Negative Prognostic Factor For Progression-free Survival Research Articles

High Serum Levels of CCL20 Are Associated with Recurrence and Unfavorable Overall Survival in Advanced Melanoma Patients Receiving Immunotherapy.

Immune checkpoint inhibition has revolutionized melanoma therapy, but many patients show primary or secondary resistance. Biomarkers are, therefore, urgently required to predict response prior to the initiation of therapy and to monitor disease progression. In this prospective study, we analyzed the serum C-C motif chemokine ligand 20 (CCL20) concentration using an enzyme-linked immunosorbent assay. Blood was obtained at baseline before the initiation of immunotherapy with anti-PD-1 monotherapy or Nivolumab and Ipilimumab in advanced melanoma patients (stages III and IV) enrolled at the University Medical Center Hamburg-Eppendorf. The CCL20 levels were correlated with clinico-pathological parameters and disease-related outcomes. An increased C-C motif chemokine ligand 20 (CCL20) concentration (≥0.34 pg/mL) at baseline was associated with a significantly impaired progression-free survival (PFS) in the high-CCL20 group (3 months (95% CI: 2-6 months) vs. 11 months (95% CI: 6-26 months)) (p = 0.0033) and could be identified as an independent negative prognostic factor for PFS in univariate (Hazard Ratio (HR): 1.98, 95% CI 1.25-3.12, p = 0.004) and multivariate (HR: 1.99, 95% CI 1.21-3.29, p = 0.007) Cox regression analysis, which was associated with a higher risk than S100 (HR: 1.74). Moreover, high CCL20 levels were associated with impaired overall survival (median OS not reached for low-CCL20 group, p = 0.042) with an HR of 1.85 (95% CI 1.02-3.37, p = 0.043) in univariate analysis similar to the established prognostic marker S100 (HR: 1.99, 95% CI: 1.02-3.88, p = 0.043). CCL20 may represent a novel blood-based biomarker for the prediction of resistance to immunotherapy that can be used in combination with established strong clinical predictors (e.g., ECOG performance score) and laboratory markers (e.g., S100) in advanced melanoma patients. Future prospective randomized trials are needed to establish CCL20 as a liquid biopsy-based biomarker in advanced melanoma.

Assessing the effectiveness and safety of surufatinib versus everolimus or sunitinib in advanced neuroendocrine neoplasms: insights from a real-world, retrospective cohort study using propensity score and inverse probability treatment weighting analysis.

While surufatinib, sunitinib, and everolimus have shown efficacy for advanced neuroendocrine neoplasms (NENs) in randomized controlled trials (RCTs), direct comparisons in a real-world setting remain unexplored. This gap highlights the clinical need to understand their comparative effectiveness and safety within the diverse Chinese population. Addressing this, our study provides insights into the real-world performance of these therapies, aiming to inform treatment selection and improve patient outcomes. A retrospective, observational study was conducted at Fudan University Shanghai Cancer Center, including patients with advanced NENs treated with surufatinib, sunitinib, or everolimus between July 2020 and April 2023. Eligibility criteria focused on histologically confirmed, locally advanced, unresectable, or metastatic NENs, with patients having received at least one month of targeted therapy. We employed inverse probability weighting (IPW) with the propensity score (PS) matching to adjust for the bias of baseline characteristics. The assessment of covariates included age, sex, performance status, primary tumor site, functional status, genetic mutations, tumor differentiation, Ki67 index, tumor grade, metastasis site, and previous therapies. The primary outcome was progression-free survival (PFS), and secondary outcomes included objective response rate (ORR), disease control rate (DCR), and adverse events (AEs). The study enrolled 123, 56, and 68 locally advanced or metastatic NEN patients treated with surufatinib, sunitinib, and everolimus, respectively. Before adjusting for confounding factors, surufatinib was used less frequently as a first-line treatment compared to sunitinib and everolimus in pancreatic NENs (pNENs) (11.1% vs. 22.1%, P=0.057). Significant differences were noted in prior treatments and tumor characteristics between surufatinib and everolimus groups in extrapancreatic NENs (epNENs) (P<0.05). Post-IPW, these disparities were resolved (P>0.05). Surufatinib demonstrated superior median PFS (mPFS) in both pancreatic [8.30 vs. 6.33 months, hazard ratio (HR) 0.592, P<0.001] and epNENs (8.73 vs. 3.70 months, HR 0.608, P<0.001) compared to everolimus or sunitinib. Notably, male gender (HR 1.75, P=0.001), functional status (HR 2.09, P=0.01), Ki67 index >20% (HR 12.7, P=0.004), previous somatostatin analogue (SSA) treatment (HR 1.73, P=0.001), germline mutation (HR 5.62, P<0.001), poor differentiation (HR 7.45, P<0.001), liver metastasis (HR 1.72, P=0.001) and multiple treatment lines (HR 1.62 for 2nd line, P=0.04; HR 1.88 for ≥3rd line, P=0.01) were identified as negative prognostic factors for PFS. Conversely, dose adjustment (HR 0.63, P=0.009) and treatment with surufatinib (HR 0.58 for pNEN, P<0.001; HR 0.62 for epNEN, P=0.002) were correlated with longer PFS. In a real-world Chinese cohort, surufatinib significantly outperformed sunitinib and everolimus in prolonging PFS among advanced NEN patients, with identifiable clinical features impacting survival, and conclusions regarding superiority should be interpreted with caution due to the retrospective design. Our findings underscore the need for prospective studies to further validate these results and explore additional predictive biomarkers for personalized treatment strategies.

Application of the Second Revision of the International Staging System (R2-ISS) in the prognostic assessment of newly diagnosed multiple myeloma

Objective: To investigate the prognostic value of the Second Revision of the International Staging System (R2-ISS) in patients with newly diagnosed multiple myeloma (NDMM) . Methods: The retrospective study was performed in 326 NDMM patients with immunomodulatory drugs and/or proteasome inhibitors as the first-line treatment attending the Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, China, from December 2012 to March 2022. The Kaplan-Meier method was used for the survival analysis, with the Log-rank test comparing the between-group differences and Cox proportional risk regression modeling A multifactorial analysis was performed. Results: ①326 patients were included in the study, 190 of whom were males. The median age was 63 years, and the median followup time was 37 months. R2-ISS can effectively predict prognosis, particularly for R-ISS Ⅱ patients. The median progression-free survival (PFS) time of R2-ISS Ⅰ, R2-ISS Ⅱ, R2-ISS Ⅲ, and R2-ISS Ⅳ was 52, 29, 20, and 15 months (P<0.001), while the median overall survival (OS) time was 91, 60, 44, and 36 months (P<0.001). Multifactor analysis revealed that ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, LDH increased, and age >65 years old were independent negative prognostic factors for OS. ISS Ⅱ, ISS Ⅲ, del (17p), t (4;14), 1q+, and LDH were independent negative prognostic factors for PFS. ②The C-index score of R2-ISS was 0.724, higher than that of R-ISS (0.678), indicating high prediction efficiency. ③The median PFS for 1q+-related double-hit in R2-ISS Ⅲ and Ⅳ were 20, 15 months (P=0.084) and the median OS were 35, 36 months (P=0.786), respectively. In R2-ISS Ⅲ, there were twenty-seven cases of 1q+-related double-hit, sixty-one cases of 1q+ single abnormality, and sixty-eight cases with no 1q+. The median PFS for the three groups were 20, 18, and 21 months (P=0.974), while the median OS was 35, 47, and 56 months (P=0.042), respectively. Adjusting the assignment of 1q+ to 1, the median PFS and OS of different R2-ISS stages differed significantly after regrouping (P<0.001) . Conclusions: The prognostic stratification value of R2-ISS is higher than R-ISS, particularly in the highly heterogeneous R-ISS Ⅱ population. Adjusting the assignment of the 1q+-related double-hit can improve R2-ISS, which should be validated in future studies with multi-center and expanded cases.

Risk of relapse and patient selection for metastatic colorectal cancer liver surgery.

96 Background: Previous data on surgery for colorectal cancer (CRC) liver metastases (CRLM) documented improvement in overall survival (OS) and low perioperative mortality, but patient (pt) selection requires complex multidisciplinary work. Predictive scores such as the Comprehensive Evaluation of Relapse Risk (CERR) estimate relapse risk after surgery and help in the pre-operative decision. Objectives: This study aims to evaluate OS and progression-free survival (PFS) in a population of pts who had surgery for CRLM, and to analyse survival outcomes by risk groups, according to the CERR score. We identified individual, anatomic and biological factors with potential prognostic impact. Methods: We retrospectively analysed the medical records of pts who had CRLM surgery between January 2012 and December 2021 in two Portuguese reference centres. Outcomes for CRLM surgery were analysed by risk groups according to the CERR score of each pt (based on nodal status, preoperative CEA/CA 19.9 values, KRAS/BRAF status, presence of extrahepatic disease and modified tumour burden score). Univariate and multivariate survival analyses were performed with the log-rank test and Cox proportional-hazards regression models. Results: A total of 174 pts were included: 66,1% (n=115) male, mean age at CRLM diagnosis 62,1 (±11,5) years, 80,5% (n=140) with isolated liver metastases. Thirty-three pts (19%) had a second surgery, independently of the CERR score (chi-square p = 0,60). Eighteen (10,3%) pts had a CERR score of 0-1 (low-risk, LR), 96 (55,2%) of 2-3 (medium-risk, MR) and 60 (34,5%) of 4-5 (high-risk, HiR). With a median (MED) follow-up of 85,1 (15,6-186,5) months (mo), 100 (57.5%) pts have died. MED OS was 88,0 mo (95% confidence interval [CI] 40,6-135,4) for LR, 46,4 mo (95% CI 38,7-54,1) for MR and 30,7 mo (95% CI 23,1-38,4) for HiR pts (p=0,02); ECOG performance status was an independent prognostic factor (p=0,002) for OS. Median PFS was 88,0 mo (95% CI 6,9-169,0) for LR, 12,9 mo (95% CI 9,1-16,7) for MR and 7,7 mo (95% CI 5,9-9,4) for HiR pts (p&lt;0,001); positive resection margins and prior induction chemotherapy (CT) were additional independent negative prognostic factors for PFS (p&lt;0,001). Conclusions: These results suggest a significant association between relapse risk after surgery for CRLM and both OS and PFS. The CERR score can be used to select potential candidates for CRLM surgery and improve the impact of this intervention in pts with CRC. The link between induction CT and worse survival may reflect selection bias as these pts possibly had a higher volume of disease and therefore received initial systemic therapy. Prospective studies are required to confirm these results.

Clinical features and surgical outcomes of high grade pleomorphic xanthoastrocytomas: a single-center experience with a systematic review.

High grade pleomorphic xanthoastrocytomas (HGPXAs) are very rare and their management and prognostic outcomes remain unclear. To better understand the disease, we aimed to evaluate the risk factors for progression-free survival (PFS) and overall survival (OS), and propose a treatment protocol based on cases from our institute and cases from the literature. The authors reviewed the clinical data of 26 patients with HGPXAs who underwent surgical treatment in Department of Neurosurgery of Beijing Tiantan Hospital between August 2014 and September 2021. We also searched the PubMed database using the keywords "anaplastic" combined with "pleomorphic xanthoastrocytoma(s)" between January 1997 and October 2022. Risk factors for PFS and OS were evaluated in the pooled cases. The authors' cohort included 11 males and 15 females with a mean age of 36.7 ± 20.3 years (range: 5.5-71 years). Gross-total resection (GTR) and non-GTR were achieved in 17 (65.4%) and 9 (34.6%) patients, respectively. Radiotherapy and chemotherapy were administered to 22 and 20 patients, respectively. After a mean follow-up of 20.5 ± 21.2 months (range: 0.5-78.1 months), 7 patients suffered tumor recurrence and 6 patients died with a mean OS time of 19.4 ± 10.8 months (range: 8-36 months). In the literature between January 1997 and October 2022, 56 cases of HGPXAs were identified in 29 males and 27 females with a mean age of 29.6 ± 19.6 years (range; 4-74 years). Among them, 24 (44.4%) patients achieved GTR. Radiotherapy and chemotherapy was administered to 31 (62%) patients and 23 (46%) patients, respectively. After a median follow-up of 31.4 ± 35.3 months (range: 0.75-144 months), the mortality and recurrence rates were 32.5% (13/40) and 70% (28/40), respectively. Multivariate Cox regression model demonstrated that non-GTR (HR 0.380, 95% CI 0.174-0.831, p=0.015), age≥30 (HR 2.620, 95% CI 1.183-5.804, p=0.018), no RT (HR 0.334,95% CI 0.150-0.744, p=0.007) and no CT (HR 0.422, 95% CI 0.184-0.967, p=0.042) were negative prognostic factors for PFS. Non-GTR (HR 0.126, 95% CI 0.037-0.422, p=0.001), secondary HGPXAs (HR 7.567, 95% CI 2.221-25.781, p=0.001), age≥30 (HR 3.568, 95% CI 1.190-10.694, p=0.023) and no RT (HR 0.223,95% CI 0.073-0.681, p=0.008) were risk factors for OS. High grade pleomorphic xanthoastrocytomas are very rare brain tumors. Children and younger adults have better clinical outcome than elderly patients. Secondary HGPXAs had worse OS than primary HGPXAs. Complete surgical excision plus RT and CT is recommended for this entity. The frequency of BRAF mutations in HGPXAs is 47.5% (19/40) in this study, however, we do not find the connections between BRAF mutations and clinical outcomes. Future studies with larger cohorts are necessary to verify our findings.

Pathomorphological Manifestations and the Course of the Cervical Cancer Disease Determined by Variations in the TLR4 Gene.

Cervical cancer (CC) is often associated with human papillomavirus (HPV). Chronic inflammation has been described as one of the triggers of cancer. The immune system fights diseases, including cancer. The genetic polymorphism of pathogen recognition receptors potentially influences the infectious process, development, and disease progression. Many candidate genes SNPs have been contradictory demonstrated to be associated with cervical cancer by association studies, GWAS. TLR4 gene activation can promote antitumor immunity. It can also result in immunosuppression and tumor growth. Our study aimed to investigate eight selected polymorphisms of the TLR4 gene (rs10759932, rs1927906, rs11536898, rs11536865, rs10983755, rs4986790, rs4986791, rs11536897) and to determine the impact of polymorphisms in genotypes and alleles on the pathomorphological characteristics and progression in a group of 172 cervical cancer subjects with stage I-IV. Genotyping was performed by RT-PCR assay. We detected that the CA genotype and A allele of rs11536898 were significantly more frequent in patients with metastases (p = 0.026; p = 0.008). The multivariate logistic regression analysis confirmed this link to be significant. The effect of rs10759932 and rs11536898 on progression-free survival (PFS) and overall survival (OS) has been identified as important. In univariate and multivariate Cox analyses, AA genotype of rs11536898 was a negative prognostic factor for PFS (p = 0.024; p = 0.057, respectively) and OS (p = 0.008; p = 0.042, respectively). Rs11536898 C allele predisposed for longer PFS (univariate and multivariate: p = 0.025; p = 0.048, respectively) and for better OS (univariate and multivariate: p = 0.010; p = 0.043). The worse prognostic factor of rs10759932 in a univariate and multivariate Cox analysis for survival was CC genotype: shorter PFS (p = 0.032) and increased risk of death (p = 0.048; p = 0.015, respectively). The T allele of rs10759932 increased longer PFS (univariate and multivariate: p = 0.048; p = 0.019, respectively) and longer OS (univariate and multivariate: p = 0.037; p = 0.009, respectively). Our study suggests that SNPs rs10759932 and rs11536898 may have the potential to be markers contributing to the assessment of the cervical cancer prognosis. Further studies, preferably with larger groups of different ethnic backgrounds, are needed to confirm the results of the current study.

T cell engager (TCE) score in patients treated with bispecific CD3 TCE in phase I clinical trials.

2573 Background: Immune prognostic scores, such as the Gustave Roussy Immune (GRIM) score have been investigated in patients (pts) treated with immune check-point blockers. We aimed to determine whether we could improve the selection of pts that could benefit from new immunotherapies such as bispecific CD3 T cell engagers (TCE) antibodies in pts treated in phase I clinical trials (CT), by building a new prognostic score. Methods: All patients treated with bispecific CD3 TCE in phase I CT from July 2018 to February 2023 at the Drug Development Department at Gustave Roussy were enrolled in the study. Univariate and multivariate analyses (UVA and MVA) were conducted on demographic, clinical and biological data to assess their prognostic value on progression free survival (PFS). MVA results were used to build a new prognostic score (TCE score). This score was then validated on overall survival (0S). The predictive ability (on PFS and OS) of the TCE score was assessed using Harrell’s C index. It was compared with the GRIM and Royal Marsden Hospital (RMH) scores predictive ability on PFS and OS. Results: A total of 67 patients (47 men, 20 women) with metastatic solid cancer or advanced hematological cancer were included. Median age was 62 years old. The most represented tumor types were prostate cancer (33%), lymphoma (25%) and small cell lung carcinoma (24%). UVA on PFS showed that elevated C-reactive protein (CRP) (HR: 2,36; 95%CI: 1,35-4,16; p = 2.10-3) and lactate dehydrogenase (LDH) (HR: 3,00; 95%CI: 1,63-5,53; p = 2.10-4) were associated with a worst PFS. In MVA, LDH (HR: 2,49; 95% CI: 1,30-4,74, p = 1.10-4) and CRP levels (HR: 1,92; 95% CI: 1,1-3,46; p = 1.10-4) were independent negative prognostic factors for PFS. The TCE score was based on MVA results (CRP&gt;10g/l: +1; LDH &gt; 250U/l: +1). It showed that pts with a high score (1-2) had a shorter PFS (median PFS: 2,8 months) and OS (median OS: 9,9 months) than low score (0) pts (median PFS: 5,8 months; median OS: not reached). TCE score’s Harrell’s C index for PFS was 0,63 and 0,64 for OS. For GRIM and RMH scores, Harrell’s C index for PFS were respectively 0,60 and 0,55. For OS it was respectively 0,58 and 0,53. Conclusions: To select patients for Bispecific CD3 TCE phase I CT, we built a new prognostic score, based on LDH and CRP levels, that can be used as prognostic of PFS and OS. TCE score is more reliable than GRIM and RMH scores to prognose PFS and OS.

VENETOCLAX‐OBINUTUZUMAB FOR PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA: 6‐YEAR RESULTS OF THE RANDOMIZED CLL14 STUDY

Background: One-year fixed-duration venetoclax-obinutuzumab (Ven-Obi) is a standard-of-care for patients (pts) with previously untreated chronic lymphocytic leukemia (CLL). Due to its ongoing follow-up, the CLL14 study provides unique insights into long-term outcomes of pts after Ven-Obi therapy. Methods: Pts with previously untreated CLL and coexisting conditions were randomized 1:1 to Ven-Obi or chlorambucil-obinutuzumab (Clb-Obi). Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included safety, rates of minimal residual disease (MRD), time to next treatment (TTNT) and overall survival (OS). Results: Of 432 enrolled pts, 216 were randomly assigned to Ven-Obi, 216 to Clb-Obi. At a median follow-up of 76.4 months (interquartile range 52.5–80.5), PFS remained superior for Ven-Obi compared to Clb-Obi (median 76.2 vs. 36.4 months; HR 0.40 [95% CI 0.31–0.52], p < 0.0001). Progressive disease (PD) occurred in 67 cases in the Ven-Obi arm with 39 second-line treatments, and in 141 cases in the Clb-Obi arm (with 103 second-line treatments). TTNT was significantly longer after Ven-Obi (6-year TTNT 65.2% vs. 37.1%; HR 0.44, 95% CI 0.33–0.58, p < 0.0001). In both arms, the most frequent second-line treatments were BTK inhibitors (61.5% in the Ven-Obi arm, 55.4% in the Clb-Obi arm). The PFS and TTNT difference between the two arms was maintained across all risk groups, including pts with TP53 mutation/deletion (median PFS 51.9 vs. 20.8 months; median TTNT 57.3 vs. 29.0 months) and unmutated IGHV status (median PFS 64.8 vs. 26.9 months; median TTNT 85.4 vs. 40.6 months). Multivariate analysis identified TP53 deletion/mutation, unmutated IGHV and lymph node size ≥5 cm as independent negative prognostic factors for PFS in pts treated with Ven-Obi. Five years after treatment completion, 17 (7.9% of the intention-to-treat population) pts in the Ven-Obi arm still had uMRD (<10−4 by NGS in peripheral blood), 22 (10.2%) had low (L)-MRD (≥10-4 and <10-2) and 23 (10.6%) high (H)-MRD (≥10-2), compared to 4 (1.9%) uMRD, 9 (4.2%) L-MRD and 18 (8.3%) H-MRD in the Clb-Obi arm. Overall, 48 deaths were reported in the Ven-Obi arm (9 PD related) and 70 in the Clb-Obi arm (26 PD related); 6-year-OS rate was 78.7% in the Ven-Obi and 69.2% in the Clb-Obi arm (HR 0.69 [0.48–1.01], p = 0.052). Second primary malignancies were reported in 30 pts in the Ven-Obi and 18 in the Clb-Obi arm; cumulative incidences 6 years after randomization were 14.2% and 8.5%, respectively (p = 0.071). No new safety signals were observed. Encore Abstract - previously submitted to EHA 2023 The research was funded by: Roche, AbbVie Keywords: chronic lymphocytic leukemia (CLL), combination therapies Conflicts of interests pertinent to the abstract O. Al-Sawaf Consultant or advisory role: AbbVie, Ascentage, AstraZeneca, BeiGene, Eli Lilly, Gilead, Janssen, Roche Honoraria: AbbVie, Adaptive, AstraZeneca, BeiGene, Eli Lilly, Gilead, Janssen, Roche Research funding: AbbVie, BeiGene, Janssen, Roche Educational grants: AbbVie, AstraZeneca, Janssen, Gilead, Roche

Serum vitamin B12 levels and response to immunotherapy.

e14542 Background: Underlying metabolic pathways have a role in regulation of response to cancer immunotherapy. Due to its immunomodulatory properties, we sought to investigate the relationship between elevated serum vitamin B12 (VitB12) and survival among individuals with cancer treated with immune checkpoint inhibitors. Methods: Data from a retrospective chart review were used to identify patients with advanced cancer initiating anti-neoplastic treatment and a concomitant VitB12 measurement (elevated: &gt; 820 ng/L), between 1/2010-1/2022 at our institution. Patients on immunotherapy (IO) and other regimens (control) were compared using Mann-Whitney test for continuous variables, and Chi-square test or Fisher's test for categorical variables. Multivariate Cox regression models were used to assess the effect of VitB12 levels on overall survival (OS) and progression free survival (PFS), with adjustment for potential confounders. Results: A total of 501 patients were included (control, n = 408; IO, n = 93). Groups were well balanced for treatment line (first line, 91.4% vs. 94%), VitB12 levels (elevated, 29.9% vs. 23.7%; mean, 762.4 ng/L vs. 687.6 ng/L) and liver function tests. Cancer diagnoses differed between groups (most common, gastrointestinal vs. lung, p &lt; 0.001). Multivariate analysis revealed that high VitB12 was negatively associated with OS in both groups (control: hazard ratio, HR 1.4, 95% CI 1.01-1.96, p = 0.04; IO: HR 2.74 as sum of linear baseline and interaction effects, in log scale), as were age (HR 1.03, 95% CI 1.02-1.04, p &lt; 0.01), male gender (HR 0.66, 95% CI 0.50-0.88, p &lt; 0.01), and neutrophil to lymphocyte ratio (NLR) (HR 1.05, 95% CI 0.48-0.99, p = 0.01). However, the only negative prognostic factor for PFS was VitB12 in the IO group alone (calculated HR 8.34). No association was observed with patient and cancer characteristics, other laboratory values, chemotherapy (p = 0.3) or biologic therapy (p = 0.8). Mean follow-up in the control and IO groups was 93 vs 54 weeks (OS), and 22 vs 33 weeks (PFS), respectively. Conclusions: Elevated VitB12 levels were negatively associated with response to immune checkpoint inhibitors, independently of other prognostic factors such as age, cancer type, treatment line and NLR. In addition to a direct role in cellular immunity, VitB12 is involved in gut microbiota balance, which in turn affects host immune responses – suggesting a possible immune-metabolic interplay. Further research is needed to elucidate the metabolic regulators of response to immunotherapy and potential strategies of intervention, in order to rationalize and broaden its clinical utility.

P52 RISK STRATIFICATION COMBINING SKY92 GENE EXPRESSION PROFILING AND TRADITIONAL FISH IN MULTIPLE MYELOMA: THE FIRST PROSPECTIVE EVIDENCE IN THE R2-ISS ERA

High-risk (HR) multiple myeloma (MM) patients still have a very poor prognosis. However, the definition of HR MM remains controversial. Currently, FISH is the most commonly used method for risk stratification in MM. According to the Second Revised International Staging System (R2-ISS), HR cytogenetics is defined as presence of at least one of the following: del(17p), t(4;14), and 1q CNA. In recent years, gene expression profiling (GEP) approaches, e.g. SKY92, have been developed for detection of HR patients. In the R2-ISS era, however, data on MM risk stratification applying SKY92 in combination with traditional FISH is still lacking. Therefore, we performed the first prospective study evaluating the prognostic value of the combined SKY92 and FISH HR detection in newly diagnosed (ND) and relapsed/refractory (RR) MM. We prospectively collected bone marrow (BM) samples and clinical data of 147 MM patients. Cytogenetics were analyzed on purified CD138 positive MM cells by FISH, and HR cytogenetics was defined according to the R2-ISS classification. SKY92 risk status was determined with MMprofiler gene expression assay. Whole genome sequencing (WGS) was performed to compare the both risk stratification systems SKY92 and FISH. We included 147 patients in our study (NDMM: n=51, RRMM: n=96). SKY92 classification was available for 121 (82.3%) patients. HR SKY92 was significantly enriched in RRMM (40/76) compared with NDMM (6/45) (P<0.0001). RRMM patients with HR SKY92 showed significantly shorter progression free survival (PFS) (P<0.0001) and overall survival (OS) (P=0.0004) than standard-risk (SR). In NDMM, HR SKY92 also indicated a significantly inferior PFS (P=0.001) in comparison with SR. Of note, samples of 26 (17.7%) patients, who showed significantly lower bone marrow infiltration than the remaining patients (median: 25% vs 55%, P=0.038), did not meet the SKY92 quality control criteria. We then combined the SKY92 classification with cytogenetic analyses by FISH, which were available in 99 patients (NDMM: n=33; RRMM: n=66). We noticed a discrepancy between both risk stratification systems, with 44 (44.4%) and 58 (58.6%) patients being classified as HR by SKY92 and FISH, respectively. In total, 28 (42.4%) RRMM patients and 6 (18.2%) NDMM patients displayed HR in both SKY92 and FISH (double-HR). Regarding survival outcome in RRMM, double-HR patients showed the worst PFS (P<0.0001) and OS (P=0.0007). In NDMM, double-HR presented a negative prognostic factor for PFS (P=0.01). To compare the FISH and SKY92 classifications, we performed WGS in 16 patients who exhibited either only HR SKY92 (n=7) or only HR FISH (n=9). Interestingly, 1 patient with bi-allelic TP53 inactivation (deletion + mutation) and 6 patients harbouring 1q CNA were determined as SR by SKY92 but as HR by FISH. The median PFS was not reached after a median follow up of 371 days in these 9 patients. Moreover, 4 out of 7 patients with only HR SKY92 but SR FISH displayed 1q CNA, which was detected only by WGS, and del1p32 was found in 1 patients. Interestingly, we found CRBN mutation in 3 out of 7 patients with only HR SKY92 but SR FISH. The remaining 2 patients did not show any known HR genomic alterations, suggesting that HR MM may be associated with other factors, e.g. epigenetic modifications. Here, we provide the first prospective evidence in the R2-ISS era that advanced risk stratification combining SKY92 and FISH may help to identify the highest-risk MM.

Obinutuzumab plus bendamustine for relapsed/refractory chronic lymphocytic leukemia and predictive and prognostic impact of genetic alterations: the phase II GABRIELL study

GABRIELL was a phase II single-arm study to evaluate the efficacy and safety of obinutuzumab plus bendamustine for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). Seventy-two patients with active disease received treatment for up to six 28-day cycles. Overall response rate was 78.6% with a median progression-free survival (PFS) of 26 months, and overall survival (OS) not reached at the end of follow-up (36 months). Undetectable measurable residual disease (≤0.01%; 36.4% in bone marrow and 53.4% in peripheral blood) correlated with a significantly longer PFS and OS (vs. >0.01). Common grade ≥3 adverse events (76.4%) were neutropenia (58.3%), thrombocytopenia (26.4%) and febrile neutropenia (11.1%). TP53 disruption was the only independent predictive factor for response (Hazard ratio; HR: 0.228). Unmutated immunoglobulin heavy chain variable region (HR: 16.061) was a negative prognostic factor for PFS. In conclusion, the combination of obinutuzumab plus bendamustine is an active and generally adequately-tolerated treatment for R/R CLL.

Biomarkers for predicting tumor response to PD-1 inhibitors in patients with advanced pancreatic cancer

ABSTRACT Pancreatic cancer is among the most lethal malignant neoplasms, and few patients with pancreatic cancer benefit from immunotherapy. We retrospectively analyzed advanced pancreatic cancer patients who received PD-1 inhibitor-based combination therapies during 2019–2021 in our institution. The clinical characteristics and peripheral blood inflammatory markers (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR], and lactate dehydrogenase [LDH]) were collected at baseline. Chi-squared and Fisher’s exact tests were used to evaluate relationships between the above parameters and tumor response. Cox regression analyses were employed to assess the effects of baseline factors on patients’ survival and immune-related adverse events (irAEs). Overall, 67 patients who received at least two cycles of PD-1 inhibitor were considered evaluable. A lower NLR was independent predictor for objective response rate (38.1% vs. 15.2%, P = .037) and disease control rate (81.0% vs. 52.2%, P = .032). In our study population, patients with lower LDH had superior progression-free survival (PFS) and overall survival(OS) (mPFS, 5.4 vs. 2.8 months, P < .001; mOS, 13.3 vs. 3.6 months, P < .001). Liver metastasis was verified to be a negative prognostic factor for PFS (2.4 vs. 7.8 months, P < .001) and OS (5.7 vs. 18.0 months, P < .001). The most common irAEs were hypothyroidism (13.4%) and rash (10.5%). Our study demonstrated that the pretreatment inflammatory markers were independent predictors for tumor response, and the baseline LDH level and liver metastasis were potential prognostic markers of survival in patients with pancreatic cancer treated with PD-1 inhibitors.

A post hoc analysis of the EPAZ trial: The role of geriatric variables in elderly soft tissue sarcoma patients on toxicity and outcome

ObjectiveThe EPAZ study (NCT01861951) showed recently that pazopanib was non-inferior to doxorubicin in patients ≥60 years treated in first line for advanced soft tissue sarcoma . The current post-hoc analysis aimed to assess the prognostic impact of frailty. MethodsGeriatric assessments were evaluated at baseline. Age >75 years, liposarcoma, ECOG = 2, G8 ≤14, instrumental activities of daily living (IADL) ≥1 and Charlson Comorbidity Index ≥2 were tested for their impact on progression-free survival (PFS), overall survival (OS), CTCAE grade 3/4 adverse events (AEs) or serious AEs (SAEs), using univariate and multivariate analysis models. Resultsunivariate analysis showed an increased risk of grade 3/4 AEs and SAEs for ECOG = 2, G8 score ≤14 or IADL ≥1, independent of treatment. The multivariate analysis exhibited for pazopanib a significantly reduced risk for grade 3/4 AEs (HR 0.53; p = 0.033), and in patients with G8 ≤14 an increased risk for SAEs (HR 2.67; p = 0.011).In the multivariate analysis, G8 ≤14 was a negative prognostic factor for PFS (HR 1.82; p = 0.009) and IADL ≥1 for OS (HR 2.02; p = 0.007). ECOG = 2 was the strongest negative predictor for PFS (HR 4.39; p = 0.001) and OS (HR 3.74; p = 0.004). Neither age nor Charlson Comorbidity Index showed any impact on PFS, OS, incidence of grade 3/4 AEs or SAEs. ConclusionsThis post hoc analysis demonstrated that age is not a denominator for outcome or toxicity in elderly patients with soft tissue sarcoma . Instead, geriatric and functional assessments should be used to counsel patients and tailor therapy to individual needs. Moreover, pazopanib has a reduced risk for grade 3/4 AEs compared to doxorubicin.

Advanced Risk Stratification in Multiple Myeloma Beyond Traditional FISH: The First Prospective Real-World Evidence for SKY92 Gene Expression Profiling

Background The prognosis of multiple myeloma (MM) has been significantly improved in the last decades. However, high-risk (HR) MM still suffers from early disease progression. Therefore, identifying HR MM patients may be a crucial step to improve the prognosis of this patient group. To date, fluorescence in situ hybridization (FISH) is the most commonly used method for risk stratification in MM. In recent years, gene expression profiling (GEP) approaches, e.g. SKY92, have been developed for detection of HR MM patients. Currently, real-world data of MM risk stratification applying SKY92 alone or in addition to traditional FISH are still missing. In this study, we provide the first prospective real-world evidence of the prognostic value of the combined SKY92 and FISH risk stratification in newly diagnosed (ND) and relapsed/refractory (RR) MM. Methods We prospectively collected bone marrow (BM) samples and clinical data of 147 MM patients. Cytogenetics were analyzed on purified CD138 positive MM cells by FISH, and HR cytogenetics was defined applying the Revised International Staging System (del(17p), t(4;14), and t(14;16)) (Palumbo et al, J Clin Oncol. 2015). SKY92 risk classification was determined with MMprofiler gene expression assay (Kuiper et al, Leukemia 2012). In addition, whole genome sequencing (WGS) was performed, and 150 bp paired-end sequences were generated on the NovaSeq6000 sequencing instruments (Illumina) with 100x coverage. Structural variations (SV) were called using Manta, and copy number variations (CNV) calling was performed with GATK4. Strelka2 variant caller was used for single nucleotide variations (SNV). Variants with global population frequencies >1% were excluded. Results We included 147 patients in our study (NDMM: n=51, RRMM: n=96). SKY92 classification was available for 121 (82.3%) patients. The median follow-up time was 344 days. HR SKY92 was significantly enriched in RRMM (40/76) compared with NDMM (6/45) (P<0.0001). RRMM patients with HR SKY92 showed significantly shorter progression free survival (PFS) (P<0.0001) and overall survival (OS) (P=0.0004) than standard-risk (SR). In NDMM, HR SKY92 also indicated a significantly inferior PFS (P=0.001) in comparison with SR. Of note, samples of 26 (17.7%) patients did not meet the SKY92 quality control criteria due to low BM infiltration (median BM infiltration: 25% vs 55% in other patients, P=0.038). We then combined the SKY92 classification with cytogenetic analyses by FISH, which were performed in 99 patients (NDMM: n=33; RRMM: n=66). We noticed a discrepancy between both risk stratification systems, with 44 (44.4%) and 42 (42.4%) patients being classified as HR by SKY92 and FISH, respectively. In total, 24 (36.3%) RRMM patients and 6 (18.2%) NDMM patients displayed HR in both SKY92 and FISH (double-HR) (Figure). Regarding survival outcome in RRMM, double-HR patients showed the worst PFS (P<0.0001) and OS (P<0.0001) when compared to the other patients (Figure). Noteworthy, RRMM patients with only HR SKY92 demonstrated significantly worse PFS than those with only HR FISH (P=0.007). In addition, double-HR presented a negative prognostic factor for PFS in NDMM (P=0.01). To further elucidate the discrepancy between FISH and SKY92 classifications, we performed WGS in 12 patients who exhibited either HR SKY92 only (n=9) or HR FISH only (n=3). Interestingly, 1 patient with bi-allelic TP53 inactivation (deletion + mutation) and 2 patients harbouring t(4;14) or t(14;16) were determined as SR by SKY92 but as HR by FISH; all the 3 patients were still in remission at the time point of data cut-off (July 2022). Moreover, we found abnormalities at chromosome 1 in 7 out of the 9 patients with HR on SKY92 only (gain1q21: n=6; del1p32: n=2) and, notably, gain1q21 and del1p32 were detected only by WGS in 3 and 2 patients, respectively. The remaining 2 patients did not show any known HR SV/CNV/SNVs, suggesting that HR MM may be associated with some other mechanisms, e.g. epigenetic modifications. Conclusion Altogether, risk classification using SKY92 performed well for detecting HR MM in the clinical routine. Here, we provide the first prospective real-world evidence that advanced risk stratification combining SKY92 and FISH may help to identify the "highest-risk" MM, which requires intensive anti-MM therapy and close monitoring in the course of the disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hyperthermic intraperitoneal chemotherapy in the treatment of recurrent ovarian cancer: When, and for whom?

The aim of this study is to evaluate the progression-free survival (PFS) of recurrent ovarian cancer (ROC) patients treated with cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC). ROC patients who underwent cytoreductive surgery plus HIPEC between 2015 and 2021 were retrospectively evaluated. Patients' demographic information and clinicopathological characteristics including cancer type, histology, platinum status, presence of ascites, type of surgery, complications, chemotherapy history, and disease progression were documented. PFS was calculated using the Kaplan-Meier method. A total of 104 patients with ROC were included. The median age was 57 years and the median follow-up time was 15 months (range: 5-69 months). In Cox regression multivariate analyses, platinum resistance (hazard ratio[HR]: 3.32, 95% confidence interval [CI]: 1.91-5.76, p = 0.00), more than one relapse prior HIPEC (HR: 2.81, 95% CI: 1.65-4.87, p = 0.024), and presence of ascites (HR: 1.88, 95% CI: 1.08-3.26, p = 0.00) were found to be negative prognostic factors for PFS. In subgroup analyses of patients with the first recurrence, the median PFS was 21 months for platinum-sensitive patients and 6 months for platinum-resistant patients (p = 0.032). HIPEC at the time of first platinum-sensitive relapse may lead to favorable PFS in the treatment ROC. However, HIPECas salvage treatment even with R0 cytoreductive surgery does not seem effective.

LGG-09. A Nationwide Service Evaluation of Safety, Radiologic and Visual Outcome Refining Bevacizumab-based Treatments in Children with Progressive Low-Grade Glioma

INTRODUCTION: Bevacizumab/Irinotecan is currently 3rd-line treatment in the UK for progressive Paediatric Low-Grade Glioma (PLGG) based on limited evidence. A nationwide service evaluation was conducted to review its safety and efficacy amongst a larger cohort. METHODS: Data from children with PLGG receiving Bevacizumab-based Treatments (BBT) from 11 UK Centres (2009-2020) were reviewed. Radiological and visual outcomes were based on standardized measurements. Clinical-radiological correlation was investigated. Time to progression from BBT stop, progression free-survival (PFS) curves and multivariate analysis of prognostic factors (p 0.05) were performed. RESULTS: 88 children with PLGG (88% OPG, 24% NF1) had BBT for radiological (43%), visual (20%) or combined (27%) progression, after 40 months (median) from diagnosis. Amongst OPG cases, visual acuity (VA) per eye (better/worse) before BBT was logMAR 0.0-0.3 (23/7) 0.3 - 1.0 (27/20), > 1.0 (14/18) and LP/NLP (8/27), with 19/8 children respectively blind (LP/NLP) in one or both eyes. Bevacizumab 10 mg/kg every 14 days (median 24 doses) was given as 3rd line+ with Irinotecan (85%) or alongside 1st/2nd line chemo (15%) leading to remarkable radiological (88%) and visual (74%) responses (stable or improved) within 3-6 months, with limited toxicity. 12% progressed on treatment, and 8% died unrelated to BBT. After initial response 65% progressed at a median of 8 months (4 - 23) after BBT, resulting in 3-year-all-causes-PFS of 16% and 3-yr-visual-PFS of 45% from start of BBT. Visual concordance with MRI was poor (36%) but increases (47%) when better-eye determines visual outcome. Lack of NF1 and diencephalic syndrome (DS) at presentation were independent negative prognostic factors for PFS. CONCLUSIONS: A remarkable but transient effect of BBT has been confirmed. Visual > radiological responses can be sustained after BBT. Variations in current BBT strategies justifies further research, including the potential upfront use alongside conventional first-line chemotherapy as sight-saving strategy.

Distinct clinical outcome of microcystic meningioma as a WHO grade 1 meningioma subtype.

To evaluate the clinicopathological characteristics, radiology, and long-term outcomes of microcystic meningiomas (MM) and compare it with other subtypes of meningiomas managed at a single neurosurgical center. A total of 87 consecutive patients who underwent surgical resection and were diagnosed as MM between 2005 and 2016 were enrolled for analysis. Clinicopathological, radiology, and prognostic information was collected and analyzed. Progression free survival (PFS) was compared with 659 patients with other subtypes of WHO grade 1 meningiomas and 167 patients with atypical meningiomas treated during the same period. Fifty six females and 31 males with MM were analyzed. Peri-tumor brain edema was frequent on T2 WI (85%).12 patients (13.8%) experienced tumor progression during the mean follow-up of 101.66 ± 40.92months. The median PFS was unavailable, and the 5, 10, and 15year progression-free rates were 96.9%, 84.0%, and 73.9%, respectively. Univariate COX analysis demonstrated skull base location and higher Ki-67 index as significant negative prognostic factors for PFS (P < 0.05); multivariate analysis identified tumor location and Ki-67 index as independent factors (P < 0.01), as well. Of note, the PFS of MM was worse than other WHO grade 1 subtypes (P < 0.001), but better than atypical meningiomas (P < 0.001), and the PFS differences were retained even when the analysis was limited to the patients receiving GTR (P < 0.05). The PFS of MM was worse than other WHO grade 1 subtypes and better than atypical meningiomas. Skull base location and higher Ki-67 index were independent negative prognostic factors in MM.

Long-term oncologic outcomes in esthesioneuroblastoma: An institutional experience of 143 patients.

Esthesioneuroblastoma (ENB) is a rare malignant neoplasm arising from the olfactory epithelium of the cribriform plate. The goal of this study was to update our oncologic outcomes for this disease and explore prognostic factors associated with survival. We performed a retrospective analysis of patients with ENB treated at a single tertiary care institution from January 1, 1960, to January 1, 2020. Univariate and multivariate analysis was performed. Overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) were reported. Among 143 included patients, the 5-year OS was 82.3% and the 5-year PFS was 51.6%; 5-year OS and PFS have improved in the modern era (2005-present). Delayed regional nodal metastasis was the most common site of recurrence in 22% of patients (median, 57 months). On univariate analysis, modified Kadish staging (mKadish) had a negative effect on OS, PFS, and DMFS (p<0.05). Higher Hyams grade had a negative effect on PFS and DMFS (p<0.05). Positive margin status had a negative effect on PFS (p<0.05). Orbital invasion demonstrated worsening OS (hazard ratio, 3.1; p<0.05). On multivariable analysis, high Hyams grade (3 or 4), high mKadish stage (C+D), and increasing age were independent negative prognostic factors for OS (p<0.05). High Hyams grade (3+4), high mKadish stage (C+D), age, and positive margin status were independent negative prognostic factors for PFS (p<0.05). High Hyams grade (3+4) was an independent negative prognostic factor for DMFS (p<0.05). Patients with low Hyams grade and mKadish stage have favorable 5-year OS, PFS, and DMFS.

Prognostic significance of laterality in lung neuroendocrine tumors

Purpose:Well-differentiated lung neuroendocrine tumors (Lu-NET) are classified as typical (TC) and atypical (AC) carcinoids, based on mitotic counts and necrosis. However, prognostic factors, other than tumor node metastasis (TNM) stage and the histopathological diagnosis, are still lacking. The current study is aimed to identify potential prognostic factors to better stratify lung NET, thus, improving patients’ treatment strategy and follow-up.Methods:A multicentric retrospective study, including 300 Lung NET, all surgically removed, from Italian and Spanish Institutions.Results:Median age 61 years (13–86), 37.7% were males, 25.0% were AC, 42.0% were located in the lung left parenchyma, 80.3% presented a TNM stage I-II. Mitotic count was ≥2 per 10 high-power field (HPF) in 24.7%, necrosis in 13.0%. Median overall survival (OS) was 46.1 months (0.6–323), median progression-free survival (PFS) was 36.0 months (0.3–323). Female sex correlated with a more indolent disease (T1; N0; lower Ki67; lower mitotic count and the absence of necrosis). Left-sided primary tumors were associated with higher mitotic count and necrosis. At Cox-multivariate regression model, age, left-sided tumors, nodal (N) positive status and the diagnosis of AC resulted independent negative prognostic factors for PFS and OS.Conclusions:This study highlights that laterality is an independent prognostic factors in Lu-NETs, with left tumors being less frequent but showing a worse prognosis than right ones. A wider spectrum of clinical and pathological prognostic factors, including TNM stage, age and laterality is suggested. These parameters could help clinicians to personalize the management of Lu-NET.

Clinical course and outcome of differentiated thyroid cancer patients with pregnancy after diagnosis of distant metastasis.

There is no sufficient data about the clinical course and outcome in thyroid cancer patients who become pregnant after diagnosis of distant metastasis (DM). The current study was conducted to collect information regarding the clinical and reproductive characteristics, and outcomes in thyroid cancer patients who became pregnant after being diagnosed with DM. Records of 125 differentiated thyroid cancer (DTC) patients with age ≤45 years at DM diagnosis who had visited Ito Hospital from January 2005 to June 2021 were retrospectively reviewed. Among those 125 patients, 28 who became pregnant after DM diagnosis were classified as pregnancy group, and the remained 97 patients were classified as comparator group. In pregnancy group, the median age at malignancy diagnosis, DM diagnosis, and first pregnancy after DM diagnosis was 25 years (range, 4-41 years), 27 years (range, 11-41 years), and 32 years (range, 25-45 years), respectively. Fifty-five pregnancies and 40 live births were reported. Other pregnancy outcomes were miscarriage (n = 14) and induced abortion (n = 1). The 10-year progression-free survival (PFS) rates of pregnant and comparator group were 92.1% and 74.4%, respectively (p = 0.018). The multivariate analysis showed that multiple 131I treatment was independent negative prognostic factor for PFS (p = 0.046). DTC patients with age ≤45 years at DM diagnosis had good survival even though they became pregnant. Our results add to the information required for counseling thyroid cancer patients who have concerns about their fertility in the future.