Lower Progression-free Survival Research Articles

Efficacy and Safety Evaluation of 177Lu-FAP-2286 in the Treatment of Advanced Lung Cancer

Purpose The aim of this study was to evaluate the efficacy and safety of peptide-targeted radionuclide therapy (PTRT) with 177Lu-FAP-2286 in advanced lung cancer. Patients and Methods This single-center prospective study included 9 patients diagnosed with advanced lung cancer. These patients met the inclusion criteria and received PTRT with 177Lu-FAP-2286. Short-term efficacy was assessed using RECIST 1.1 and PERCIST 1.0 criteria. Long-term efficacy was evaluated through overall survival, progression-free survival (PFS), overall response rate, EORTC QLQ-C30 v3.0, Eastern Cooperative Oncology Group, and Karnofsky Performance Status. Toxicity response was assessed using CTCAE v5.0. Results The results based on RECIST 1.1 and PERCIST 1.0 criteria were comparable, with 44% of patients showing a partial metabolic response, 33.3% with stable metabolic disease, and 22.22% with progressive metabolic disease. The highest metabolic response after treatment reached 66.89%, and the overall response rate could reach 77.78%. In the long-term efficacy assessment, the median overall survival and PFS were 10 months and 6 months, respectively. The 2 patients with the lowest PFS (3 months) started PTRT relatively late. EORTC QLQ-C30 v3.0, Eastern Cooperative Oncology Group, and Karnofsky Performance Status scores showed that the overall health status, symptom response, and quality of life of patients improved after 177Lu-FAP-2286 treatment. The most noticeable improvements in clinical symptoms were dyspnea and cancer-related pain. No grade III/IV toxicity events were observed during follow-up period, and fibrinogen decreased significantly after treatment. Conclusions 177Lu-FAP-2286 has the potential to be a viable PTRT option for patients with advanced lung cancer.

Abstract PO4-13-12: PIK3CA mutational status in tissue & plasma as a prognostic tool in HR+/HER2- breast cancer (BC)

Abstract Background: Activating mutations of PIK3CA gene are described in about 30-40% of BC. They confer overall worse prognosis and resistance to endocrine and chemotherapeutic therapy. Concordance between testing methods (tissue & plasma) are not widely studied. We aim to correlate tissue & plasma assays and to analyze the discordant cases and prognostic value of PIK3CA mutations (PIK3CAm) in HR+/HER2- BC. Methods: We performed a retrospective and unicentric analysis of PIK3CA mutational status in tissue & plasma samples in patients (pts) with HR+/HER2- BC from February/21 to April/23. PIK3CA test: Cobas®PIK3CA Mutation Kit. We correlated both diagnostic methods. Kaplan-Meier and Cox models were used to analyze progression-free survival (PFS) and comparison outcomes in PIK3CAm vs wild-type (wt). Results: We analyzed 225 samples from 161pts with HR+/HER2- BC (149 in tissue & 76 in plasma). PIK3CA mutations were detected in 62pts (38.5%), of which 39.6% (59pts) were detected in tissue and 11.8% (9pts) in plasma. Hotspot mutations: H1047X (45.7%), E545X (20%) and E542K (12.8%). In advanced disease, metastatic BC (mBC), tissue & plasma concordance was conducted in 64 cases, with overall correlation rate of 70.3%. We found PIK3CAm in 28pts: by both methods in 9pts (32.1%) and exclusively tissue detection in 19 cases (67.8%). Plasma detection was correlated with the presence of ≥3 metastatic sites (66.7% vs 31.6%; p=0.08) and with collection of samples during disease progression (66.7% vs 47.4%; p=0.43). 80pts received treatment with CDK4/6 inhibitors + endocrine therapy. PFS was slightly shorter in PIK3CAm vs wt (24m vs 30m; HR=1.39 [95%CI,0.7-2.4], p=0.26). A sub-analysis was performed based on exons 9 & 20, showing a significantly lower PFS in PIK3CAm exon 9 vs 20 population (9.7m vs 30.3m; HR=2.84 [95%CI,1.1-7.4], p=0.02). In addition, plasma detection of PIK3CAm was associated with worse PFS compared with PIK3CAm detected only in tissue (12.4m vs 29.3; HR=2.4 [95%CI,0.8-6.5], p=0.08). Although we observed a trend towards a poorer PFS in pts with visceral involvement in PIK3CAm (21.9m vs 30.1m; HR=2.82 [95%CI,0.6-12.3], p=0.14), in a multivariate analysis, mutations in exon 9 were an independent poor prognostic factor regardless visceral involvement and detection in plasma; p=0.05. Conclusions: Our results support the PIK3CA determination in tissue as the diagnostic method of choice, although further studies could better define the role of liquid biopsy in the detection of PIK3CAm. In our population, the presence of PIK3CAm confers poorer prognosis in luminal BC, being significantly worse in mutation carriers in exon 9 regardless visceral involvement and plasma mutation detection. Table. Tissue & plasma correlation in patients with PIK3CA mutational status tested in our population (mBC). Citation Format: Eduardo Terán Brage, Rebeca Lozano Mejorada, Aline Rodrigues Françoso, José Antonio Muñóz Leon, Álvaro López Gutiérrez, Luis Figuero-Pérez, Daniel Morchón Araujo, María Garijo Martínez, Jonnathan Roldán Ruiz, María Mar Abad Hernández, Magdalena Sancho de Salas, Emilio Fonseca Sánchez, César Augusto Rodríguez Sánchez. PIK3CA mutational status in tissue & plasma as a prognostic tool in HR+/HER2- breast cancer (BC) [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 PO4-13-12.

Prognostic impact of genetic abnormalities in 536 first-line chronic lymphocytic leukaemia patients without 17p deletion treated with chemoimmunotherapy in two prospective trials: Focus on IGHV-mutated subgroups (a FILO study).

The potential prognostic influence of genetic aberrations on chronic lymphocytic leukaemia (CLL) can vary based on various factors, such as the immunoglobulin heavy variable (IGHV) status. We conducted an integrative analysis on genetic abnormalities identified through cytogenetics and targeted next-generation sequencing in 536 CLL patients receiving first-line chemo(immuno)therapies (CIT) as part of two prospective trials. We evaluated the prognostic implications of the main abnormalities, with specific attention to their relative impact according to IGHV status. In the entire cohort, unmutated (UM)-IGHV, complex karyotype, del(11q) and ATM mutations correlated significantly with shorter progression-free survival (PFS). Focusing on the subset of mutated IGHV (M-IGHV) patients, univariate analysis showed that complex karyotype, del(11q), SF3B1 and SAMHD1 mutations were associated with significant lower PFS. The prognostic influence varied based on the patient's IGHV status, as these abnormalities did not affect outcomes in the UM-IGHV subgroup. TP53 mutations had no significant impact on outcomes in the M-IGHV subgroup. Our findings highlight the diverse prognostic influence of genetic aberrations depending on the IGHV status in symptomatic CLL patients receiving first-line CIT. The prognosis of gene mutations and cytogenetic abnormalities needs to be investigated with a compartmentalized methodology, taking into account the IGVH status of patients receiving first-line BTK and/or BCL2 inhibitors.

Upregulation of the Renin-Angiotensin System Is Associated with Patient Survival and the Tumour Microenvironment in Glioblastoma.

Glioblastoma is a highly aggressive disease with poor survival outcomes. An emerging body of literature links the role of the renin-angiotensin system (RAS), well-known for its function in the cardiovascular system, to the progression of cancers. We studied the expression of RAS-related genes (ATP6AP2, AGTR1, AGTR2, ACE, AGT, and REN) in The Cancer Genome Atlas (TCGA) glioblastoma cohort, their relationship to patient survival, and association with tumour microenvironment pathways. The expression of RAS genes was then examined in 12 patient-derived glioblastoma cell lines treated with chemoradiation. In cases of glioblastoma within the TCGA, ATP6AP2, AGTR1, ACE, and AGT had consistent expressions across samples, while AGTR2 and REN were lowly expressed. High expression of AGTR1 was independently associated with lower progression-free survival (PFS) (p = 0.01) and had a non-significant trend for overall survival (OS) after multivariate analysis (p = 0.095). The combined expression of RAS receptors (ATP6AP2, AGTR1, and AGTR2) was positively associated with gene pathways involved in hypoxia, microvasculature, stem cell plasticity, and the molecular characterisation of glioblastoma subtypes. In patient-derived glioblastoma cell lines, ATP6AP2 and AGTR1 were upregulated after chemoradiotherapy and correlated with an increase in HIF1A expression. This data suggests the RAS is correlated with changes in the tumour microenvironment and associated with glioblastoma survival outcomes.

Abstract LB277: Exposure response and safety analysis of osimertinib in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of locally advanced or metastatic NSCLC patients with EGFRm (FLAURA2)

Abstract Osimertinib (Osi) is a potent, CNS-active irreversible inhibitor of epidermal growth factor receptor-mutate (EGFRm) and T790M mutations. It is currently approved as the standard of care in patients with locally advanced (Stage IIIB or IIIC) or metastatic (Stage IV) EGFR T790M mutation-positive NSCLC whose disease has progressed on or after EGFR-TKI therapy and as the first-line agent in patients with locally advanced or metastatic EGFRm NSCLC. FLAURA2 is a global, randomized, open-label, multi-center phase III clinical study to investigate the safety and efficacy of Osi 80 mg once daily in combination with platinum-pemetrexed chemotherapy compared to Osi monotherapy, as a first-line treatment in patients with locally advanced or metastatic EGFRm NSCLC. This study is ongoing and an sNDA has been submitted for approval. The objectives of this current analyses were to 1) assess the exposure-efficacy relationship between population PK model-derived Osi exposure metrics (AUCss, Cmaxss, Cminss), and PFS in patients from the investigational arm (Osi + chemotherapy arm, n=244) of FLAURA2 study and 2) assess the relationship between Osi exposure metrics and key safety endpoints. The exposure response (ER) relationship between Osi and progression free survival (PFS) in patients enrolled in the investigational arm of FLAURA2 was assessed. Kaplan Meier plots with patients stratified by quartile exposure of Osi in the investigational arm indicated no clear ER relationship, though there appears to be a trend of lower PFS with highest AUCss quartile. A stepwise Cox proportional hazard analysis indicated that the effect of Osi exposure metrics were not statistically significant associated with PFS; however, the number of pemetrexed cycles appeared to be a significant covariate on PFS. The relationship between Osi exposure metrics and AEs CTCAE Grade 3 and above causally related to Osi, as well as AESIs from the investigational arm of FLAURA2 study were explored. The graphical exploration and logistic regression analysis did not identify statistically significant relationship of Osi exposures on CTCAE ≥ Grade 3 adverse events (AEs) causally related to Osi, AEs leading to Osi dose interruptions/reductions/discontinuations, and AESIs including ≥ Grade 3 haematological AEs, cardiac effects, left ventricular ejection fraction decrease and ≥ Grade 1 interstitial lung disease causally related to Osi. In conclusions, no statistically significant relationships between exposure of Osi and response were observed, supporting the recommended dose of Osi of 80 mg daily in the FLAURA2 patient population. Overall, the recommended dose of Osi as monotherapy or in combination with chemotherapy is 80 mg once daily, with a dose reduction to 40 mg daily if unacceptable toxicity is observed. Citation Format: Jincheng Yang, Damilola Olabode, Aarti Sawant, Karthick Vishwanathan, Srinivas Bachina, Alexandar Todd, Dana Ghiorghiu, Yuri Rukazenkov, Alex Phipps, Diansong Zhou, Azar Shahraz. Exposure response and safety analysis of osimertinib in combination with pemetrexed and platinum-based chemotherapy for the first-line treatment of locally advanced or metastatic NSCLC patients with EGFRm (FLAURA2) [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 LB277.

Abstract 2493: Prospective evaluation of predictive biomarkers for Palbociclib (P) and endocrine therapy (ET) benefit in hormone receptor (HR)-positive [+]/human epidermal growth factor receptor 2 (HER2)-negative [-] advanced breast cancer (ABC) patients (pts) from PARSIFAL clinical trial: The transFAL sub-study

Abstract BACKGROUND Combining cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i) with first-line ET is the standard of care for pts with HR[+]/HER2[-] ABC. PARSIFAL was a randomized, open-label, phase II trial that evaluated the efficacy and safety of first line P plus fulvestrant (F) or letrozole (L) in this pts population. Both treatments had comparable efficacy and safety results (JAMAOncol. 2021;7(12):1791-1799). Although multiple CDK4/6i clinical outcomes biomarkers have been reported, the only validated predictive factor for response is HR positivity. TransFAL, a translational study of PARSIFAL, assessed a comprehensive set of biomarkers of sensitivity/resistance to P plus ET. MATERIALS AND METHODS TransFAL employed a sample biorepository from PARSIFAL comprising formalin-fixed paraffin-embedded (FFPE) tissue and blood samples obtained from pts included in either study arm. Tumor samples (N=33) derived from the primary tumor at initial diagnosis or from primary tumor or metastatic lesions at study entry. Blood samples were obtained at baseline (N=73) and disease progression (N=22). Pts were categorized as sensitive or resistant based on progression-free survival (PFS). CDK4/6 pathway activation was assessed by immunohistochemistry for CDK4, CDK6, Rb, pRb, ER, PgR, and Ki67. Proteins extracted from FFPE slides were analyzed using hierarchical clustering, significance analysis of microarrays, and probabilistic graphical models. RNA expression and circulating tumor DNA (ctDNA) analysis were assessed by next-generation sequencing (NGS) and analysis of panel of 56 genes/gene regions, respectively. RESULTS A worse median PFS was found in pts with CDK6 positive (≥ 1% positive cells; p < 0.001) and high Ki67 (≥ 10% positive cells; p = 0.013)at baseline. ctDNA density at baseline was significantly higher for resistant (PFS < 9 months; 17.1 ng/mL) pts compared to sensitive (PFS > 31 months; 11.3 ng/mL) pts (p < 0.001). Most pts (83%) presented a genomic alteration detected in ctDNA, TP53 (28%) and PIK3CA (28%) being the most frequently mutated genes. Pts (9%) who harbored ARID1A mutation had lower PFS (p = 0.052). ESR1 mutations at progression were numerically higher in the L arm (37.5%) compared to F arm (14.3%); (p=0.31), but numbers were low. Proteomic and RNA analyses did not yield confirmable distinctive expression pattern between resistant/sensitive pts… CONCLUSIONS High Ki67 levels and CDK6 expression in the tumor and high ctDNA density, but not proteomic or RNA sequencing data, were associated to poor outcome in this analysis of pts treated with CDK4/6i and ET. This data adds to the growing evidence of poor prognosis biomarkers in this setting, highlighting the need of novel strategies for these pts. Citation Format: Joan Albanell, Angelo Gámez Pozo, Carlos L. Arteaga, Meritxell Bellet, Federico Rojo, Abel González, Beatriz Bellosillo, Violeta Serra, Petra Gener, José Antonio Guerrero, Laura López-Montero, Mario Mancino, Jose Rodríguez-Morató, Leonardo Mina, José Manuel Pérez-García, Javier Cortés, Antonio Llombart-Cussac. Prospective evaluation of predictive biomarkers for Palbociclib (P) and endocrine therapy (ET) benefit in hormone receptor (HR)-positive [+]/human epidermal growth factor receptor 2 (HER2)-negative [-] advanced breast cancer (ABC) patients (pts) from PARSIFAL clinical trial: The transFAL sub-study [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 2493.

Prognostic Significance of the Cribriform Pattern in Prostate Cancer: Clinical Outcomes and Genomic Alterations.

Given the diverse clinical progression of prostate cancer (PC) and the evolving significance of histopathological factors in its management, this study aimed to explore the impact of cribriform pattern 4 (CP4) on clinical outcomes in PC patients and examine its molecular characteristics. This retrospective study analyzed data from The Cancer Genome Atlas (TCGA) database and included PC patients who underwent radical prostatectomy (RP) and had pathology slides available for the assessment of CP4. A multivariable competing risk regression analysis was used to assess the association between CP4 and progression-free survival (PFS) while adjusting for established PC prognostic factors. The frequency of genomic alterations was compared between patients with and without CP4 using the Fisher's exact test. Among the 394 patients analyzed, 129 (32.74%) had CP4. After a median follow-up of 40.50 months (IQR: 23.90, 65.60), the presence of CP4 was significantly associated with lower PFS (AHR, 1.84; 95% CI, 1.08 to 3.114; p = 0.023) after adjusting for covariates. Seven hub genes-KRT13, KRT5, KRT15, COL17A1, KRT14, KRT16, and TP63-had significantly lower mRNA expression levels in patients with CP4 compared to those without. PC patients with CP4 have distinct genomic alterations and are at a high risk of disease progression following RP. Therefore, these patients may benefit from additional post-RP treatments and should be the subject of a prospective randomized clinical trial.

Improved survival over time with immunotherapy in locally advanced and metastatic cutaneous squamous cell carcinomas

PurposeCutaneous squamous cell carcinoma (cSCC) is the second most common cancer in white-skinned populations. There is little information on the epidemiology of cSCC, and even less on advanced cases (acSCC). Therefore, we analyzed acSCC patients to describe their characteristics, management, and outcomes over time.MethodsA single-center retrospective study was conducted over a period of 5 years, including all patients who started systemic therapy for acSCC. The patient characteristics, cSCC management, response to therapy, and survival were recorded. Patients were stratified into equal chronological periods (periods 1 and 2). A subgroup analysis was performed to compare patients who received immunotherapy (group 1) with those who did not (group 2).ResultsThe study included 127 patients, and patient numbers increased by an average of 19.7% per year. Most patients were male (88/127), elderly (mean 81.6 years), with comorbidities, and 27.6% were immunocompromised. The median overall survival (OS) was higher in period 2 (20 months) than in period 1 (10 months) (hazard ratio [95% confidence interval] = 0.62 [0.39; 0.98], p = 0.04). The risk of progression increased with age and immunosuppression. Of the 64 patients who received second-line therapy, 38 had immunotherapy (group 1) and 26 received other therapies (group 2). Immunotherapy reduced mortality and progression by 71% (p = 0.004) and 67% (p = 0.002), respectively.ConclusionsPatients with acSCC are usually very frail and elderly. OS increased over time, with a twofold improvement between periods 1 and 2, whereas progression-free survival (PFS) did not increase. Access to immunotherapy reduced mortality in a majority of patients in period 2. Immunosuppression and advanced age were associated with lower PFS.

The clinical impact of plasma estrogen receptor-1 mutation in patients with metastatic breast cancer: A meta-analysis.

The relevance of the discovered plasma ESR1 mutations in positive metastatic breast cancer (BC) patients who had progressing disease after aromatase inhibitor (AI)-based therapy is still being debated. We conducted this meta-analysis to explore the prognostic and predictive role of plasma ESR1 mutations in patients with progressive BC who have previously received AI therapy. We searched for relevant studies in the PubMed, Embase and Cochrane Library databases to be included in the meta-analysis. This study was performed to compute combined hazard ratios (HRs) with 95% confidence intervals (95% CIs) for the progression-free survival (PFS) rate and overall survival (OS) rate. Subgroup and sensitivity analyses were also performed. The heterogeneity between studies was evaluated using the I2 statistic. In this meta-analysis, a total of 1,844 patients with metastatic BC and positive for estrogen receptors (ERs) were enrolled from 8 articles. The analysis revealed that patients with circulating ESR1 mutations had significantly worse PFS (HR: 1.34; 95% CI: 1.17-1.55; p < 0.001) and OS (HR: 1.59; 95% CI: 1.31-1.92; p < 0.001) compared to wild-type ESR1 patients. Subgroup analysis showed that the types of plasma ESR1 mutations were associated with differences in the prognosis of metastatic BC. The D538G mutation showed a statistically significant lower PFS (p = 0.03), while the Y537S mutation was not significantly correlated with PFS (p = 0.354). According to the findings of this meta-analysis, the assessment for plasma ESR1 mutations may provide prognostic and clinical guidance regarding subsequent endocrine therapy decisions for ER-positive, metastatic BC patients who had received prior therapy with AIs.

Impact of Dysregulated LINC01559 and LINC01410 Expression on the Diagnosis and Survival of Non-Small Cell Lung Cancer.

Lung cancer is a widely recognized cancer with a very low survival rate, as it is mostly diagnosed at advanced stages. The most prevalent type of lung cancer is non-small cell lung cancer (NSCLC). LncRNAs are widely involved in cancer progression and migration. Therefore, we intended to estimate the circulatory expression levels of LINC01559 and LINC01410 in NSCLC and their roles in tumor prognosis evaluation as less invasive potential markers. The relative expression levels of the plasma cell-free lncRNAs LINC01559 and LINC01410 in seventy patients with NSCLC and seventy healthy subjects as controls were measured by real-time PCR. Enzyme-linked immunosorbent assays were utilized to measure carcinoembryonic antigen (CEA) concentrations. The LINC01559 and LINC01410 expression levels were significantly increased in NSCLC patients versus controls. Both lncRNAs showed good performance in the ROC curve analysis with high sensitivity and specificity for distinguishing patients from controls. LINC01559 had the highest AUC in the ROC curve analysis (0.96, 95 CI% CI: 0.93-0.99) for distinguishing patients from controls, while LINC01410 had the highest AUC (0.77, 95 CI% CI: 0.65-0.89) for differentiating metastatic tumors from nonmetastatic tumors. High expression levels of LINC01410 and LINC01559 were associated with low overall survival (log rank = 47.04 and 28.18, respectively, P < 0.001) and low progression-free survival (log rank = 40.68 and 28.77, respectively (P < 0.001)) and with the presence of metastasis. We suggest that LINC01559 and LINC01410 can be used as valuable, high-performing biomarkers in NSCLC diagnosis and prognosis prediction.

Outcomes and prognostic factors of advanced biliary tract cancers in Saudi Arabia.

460 Background: Biliary tract cancers which include gallbladder adenocarcinoma, intrahepatic and extrahepatic cholangiocarcinoma are rare, and carry a poor prognosis. There is limited data on biliary tract cancers in the Saudi population. Methods: This single center retrospective study was conducted with data of eligible cases from the last 4 years. Survival, chemotherapy regimens, and variables such as neutrophil to lymphocyte ratio (NLR), and other potential prognostic variables were collected. Results: The study included 155 patients of which 75 had intrahepatic cholangiocarcinoma and 74 had gallbladder adenocarcinoma. The majority were females at 63% of patients. Overweight to obese patients represented 59% of the study cohort. The majority of patients (62%) had an ECOG performance status of 2 and below. Comprehensive genomic profiling was done to 20% of cholangiocarcinoma cases. Elevated CA19-9 tumor marker (&gt; 37 micromol/L) was found in 57% of patients. De novo metastatic disease affected 82% of patients. One third of patients (33%) were not fit for first line chemotherapy, and were given best supportive care. First line chemotherapy of platinum + gemcitabine was given to 53% of fit patients, followed by gemcitabine alone given to 38%, followed by 5-Fluorouracil chemotherapy given to 9% of patients. Very few patients lived for 12 months or more at 16%. There was a significant association between NLR and progression free survival (PFS) with median PFS being 3.5 months in the NLR &gt; 3 group (95% CI 1.2-6 months) versus median PFS of 9.8 months in the NLR &lt; 3 group (95% CI 7.5-12 months, p=0.019). Conclusions: Biliary tract cancers still carry a poor prognosis. NLR ratio of more than 3 was found to predict a low PFS.

Impact of surgical approach on progress of disease by type of histology in stage IA endometrial cancer: a matched-pair analysis

BackgroundTo compare the impact of surgical approach on progression free survival (PFS) stratified by histologic type in women diagnosed with stage IA endometrial cancer.MethodsMyometrial invasion is classified into no myometrial invasion, <50% and ≥50%, with only no myometrial invasion and <50% are included in stage IA patients. A retrospective study is designed by collecting data from women diagnosed as stage IA endometrial cancer from January 2010 to December 2019 in a tertiary hospital. A propensity score is conducted for 1:1 matching in the low-risk histologic patients. Progression free survival and disease-specific survival data are evaluated by the Kaplan–Meier method and compared by the log-rank test in both the whole population and the matched-pair groups. A sub-group analysis is performed to figure out risk factors associated with the effect of surgical approach on PFS and disease-specific survival (DSS).Results534 (84.49%) low-risk histologic endometrial cancer women, with 389 (72.85%) operated by minimally invasive surgery and 145 (27.15%) by open approach, and 98 (15.51%) high-risk histology, with 71 (72.45%) by laparoscopy and 27 (27.55%) by open surgery, are included. Compared to open surgery, laparoscopy results in lower progression free survival in low-risk patients before and after matching (p = 0.039 and p = 0.033, respectively), but shows no difference in high-risk patients (p = 0.519). Myometrial invasion is associated with lower progression free survival in laparoscopy in low-risk histology (p = 0.027).ConclusionSurgical approaches influence progression free survival in stage IA low-risk histologic diseases, especially in those with myometrial invasion, but not in high-risk histologic endometrial cancer.

Impact of prognostic nutritional index change on prognosis after colorectal cancer surgery under propofol or sevoflurane anesthesia

BackgroundThe alteration of the prognostic nutritional index (PNI) or the utilization of distinct anesthesia strategies has been linked to the prognosis of various cancer types, but the existing evidence is limited and inconclusive, particularly for colorectal cancer (CRC). Our objective was to evaluate the association between PNI change and progression free survival (PFS) and overall survival (OS) in patients treated with CRC surgery after propofol-based or sevoflurane-based anesthesia.MethodsWe conducted a retrospective analysis of 414 patients with CRC who underwent surgical resection. Among them, 165 patients received propofol-based total intravenous anesthesia (TIVA-P), while 249 patients received sevoflurane-based inhalation anesthesia (IA-S). The PNI change (ΔPNI) was calculated by subtracting the pre-surgery PNI from the post-surgery PNI, and patients were categorized into high (≥ -2.25) and low (< -2.25) ΔPNI groups. Univariate and multivariate analyses were employed to evaluate the effects of the two anesthesia methods, ΔPNI, and their potential interaction on PFS and OS.ResultsThe median duration of follow-up was 35.9 months (interquartile range: 18–60 months). The five-year OS rates were 63.0% in the TIVA-P group and 59.8% in the IA-S group (hazard ratio [HR]: 0.96; 95% confidence interval [CI]: 0.70–1.35; p = 0.864), while the five-year PFS rates were 55.8% and 51.0% (HR: 0.92; 95% CI: 0.68–1.26; p = 0.614), respectively. In comparison to patients in the low ΔPNI group, those in the high ΔPNI group exhibited a favorable association with both OS (HR: 0.57; 95% CI: 0.40–0.76; p < 0.001) and PFS (HR: 0.58; 95% CI: 0.43–0.79; p < 0.001). Stratified analysis based on ΔPNI revealed significant protective effects in the propofol-treated participants within the high ΔPNI group, whereas such effects were not observed in the low ΔPNI group, for both OS (p for interaction = 0.004) and PFS (p for interaction = 0.024).ConclusionsOur data revealed that among patients who underwent CRC surgery, those treated with TIVA-P exhibited superior survival outcomes compared to those who received IA-S, particularly among individuals with a high degree of PNI change.

Outcomes of allogeneic hematopoietic stem cell transplantation for relapsed or refractory diffuse large B-cell lymphoma.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a currative treatment modality for diffuse large B-cell lymphoma (DLBCL) because of the intrinsic graft-versus-lymphoma effect. However, limited information is available regarding which patients with relapsed or refractory DLBCL are likely to benefit from allo-HSCT. We retrospectively analyzed data from 1268 DLBCL patients who received allo-HSCT. The overall survival and progression-free survival (PFS) rates were 30.3% and 21.6% at 3 years, respectively. Multivariate analysis revealed that stable or progressive disease at transplantation, male patient, poorer performance status at transplantation, and shorter intervals from previous transplantation were associated independently with a lower PFS. Four prognostic factors were used to construct a prognostic index for PFS, predicting 3-year PFS of 55.4%, 43.7%, 20.4% and 6.6%, respectively. The prognostic model predicted relapse rates following allo-HSCT accordingly (P < 0.0001), whereas did not predict transplantation-related mortality (P = 0.249). The prognostic index can identify a subgroup of DLBCL patients who benefit from allo-HSCT and it is worthwhile to evaluate whether this model is also applicable to patients undergoing allo-HSCT in cases of relapse after chimeric antigen receptor engineered T-cell therapy, although the application of allo-HSCT has been declining with the increase of novel immunotherapies.

Clinical characteristics and prognosis of newly diagnosed multiple myeloma patients with FGFR3 gene mutations

Objective: This study aimed to investigate the influence of FGFR3 gene mutations on the clinical characteristics and prognosis of patients with newly diagnosed multiple myeloma (NDMM) . Methods: A total of 198 patients with NDMM admitted to the Department of Hematology in Jiangsu Province Hospital between January 2016 and February 2023 were retrospectively analyzed. Next-generation sequencing and cytoplasmic light chain immunofluorescence with fluorescence in situ hybridization were performed for all patients. The prognostic significance of FGFR3 mutation and clinical features were analyzed using the Log-rank test and Cox proportional hazards model. Results: Among 198 patients, 28 carried the FGFR3 gene mutation. These patients had significantly lower serum albumin levels, higher β(2)-microglobulin levels, advanced Revised International Staging System stages, more frequent occurrence of t (4;14) , and shorter median progression-free survival (PFS) time (28 months vs 33 months, P=0.024) and overall survival (OS) time (54 months vs undefined, P=0.028) than patients without FGFR3 mutation. Additionally, patients carrying either FGFR3 mutation or t (4;14) had lower PFS (30 months vs 38 months, P=0.012) and OS (54 months vs undefined, P=0.017) than those without. The Cox proportional hazards model identified FGFR3 mutation as an independent risk factor for PFS and OS. Conclusion: FGFR3 gene mutation was an unfavorable independent prognostic predictor for NDMM.

Gene interaction network analysis in multiple myeloma detects complex immune dysregulation associated with shorter survival

The plasma cell cancer multiple myeloma (MM) varies significantly in genomic characteristics, response to therapy, and long-term prognosis. To investigate global interactions in MM, we combined a known protein interaction network with a large clinically annotated MM dataset. We hypothesized that an unbiased network analysis method based on large-scale similarities in gene expression, copy number aberration, and protein interactions may provide novel biological insights. Applying a novel measure of network robustness, Ollivier-Ricci Curvature, we examined patterns in the RNA-Seq gene expression and CNA data and how they relate to clinical outcomes. Hierarchical clustering using ORC differentiated high-risk subtypes with low progression free survival. Differential gene expression analysis defined 118 genes with significantly aberrant expression. These genes, while not previously associated with MM, were associated with DNA repair, apoptosis, and the immune system. Univariate analysis identified 8/118 to be prognostic genes; all associated with the immune system. A network topology analysis identified both hub and bridge genes which connect known genes of biological significance of MM. Taken together, gene interaction network analysis in MM uses a novel method of global assessment to demonstrate complex immune dysregulation associated with shorter survival.

Acute Myeloid Leukemia in Elderly, Unfit Patients: Analysis of Turkish AML Prospective Registry Database, on Behalf of Acute Leukemia Working Group of Turkish Society of Hematology

Objective: Low dose Ara-C and hypomethylating agents (HMAs) - decitabine (DEC) and azacitidine (AZA) - have made it possible to treat more elderly patients with acute myeloid leukemia (AML). Both HMAs demonstrated efficacy in monotherapy and in combination with targeted therapies. We analyzed the outcomes of elderly and unfit patients with newly diagnosed AML in our population. Methods: Analyses of our database revealed 222 eligible AML patients from diagnosed between January 2013 to December 2020. All patients were received low intensity treatments including AZA +/- venetoclax, DEC and low dose Ara-C. The effects of cytogenetic risk group, response rate, treatment type on overall survival (OS) and PFS (progression-free survival) were evaluated. Survival analyses were performed with the Kaplan-Meier method and log-rank test. A p-value of &amp;lt;0.05 was considered statistically significant. Results: Median age was 73 years (51-89). Eastern Cooperative Oncology Group (ECOG) performance score was &amp;lt;2 and ≥2 for 75 patients (36.8%) and 147 patients (63.2%), respectively. Of the patients 8.2% had favorable, 76.9% intermediate and 15.0% adverse risk according to European Leukemia Network (ELN) risk classification. Extramedullary involvement was present in 4.5%. Low dose treatment regimens included AZA in 119 patients (53.6%), DEC in 38 (17.6%), low dose ARA-C in 26 (11.7%) and AZA + venetoclax in 39 (17.1%). Complete remission was achieved in 61 patients (27.5%), whereas 39 patients (17.6%) had partial remission (PR) and 64 (28.8%) had stable/progressive disease (SD/PD). Overall response rate was 48.1%. CR rate was higher with AZA + venetoclax (44.7%, p=0,005) and other regimens had similar outcomes. Median OS was 10.3 months. No significant difference difference in PFS was observed between the regimens. However, the lowest PFS was observed with low-dose Ara-C (p=0.33). ELN risk groups revealed no significant effect on PFS and OS (p=0.77 and p=0.82, respectively). Infections were the most common cause of death (42.7%). Conclusions: The prognosis of AML in the elderly remains poor. HMA monotherapy is effective among elderly and unfit patients. However, combination therapies may be more effective and safe. The incorporation of targeted therapies may provide additional benefit in this patient group. However, the accessibility of several novel targeted drugs is still very limited in many countries.

Impact of Age on Outcome in Newly Diagnosed Multiple Myeloma Patients Undergoing Upfront Autologous Hematopoietic Cell Transplantation from the Worldwide Network for Blood and Marrow Transplantation Global Study

Background ： Induction therapy with proteasome inhibitors and immunomodulatory agents followed by autologous hematopoietic cell transplantation (HCT) is considered standard of care in front line multiple myeloma (MM) treatment. Utilization of autologous HCT is increasing worldwide in younger and older patients in light of improvements in supportive care and infrastructure. However, global perspectives on patterns of patient age and the impact of age on outcomes in this population are scarce. In the current analysis of global registry data, we focused on the age distribution and the association of age with outcomes after HCT worldwide. Methods: Data were provided by the Worldwide Network for Blood and Marrow Transplantation through the European Society for Blood and Marrow Transplantation (EBMT), the Center for International Blood and Marrow Transplantation (CIBMTR), the Australia and New Zealand Transplant and Cellular Therapy Registry (ANZTCTR), the Asian Pacific Blood and Marrow Transplant Group (APBMT), the Eastern Mediterranean Blood and Marrow Transplant Group (EMBMT), the Latin American Bone Marrow Transplant group (LABMT), and the Ottawa hospital myeloma registry. The study included newly diagnosed MM patients transplanted between 2013 and 2017. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS), incidence of relapse, and non-relapse mortality (NRM). The probability of OS and PFS was estimated based on the Kaplan-Meier method and differences were analyzed using the log-rank test. The incidences of relapse and NRM were modeled using the crude cumulative incidence estimator and compared between groups with Gray's test. Multivariate analyses were performed using Cox (cause-specific) proportional hazards models including a random effect for country. Age at HCT was modeled as a categorical variable (18-39, 40-64, 65-69, 70-74, and ≥75 years). Models further included patient sex, year of HCT, stage of disease at HCT, Karnofsky score, myeloma subclassification, conditioning dosage, interval between diagnosis and HCT, HCT comorbidity index, ISS at diagnosis, and cytogenetic risk score. Results: In total, 61,725 patients were included in this study; 37,459 (60.1%), 16,217 (26.3%), 3,164 (5.1%), 3,122 (5.1%), 543 (0.9%), 524 (0.8%), 339 (0.5%), 188 (0.3%), and 169 (0.3%) from EBMT, CIBMTR, ANZTCTR, Japan (APBMT), EMBMT, Taiwan (APBMT), LABMT, Ottawa, and Malaysia (APBMT), respectively. The median age at HCT was 60.8 (interquartile range: 54.6-65.8) years. The percentage of patients in the age groups 18-39, 40-64, 65-69, 70-74, and ≥75 years, varied considerably; 2%, 68.9%, 21.8%, 6.5%, and 0.8%, respectively (Table 1). The proportion of &amp;lt;40 years was higher in Malaysia, LABMT, and EMBMT (4-6%) compared to EBMT, CIBMTR, Japan, and ANZTCTR (2%). In contrast, the proportion of patients ≥65 years was higher in EBMT, CIBMTR, ANZTCTR, and Japan (&amp;gt;20%) compared to Malaysia, LABMT, and EMBMT (7-13%). The following patterns were observed in the age groups 18-39, 40-64, 65-69, 70-74, and ≥75 years, respectively. Melphalan 200 mg/m 2 for conditioning was used more frequently in younger patients (78.4%, 75.4%, 63.2%, 40.6%, and 28.3%, respectively). In 60.7% of the group ≥75 years, a lower dose of melphalan 140 mg/m 2 was chosen. OS was lower with older age (p&amp;lt;0.001) and was 86%, 83%, 81%, 78%, and 75% at 3 years, respectively (Figure and Table 1). PFS was similarly associated with older age (56%, 51%, 50%, 47%, and 45% at 3 years, respectively (p&amp;lt;0.001)). The cumulative incidence of relapse was not significantly different (15%, 16%, 15%, 16%, and 16% at 1 year, respectively (p=0.74)), but the cumulative incidence of NRM was higher with older age (p&amp;lt;0.001) and was 0%, 1%, 2%, 2%, and 4% at 1 year, respectively. On multivariate analysis, older age was associated with lower OS (overall p&amp;lt;0.0001), lower PFS (overall p=0.003), and higher NRM (overall p&amp;lt;0.0001), but not with the risk of relapse (overall p=0.79). Conclusions: There is considerable global variability in the age distribution of patients receiving HCT. Globally, 2% of patients receiving front line HCT for myeloma are aged &amp;lt;45 and 0.8% are &amp;gt;75 years. Advancing age was a significant risk factor for OS and PFS due to differences in NRM, but even in patients &amp;gt;75 years NRM was very low.

Pre-Graft Immune Status Predicts Survivals and Relapse in Adults Receiving Matched Peripheral Blood Stem Cell Allotransplants for Myeloid Malignancies

Background The impact on outcomes of pre-graft immune status has not been explored so far in recipients of allogeneic stem cell transplant (allo-SCT). Patients and Methods This was a retrospective and monocentric study including all consecutive adults who underwent a peripheral blood stem cell (PB) allo-SCT for a hematological malignancy between May 2017 and December 2021 in our Hematology Department. Immune status was routinely evaluated before transplant in each patient. Absolute lymphocyte (ALC) and monocyte counts were obtained from complete blood counts, while absolute counts of lymphocyte subsets (CD3+, CD4+ and CD8+ T cells, B and NK cells) were assessed by multiparameter flow cytometry, and gamma globulin levels by standard serum electrophoresis. We evaluated the impact of these parameters, considered as continuous variables, on overall survival (OS), progression-free survival (PFS), graft-versus-host disease (GVHD)-free, progression-free survival (GRFS), non-relapse mortality (NRM), and relapse incidence (RI), according to the type of the disease (myeloid vs. lymphoid) and the type of the donor (matched vs. haploidentical). Results This study included 264 patients with a median age of 59 years old (range 20-73, Table). A majority had a myeloid malignancy (75%, n=196) and received a graft from a matched donor (64%, n=170, sibling n=46; matched unrelated n=124) and a reduced-intensity conditioning regimen (80%, n= 211). Almost all (96%) patients with a matched donor received anti-thymoglobulin as GVHD prophylaxis while it was the case for 79% of those receiving a graft from a haploidentical donor. With a median follow-up of 32 months estimated by reversed Kaplan Meier analysis, 3-year (y) OS, PFS, and GRFS were respectively 53%, 46% and 31%, while 3-y NRM and RI were 28% and 25%, for the whole cohort. Pre-graft immune status was evaluated at a median of 20 days before transplant, showing significant higher median T and B cell counts and gamma globulin level in patients with myeloid malignancy, reflecting probably the less immunosuppressive intensity of chemotherapies received before transplant ( Table). Considering myeloid malignancies, OS and NRM were not impacted by the pre-graft immune status. In multivariate analysis, adjusting for disease type, status, donor type (sibling versus [vs] unrelated), and conditioning (RIC vs MAC vs sequential), a higher ALC was associated with significant lower PFS (hazard ratio [HR] 1.39, 95%CI: 1.11-1.74, p=0.004) and GRFS (HR: 1.30, 1.07-1.59, p=0.009), and a significant higher risk of relapse (HR 1.85, 1.32-2.59, p=&amp;lt;0.001), but this was true only in case of a matched transplant. Interestingly, T-cell subsets were associated with relapse (CD3: HR 1.94, p&amp;lt;0.001; CD4: HR 2.34, p=0.004; CD8: HR 2.34, p&amp;lt;0.001), but not B-cells (HR 2.23, p=0.56), gamma-globulin levels (HR 0.98, p=0.68), nor NK-cells (HR 2.72, p=0.17). T cell subsets, B cells, NK cells, gamma-globulin and monocytes were not associated with PFS and GRFS. Also, to highlight the adverse effect of an elevated ALC, and using a ROC curve, a threshold of 1.23 Giga/L was retained as the best cut-off to predict relapse. This was then applied to create a visual comparison of PFS, GRFS and RI ( Figure), revealing an early increased RI in patients with ALC &amp;gt; 1.23 Giga/L (3-month relapse rate: 13% vs 2.3%, p=0.03). Finally, the pre-graft immune status did not impact the outcomes of patients receiving a PB haplotransplant for a myeloid malignancy. This was true also for those who received a PB matched or again a haploidentical transplant for a lymphoid disease. Conclusions This retrospective analysis suggests that higher ALC at transplant predicts lower PFS and GRFS due to higher RI in adults receiving a PB matched transplant for a myeloid malignancy. Patients with a myeloid malignancy had also a better immune status at transplant which may reflect less immunosuppressive treatments received before transplant. Paradoxically, this better immune status may interfere with allogeneic T lymphocytes by reducing the graft-versus-leukemia effect. Thus, increasing immunosuppression (via the conditioning or drugs used for GVHD prophylaxis) may improve outcome in some specific sub-groups of patients with higher autologous T lymphocytes at transplant.

French Early Nationwide Idecabtagene Vicleucel (Ide-Cel) Chimeric Antigen Receptor (CAR) T-Cell Therapy Experience in Patients with Relapsed/Refractory Multiple Myeloma (FENIX): Update of the IFM Study from the Descar-T Registry

Introduction Prognosis of patients with relapsed/refractory multiple myeloma (RRMM) is poor, particularly in triple-class refractory patients (refractory to a proteasome inhibitor, an immunomodulatory drug and an anti-CD38 monoclonal antibody). Idecabtagene vicleucel (Ide-Cel) is the first chimeric antigen receptor (CAR) T-cell therapy targeting the B-cell maturation antigen (BCMA) approved by both the European Medicines Agency and the US FDA and the only one available in France through the Early Access Program for treatment (≥ 3 lines) of RRMM. Here we present an update of characteristics and outcome of patients enrolled in this program. Methods We conducted a multicenter, retrospective, observational study that included all consecutive patients with RRMM registered in the DESCAR-T database of patients treated with CAR T therapy, who underwent apheresis up to November 2022 to be treated by commercial Ide-Cel in France. The main objective was to analyze efficacy in terms of response rates, progression free survival (PFS) and overall survival (OS). Secondary objectives included evaluation of safety in terms of cytokine release syndrome (CRS), neurotoxicity, cytopenia, infections and management of relapse including subsequent anti myeloma therapies (sAMT). Results From June 2021 to November 2022, 207 patients were registered in DESCAR-T and underwent leukapheresis to be treated with Ide-cel, 164 (79%) were infused; 43 were not infused: 13 due to rapidly progressive disease or death and 5 due to manufacturing failure. Fifty seven (28%) patients did not meet KarMMa inclusion criteria: cytopenia (n=23), kidney failure (n=13), performance score (PS) &amp;gt;1 (n=15), prior anti BCMA drug conjugate antibody (n=8), prior allograft (n=5). Median age of the 164 patients was 60.5 years (range 34-82), 59% were male, median number of prior treatment lines was 4 (range 2-12) including prior autologous stem cell transplantation in 147 (90%); 130 (80%) were triple-refractory, 47 (29%) were penta-refractory. At diagnosis, 12 (16%) patients had R-ISS stage III disease (89 missing). High tumor burden (&amp;gt; 30% BMPCs) was present in 71 patients (54%) (33 missing). High risk cytogenetic abnormalities defined by del(17p) or t(4;14) were present in 63 patients (58%) (56 missing) and 15 (23%) had extramedullary disease (EMD) (98 missing). One hundred and forty-two (87%) received bridging therapy of which 39 (27%) responded: 25 had partial response (PR); 8 very good partial response (VGPR); 6 complete response (CR). Median time from apheresis to infusion was 62 days. Median follow-up after infusion was 6.2 months. In the first 3 months, overall response rate was 82% (n=134), best achieved response was CR, VGPR and PR in 60 (38%), 36 (23%) and 38 (24%) respectively. Median PFS was 11.6 months (95% CI (7.1; NA)). The 12-month OS was 73% (95% CI (64; 84)). In the first 6 months post-infusion, MRD was analyzed for 45 patients and reached negativity rate in 77%. In univariate analysis, only EMD had a significant impact on PFS: median PFS was 6.3 months (95% CI (3; NA)) for patients with EMD (p = 0.003; HR 3.5, 95% CI (1.55; 7.9)). CRS occurred in 146 (89%) patients, with only 3 cases (2%) of grade ≥ 3. Neurotoxicity occurred in 19 (12%) patients (5 with grade ≥ 3). Ninety-eight (60%) patients received tocilizumab, and 37 (23%) received steroids. Persistent grade ≥ 3 thrombocytopenia, anemia and neutropenia at M1 were observed in 55 (34%), 20 (12%) and 90 (55%) patients, respectively. Forty (24%) patients presented infections grade ≥ 3 in the first six months after infusion. Fifty-two patients progressed during follow-up. 34/52 patients (65%) received a sAMT. Median time from relapse to first administration of sAMT was 0.6 months. Eighteen received bispecific antibodies including 12 anti-BCMA and 6 anti-GPRC5D. Among these 34 patients, a total of 13 (38%) died. Overall, at data cut-off, 26 patients had died, including 9 after disease progression, 4 of acute toxicity and 2 of sepsis. Conclusion This updated study confirms safety and efficacy of Ide-cel in patients with RRMM in real world settings. Response rates and safety were comparable to those reported in the registration trial (Munshi et al., 2021) and American real world study (Hansen et al., 2023). Importantly, patients with EMD had a significant lower PFS. Prognosis data at relapse following ide-cel require a longer follow up and will be presented at ASH.