Baseline Lactate Dehydrogenase Levels Research Articles

Serum lactate dehydrogenase as a prognostic marker for treatment response in IDH wild-type glioblastoma patients undergoing stupp protocol.

Elevated lactate dehydrogenase (LDH), a marker of tumor aggressiveness and metabolic alterations, may predict treatment response and overall survival across various tumors. This study investigates the correlation between serum LDH levels and clinical outcomes in glioblastoma patients treated with radiotherapy (RT) and temozolomide (TMZ). This retrospective study analysed patients with IDH wild-type glioblastoma (IDH-wt GB) treated at the Radiotherapy Department of Azienda Ospedaliero-Universitaria Senese from 2018 to 2023. Clinical data, including hematologic parameters (e.g., LDH), imaging (MRI), and MGMT promoter methylation status, were collected. All patients received RT and TMZ following the Stupp protocol. Serum LDH levels were measured one week before RT, and Radiological Response (RR) was assessed using RANO criteria. Overall survival (OS), progression-free survival (PFS), and RR were primary endpoints. Statistical analyses included Kaplan-Meier, Cox regression, and decision tree analysis for LDH cut-off determination. In a cohort of 147 IDH wild-type glioblastoma patients treated with the Stupp protocol, the median OS was 14 months and median PFS was 8 months. Elevated baseline LDH levels were associated with significantly poorer outcomes, showing a median OS of 9 months versus 20 months and a median PFS of 6 months versus 13 months for lower LDH levels (p < 0.001 and p = 0.0001, respectively). LDH levels also correlated with RR (p = 0,001), Multivariate analysis confirmed high LDH as an independent predictor of worse OS (HR = 2.31) and PFS (HR = 2.60), suggesting its utility as a prognostic biomarker. Elevated LDH levels before starting the Stupp protocol are clinically significant as they predict poorer overall survival and progression-free survival in glioblastoma patients and worse RR. Incorporating LDH measurements into treatment planning can help identify patients at higher risk of poor outcomes, allowing for more tailored and potentially aggressive treatment strategies to improve management and therapeutic responses in glioblastoma.

Association of serum lactate dehydrogenase with prognosis and tumor metabolism in patients with hepatocellular carcinoma treated with atezolizumab plus bevacizumab therapy.

Treatment outcomes are predicted by analyzing peripheral blood markers such as serum lactate dehydrogenase (LDH). We conducted this study to investigate whether serum LDH levels can predict the prognosis of patients treated with atezolizumab plus bevacizumab (ATZ/BEV) therapy for hepatocellular carcinoma (HCC) and whether LDH levels correlate with metabolic changes. We enrolled 66 HCC patients treated with ATZ/BEV. Based on the change in serum LDH levels before and after treatment, the patients were divided into two groups, and the prognosis of each group was examined. Moreover, the association of LDH levels with tumor metabolism was analyzed by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). There were 32 patients categorized as the LDH-decrease group. Kaplan-Meier survival analysis indicated worse progression-free survival (PFS) in the LDH-increase group than in the LDH-decrease group (p = 0.0029). Multivariate analysis showed that an increase in the LDH level was an independent risk factor for worse PFS (p = 0.0045). The baseline LDH level correlated significantly with a high maximum standardized uptake value of 18F-FDG, according to the PET/CT findings. Transcriptomic analyses of specimens resected after ATZ/BEV therapy showed downregulated mitochondria-related pathways. Serum LDH levels are a potential prognostic marker and an indicator of tumor metabolism.

A phase 3 trial of fixed dose combinations of fianlimab (anti–LAG-3) + cemiplimab (anti–PD-1) versus relatlimab + nivolumab in patients with unresectable or metastatic melanoma.

TPS9611 Background: Fianlimab (anti–lymphocyte activation gene 3 [LAG-3]) and cemiplimab (anti–programmed cell death-1 [PD-1]) are high-affinity, fully human, immunoglobulin G4 monoclonal antibodies. Concurrent LAG-3 blockade may enhance the efficacy of anti–PD-1 therapies. Relatlimab (anti–LAG-3) + nivolumab (anti–PD-1) monoclonal antibodies demonstrated benefit in progression-free survival (PFS) in advanced melanoma (Mel) patients compared with nivolumab alone in the RELATIVITY-047 study. In a multicohort Phase 1 study (NCT03005782), fianlimab + cemiplimab demonstrated reproducibly high clinical activity (objective response rate [ORR]: 61%, N=98) in three independent cohorts of advanced PD-(L)1–naïve metastatic Mel patients with an acceptable safety profile. Methods: This is a randomized, open-label, multicenter Phase 3 study (NCT06246916) comparing the fixed dose combination (FDC) of fianlimab + cemiplimab to the FDC of relatlimab + nivolumab in patients with unresectable or metastatic Mel. The primary objective is to demonstrate superiority of fianlimab + cemiplimab compared with relatlimab + nivolumab as measured by ORR assessed by blinded independent central review (BICR). This study will be conducted at approximately 80 sites across North America. Key inclusion criteria are: (1) aged ≥18 years; (2) histologically confirmed unresectable stage III or IV (metastatic) Mel; (3) no prior systemic therapy for unresectable or metastatic Mel; patients with adjuvant and/or neoadjuvant systemic therapies are eligible with a treatment-free and disease-free interval of &gt;6 months; (4) measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1; (5) Eastern Cooperative Oncology Group performance status of ≤1; (6) adequate bone marrow, hepatic, and kidney function. Approximately 560 patients will be randomized in a 1:1 ratio to two treatment arms: Arm A: FDC of fianlimab (Dose 1) + cemiplimab (Dose 2) every 3 weeks intravenously (IV); Arm B: FDC of relatlimab 160 mg + nivolumab 480 mg every 4 weeks IV. All patients will be stratified based on metastatic stage (stage III vs M1a–b vs M1c–d), baseline lactate dehydrogenase level (≤ vs &gt; upper limit of normal), and prior adjuvant and/or neoadjuvant systemic therapy. Patients will receive treatment until disease progression, unacceptable toxicity, withdrawal of consent, a study withdrawal criterion is met, or the sponsor terminates the study. The primary endpoint is ORR and key secondary endpoints are PFS and overall survival. Additional secondary endpoints are duration of response, disease control rate, investigator-assessed ORR and PFS, safety, pharmacokinetics, and immunogenicity. Clinical trial information: NCT06246916 .

KP104, a Bifunctional C5 Antibody/Factor H Fusion Protein, Effectively Controls Both Intravascular and Extravascular Hemolysis: Interim Results from a Phase 2 Study in Complement Inhibitor-Naïve PNH Patients

Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disease characterized by intravascular and extravascular hemolysis (IVH and EVH) mediated by complement activation through both the terminal and alternative pathways (TP and AP). The current treatment options for PNH are limited to addressing only a single complement pathway, resulting in either unresolved EVH with TP inhibitors or potentially exposing patients to the risk of life-threatening breakthrough hemolysis with AP inhibitors (Notaro et al. N Engl J Med 2022;387:160-6). KP104 is an innovative fusion protein comprised of a humanized anti-C5 mAb and the functional domain of complement regulator factor H to inhibit both TP and AP activation. We report here the interim results from a phase 2 study of KP104 in complement inhibitor-naïve PNH patients. Methods This open-label Phase 2 clinical trial (NCT05476887) aims to assess the efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of KP104 in patients diagnosed with PNH who have not received prior complement inhibitors. The primary objectives of the study are to evaluate key clinical markers including lactate dehydrogenase (LDH) and hemoglobin (Hgb) levels, transfusion requirements, and FACIT-fatigue scores. The first part of the study consists of three cohorts, with an enrollment of 6 patients per cohort. The study includes an initial treatment period of 12 or 13 weeks of KP104 dosing regimen, followed by a 9-month extension treatment period. The specific dosing regimens for each cohort are as follows: Cohort 1: 1,200 mg IV (Day 1) + 720 mg SC QW (starting Day 8) Cohort 2: 2,400 mg IV (Day 1) + 1,920 mg SC Q2W (starting Day 8) Cohort 3: 3,600 mg IV (Day 1) + 2,880 mg SC Q2W (starting Day 8) Results Interim results include data from 15 patients who completed 16/17 weeks of treatment (6 patients each from Cohort 1 and 2, and 3 from Cohort 3), as of the data cutoff on July 12 th, 2023. Among these patients (4 males and 11 females, mean (±SD) age 33(±12) years, a median of 3 transfusions were required 12 months prior to the study and 9 patients were previously diagnosed with aplastic anemia. Baseline mean (SD) Hgb and LDH levels were 7.0 (±1.5) g/dL and 1,824 (±512) U/L, respectively. By week 16/17, all 15 patients demonstrated positive clinical improvements. Mean (SD) Hgb levels increased by 4.9 (±1.7) g/dL, 5.8 (±1.6) g/dL, and 5.8 (±2.8) g/dL over baseline, and mean (SD) LDH levels reduced by 88.0 (±3.67) %, 83.5 (±7.45) %, and 89.5 (±4.05) % over baseline for Cohort 1, 2 and 3, respectively. Additionally, 9/15 (60%) patients achieved hemoglobin levels ≥12 g/dL (3/6, 5/6 and 1/3 for Cohort 1, 2 and 3, respectively), and all 15 patients had LDH levels below 1.5xULN. None of the 15 patients required transfusions or encountered any thromboembolic events after receiving KP104 treatment. Positive changes were observed in absolute reticulocyte count and bilirubin levels, along with significant enhancements in FACIT-fatigue scores seen in all 3 cohorts, with mean (SD) increases of 13.8 (±7.91), 12.8 (±9.15), and 9.3 (±10.69) for Cohorts 1, 2, and 3, respectively. Dose-dependent reductions in two PD biomarkers, C3b deposition and free C5 levels, further confirmed KP104's dual mechanism of AP and TP inhibition. KP104 was well tolerated, with no serious adverse events or treatment-emergent adverse events (TEAEs) that led to drug discontinuation or study withdrawal. 10/15 (67%) patients reported at least one mild or moderate TEAE, with no observed dose dependency. The most frequently reported TEAEs included transient injection site induration, headache, and COVID-19 infection, all of which were promptly or duly resolved. A single occurrence of clinical breakthrough hemolysis, observed in the lowest dose cohort and concurrent with an episode of gastroenteritis, was quickly resolved after an extra dose. Conclusion The interim results of this phase 2 study demonstrate the safety and efficacy of KP104 in effectively controlling IVH and EVH in complement inhibitor-naïve PNH patients. The findings provide compelling clinical evidence that a bifunctional inhibitor targeting the AP and TP can properly address the current treatment gaps associated with single complement pathway inhibitors, potentially eliminating the need for cumbersome and costly combination therapies (Notaro et al. N Engl J Med 2022;387:160-6).

Exposure-Response Relationships between the Complement Factor B Inhibitor Iptacopan and Lactate Dehydrogenase (LDH) and Hemoglobin (Hb) in Patients (Pts) with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Background: PNH is an ultrarare disease characterized by complement-mediated hemolysis and subsequent anemia, bone marrow failure and thrombosis. In pts not treated with complement inhibitors, intravascular hemolysis (IVH) results from unregulated progression of the complement system and membrane attack complex formation. IVH is controlled in pts treated with anti-C5 therapy, but extravascular hemolysis (EVH) may emerge and cause persistent anemia. High LDH levels are a marker of ongoing IVH, while anemia can result from both IVH and EVH. Iptacopan is the first oral proximal complement inhibitor targeting factor B to selectively inhibit the alternative pathway of the complement cascade. As shown in PNH Phase III trials (APPLY-PNH [NCT04558918] and APPOINT-PNH [NCT04820530]), iptacopan can achieve good control of hemolysis. Aim: To support the dose selection for iptacopan, this analysis characterizes the exposure-response relationships between iptacopan and efficacy measures (LDH and Hb) in pts with PNH. The effect of prior anti-C5 treatment status has also been evaluated. Methods: This analysis is based on data from 4 clinical trials enrolling pts with PNH.Final data were used from the completed Phase II trials X2201 (NCT03439839; pts with active hemolysis despite anti-C5 therapy received concomitant iptacopan) and X2204 (NCT03896152; anti-C5-naïve pts received iptacopan monotherapy), in which iptacopan was administered orally in doses ranging from 25 to 200 mg twice daily (bid). Data up to the cut-off dates of 26 September 2022 and 2 November 2022 were used from the Phase III trials, APPLY-PNH (pts previously treated with anti-C5) and APPOINT-PNH (pts not treated with complement inhibitors including anti-C5), respectively, in which oral iptacopan was administered at 200 mg bid. A longitudinal mixed-effects modeling approach was applied to LDH and Hb. To account for the delay between exposure and response, indirect response models were developed for LDH and Hb. The models were used to predict the long-term (6 months) LDH and Hb responses for various iptacopan bid dose levels and to estimate (using simulation) the proportion of pts achieving LDH ≤1.5 × upper limit of normal (ULN) and Hb ≥12 g/dL. Results: The modeling dataset contained 161 pts with PNH; 94 (58%) were female, and median (range) age was 45 (18-84) years. For modeling of LDH and Hb levels, 2812 and 2587 samples were used, respectively, as well as 1577 pharmacokinetic samples. In total, 53 (33%) pts had not received anti-C5 treatment. Of the remaining 108 pts, 16 (15%) received iptacopan as add-on therapy to anti-C5 (pts from X2201) and 92 (85%) had previously received anti-C5 (pts from APPLY-PNH). The indirect response models were considered biologically plausible and adequately described the data using a common EC 50 value to both anti-C5-naïve pts and pts currently receiving or who previously received anti-C5. The estimated concentration of iptacopan required to achieve 90% of the maximum response (EC 90) of LDH was 268 ng/mL (90% confidence interval [CI] 238, 302), irrespective of prior anti-C5 treatment status ( Figure). The estimated typical LDH value after iptacopan treatment at an exposure &amp;gt;EC 90 was 237 U/L (90% CI 224, 250) within the normal LDH range (&amp;lt;250 U/L). Iptacopan 200 mg bid was the dose at which the highest proportion of pts (86%) achieved LDH ≤1.5 × ULN. While baseline LDH levels differed between anti-C5-naïve pts and pts currently receiving or who previously received anti-C5, similar proportions of these pts achieved LDH ≤1.5 × ULN (84% and 88%, respectively). The estimated EC 90 of Hb ≥12 g/dL was 1968 ng/mL (90% CI 1661, 2333) ( Figure); 89% of all pts were expected to reach EC 90 exposure at iptacopan 200 mg bid. The estimated Hb value after treatment with iptacopan at an exposure &amp;gt;EC 90 was 12.7 g/dL (90% CI 12.4, 13.0). 70% of pts were expected to achieve Hb normalization (≥12 g/dL) with iptacopan 200 mg bid. Similar proportions of anti-C5-naïve pts and pts who were currently receiving or who previously received anti-C5 achieved Hb ≥12 g/dL (71% and 68%, respectively). Conclusions: Indirect response models were developed to describe the exposure-response relationships between iptacopan and efficacy measures (LDH and Hb) in pts with PNH. The analysis demonstrated that 200 mg bid is the dose of oral iptacopan that achieves LDH ≤1.5 × ULN and Hb normalization in the highest proportion of patients regardless of prior treatment status.

High serum lactate dehydrogenase as a predictor of cardiac insufficiency at follow-up in elderly patients with acute myocardial infarction

BackgroundImpairment of cardiac function progresses after acute myocardial infarction (AMI). Lactate dehydrogenase (LDH), a marker of cardiac injury and an enzyme in anaerobic glycolysis, is suggested as a risk factor for patient mortality in inflammatory diseases. MethodsIn this study, 448 older and 445 younger AMI patients were recruited and followed up. The effect of baseline serum LDH on post-infarction cardiac function was assessed at follow-up. ResultsElderly patients in the high baseline LDH group had a high risk of being diagnosed with cardiac insufficiency during follow-up (adjusted hazard ratio: 3.643, P = 0.007), and the follow-up left ventricular ejection fraction of the quartile subgroup tended to decrease with increasing in baseline serum LDH (adjusted odds ratio: 1.301, P = 0.001) for each 100 U/L increase. The LVDd and LVVd of elderly patients in the high LDH group were not significantly different from those of patients in the normal LDH group at baseline but were further increased in the high LDH group at follow-up. In younger patients, the effect of LDH on post-infarction cardiac structure and function was similar to that in older patients, but unlike older patients, Cox regression analysis showed that LDH was not the predominant influence. ConclusionLongitudinal changes in cardiac function were independently associated with high baseline serum LDH levels in patients with AMI. Baseline LDH levels are superior to other myocardial injury markers and may be a useful parameter in predicting future cardiac dysfunction after AMI, especially in the elderly.

Development and validation of a survival nomogram and calculator for male patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate and/or enzalutamide

BackgroundDespite the widespread availability of medication choices for metastatic castration-resistant prostate cancer (mCRPC), biomarkers to predict the efficacy of each mCRPC treatment have not yet been established. This study developed a prognostic nomogram and a calculator to predict the prognosis of patients with mCRPC who received abiraterone acetate (ABI) and/or enzalutamide (ENZ).MethodsIn total, 568 patients with mCRPC who underwent ABI and/or ENZ between 2012 and 2017 were enrolled. A prognostic nomogram based on the risk factors was developed using the Cox proportional hazards regression model and clinically important factors. The discriminatory ability of the nomogram was assessed according to the concordance index (C-index). A 5-fold cross-validation was repeated 2000 times to estimate the C-index, and the means of the estimated C-index for the training and validation sets were determined. A calculator based on this nomogram was then developed.ResultsThe median overall survival (OS) was 24.7 months. Multivariate analysis showed that the time to CRPC, pre-chemotherapy, baseline prostate-specific antigen, baseline alkaline phosphatase, and baseline lactate dehydrogenase levels were independent risk factors for OS (hazard ratio [HR]: 0.521, 1.681, 1.439, 1.827, and 12.123, p = 0.001, 0.001, < 0.001, 0.019, and < 0.001, respectively). The C-index was 0.72 in the training cohort and 0.71 in the validation cohort.ConclusionsWe developed a nomogram and calculator to predict OS in Japanese patients with mCRPC who received ABI and/or ENZ. Reproducible prognostic prediction calculators for mCRPC will facilitate greater accessibility for clinical use.

Pretreatment Serum Lactate Dehydrogenase and Metastases Numbers as Potential Determinants of Anti-PD-1 Therapy Outcome in Nasopharyngeal Carcinoma.

We aimed to investigate the determinant factors of anti-PD-1 therapy outcome in nasopharyngeal carcinoma (NPC). In this retrospective study, we included 64 patients with recurrent/metastatic NPC. The association of patients' characteristics, C-reactive protein (CRP), neutrophil to lymphocyte ratio (NLR), and lactate dehydrogenase (LDH) with survival benefit of anti-PD-1 therapy were analyzed using Cox regression models and Kaplan-Meier analyses. Patients were divided based on the median value of CRP, NLR or LDH into different subgroups. At a median follow-up time of 11.4months (range: 1-28months), median progression-free survival (PFS) and overall survival (OS) were 1.9months (95% CI, .18-3.6) and 15months (95% CI, 10.9-19.1) months, respectively. Pretreatment metastases numbers was significant predictor of PFS (HR = 1.99; 95% CI 1.10-3.63; P = .024) and OS (HR = 2.77; 95% CI 1.36-5.61; P = .005). Baseline LDH level was independent predictor of OS (HR = 7.01; 95% CI 3.09-15.88; P < .001). Patients with LDH level >435U/L at the baseline had significantly shorter PFS and OS compared to patients with LDH level ≤435U/L (median PFS: 1.7 vs 3.5months, P = .040; median OS: 3.7 vs 18.5months, P < .001). Patients with non-durable clinical benefit (NDB) had significantly higher LDH level at the baseline compared to patients who achieved durable clinical benefit (DCB) (P = .025). Post-treatment levels of CRP, LDH, and NLR were decreased compared to baseline in patients with DCB (P = .030, P = .088, and P = .066, respectively), whereas, there was a significant increase in post-treatment level of LDH compared with baseline in patients with NDB (P = .024). LDH level at the baseline was an independent predictor of OS and pretreatment metastases numbers was a significant predictor of PFS and OS.

Risk factors of in-hospital mortality in patients with pneumocystis pneumonia diagnosed by metagenomics next-generation sequencing.

ObjectivesThe metagenomic next-generation sequencing (mNGS) test is useful for rapid and accurate detection and identification of pathogenic microorganisms. The aim of the present study was to investigate the factors associated with in-hospital mortality in pneumocystis pneumonia (PCP) patients with mNGS-assisted diagnosis.MethodsOur study enrolled 154 patients with mNGS-positive PCP from August 2018 to February 2022 at the First Affiliated Hospital of Zhengzhou University respectively. Patients were divided into the survivor group (n=98) and the death group (n=56) according to whether in-hospital death occurred. Baseline characteristics, patients’ pre-hospital symptoms and patients’ CT imaging performance during hospitalization were carefully compared between the two groups. Risk factors for the occurrence of in-hospital death were sought by selecting indicators that were significantly different between the two groups for modelling and performing multiple logistic regression analysis.ResultsCompared with the in-hospital death patients, the survivors were younger and had higher levels of albumin (ALB) (age: 50.29 ± 14.63 years vs 59.39 ± 12.27 years, p<0.001; ALB: 32.24 ± 5.62 g/L vs 29.34 ± 5.42g/L, p=0.002; respectively), while the levels of lactate dehydrogenase (LDH) and C-reactive protein CRP were lower (LDH: 574.67 ± 421.24 U/L vs 960.80 ± 714.94 U/L, p=0.001; CRP: 54.97 ± 55.92 mg/L vs80.45 ± 73.26 mg/L, p=0.018; respectively). Multiple logistic regression analysis revealed that age, the baseline LDH and CRP levels were all positively associated with high in-hospital mortality [age: OR(95%CI): 1.115 (1.062-1.172), p<0.001; LDH: OR(95%CI): 1.002 (1.001-1.003), p<0.001; CRP: OR(95%CI): 1.008 (1.000-1.017), p=0.045; respectively] while the platelet counts was negatively associated with it [OR(95%CI): 0.986 (0.979-0.992), p<0.001].ConclusionsOld age, high baseline levels of LDH and CRP and low platelet counts were risk factors of the in-hospital mortality in mNGS positive PCP patients.

Benefit and toxicity of programmed death-1 blockade vary by ethnicity in patients with advanced melanoma: an international multicentre observational study.

Programmed cell death receptor-1 (PD-1) monotherapy is a standard treatment for advanced cutaneous melanoma, but its efficacy and toxicity are defined in white populations and remain poorly characterized in other ethnic groups, such as East Asian, Hispanic and African. To determine the efficacy and toxicity of PD-1 monotherapy in different ethnic groups. Clinical data for patients with unresectable or advanced melanoma treated with anti-PD-1 monotherapy between 2009 and 2019 were collected retrospectively from five independent institutions in the USA, Australia and China. Tumour response, survival and immune-related adverse events (irAEs) were compared by ethnicity (white vs. East Asian/Hispanic/African) across different melanoma subtypes: nonacral cutaneous (NAC)/unknown primary (UP) and acral/mucosal/uveal. In total, 1135 patients were included. White patients had significantly higher objective response rate (ORR) [54%, 95% confidence interval (CI) 50-57% vs. 20%, 95% CI 13-28%; adjusted P < 0·001] and longer progression-free survival (14·2 months, 95% CI 10·7-20·3 vs. 5·4 months, 95% CI 4·5-7·0; adjusted P < 0·001) than East Asian, Hispanic and African patients in the NAC and UP subtypes. White ethnicity remained independently associated with a higher ORR (odds ratio 4·10, 95% CI 2·48-6·81; adjusted P < 0·001) and longer PFS (hazard ratio 0·58, 95% CI 0·46-0·74; adjusted P < 0·001) in multivariate analyses after adjustment for age, sex, primary anatomical location, metastasis stage, baseline lactate dehydrogenase level, mutational status and prior systemic treatment. White and East Asian/Hispanic/African patients shared similar ORR and progression-free survival in acral/mucosal/uveal melanomas. Similar melanoma-subtype-specific ethnic discrepancies were observed in complete response rate and overall survival. White patients had higher rates of gastrointestinal irAEs but lower rates of endocrine, liver and other rare types of irAEs. These differences in irAEs by ethnicity were not attributable to varying melanoma subtypes. Ethnic discrepancy in clinical benefit is specific to melanoma subtype, and East Asian, Hispanic and African patients with NAC and UP melanomas have poorer clinical benefits than previously recognized. The ethnic discrepancy in toxicity observed across different melanoma subtypes warrants an ethnicity-based irAE surveillance strategy. More research is needed to elucidate the molecular and immunological determinants of these differences. What is already known about this topic? There is a great difference in response to immunotherapy between different subtypes of melanoma (cutaneous, mucosal, acral and uveal) in patients with advanced disease. What does this study add? Our data show for the first time that there are differences between different ethnic groups in terms of both response and toxicity to immunotherapy beyond the well-appreciated discrepancies due to melanoma subtype.

Immunohistochemical subtyping of diffuse large B-cell lymphoma into germinal center B-cell and activated B-cell subtype, along with correlation of the subtypes with extranodal involvement, serum lactate dehydrogenase, and positron emission tomography scan-based response assessment to chemotherapy

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in Indian population and is divided into the prognostically important subtypes, germinal center B-cell (GCB) and activated B-cell-like (ABC), using immunohistochemistry-based algorithm. The present study aims to evaluate the influence of immunohistochemical derived DLBCL subtype, GCB or ABC on prognostically significant variables - extranodal involvement and serum lactate dehydrogenase (LDH) level at presentation, and response to chemotherapy assessed on pre- and posttreatment fluorodeoxyglucose-positron emission tomography study. This was a retro-prospective, 2-year observational study at a tertiary health-care center, New Delhi. The study population includes a total 236 cases of DLBCL. According to the Hans algorithm, DLBCL cases were allocated to the GCB and ABC subgroups. For comparison of mean values, independent t-test and analysis of variance were used. For this purpose, we used SPSS 20.0 software. P < 0.05 was considered as statistically significant. Ninety-eight patients (41.5%) had GCB immunophenotype and 138 patients (58.5%) were ABC. A significant difference was observed between mean baseline level of LDH between GCB and ABC subtypes (P < 0.05). The proportion of cases with extranodal involvement was comparatively higher in ABC subtype (P < 0.05). Association between response to chemotherapy with DLBCL immunophenotypes was found to be highly significant (P < 0.00). The response rates were much better in GCB subtype. The mean baseline level of LDH is significantly higher in ABC subtype. The proportion of cases with extranodal involvement was comparatively higher in ABC and shows poor response to chemotherapy as compared to GCB. Baseline LDH level was found to be important prognostic marker in the DLBCL.

Abstract 1262: Gender bias in the association of pre-treatment cytokine signatures with response and survival in B cell lymphoma patients treated with anti-CD19 CAR T-cell therapy

Abstract Introduction: Despite the exceptional promise of anti-CD19 CAR T-cell therapy, 40-60% of relapsed or refractory large B-cell lymphoma (R/R LBCL) patients exhibit poor response and survival. Therefore, identification of pre-treatment markers of response to anti-CD19 CAR T-cell therapy is essential. Immune responses to infections and many autoimmune diseases exhibit gender bias, but it is not known if gender influences response to CAR T-cell therapy. We performed serum profiling to identify pre-treatment cytokines and chemokines associated with response and survival in male and female LBCL patients treated with axicabtagene ciloleucel (axi-cel). Methods: Serum samples were collected from peripheral blood at the time of leukapheresis from 42 R/R LBCL patients treated with axi-cel. Multiplexed bead arrays were used to quantify baseline levels of 51 serum cytokines, chemokines and cytotoxic proteins. Unpaired Wilcoxon test was used to analyze the association of baseline cytokine levels with 3-month response, and Kaplan-Meier survival analysis for association with survival outcomes. Statistical analyses were performed using R and p&amp;lt;0.05 was considered significant. Results: The median age of patients was 61 y, and 62% of the patients were male. All patients had been previously treated with R-CHOP or R-EPOCH, and had a median of 3 prior lines of therapy, including 47.6% with autologous stem cell transplantation. Male non-responders (stable/progressive disease) had significantly higher baseline levels of IL-6, IL-8, IL-1RA, MIP-1α, GM-CSF and CRP compared to responders (complete/partial response). Higher levels of IL-6, IL-8, IL-27, and CRP were significantly associated with poor overall survival (OS), and IL-6, IL-8, MIP-1β, and CRP with poor progression-free survival (PFS) in male patients. Baseline metabolic tumor volume (MTV) and lactate dehydrogenase (LDH) levels were also significantly higher in male patients with poor OS and PFS. Finally, baseline IL-8 and CRP were significantly associated with baseline MTV and LDH levels in male patients. Conclusions: Our data show that pre-treatment proinflammatory proteins IL-8, IL-6, CRP are associated with poor response and survival in axi-cel-treated male but not female LBCL patients. The correlation of high levels of these factors with high pretreatment tumor burden in male non-responder R/R LBCL patients is suggestive of an immunosuppressive tumor microenvironment that is unlikely to support optimal expansion of anti-CD19 CAR T cells, resulting in poor response and survival outcomes. Citation Format: Manishkumar S. Patel, Akansha Jalota, Agrima Mian, Peter Bazeley, Sara A. Hunter, Brian T. Hill, Neetu Gupta. Gender bias in the association of pre-treatment cytokine signatures with response and survival in B cell lymphoma patients treated with anti-CD19 CAR T-cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1262.

Prognostic Value of Lactate Dehydrogenase in Second-Line Immunotherapy for Advanced Esophageal Squamous Cell Carcinoma.

Background: Immunotherapy is recommended by the NCCN (National Comprehensive Cancer Network) guidelines as the standard second-line treatment for advanced esophageal squamous cell carcinoma (ESCC). Patients with advanced ESCC can benefit from immunotherapy, but the overall survival time (OS) is still not satisfactory. Therefore, it is of great importance to select effective prognostic indicators. Methods: A retrospective follow-up study was conducted from January 2018 to January 2020 among 44 patients with advanced ESCC treated with second-line immune checkpoint inhibitors (programmed death -1 blocking agents) in our hospital. The cutoff values of baseline lactate dehydrogenase (LDH), LDH level at week 8, serum albumin, hemoglobin, neutrophils, monocytes, and platelets were obtained by receiver operating characteristic (ROC) curves. The Kaplan-Meier method was used to analyze the relationship between LDH at baseline, LDH level at week 8, and LDH changes during treatment with progression-free survival (PFS) and OS time. The Cox proportional hazards model was used for univariate and multivariate analyses to determine the predictors of OS. Results: In univariate analysis, we found patients with lower baseline LDH levels (cutoff value: 200 U/L) had a better median PFS (8 months vs. 3 months; HR = 2.420, 95% CI: 1.178–4.971, p = 0.016) and OS (14 months vs. 6 months; HR = 3.637, 95% CI: 1.638–8.074, p = 0.004). The level of LDH at week 8 and the changes in LDH during treatment were not significantly associated with PFS or OS. The multivariate analyses showed that baseline LDH was an independent predictor of PFS (HR = 2.712, 95% CI: 1.147–6.409, p = 0.023) and OS (HR = 6.260, 95% CI: 2.320–16.888, p < 0.001), and the monocyte count (HR = 0.389, 95% CI: 0.162–0.934, p = 0.035) was significantly associated with OS. Conclusion: Serum LDH is a powerful independent factor for PFS and OS in advanced ESCC patients treated with anti-PD-1 therapy.

Sex differences in the pre-treatment cytokine signatures associated with response and survival in B cell lymphoma patients treated with anti-CD19 CAR T-cell therapy

Abstract Many autoimmune diseases, and in some instances, immune response to infections exhibit gender bias. However, it is not known if gender influences the response of lymphoma patients to anti-CD19 CAR T-cell therapy. To address this, we profiled 51 pre-treatment serum cytokines and chemokines to identify those that were differentially associated with response and survival in male vs. female relapsed/refractory large B-cell lymphoma (R/R LBCL) patients treated with Axicabtagene ciloleucel. Male non-responders (stable/progressive disease) had significantly higher baseline levels of IL-6, IL-8, IL-1RA, MIP-1α, GM-CSF and CRP compared to responders (complete/partial response). Higher levels of IL-6, IL-8, IL-27, and CRP were significantly associated with poor overall survival (OS), and IL-6, IL-8, MIP-1β, and CRP with poor progression-free survival (PFS) in male but not female patients. Baseline metabolic tumor volume (MTV) and lactate dehydrogenase (LDH) levels were also significantly higher in male patients with poor OS and PFS. Finally, baseline IL-8 and CRP were significantly correlated with baseline MTV and LDH levels in male but not female patients. Taken together, elevated baseline levels of IL-8, IL-6, CRP with high pretreatment tumor burden in male non-responder R/R LBCL patients point to an immunosuppressive tumor microenvironment that can potentially hinder anti-tumor activity prior to treatment and CAR T-cell expansion upon treatment in these patients, and result in poor outcomes.

Selected Articles from This Issue

Carboplatin is commonly used for treating many solid cancers, but many patients develop resistance, necessitating combination treatment. Preclinical studies have shown that the combination of ceralasertib, an ATR inhibitor, and carboplatin may hold clinical promise. Here, Yap and colleagues report the results of a multicenter phase I study of ceralasertib plus carboplatin in patients with advanced solid cancers. This combination was well tolerated and showed potential clinical activity, with 18 of 34 patients showing stable disease. Two patients with absent or low ATM or SLFN11 protein expression achieved confirmed partial responses. Further clinical study is necessary to validate the clinical utility of this combination.The randomized phase III coBRIM study (NCT01689519) demonstrated that the addition of cobimetinib to vemurafenib improved progression-free survival (PFS) and overall survival (OS) in patients with previously untreated BRAFV600-positive advanced melanoma. Ascierto and colleagues report long-term follow-up of this study. Over at least 5 years of follow-up. results of PFS and OS benefits remain for cobimetinib plus vemurafenib compared with vemurafenib monotherapy. Normal baseline lactate dehydrogenase levels, low tumor burden, and a complete response were associated with extended OS and PFS. These results confirm the clinical utility of this combination.The combined targeting of PD-1 and CTLA-4 has provided benefit to patients with advanced melanoma, but toxicity has been a challenge, primarily due to ipilimumab. To further tailor dosing of ipilimumab, Long and colleagues conducted a clinical trial assessing standard-dose pembrolizumab plus alternative ipilimumab dosing regimens in patients with advanced melanoma. All patients received pembrolizumab at 200 mg every 3 weeks plus ipilimumab at either 50 mg (PEM200+IPI50) every 6 weeks or 100 mg (PEM200+IPI100) every 12 weeks. The PEM200+IPI50 regimen reduced both treatment-related adverse events and immune-mediated adverse events compared to PEM200+IPI100. The ORR was 55% in PEM200+IPI50 and 61% in PEM200+IPI100. Based on these data, further clinical trials of PD-1 inhibitors with alternative ipilimumab dosing are warranted.Adoptive cell transfer of tumor-infiltrating lymphocytes (ACT-TIL) can mediate durable complete responses in patients with metastatic melanoma after a single treatment. To evaluate ACT-TIL in the era of checkpoint inhibition and targeted molecular therapy, Seitter and colleagues analyzed a cohort of 226 patients treated as part of ACT-TIL clinical trials. Patients who had received PD-1 blockade or MAPK inhibitors prior to ACT-TIL demonstrated a lower objective response rate and shorter melanoma-specific survival after ACT-TIL than patients who were naïve to those treatments. These data suggest a potential role for ACT-TIL as a front-line therapy for eligible patients.

5-Year Outcomes with Cobimetinib plus Vemurafenib in BRAFV600 Mutation-Positive Advanced Melanoma: Extended Follow-up of the coBRIM Study.

The randomized phase III coBRIM study (NCT01689519) demonstrated improved progression-free survival (PFS) and overall survival (OS) with addition of cobimetinib to vemurafenib compared with vemurafenib in patients with previously untreated BRAFV600 mutation-positive advanced melanoma. We report long-term follow-up of coBRIM, with at least 5 years since the last patient was randomized. Eligible patients were randomized 1:1 to receive either oral cobimetinib (60 mg once daily on days 1-21 in each 28-day cycle) or placebo in combination with oral vemurafenib (960 mg twice daily). 495 patients were randomized to cobimetinib plus vemurafenib (n = 247) or placebo plus vemurafenib (n = 248). Median follow-up was 21.2 months for cobimetinib plus vemurafenib and 16.6 months for placebo plus vemurafenib. Median OS was 22.5 months (95% CI, 20.3-28.8) with cobimetinib plus vemurafenib and 17.4 months (95% CI, 15.0-19.8) with placebo plus vemurafenib; 5-year OS rates were 31% and 26%, respectively. Median PFS was 12.6 months (95% CI, 9.5-14.8) with cobimetinib plus vemurafenib and 7.2 months (95% CI, 5.6-7.5) with placebo plus vemurafenib; 5-year PFS rates were 14% and 10%, respectively. OS and PFS were longest in patients with normal baseline lactate dehydrogenase levels and low tumor burden, and in those achieving complete response. The safety profile remained consistent with previously published reports. Extended follow-up of coBRIM confirms the long-term clinical benefit and safety profile of cobimetinib plus vemurafenib compared with vemurafenib monotherapy in patients with BRAFV600 mutation-positive advanced melanoma.

MO368THE INCIDENCE AND RISK FACTORS FOR ACUTE KIDNEY INJURY IN PATIENTS TREATED WITH IMMUNE CHECKPOINT INHIBITORS: A REAL-LIFE STUDY

Abstract Background and Aims The immune checkpoint inhibitors (ICIs) became a vital part of cancer treatment. The ICIs seem to be safer than chemotherapy for kidneys in clinical trials. However, recent observational studies from high-resource settings pointed out the possible underreporting of renal adverse events like acute kidney injury (AKI) in the clinical trials due to focusing only to the renal immune-related adverse events. Additionally, clinical trials generally enroll a fitter population with lesser comorbidities and include mostly treatment-naive patients making studies in real-life cohorts imperative for evaluating the AKI rates during ICI treatment. From these points, we aimed to evaluate the AKI rates and predisposing factors in ICI-treated patients. Method This retrospective study has evaluated the data of adult metastatic cancer patients treated with ICIs in Hacettepe University Cancer Center from 01.2014 to 12.2019. All patients other than the ones treated within the context of clinical trials or followed in other institutions after the first dose of ICIs were included. Baseline demographics, cancer types, patient weight and heights, ICI type and the number of cycles, serum creatinine and the estimated GFR values under treatment, regular medications, and comorbidities were recorded. AKI was defined by Kidney Disease Improving Global Outcomes criteria. The predisposing factors to AKI development were evaluated with the univariate and multivariate analyses. Results A total of 147 patients were included in the analyses. Median age was 61 [interquartile range (IQR) 51-67], and 69.4% of the patients were male. Patients were given a median of 8 (IQR 5-17) ICI cycles. Patients with melanoma (24.5%), non-small cell lung cancer (15%), and renal cell carcinoma (25.9%) comprised almost 2/3 of the cohort and 72.8% of the patients were treated with nivolumab. Hypertension was the most common comorbidity (38.1%), followed by chronic kidney disease (21.2%) and type 2 diabetes (19.7%). Median Charlson Comorbidity Index (CCI) was 8 (7-9). Median follow-up was 10.3 (IQR 6.3-19.4) months, and patients had median 9 (IQR 5-18) serum creatinine measurements. During the follow-up, 28 patients (19%) had at least one AKI episode with multiple AKI episodes in 3 patients (10.7%). The median time to AKI development was 2.53 (IQR 1.39-6.19) months. Almost all AKI events were mild (grade 1 or 2 in 27/28) and reversible (25/28). In univariate analyses, coronary artery disease (CAD) (p=&amp;lt;0.001), chronic kidney disease (CKD) (p=0.002), previous nephrectomy (p=0.015), iodinated contrast exposure in the week before immunotherapy (p=0.035), the use of renin-angiotensin-aldosterone system inhibitors (p=0.046) or proton pump inhibitors (PPI) (p=0.041) was associated with an increased AKI risk. The association between diabetes (p=0.067), higher CCI (9 vs. ≥9, p=0.107), baseline lactate dehydrogenase levels (p=0.177), and performance status (ECOG 0 vs. ≥1, p=0.235) and AKI risk did not reach statistical significance. In multivariate analyses, patients with CKD (OR: 3.719, 95% CI: 1.375- 10.057, p=0.010) or CAD (OR: 4.774, 95% CI: 1.803- 12.641, p=0.002) had increased AKI risk. Additionally, regular PPI use (OR: 2.734, 95% CI: .991- 7.542, p=0.052) had borderline statistical significance for AKI development. The development of AKI was not associated with decreased survival (HR: 0.726, 95% CI: 0.409-1.291, p=0.276). Conclusion In this study, we observed AKI development under ICIs in almost one in five cancer patients. The increased AKI rates in patients with CAD, CKD, or regular PPI use pointed out the need for better onco-nephrology collaboration in all ICI-treated patients, with a particular emphasis in these high-risk patients.

LDH as prognostic factor in second line treatment for advanced gastric cancer: The LINE study.

e16102 Background: Lactate dehydrogenase (LDH) is recognized as indirect marker of tumor hypoxia and angiogenesis for several solid tumors. Ramucirumab is the first antiangiogenic agent approved for second-line therapy in advanced gastric cancer (GC), alone or in association with chemotherapy. To date, no reliable biomarkers can predict the potential benefit from anti-VEGFR2 treatment. This retrospective multicenter study aimed to assess the prognostic role of baseline LDH levels in patients (pts) undergoing second-line treatment for advanced GC. Methods: The study analyzed a retrospective cohort of consecutive advanced GC pts treated with second line therapy at IRCCS, CRO of Aviano and at Mauriziano Hospital of Torino, Italy, from 2010 to 2020. LDH levels prior to second-line treatment were classified as low-normal or high and standardized according to the upper limit of the reference range. To better determine the optimal LDH cut-off value, ROC analysis was performed (using PFS &lt; 3 months as binary outcome). Normalized LDH values were subsequently sorted according to the ROC curve cut-off in order to test the association with overall survival (OS) through the Kaplan-Meier method and compared using the Log-Rank test. A multivariate Cox regression analysis assessed the prognostic impact of normalized LDH levels for OS calculated from the start of second line treatment. Results: Overall, 125 pts were enrolled. Of these, 81 pts (64.80%) received ramucirumab alone or plus paclitaxel as second line treatment, while 44 (35.20%) had taxanes or fluoropyrimidines combined with irinotecan. Median age was 68 years, 93% had an ECOG PS ≤ 1, 64.80% was first diagnosed with metastatic disease and 40.80% underwent primary tumor resection. Median second line PFS and OS were 4.2 and 7.9 months, respectively. Baseline LDH values were available for 99 pts. ROC analysis identified a normalized LDH value of 0.83 as the optimized cut-off point to define pts with poor prognosis. At univariate analyses, surgery of the primary tumor (HR 0.51, 95% CI 0.31-0.82, p = 0.005) was associated with better OS, while low-normal BMI ( &lt; 25 kg/m2) at second line start (HR 1.99, 95% CI 1.21-3.28, p = 0.007), normalized LDH values ≥ 0.83 (HR 1.86, 95% CI 1.13-3.07, p = 0.015) and PS &gt; 1 (HR 5.65, 95% CI 2.29-13.92, p &lt; 0.001) were associated with poorer outcome. At multivariable model, only PS &gt; 1 was independently associated with poor prognosis (HR 9.93, 95% CI 3.27-30.08, p &lt; 0.001). Subgroup analyses showed no significant heterogeneity in OS outcome according to normalized LDH levels between patients treated with or without ramucirumab. Conclusions: Elevated LDH levels are indicators of worse outcome in advanced gastric cancer pts. Notably, the LDH cut-off value identified a poor prognosis subgroup among pts with normal baseline levels, suggesting that current laboratory ranges could be suboptimal for patient stratification.

UPAR+ extracellular vesicles: a robust biomarker of resistance to checkpoint inhibitor immunotherapy in metastatic melanoma patients

BackgroundEmerging evidence has highlighted the importance of extracellular vesicle (EV)-based biomarkers of resistance to immunotherapy with checkpoint inhibitors in metastatic melanoma. Considering the tumor-promoting implications of urokinase-type plasminogen activator receptor...

Recent advances in molecular targeted therapy for unresectable and metastatic BRAF-mutated melanoma.

The clinical outcome of BRAF-mutated advanced melanoma has been improved by both molecular targeted therapies and immune checkpoint inhibitors. Long-term follow-up data reveal durable clinical responses in patients receiving first-line combinations of BRAF inhibitors plus MEK inhibitors, particularly those showing a complete response. Clinical outcomes are also associated with the lactate dehydrogenase levels and the number of metastatic organs. Although brain metastasis is frequently difficult to control, systemic therapy is preferred in cases with small and asymptomatic brain metastases associated with progressive extra-cranial disease. Control of intra-cranial disease with BRAF inhibitors plus MEK inhibitors is comparable with that of immune checkpoint inhibitors, although immune checkpoint inhibitors are superior to targeted therapies with respect to survival. The BRAF inhibitors plus MEK inhibitors regimen is well-tolerated, and toxicities are usually manageable and reversible, but differ according to the specific regimen used. Guidelines in the United States, Europe, and Japan recommend targeted therapy for patients who need early tumor responses. A meta-analysis of retrospective data shows that the baseline lactate dehydrogenase level is significantly higher in patients treated with BRAF inhibitors plus MEK inhibitors than in those treated with immune checkpoint inhibitors, suggesting that clinicians tend to use BRAF inhibitors plus MEK inhibitors for more advanced disease. Since there is insufficient efficacy and safety data on the use of targeted therapies for acral and mucosal melanoma, a retrospective analysis may be useful. The combination of molecular targeted therapy plus immune checkpoint inhibitors is expected to elicit further improvement. The results of several trials using combination or sequential therapies will be available in the next few years.