, single center study on a cohort of 74 MM patients who received an upfront ASCT between 2011 and 2021 after a novel agent-based induction at the Hematological and BMT Unit of the University Hospital of Parma (Italy). The primary end point of the study was the assessment of possible predictive markers for ER, defined as progressive disease that occurred within 18 months from the time of ASCT. Clinical, biochemical and cytogenetics features of the cohort of MM patients were evaluated (Table 1). Definitions of response and progression were used according to the International Myeloma Working Group (IMWG) response criteria. All statistical analyses were done by SPSS Statistics. The characteristics of cohorts were summarized using the median value for continuous variates and the frequency for categorical ones. The Pearson chi-square test and Student t-test were used to identify differences between groups for categorical and continuous variables, respectively. Kaplan-Meier Curve with log-rank test were used to analyze survival data. The bivariate logistic analysis was conducted to recognize independent factors predicting ER, subsequently Cox regression analysis was performed to confirm the validity of multivariate analysis for survival data. The cohort characteristics were summarized in table 1. Among the 74 MM patients included in the study, a total of 19 patients (25.5) experienced ER, with mean time to relapse of 15.6 (18.0) months. Univariate statistical analysis identified as possible predictive markers for early relapse at diagnosis: IgA MM (p &amp;lt; 0.05), elevated serum LDH level (p &amp;lt; 0.05), C-CRAB criteria (p &amp;lt; 0.05), high risk cytogenetic aberrations (p &amp;lt; 0.05), stage R-ISS III (p &amp;lt; 0.001) and stage R2-ISS III or IV (p &amp;lt; 0.001). Multivariate statistical analysis confirmed IgA isotype (p &amp;lt; 0.05) and higher stage according to R2-ISS (p &amp;lt; 0.001) as effectively independent predictive risk factors for ER. Time-to-event analysis displayed a mean progression free survival (PFS) from transplant of 24.7 (16.0) months and 32.5 (19.0) months for those with IgA MM and stage R2-ISS III or IV, respectively. In the group of patients with IgA isotype the mean OS from transplant was 49.5 (30.0) months, while the mean OS from diagnosis was 58.0 (35.0) months without statistically significant differences compared to counterpart. In the group of patients with stage R2-ISS III or IV the mean OS from transplant was 48.2 (41.0) months, while the mean OS from diagnosis was 56.5 (49.0) months. Finally, in ER cohort the mean OS from diagnosis was 47.1 (35.0) in comparison with the 75.0 (71.0) months of non-ER cohort. In conclusion, this retrospective study was able to identify the main features of newly diagnosed early relapsed MM patients eligible to ASCT identifying the IgA isotype and the R2-ISS score system as the main predictive prognostic factors for early relapse in this cohort of patients.

An Assessment of Marrow-Infiltrating T Cells in Early Relapsed Hematologic Cancer Patients Post Allogeneic Hematopoietic Stem Cell Transplantation

Background: Relapse is the major treatment failure of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. Especially, early relapse had seriously bad prognosis. And tumor-infiltrating T cells play an important role in disease progression and recurrence. However, there is lack of data about the marrow-infiltrating T cell of early relapsed patients compared to those with complete remission (CR) at an early timepoint after HSCT. Therefore, we analyzed the differentiation stage and expression of inhibitory receptors of the marrow-infiltrating T cell in the early stages of allogeneic HSCT. Method: A total of 40 samples from patients treated at Chungnam National University Hospital were collected between April 2021 and October 2022. We used flow cytometry to classify T cells into five subtypes using CD45RA, CD95, and CCR7: naïve, stem cell memory (SCM), central memory (CM), effector memory (EM) and effector memory with positive CD45RA (EMRA). Otherwise, we analyzed regulatory T cell (Treg) by defining as CD25 highCD127 low and divided them into three categories using CD25 and CD45RA: naïve, active and non-suppressive Treg. We defined early relapse (ER) as relapse within 6 months of allogeneic HSCT. High-throughput single-cell RNAseq assays from BM lymphocytes isolated by density gradients were performed to determine the expression and cell composition of previously irradiated markers. Results: With this approach, marrow-infiltrating T cells were analyzed in 40 patients (10 patients with early relapse) with a median age of 57 years (ranged from 30 to 71). AML is the most common disease at 60%, followed by MDS (20%), ALL (15%) and PMF (2.5%). Stem cell sources were 32.5% from matched sibling donor, 37.5% from haplo-identical donor and 27.5% from matched unrelated donor. All patients received mobilized peripheral blood stem cell transplantation. Marrow-infiltrating CD3+T cell counts were lower in patients with allogeneic HSCT compared to normal subjects (CD3+T cells: 13.89% in HSCT patient and 9.116% in ER patients vs. 34.19% in normal subjects, p&amp;lt; 0.0001). In addition, CD3+CD8+T cells were higher in CR than ER patients (CD3+CD8+T cells: 50.39% in CR vs. 30.41% in ER patients, p&amp;lt; 0.0033). In HSCT patients, naïve was higher, and EM and EMRA were lower than those in normal subjects among CD4+T cells (naïve; 8.629% in ER patients and 5.119% in CR patient's vs 45.76% in normal subjects, p&amp;lt; 0.0001/EM; 54.04% in ER patients and 55.93% in CR patients vs 18.61 in normal subject, p= 0.0003 and p&amp;lt; 0.0001 respectively). Of CD3+T cells, the proportion and expression level of TIM-3 was higher ER patients than in CR patients (56.33% in ER patients vs 39.20% in CR patients, p= 0.0185/MFI; 1873 in ER patients vs. 826.7 in CR patients, p= 0.0331). Of CD4+T cells, the percentage of TIM-3 was lower in normal subjects than in allogeneic HSCT patients (7.794% in normal vs 30.11% in CR patients and 26.04% in ER patients, p= 0.0002 and p= 0.0102 respectively). In patients with ER, naïve and EM was higher than those in CR patients among CD8+T cells (naïve; 8.680% in ER patients vs 4.066% in CR patients, p= 0.4001 /EM; 54.44% in ER patients vs 44.33% in CR patients, p= 0.3039). Of CD8+ EMRA T cell, the expression of TIM-3 was higher in ER patients than in CR patients (MFI; 1441 in HSCT patients vs 421.7 in normal, p=0.1038). Otherwise, of CD3+CD4-CD8-, The percentage of TIM3 was higher in ER patients than CR patients (80.33 % in ER patients vs 62.49% in CR patients, p= 0.0333). Treg levels were no significant difference between CR and ER. We have obtained single-cell sequencing data from two CR (complete response) patients and two ER (early relapse) patients, representing each group. Since the classified groups exhibited ambiguous phenotypes, they were reclassified based on specific markers of cell groups. The reclassified groups showed a higher proportion of HCS (Hematopoietic Stem Cell)-like cells in relapsed patients (+10.14%, P=0.368) and a lower proportion of CD8+ T cells (-13.40%, p=0.068). The HSC-like cells in relapsed patients exhibited higher expression of TIM3 ligand than in CR patients Conclusion: Among the IRs, TIM3 had the highest expression of all cell groups (CD4 T cells, CD8 T cells and Treg) compared with other IRs at the early stage of allogeneic HSCT. So, TIM3 might be a potential target for preventing relapse in hematologic cancer patients after allogeneic HSCT in the future.

Effect of a Crossover and Resistance Exercise Routine on IL-15 in Adults with Type B Acute Lymphoblastic Leukemia during the Induction Phase. Randomized Pilot Study

Background: IL-15 is a proinflammatory myokine essential for activating NK cells and CD8+ T lymphocytes, and its overexpression has been associated with decreased survival in patients with Acute Lymphoblastic Leukemia (ALL). Physical exercise has been shown to be safe, feasible, and beneficial in hematological cancers. This requires the activation of muscles that secrete cytokines such as IL-15, causing immune mobilization and accumulating CD8 T cells. The objective was to compare the effect of two exercise strategies on IL-15 and survival prognosis in adult patients diagnosed with de novo ALL. Material and Methods: A blind randomized clinical study was carried out where twenty-three peripheral blood samples were obtained pre- and post-exercise from patients classified into three types of intervention: resistance exercise (GER), crossover exercise (GEC), and control group (GC). Ethical disclosure: All patients gave written informed consent for the study and data collection. This three-arm, prospective, randomized, blinded, open-label pilot study (ratio 1:1:1) was conducted in accordance with the Declaration of Helsinki. Results: The results showed that the changes in IL-15 levels during the intervention were not significant in any of the groups (GC p= 0.237, GER p= 0.866, and GEC p= 0.678). However, 78.26% of patients achieved remission at the end of induction, while only 21.73% experienced a relapse. There were no deaths during the study. Conclusions: Although IL-15 compliance levels in GER and GC were similar, GER patients had a better prognosis. It is suggested that resistance exercises may help improve survival prognosis and reduce early relapses in patients with ALL. Keywords Interleukin-15; exercise; Acute lymphoblastic leukemia; chemotherapy; body composition

Patients with Relapsed Large B-Cell Lymphoma after 12 Months Have a Similarly Poor Prognosis As Patients with a Relapse before 12 Months

Recently, ZUMA-7 study patients with early relapsed LBCL (&amp;lt;12 months after first-line immunochemotherapy) who were treated directly with CAR T-cell therapy in second-line instead of third-line, had a significantly better overall survival (OS) compared to patients who were treated with standard salvage treatment consisting of high-dose chemotherapy followed by autologous stem-cell transplantation (HDT-ASCT). Despite non-protocolled cross-over to CAR T-cell therapy in third-line for 57% of patients in the HDT-ASCT arm, a significant difference in OS of 9% remained, suggesting that patients benefit if the most effective therapy is applied at an early stage. On the basis of these results, the paradigm of HDT-ASCT shifted to CAR T-cell therapy as second-line therapy for patients who have refractory or early relapsed disease &amp;lt;12 months. However, patients with a late relapse (&amp;gt;12 months) are still unable to receive CAR T-cell therapy until the third-line. A main argument is that late relapsed LBCL is considered to be still chemo sensitive and therefore these patients would have a better OS following HDT-ASCT salvage. The aim of this study was to compare the responses of LBCL patients with an early (&amp;lt;12 months) versus a late (&amp;gt;12 months) relapse onset, to see whether this argument is justified in real world. All patients diagnosed with LBCL between 2005 and 2020 in the province Friesland, The Netherlands, were included (n=877). Detailed patient characteristics and outcomes of patients in first-line, relapsed setting and beyond were analyzed. OS was calculated from relapse onset. Median follow-up was 7.0 years from diagnosis (range 0.01-15.6). In the first line, 729 patients (83.1%) were treated with curative intent. Early relapse (refractory and &amp;lt;12 months after first-line therapy) and late relapse (&amp;gt;12 months) occurred in 120 (16.4%) and 70 patients (9.6%), respectively. Patients with an early relapse show a 2-year and 5-year OS of 21.5% and 18.3%. Compared to early relapse, patients with a late relapse show a slightly favorable OS of 36.1% at 2 years, yet an almost similar OS at 5 years of 19.6%. Main cause of death for both groups were lymphoma, including treatment related complications (93.9% in early and 82.6% in late relapse). Second-line salvage therapy, consisting of HDT was initiated in 53 patients (44.2%) with early and 22 patients (31.4%) with late relapsed disease. Of these, only 16 patients (30.1%) with an early relapse and 11 patients (50%) with a late relapse obtained a sufficient response and maintained an acceptable clinical performance to undergo ASCT. Patients who completed ASCT, had a 5-year OS of 73.3% (early relapse) versus 49.2% (late relapse). In contrast, early and late relapsed patients who initiated salvage HDT but did not reach ASCT showed a 5-year OS of only 8.3% and 18.2%, respectively. This OS was comparable to the 67 patients (55.8%) with an early relapse who were upfront ineligible to start salvage HDT (5-year OS 10.2%). For HDT-ineligible patients with a late relapse (n=48, 68.6%) OS was similarly disappointing with a 5-year OS of 14.6% In conclusion, these real-world data contradict the argument that LBCL patients with a late relapse (&amp;gt;12 months) have an advantage over patients with early relapse (&amp;lt;12 months) in their potential to reach a long-term remission and survival with HDT-ASCT. This supports the evaluation of early application of CAR T-cell therapy in second-line, also for DLBCL patients who relapse beyond 12 months.

Novel Agents May be Preferable to Standard Chemotherapy in Second-Line for Early Relapsing Follicular Lymphoma (FL) Patients

Introduction Early progression of FL after first line treatment is associated with poor outcomes. Disease progression within 24 months of initial therapy (POD24) is well-established adverse prognostic factor, while maintaining a complete remission (CR) at 30 months after initiation of induction therapy is considered a good surrogate for a prolonged progression-free survival (PFS). Nevertheless, treatment strategies in the second-line setting for these early relapsing patients are not clearly established, being their management heterogeneous across centers. The aim of our study was to analyze treatment patterns in this setting and to compare outcomes for patients who received chemotherapy (CT)-based regimens and immunotherapy (IT) approaches. Methods We conducted a retrospective review of patients diagnosed with grade 1-3a FL treated with upfront (CT) that progressed within 30 months of initial therapy (POD30) in 9 centers from January 2015 to June 2023. Patients who received single agent monoclonal antibodies or radiotherapy as first line treatment, and patients with FL grade 3b or histological transformation were excluded from the analysis. We defined 2 groups of patients according to the second-line regimen: the CT group, comprised by patients who received bendamustine-based regimens or other CT combinations, and the IT group that included patients who received monoclonal antibodies with lenalidomide and/or CD20xCD3 bispecific antibodies. Outcomes of interest were overall and complete response rate (ORR/CRR), PFS and overall survival (OS). Results Among 114 POD30 FL patients, 93 received CT and 21 received IT as second line treatment. Median age for the overall cohort was 56 years, with no differences according to salvage therapy (57 vs 53 years, p=0.19). Fifty-nine patients (52%) were female and 104 (94%) presented an advanced stage disease. Most of the patients in both groups had a high-risk FL at diagnosis (68% vs 67%, p=0.89) and at the time of first relapse (51% vs 24%, p=0.03), respectively. Distribution of first line treatment was well balanced between both groups. CHOP-based regimens were administered in 81% patients from the CT group and 90% in the IT group while bendamustine-based regimens were administered in 6% patients from the CT group and 10% in the IT group. In terms of best response to frontline therapy, 28 patients (25%) attained a CR, 59 patients (52%) a partial response (PR), 7 patients (6%) a stable disease (SD) and 20 patients (18%) a progressive disease (PD). Maintenance treatment was administered in 78 patients (68%), 59 patients (63%) from the CT group and 19 patients (90%) from the IT group ( p=0.03). Second-line treatment in the CT group included bendamustine-based regimens (n=40, 43%), ESHAP (n=31, 33%), gemcitabine-based (n=7, 8%), and other regimens (n=15, 16%), while the IT cohort comprised patients treated with lenalidomide in combination with monoclonal antibodies (n=5, 24%) and bispecific antibodies (n=16, 76%). For the full set of patients, best response included CR in 47 patients (43%), PR in 23 patients (21%), SD in 10 patients (9%) and PD in 30 patients (18%). For the CT and IT groups, there were no significant differences in terms of ORR (64% vs 60%, p=0.66) or CRR (42% vs 45%, p=0.87), respectively. Autologous stem cell transplantation (ASCT) was performed as a consolidative strategy in 27 patients (24%) from the overall cohort (29% for the CT cohort and 5% for the IT, p=0.05). Median follow up was 39.2 from diagnosis and 15.4 months from second-line treatment. Median PFS for patients receiving CT as second line of treatment was 11 months (95% CI: 6.3 - 15.2), compared to 16 months (95% CI: 13.01 - NA) for patients receiving IT (HR: 0.5, CI 95% 0.25-1; p=0.05). Finally, median OS for patients receiving CT as salvage therapy was 45.6 months (95% CI: 24.15% - NA), while median OS was not reached for patients receiving IT (HR: 0.19, CI 95% 0.03-1.4; p=0.1). Conclusions Treatment approaches for early relapsing FL are heterogeneous across centers, with many patients receiving chemotherapy as salvage therapy. Nevertheless, in our study a trend to a prolonged PFS and OS is observed in the group of patients receiving immunotherapy as salvage treatment. Novel agents such as lenalidomide and bispecific antibodies alone or in combination seem to improve the outcome in this population of FL with poor prognosis.

346P An assessment of marrow-infiltrating T cells in early relapsed hematologic cancer patients after allogeneic hematopoietic stem cell transplantation

346P An assessment of marrow-infiltrating T cells in early relapsed hematologic cancer patients after allogeneic hematopoietic stem cell transplantation

Time to recurrence and its relation to survival after recurrence in patients resected for stage III colon cancer

BackgroundIt is intuitively thought that early relapse is associated with poor survival after recurrence (SAR) in resected colon cancer (CC) patients, but this has never been formally studied. MethodsWe pooled data from stage III patients treated with oxaliplatin-based adjuvant therapy in two phase III trials, to analyse time to recurrence (TTR) and its relationship with SAR. TTR and SAR were also studied according to molecular status (mismatch repair (MMR), RAS, and BRAFV600E). Early relapsing patients were defined as patients having a TTR event within 12 months after starting adjuvant chemotherapy. Results4548 stage III CC patients were included in the present analysis. Deficient MMR (dMMR) CC patients experienced fewer recurrences than proficient (p)MMR CC patients (18.8% versus 27.6%) but had a significantly shorter median TTR (mTTR; 0.74 versus 1.40 years, p < 0.0001). In pMMR patients, BRAF and RAS mutations were also associated with earlier mTTR as compared to double wild-type (WT) patients (0.99 versus 1.38 versus 1.54 years, respectively, p < 0.0001). Early recurrence occurred in 397 patients and was associated with a median SAR (2.2 versus 3.3 years, p = 0.0007). However, this association was mainly due to pMMR/RAS and BRAFV600E mutated tumours and was not confirmed in dMMR and pMMR/double WT subgroups. ConclusionIn resected stage III CC treated with standard oxaliplatin-based adjuvant therapy, TTR varies between dMMR, pMMR/RAS, or BRAFV600E mutated and pMMR/double WT tumours. In addition, early relapse is associated with poor survival, mainly due to patients resected for a pMMR/RAS or BRAFV600E mutated tumour.

Identification of predictive factors for early relapse in patients with unresectable stage III non-small cell lung cancer receiving consolidation durvalumab after concurrent chemoradiation therapy.

Patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC) receiving definitive concurrent chemoradiation therapy (CCRT) benefit from durvalumab consolidation therapy. However, predictive factors for early relapse during durvalumab maintenance have not yet been identified. The present study included the lung cancer cohort of the Catholic Medical Centers at the Catholic University of Korea from January 2018 to December 2021. A total of 51 NSCLC patients treated with durvalumab consolidation therapy after definitive CCRT were included in the analysis. Early relapse was defined as patients experiencing relapse within 6 months of starting initial durvalumab therapy. Among the 51 patients, 15 (29.4%) relapsed during the study period. Median time from initial therapy of durvalumab to progression was 451.00 ± 220.87 days (95% confidence interval [CI]: 18.10-883.90) in overall patients. In multivariate analysis, younger age (adjusted odds ratio [aOR], 0.792; 95% CI: 0.642-0.977; p = 0.030), higher pack-years (aOR, 1.315; 95% CI: 1.058-1.635; p = 0.014), non-COPD (aOR, 0.004; 95% CI: 0.000-0.828; p = 0.004) and anemia (aOR, 234.30; 95% CI: 1.212-45280.24; p = 0.042), were independent predictive factors for early relapse during durvalumab consolidation therapy. Younger age, higher number of pack-years, non-COPD, and anemia were independent predictive factors for early relapse during durvalumab consolidation therapy in patients with unresectable stage III NSCLC after definitive CCRT. Careful patient selection and clinical attention are needed for high-risk individuals.

A three-gene signature marks the time to locoregional recurrence in luminal-like breast cancer

Gene expression profiling (GEP)-based prognostic signatures are being rapidly integrated into clinical decision making for systemic management of breast cancer patients. However, GEP remains relatively underdeveloped for locoregional risk assessment. Yet, locoregional recurrence (LRR), especially early after surgery, is associated with poor survival. GEP was carried out on two independent luminal-like breast cancer cohorts of patients developing early (≤5 years after surgery) or late (>5 years) LRR and used, by a training and testing approach, to build a gene signature able to intercept women at risk of developing early LRR. The GEP data of two in silico datasets and of a third independent cohort were used to explore its prognostic value. Analysis of the first two cohorts led to the identification of three genes, CSTB, CCDC91 and ITGB1, whose expression, derived by principal component analysis, generated a three-gene signature significantly associated with early LRR in both cohorts (P value <0.001 and 0.005, respectively), overcoming the discriminatory capability of age, hormone receptor status and therapy. Remarkably, the integration of the signature with these clinical variables led to an area under the curve of 0.878 [95% confidence interval (CI) 0.810-0.945]. In in silico datasets we found that the three-gene signature retained its association, showing higher values in the early relapsed patients. Moreover, in the third additional cohort, the signature significantly associated with relapse-free survival (hazard ratio 1.56, 95% CI 1.04-2.35). Our three-gene signature represents a new exploitable tool to aid treatment choice in patients with luminal-like breast cancer at risk of developing early recurrence.

Real-world clinical and survival outcomes of patients with early relapsed triple-negative breast cancer from the ESME national cohort

BackgroundEarly metastatic relapse of triple-negative breast cancer (mTNBC) after anthracyclins and/or taxanes based (A/T) primary treatment represents a highly aggressive cancer situation requiring urgent characterisation and handling. Epidemio-Strategy-Medico-Economical-Metastatic Breast Cancer (ESME-MBC) database, a multicenter, national, observational cohort (NCT03275311) provides recent data on this entity. MethodsAll ESME patients diagnosed between 2008 and 2020 with mTNBC occurring as a relapse after a systemic neoadjuvant/adjuvant taxane and/or anthracycline-based chemotherapy were included. Early relapses were defined by a metastatic diagnosis up to 12 months of the end of neo/adjuvant A/T chemotherapy. We assessed overall survival (OS) and progression-free-survival under first-line treatment (PFS1) by early versus late relapse (≥12 months). ResultsPatients with early relapse (N = 881, 46%) were younger and had a larger tumour burden at primary diagnosis than those with late relapses (N = 1045). Early relapse rates appeared stable over time. Median OS was 10.1 months (95% CI 9.3–10.9) in patients with early relapse versus 17.1 months (95% CI 15.7–18.2) in those with late relapse (adjusted hazard-ratio (aHR): 1.92 (95% CI 1.73–2.13); p < 0.001). The median PFS1 was respectively 3.1 months (95% CI 2.9–3.4) and 5.3 months (95% CI 5.1–5.8); (aHR: 1.66; [95% CI 1.50–1.83]; p < 0.001). Among early relapsed patients, a higher number of metastatic sites, visceral disease but not treatment types, were independently associated with a poorer OS. ConclusionThese real-world data provide strong evidence on the dismal prognosis, higher treatment resistance and major unmet medical need associated with early relapsed mTNBC.Database registration: clinicaltrials.gov Identifier NCT032753

Long term follow-up analysis of plasma miR371 expression to detect early relapse in patients with clinical stage I testicular germ cell tumors on surveillance.

5006 Background: Clinical Stage I (CSI) is the most common presentation of germ cell testicular tumors (GCT) and patients are usually managed with active surveillance, in absence of reliable biomarkers of relapse. Circulating plasma miR371a-3p (miR371) has demonstrated high sensitivity and specificity in advanced non teratoma GCT. However, its operating characteristics and power to detect early relapse are still undefined. Methods: CSI GCT patients enrolled in the British Columbia provincial biobank with available plasma samples after radical orchiectomy were included in this study. Plasma miR371 was qualitatively assessed by RT-PCR. Sensitivity, specificity, negative and positive predictive values (NPV, PPV) and AUC in predicting tumor recurrence were evaluated in the post-orchiectomy blood samples and/or during the follow-up prior to or at the time of the clinically evident relapse. Relapse free survival (RFS) was correlated to post-orchiectomy miR371 status. Results: One-hundred-one patients were analyzed, 35 (34.6%) experienced a disease relapse with a median follow-up of 41 months. miR371 was positive in 22/35 of the relapsed patients. The specificity and PPV were 100% (95% CI: 94.5 - 100 for both), sensitivity 62.8% (95% CI: 44.9 - 78.5), NPV 83.5% (95%CI: 76.7 - 88.6) and AUC 0.81 (95% CI: 0.71 - 0.91). No false positive results were observed. The RFS of the patients with positive post-orchiectomy miR37 was significantly shorter (median: 3.5 months vs. not reached; p&lt;0.0001) compared to the patients with a negative post-orchiectomy miR371 (HR: 16.9; 95% CI: 2.1 - 135.7; p&lt;0.0001). miR371 sensitivity correlated with tumor burden, time between tumor relapse and miRNA testing and histology (nonseminoma &gt; seminoma). Conclusions: miR371 has high specificity and PPV in detecting GCT at an early stage and could be used to predict GCT relapse during surveillance and to guide treatment selection after orchiectomy. Further studies have been planned for validation of miR371 clinical utility.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: DLBCL that fails to achieve a complete response (CR) or relapses early after standard immunochemotherapy (IC, e.g., R-CHOP or similar) is referred to as primary refractory DLBCL (prDLBCL) and has a poor prognosis. Different definitions of prDLBCL have been used in literature, and it is uncertain which definition of primary refractory correlates most closely with survival outcomes. In this study, we examined the association of time to refractory status with survival outcomes in patients with prDLBCL. Methods: Adult patients diagnosed with DLBCL between 2015 and 2020 and seen at an academic center included in the lymphoma epidemiology of outcomes (LEO) cohort were included. PrDLBCL was defined as no response or progressive disease (PD) during frontline IC (primary progressive disease, PD), partial response (PR) at end of treatment (EOT PR), or relapse with 12 months after achieving CR at EOT (early relapse). Clinical characteristics, treatment and response data (by Lugano 2014 response criteria), and follow-up data were abstracted from LEO. Results: Out of 2747 DLBCL patients, 310 (11.3%) had prDLBCL, 147 with PD, 66 with EOT PR, and 97 with early relapse. No significant differences in age, gender, race, number of extranodal sites, stage, IPI, or cell of origin were found between the 3 groups. The proportion of MYC and BCL2/BCL6 rearrangements or Myc/Bcl2 double expressor was small and not different among the 3 groups. Salvage therapies were mainly platinum based high-dose chemotherapy (57%), MTX-based therapy for CNS relapse (12%), or targeted therapies (9%). Patients with PD had significantly lower CR/PR rates (19.6%/19.6%) to second line therapy compared to patients with EOT PR (32.1%/30.4%) or early relapse (50.6%/19.1%)(P < 0.001). The 2-year overall survival (OS) rate was 31% for patients with PD, which was significantly worse compared to patients with EOT PR (2-year OS 50%) or early relapse (2-year OS 58%)(P = 0.001)(Figure 1A). In patients with early relapse, the 2-year OS was not significantly different among those who relapsed within 3 months or between 3 and 6 months but appeared better for those relapsing between 6 and 12 months (Figure 1B). Our findings validate the results in our previously reported Mayo cohort, other than the survival improvement in early relapsing patients between 6 and 12 months in LEO. Keyword: Aggressive B-cell non-Hodgkin lymphoma Conflicts of interests pertinent to the abstract. Y. Wang Employment or leadership position: Merck - immediate family member Consultant or advisory role: Loxo; Incyte; Innocare; TG Therapeutics; Kite, A Gilead Company; Lilly; Janssen; BeiGene Stock ownership: Merck - immediate family member Honoraria: Kite, A Gilead Company Research funding: InnoCare; Incyte; Novartis; Genentech; Loxo; MorphoSys; Genmab M. J. Maurer Employment or leadership position: Exact Sciences - immediate family member Consultant or advisory role: Genmab; Adpative Biotechnologies Stock ownership: Exact sciences - immediate family member Research funding: MorphoSys; Bristol Myers Squibb; roche/Genentech; Genmab S. Ayyappan Consultant or advisory role: TG Therapeutics, Seattle Genetics, BeiGene, Intellisphere LLC, Fate Therapeutics, AstraZeneca Pharmaceuticals, Abbvie Research funding: Genmab, Regeneron, Genentech T. M. Habermann Consultant or advisory role: Celgene; Kite/Gilead Research funding: Genentech Other remuneration: Uncompensated: Tess Therapeutics; Loxo/Lilly; MorphoSys; Incyte; BeiGene J. R. Cerhan Consultant or advisory role: Bristol-Meyers-Squibb; Protagonist Therapeutics Research funding: NanoString Technologies; Celgene; Genentech; Genmab; Other remuneration: Uncompensated: Regeneron G. S. Nowakowski Consultant or advisory role: Celgene; MorphoSys; Genentech; Selvita; Debiopharm Group; Kite/Gilead; TG Therapeutics; Kymera; Karyopharm Therapeutics; Ryvu Therapeutics; Bantham Research funding: Celgene; NanoString Technologies; MorphoSys

Abstract 6757: Identification of predictive factors for early relapse in patients with unresectable stage III NSCLC receiving consolidation durvalumab after concurrent chemoradiation

Abstract Background: Patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC) receiving definitive concurrent chemoradiation (CCRT) benefit from durvalumab consolidation therapy. However, predictive factors for early relapse during durvalumab maintenance were not identified. Patients and Methods: The present study used the lung cancer cohort of the Catholic Medical Centers at the Catholic University of Korea from 2018 to 2021. In all, 51 NSCLC patients that were treated with durvalumab consolidation therapy after definitive CCRT. Early relapse was considered if it occurred within 6 months of starting initial durvalumab therapy. Results: During study period, 15 (29.4%) relapsed among 51 included patients. Median time from initial therapy of durvalumab to progression was 107.73 ± 47.69 days in early relapse group. In mutivariate analysis, younger age (HR 0.713, 95% CI 0.572-0.888, P=0.003), higher pack years (HR 1.311, 95% CI 1.109-1.549, P=0.001), non-COPD (HR 0.030, 95% CI 0.001-0.677, P=0.027), anemia (HR 23.30, 95% CI 2.030-267.48, P=0.011) and stage IIIC (vs. stage IIIA) (HR 17.890, 95% CI 1.997-160.243, P=0.010) were independent predictive factors for early relapse during durvalumab consolidation therapy. Conclusion: Younger age, higher pack years, non-COPD, anemia and stage IIIC were independent predictive factors for early relapse during durvalumab consolidation therapy in patients with unresectable stage III NSCLC after definitive CCRT. Careful patient selection and clinical attention are needed for high-risk individuals. Citation Format: Chang Dong Yeo, Hye Seon Kang, In Kyoung Kim, Sang Haak Lee, Jin Woo Kim. Identification of predictive factors for early relapse in patients with unresectable stage III NSCLC receiving consolidation durvalumab after concurrent chemoradiation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6757.

Matching-adjusted indirect comparison of isatuximab plus carfilzomib and dexamethasone with daratumumab plus lenalidomide and dexamethasone in relapsed multiple myeloma.

Lenalidomide-based regimens are commonly used for early relapse in patients with relapsed and/or refractory multiple myeloma (RRMM) receiving at least one prior line of therapy. In the absence of head-to-head comparison, matching-adjusted indirect comparison (MAIC) was conducted to demonstrate efficacy and safety of isatuximab+carfilzomib+dexamethasone (Isa-Kd) versus daratumumab + lenalidomide + dexamethasone (Dara-Rd) in RRMM. Patient-level data from IKEMA trial (Isa-Kd, n=179) were matched to aggregate data from POLLUX (Dara-Rd, n=286). Hazard ratios (HR) and 95% confidence intervals (CI) for progression-free survival (PFS) and overall survival (OS) were generated by weighted Cox proportional hazard models. Odds ratios (OR), 95% CI, and p-value were calculated for ≥very good partial response (≥VGPR) and treatment-emergent adverse events (TEAEs). After matching, no significant differences were observed between Isa-Kd and Dara-Rd in baseline characteristics except for patients with >3 prior lines (0.0% vs. 4.9%). Isa-Kd showed significantly better PFS (HR [95% CI]: 0.46 [0.24-0.86]; p=0.0155), statistically non-significant improvement favoring Isa-Kd in OS (0.47 [0.20-1.09]; 0.0798), and ≥VGPR (OR [95% CI]: 1.53 [0.89-2.64]; p=0.1252) than Dara-Rd. Odds of occurrence were significantly lower for some all-grade and grade 3/4 TEAEs with Isa-Kd than Dara-Rd. These results support Isa-Kd as an efficacious treatment for early relapse in non-lenalidomide refractory patients.