Worse Median Overall Survival Research Articles

Co-Mutational Patterns with BCOR Influences Biological Characteristics and Clinical Outcomes of Myeloid Neoplasms

Introduction BCL6 co-repressor ( BCOR), a tumor suppressor gene located on chromosome X (locus Xp11.4) is involved in hematopoiesis via non-canonical polycomb repressive complex 1 (PRC1). The prevalence of BCOR mutation in myeloid neoplasms (MN) is approximately 5%, and it is also implicated in clonal hematopoiesis. In the 2022 ELN, WHO, and ICC classifications, BCOR is categorized as a myelodysplasia-related gene. Mutational patterns include frequent co-occurrence with DNMT3A and RUNX1 in AML and mutual exclusivity with NPM1 mutations. Although it has been theorized that BCORMT may cooperate preferentially with certain groups of genes, the prognostic significance of the BCOR co-mutational landscape has yet to be fully studied. Methods The total cohort (n = 20149) consists of 624 MN patients (169 primary (p) AML, 136 secondary (s) AML, 84 MDS, 34 MDS/MPN, 66 MPN, and 135 with other MN) from Karmanos Cancer Institute, publicly available metanalytic cohort consisting of various sub-studies (Awada et al., 2021; Kewan et al., 2023), and cohorts from open-access cancer genomics resource cBioPortal and AACR GENIE (v13.1) (Cerami et al., 2012; Gao et al., 2013). Clinical and genomic characteristics were reviewed. Chi-square and T-tests were used for analysis of various parameters as described, and Kaplan-Meier and log-rank methods were used to estimate overall survival (OS). The prevalence of BCORMT, co-occurring mutations, and their outcomes were analyzed based on co-mutational patterns. Results A total of 745 (3.7%) patients carried BCORMT. Male: Female ratio was 1.48, with a median age of 68 ys.(IQR 59-75). BCORMTshowed a trend to be most frequent in pAML compared to other MN (54 vs 46%, p=0.33). BCORMT was less associated with abnormal karyotype vs. BCORWT [41 vs. 51%, p=0.0002]. Median variant allele frequency (VAF) was 45% (IQR 22-69), and most mutations were frameshift (41%) followed by nonsense (27%), and missense (22%). Median OS was not different between BCORWT and BCORMT patients [21.9 vs. 19.6 mo., p=0.089] in the entire cohort. Oncoprint analysis centered around BCOR revealed frequent co-mutations with RUNX1, DNMT3A, TET2 and ASXL1. As a result, the patients were divided into 10 groups (groups A-J), and the OS was analyzed between groups and compared with BCORWT. Patients with BCOR/TET2, BCOR/RUNX1/TET2, and BCOR/ASXL1 (groups G, B, and H resp.) had the lowest median OS with 14.5 mo., 16.7 mo., and 17.4 mo., resp. However, no significant differences in median OS were observed between the compared groups except those involving BCOR/ASXL1 vs. BCOR/Others and BCORWT. BCOR/ASXL1 patients had significantly lower median OS compared to BCOR/Others [17.4 vs. 22.5 mo., p=0.022] and BCORWT [17.4 vs. 21.9 mo., p=0.017]. Further BCORMT and ASXL1MT comutational analysis irrespective of other co-occurring mutations, revealed that in those with BCORMT, ASXL1 co-mutation was seen in 143 (19.2%) patients. BCOR and ASXL1 co-mutation were primarily enriched in primary AML (49%), followed by sAML (25%). Median BCOR VAF was higher than ASXL1 [39 vs. 31%, p<0.0001]. The most associated mutational categories in this subgroup were related to myeloid transcription factors (TF) ( RUNX1, CEBPA; 62%), spliceosome ( SRSF2, U2AF1, SF3B1, ZRSR2; 22%), and DNA methylation family ( DNMT3A, TET2, IDH1/2; 8%). BCORMT/ ASXL1MT/DNA Methylation mutations had poorer median OS compared to BCORMT/ ASXL1MT/Spliceosome mutations [9.2 vs. 17.4 mo., p=0.044]. Whereas BCORMT/ ASXL1MT/Myeloid TF and BCORMT/ ASXL1MT/Spliceosome mutations had no significant survival difference compared to BCORWT, patients with BCORMT/ ASXL1MT/DNA Methylation had worse median OS [9.2 vs. 21.9 mo., p=0.007]. Conclusion This large cohort study confirms common BCOR co-mutation patterns and reveals prognostic differences in patients with co-occurring ASXL1 mutation. We demonstrated BCORMT with ASXL1MT without concurrent RUNX1MT, DNMT3AMT, and TET2MT had poorer overall survival. Furthermore, patients with BCORMT, ASXL1MT, and concomitant DNA methylation-related gene mutations had worse outcomes compared to those with concomitant spliceosome mutation and BCORWT. Our findings suggest that co-mutational patterns of BCOR may further clarify diagnosis and classification schemes, highlighting potential synergies among subcategories of gene mutations and their prognostic value.

Real World Outcomes of Black Americans with Mantle Cell Lymphoma

Introduction Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 6-8% of all NHL cases. MCL generally affects older, White, male patients, having a significantly lower incidence in Black patients. Thus, clinical outcomes of Black Americans with MCL are poorly characterized, though multiple sources have reported relatively poor survival outcomes when compared to their White counterparts. We aimed to evaluate the overall survival outcomes and explore potential factors contributing to poor survival outcomes for Black patients with MCL in the United States. Methods The National Cancer Database was used to identify MCL patients diagnosed from 2004-2020. Demographic and treatment characteristics were compared between White and Black MCL patients, by self-identified race. Patients of other races were excluded. Kaplan Meier and adjusted Cox regression survival analysis were used to compare overall survival (OS) by race, and stratified for age ≤ 65 or age > 65 years old. Finally, a propensity matched analysis was performed to compare OS in Black and White Americans matched by age, comorbidity burden, insurance status, and zip code income. Results A total of 34,872 patients with MCL were identified, of which 93.1% (N=32,407) were White, 4.2% (N=1,465) were Black, and 1.7% (N=942) identified as another race and were excluded from the dataset. Black patients were more likely to be female (34% Black vs. 29% White), have a younger age at diagnosis (mean age 65 years [SD ± 13] vs. 68 years [SD ± 12], p<0.001), more likely to have ≥1 co-morbidity (30% vs. 23%), and more likely to be uninsured (4% vs. 2%) when compared to White patients. Both Black and White patients had equal rates of stage IV disease (68% vs. 68%) and receipt of systemic therapy at diagnosis (84% vs. 84%), however White patients were more likely to receive stem cell transplant compared to Black patients (13% vs.11%). With a median follow-up of 40 months, the median OS for all MCL patients was 70 months (95% CI 66-71). Compared to White patients of the same age, Black patients age ≤ 65 years had worse median OS (116 months [95% CI 92-139] vs. 140 [95% CI 134-146] months for White patients) along with decreased 1-year (87% vs. 90%), 5-year (62% vs. 70%) and 10-year OS (38% vs. 55%), (all p <0.001). For MCL patients age > 65 years old, Black MCL patients had shorter median OS compared to their White counterparts (36 months [95% CI 28-43] vs. 43 months [95% CI 41-44]), and decreased 1-year (70% vs. 75%) and 5-year OS (40% vs. 41%) (all p=0.030), though by ten years there was no survival disparity. On age-adjusted cox regression, Black race was associated with increased hazard for all-cause death for MCL patients (hazard ratio [HR] 1.17, CI 1.08-1.26; p<0.001). However, when Black and White patients were 1:1 propensity score matched by age, co-morbidity score, insurance status, and income quartile of zip code, there was no significant difference in risk of death by race alone (HR 0.99, CI 0.91-1.08; p=0.61). Conclusion This is the largest study to-date evaluating outcomes among Black patients with MCL. Patients who are Black with MCL are more likely to present at a younger age, have female predominance, and have worse overall survival outcomes than White patients of similar age. Notably, we found that this survival difference was lost when controlling for surrogate markers of healthcare access, such as insurance and income. This study highlights existing disparities for Black patients with MCL, which appear to be related to socioeconomic disparities that may impact access to treatment, supportive care, and other vital aspects of care for MCL. Future studies may seek to evaluate the role of known high risk features for MCL such as TP53 status or blastoid/pleomorphic morphology in these populations. Interventions aimed at improving healthcare access for underserved populations, including racial minorities, are essential.

Benchmarking of the Cervical Cancer Care Cascade and Survival Outcomes After Radiation Treatment in a Low- and Middle-Income Country Setting.

Timely radiation treatment (RT) is critical in cervical cancer treatment, but patients in low- and middle-income countries (LMICs) in sub-Saharan Africa often face barriers that delay care. Time to care was benchmarked in a multidisciplinary team (MDT) setting in Botswana. Time intervals between steps in care were recorded for 230 patients reviewed at MDT between January 2016 and July 2018. Associations between RT delay and overall survival (OS) were evaluated using Kaplan-Meier curves and multivariable Cox proportional hazards models. For patients who received RT (n = 187; 81.3%), the median biopsy to pathology reporting interval was 25 (IQR, 19-36) days and was 57 (IQR, 28-68) days for patients who did not (P = .003). Intervals in care did not differ between patients who did and did not receive RT. Among treated patients, the uppermost quartile interval from pathology reporting to RT initiation was ≥111 days and that from RT simulation to initiation was ≥12 days. Among patients receiving a RT dose of ≥65 Gy (n = 100), the delay from RT simulation to initiation of >12 days was associated with worse median OS (2.0 v 4.6 years; P = .048); this association trended toward, although did not meet, statistical significance on multivariable analysis (hazard ratio, 2.35; 95% CI, 0.95 to 5.85; P = .07). The MDT-coordinated care model allows for systematic benchmarking of the patient treatment cascade. Barriers to timely treatment exist for this cohort in Botswana, and RT delay may be associated with OS of patients receiving curative treatment. Interventions to accelerate the timing of the radiation oncology care cascade may improve clinical outcomes in this LMIC setting.

Serum Interleukin 6 Level is Associated With Overall Survival and Treatment Response in Gastric and Gastroesophageal Junction Cancer.

To identify novel prognostic and predictive biomarkers for gastric and gastroesophageal junction (G+GEJ) adenocarcinoma. There are few biomarkers to guide treatment for G+GEJ. The systemic inflammatory response of G+GEJ patients is associated with survival. In this study, we evaluated the relationship of circulating serum cytokine levels with overall survival (OS) and pathologic tumor regression grade (TRG) in G+GEJ patients. We queried the UT Southwestern gastric cancer biobank to identify consecutive patients diagnosed with G+GEJ from 2016 to 2022; these patients had pretreatment serum collected at diagnosis. For patients who received neoadjuvant therapy, an additional serum sample was collected immediately before surgical resection. An unbiased screen of 17 cytokines was measured in a discovery cohort. A multivariable Cox proportional hazards model was used to assess the association of cytokine concentration with OS. Findings were validated in additional patients. In patients who received neoadjuvant therapy, we assessed whether the change in interleukin 6 (IL-6) after therapy was associated with TRG. Sixty-seven patients were included in the discovery cohort, and IL-6 was the only pretreatment cytokine associated with OS; this was validated in 134 other patients (hazard ratio: 1.012 per 1pg/mL increase, 95% CI: 1.006-1.019, P = 0.0002). Patients in the top tercile of IL-6 level had worse median OS (10.6 months) compared with patients in the intermediate (17.4 months) and bottom tercile (35.8 months, P < 0.0001). Among patients who underwent neoadjuvant therapy (n = 50), an unchanged or decrease in IL-6 level from pretreatment to posttreatment, had a sensitivity and specificity of 80% for predicting complete or near-complete pathologic tumor regression (TRG 0-1). Pretreatment serum level of IL-6 is a promising prognostic biomarker for G+GEJ patients. Comparing pre and post-neoadjuvant IL-6 levels may predict pathologic response to neoadjuvant therapy.

Leptomeningeal metastases in glioma revisited: incidence and molecular predictors based on postcontrast fluid-attenuated inversion recovery imaging.

Leptomeningeal metastases (LMs) in glioma have been underestimated given their low incidence and the lack of reliable imaging. Authors of this study aimed to investigate the real-world incidence of LMs using cerebrospinal fluid (CSF)-sensitive imaging, namely postcontrast fluid-attenuated inversion recovery (FLAIR) imaging, and to analyze molecular predictors for LMs in the molecular era. A total of 1405 adult glioma (World Health Organization [WHO] grade 2-4) patients underwent postcontrast FLAIR imaging at initial diagnosis and during treatment monitoring between 2001 and 2021. Collected molecular data included isocitrate dehydrogenase (IDH) mutation, 1p/19q codeletion, H3 K27 alteration, and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. LM diagnosis was performed with MRI including postcontrast FLAIR sequences. Logistic regression analysis for LM development was performed with molecular, clinical, and imaging data. Overall survival (OS) was compared between patients with and those without LM. LM was identified in 228 patients (16.2%), 110 (7.8%) at the initial diagnosis and 118 (8.4%) at recurrence. Among the molecular diagnostics, IDH-wildtype (OR 3.14, p = 0.001) and MGMT promoter unmethylation (OR 1.43, p = 0.034) were independent predictors of LM. WHO grade 4 (OR 10.52, p < 0.001) and nonlobar location (OR 1.56, p = 0.048) were associated with LM at initial diagnosis, whereas IDH-wildtype (OR 5.04, p < 0.001) and H3 K27 alteration (OR 3.39, p = 0.003) were associated with LM at recurrence. Patients with LM had a worse median OS than those without LM (16.7 vs 32.0 months, p < 0.001, log-rank test), which was confirmed as an independent factor on multivariable Cox analysis (p = 0.004). CSF-sensitive imaging aids the diagnosis of LM, demonstrating a high incidence of LM in adult gliomas. Furthermore, molecular markers are associated with LM development in glioma, and patients with aggressive molecular markers warrant imaging surveillance for LM.

Factors affecting outcomes of Yttrium-90 radioembolization in heavily pretreated patients with intrahepatic cholangiocarcinoma.

Transarterial radioembolization (TARE) is a liver-directed treatment for unresectable intrahepatic cholangiocarcinoma (ICC). The aim of this study is to evaluate factors affecting outcomes of TARE in heavily pretreated ICC patients. We evaluated pretreated ICC patients who received TARE from January 2013 to December 2021. Prior treatments included systemic therapy, hepatic resection, and liver-directed therapies, including hepatic arterial infusion chemotherapy, external beam radiation, transarterial embolization, and thermal ablation. Patients were classified based on history of hepatic resection and genomic status based on next-generation sequencing (NGS). The primary endpoint was overall survival (OS) after TARE. Fourteen patients with median age 66.1 years (range, 52.4-87.5), 11 females and 3 males, were included. Prior therapies included systemic in 13/14 patients (93%), liver resection in 6/14 (43%), and liver-directed therapy in 6/14 (43%). Median OS was 11.9 months (range, 2.8-81.0). Resected patients had significantly longer median OS compared to unresected patients (16.6 versus 7.9 months; p=0.038). Prior liver-directed therapy (p=0.043), largest tumor diameter >4 cm (p=0.014), and >2 hepatic segments involvement (p=0.001) were associated with worse OS. Nine patients underwent NGS; 3/9 (33.3%) and had a high-risk gene signature (HRGS), defined as alterations in TP53, KRAS, or CDKN2A. Patients with a HRGS had worse median OS (10.0 versus 17.8 months; p=0.024). TARE may be used as salvage therapy in heavily treated ICC patients. Presence of a HRGS may predict worse OS after TARE. Further investigation with more patients is recommended to validate these results.

Serum IL-6 level to predict survival and treatment response in gastric and gastroesophageal junction cancer.

444 Background: There are few biomarkers to guide treatment for gastric and gastroesophageal junction adenocarcinoma (G+GEJ). The systemic inflammatory response, which is reflected by circulating serum cytokine levels, of G+GEJ patients is associated with survival. In this study, we evaluated the relationship of circulating serum cytokine levels with overall survival (OS) and pathologic tumor regression grade (TRG) in G+GEJ patients. Methods: A retrospective review of a prospectively maintained biobank was performed to identify patients diagnosed with G+GEJ from 2016-2022. Pre-treatment serum was collected at the time of diagnosis. For patients who received neoadjuvant therapy, an additional serum sample was collected immediately prior to surgical resection. A multivariable Cox proportional hazards model was used to assess the association of cytokine concentration with OS. In patients who received neoadjuvant therapy, we assessed whether the change in IL-6 (ΔIL-6) after therapy was associated with TRG. Results: We first measured the pre-treatment levels of 17 different cytokines in a 67-patient cohort to determine if certain circulating cytokines were prognostic for OS. In a multivariable analysis adjusted for clinical stage and the expression level of the other cytokines, the only circulating cytokine level that was independently associated with OS was IL-6 (HR: 1.06 per 1 pg/ml increase, 95% CI: 1.04-1.08). We then analyzed the serum IL-6 level in an additional 134 patients, resulting in a final cohort of 201 patients. Serum IL-6 level ranged from 0.3-196.7 pg/ml. In a multivariable analysis adjusted for age, sex, clinical stage, pathologic differentiation, Lauren classification, H. pylori status and neutrophil-to-lymphocyte ratio, IL-6 level was independently associated with OS (HR: 1.012 per 1 pg/ml increase, 95% CI: 1.006-1.019). Patients in the top tercile of pre-treatment IL-6 level had worse median OS (10.6 months) compared to patients in the intermediate (17.4 months) and bottom tercile (35.8 months, p &lt; 0.0001). Among patients who received neoadjuvant therapy (n = 50), ΔIL-6 ≤ 0 had a sensitivity of 80% and specificity of 80% for predicting complete or near-complete pathologic tumor regression (TRG 1). Conclusions: Pre-treatment serum level of IL-6 is a promising prognostic biomarker for patients with G+GEJ. ΔIL-6 may predict response to neoadjuvant therapy.

Clinical Outcomes After Progression on First-Line Therapies in IDH1 Mutated Versus Wild-Type Intrahepatic Cholangiocarcinoma Patients.

Isocitrate dehydrogenase-1 (IDH1) mutations occur in a significant proportion of intrahepatic cholangiocarcinomas (iCCAs). No data are available regarding the prognostic impact of IDH1 mutations in advanced iCCA patients after progression on first-line therapies. We investigated the role of IDH1 mutation in advanced iCCA after progression on first-line therapies. After progression on first-line therapies for advanced iCCA, consecutive patients were retrospectively collected. The IDH1 status was tested at baseline. This analysis aimed to examine the association between the presence of IDH1 missense mutations and survival outcomes in patients with advanced iCCA treated with a second-line therapy. The analysis included 119 patients; 56/119 (47%) were IDH1 mutated (IDH1m) and 63/119 (53%) were IDH1 wild type (IDH1 WT). At univariate analysis for overall survival (OS), the presence of IDH1 mutation was associated with a worse median OS (mOS; 8.2 vs. 14.1 months; hazard ratio [HR] 1.9, 95% confidence interval [CI] 1.2-3.0, p=0.0047). Patients harboring IDH1 mutations showed a worse objective response rate (ORR) compared with patients without IDH1 mutation, whereas no significant differences in disease control rate (DCR) were found. Multivariate analysis confirmed IDH1 mutations as an independent negative prognostic factor for OS (HR 1.7, 95% CI 1.1-2.7, p=0.0256). By evaluating only patients receiving FOLFOX as second-line therapy, no statistically significant differences were found in terms of both OS and PFS between IDH1m and IDH1WT patients. In this subset of patients, those harboring an IDH1 mutation showed a worse ORR and DCR compared with those without. Finally, at univariate analysis for OS from third-line treatment, the presence of an IDH1 mutation was associated with a trend toward a worse mOS (6.0 vs. 11.9 months; HR 1.6, 95% CI 0.8-3.2, p=0.25). The present analysis constitutes the first evidence of a negative prognostic impact of IDH1 mutations in a cohort of patients treated after progression on first-line therapies in contrast to IDH1 inhibitors.

Survival Outcomes Associated With the Size of Opioid Prescriptions in the Management of Chronic Pain Related to Advanced Nasopharyngeal Carcinoma.

Patients with advanced nasopharyngeal carcinoma (ANC) often experience chronic pain. Opioids are generally recommended to treat tumor-related pain, but increased opioid use may lead to detrimental aftereffects, particularly with respect to tumor progression, resulting in reduced quality of life and increased risk of death. Our objective was to investigate whether the high size of opioid prescriptions is associated with poor overall survival (OS) in patients with ANC. A consecutive cohort of patients with newly diagnosed ANC who underwent high or low opioid prescription size treatment during 2012-2019 was retrospectively identified from our medical institutions. Survival was estimated with the Kaplan-Meier method with a log-rank test. Multivariate binary logistic regression was used to assess the association between opioid use and OS, adjusting for age, sex, body mass index (BMI), Eastern Collaborative Oncology Group performance status (ECOG PS), and ANC histology. The criterion to distinguish between the high opioid prescription size group [HD] and the low opioid prescription size group [LD] was 5mg of oral morphine equivalents (OME) per 24hours. The cohort consisted of 244 consecutive patients (HD: n = 120, median age = 66 years [range, 40-81 years]; LD: n = 124, median age = 65 years [40-82years]. Patients who underwent treatment with a high opioid prescription size had a worse median OS than those who underwent treatment with a low opioid prescription size (5.1 vs 6.6 months), and the high opioid prescription size was associated with a remarkable 48% higher risk of death than the low opioid prescription size (HR 1.48, 95% CI 1.11-1.98; P = .005). The cumulative dose of opioids greater than or equal to 500mg of OME was associated with a higher risk of death, adjusted for age, sex, BMI, ECOG PS, and ANC histology. In patients with newly diagnosed ANC experiencing palliative care, a high opioid prescription size may be associated with shorter OS than a low opioid prescription size.

G-CSF Administration Is Associated with Worse Treatment Response and Survival after CAR T-Cell Therapy

Background: Chimeric antigen receptor T (CAR T)-cell therapy has led to unprecedented responses in patients with relapsed/refractory non-Hodgkin's lymphoma and heavily treated multiple myeloma. Despite impressive and relatively durable response rates, CAR T-cell therapy does not work for all patients and most patients tend to relapse. Recent correlative data from patients with decade-long remissions after CAR T-cell therapy showed that the initial response phase is driven by CD8+ CAR T-cells with a long-term remission phase dominated by CD4+ CAR T-cell phenotypes [Melenhorst JJ et al. Nature, 602(7897), 503-509]. Preclinical data has shown that G-CSF directly influences the effector function of cytotoxic CD8+ T cells and may lead to reduced reactivity [Franzke A et al. (2003) Blood, 102(2), 734-739 & Bunse CE et al. (2016). Clinical & Experimental Immunology, 185(1), 107-118]. Studies outlining the prognostic impact of G-CSF among patients treated with CAR T-cell therapy remain limited. There are no consensus guidelines for management of prolonged cytopenia using growth factor support, with wide variations in guiding practice amongst physicians or institutions. In this study, we recorded the utilization of G-CSF in a cohort of 80 consecutive patients treated with CAR T-cell therapy at our institution. We analyzed its potential impact on treatment response and survival after CAR T-cell therapy. Methods: This is a retrospective analysis of consecutive adult patients with an underlying B cell non-Hodgkin lymphoma (n=60) or multiple myeloma (n=20) treated with CAR T-cell therapy from 2016-2022. Baseline characteristics, laboratory measurements and clinical events following CAR T-cell therapy were collected by review of patients' electronic medical record. Medication records were reviewed to determine exposure to G-CSF, starting on day +1 through day +30 following CAR T-cell infusion. We used a chi square test or Fisher's exact test to compare proportions between groups. We calculated unadjusted and adjusted hazard ratios (HR) and 95% confidence intervals (CI) for overall survival (OS) and progression-free survival (PFS) and compared survival between the groups using the Mantel Cox log rank test. Results: Of 80 patients treated with CAR T-cell therapy, 76.2% (61/80) developed neutropenia with nadir ANC <500/uL before day +30. The median time to onset of neutropenia was +1 day, and 26.2% (21/80) of patients were neutropenic at the time of CAR T-cell infusion. In this cohort, 68.7% (55/80) of patients received G-CSF for management of severe neutropenia between days +1 and +30. Median time to initiation of G-CSF was 4 days (range 1-23 days) after treatment. Use of G-CSF did not decrease median length of stay compared to patients who did not receive G-CSF (20.5 vs 19 days). Administration of G-CSF was associated with worse treatment response at day 30, with only 65.5% (36/55) of patients in the G-CSF group attaining complete or partial response, compared to 88% (22/25) of patients in the non-G-CSF group with partial response or better (p=0.04). Patients who received G-CSF had significantly worse PFS (4.43 vs 63.1 months; p=0.01 with HR 2.23 95% CI 1.2 to 4.123 and OS (13.7 vs 67.8 months; p=0.001 with HR 3.62 95% CI 1.88 to 7.02) compared to patients not treated with G-CSF. On multivariate analyses, differences in survival with G-CSF use persisted despite adjusting for prior lines of therapy, HSCT status, development of CRS and underlying disease for PFS (adjusted HR 3.66; 95% CI 1.67-8.03) and OS (adjusted HR 4.66; 95% CI 1.70-12.76). Although patients with underlying myeloma had worse median OS when compared to patients with lymphoid malignancy (10.8 vs 24.8 months, respectively), both groups had significantly worse OS when compared to patients in the non-G-CSF group (67.8 months, p=0.001 and p=0.002 respectively). Among patients who received G-CSF, three or more prior lines of therapy was associated with worse OS (11.5 months), but patients who received <3 prior lines of therapy also had a significantly worse OS compared to the non-G-CSF group (p=0.03; HR 3.3 with 95% CI 1.1 to 9.8). Conclusion: In this single institution retrospective study, administration of G-CSF within 30 days of CAR T-cell infusion is associated with worse treatment response, PFS and OS irrespective of underlying disease, prior lines of therapy or HSCT status. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

EPID-05. LEPTOMENINGEAL METASTASES IN GLIOMA REVISITED: HIGH INCIDENCE AND THEIR MOLECULAR PREDICTORS BASED ON RECENT IMAGING AND MOLECULAR DIAGNOSTICS

Abstract BACKGROUND Leptomeningeal metastases (LM) in glioma has been underestimated due to low incidence and lack of reliable imaging. This study aimed to investigate a real-world incidence of LM using a CSF-sensitive MR imaging technique and analyze molecular predictors for LM in the molecular era. METHODS Total 1,405 adult glioma patients underwent post-contrast fluid attenuated inversion recovery (FLAIR) imaging at initial diagnosis and during treatment monitoring between March 2001 and October 2021. Molecular data included isocitrate dehydrogenase (IDH) mutation, 1p/19q co-deletion, H3 K27M alteration, and O6-methylguanine-methyltransferase (MGMT) promoter methylation status. Multivariable logistic regression analysis for LM development was performed in molecular data, clinical data, and imaging characteristics. Median overall survival (OS) was compared between patients with and without LM using Kaplan-Meier survival curves and log-rank test. RESULTS LM was identified in 16.2% of glioma (228 of 1405), with 7.8% (110 of 1405) at initial diagnosis, and 8.4% (118 of 1405) at recurrence. Among molecular diagnostics, IDH-wildtype (odds ratio [OR] 3.14, P = .001) and MGMT promoter unmethylation (OR 1.43, P = .034) were independent predictors of LM. WHO grade 4 (OR 10.52, P &amp;lt; .001) and nonlobar location (OR 1.54, P =.048) were associated with LM at initial diagnosis, whereas IDH-wildtype (OR 5.04, P &amp;lt; .001) and H3 K27M alteration (OR 3.39, P =.003) were significantly associated with LM at recurrence. Patients with LM had a worse median OS than those without LM (16.7 vs. 32.0 months, log-rank test; P &amp;lt; .001). CONCLUSIONS CSF-sensitive MR imaging diagnostics aid diagnosis of LM and reduced an underdiagnosed condition in adult gliomas. Molecular markers affect LM at initial diagnosis and at recurrence, and patients with aggressive molecular markers warrant imaging surveillance of LM.

Prognostic Value of Neutrophil Percentage-to-Albumin Ratio in Patients with Oral Cavity Cancer.

Simple SummaryInflammatory response and nutritional status play crucial roles in oral cavity squamous cell carcinoma (OSCC). Increasing evidences suggest the prognostic utility of neutrophil percentage-to-albumin ratio (NPAR) in human malignancies. In this study, we enrolled 368 patients with operated OSCC to investigate the prognostic role of NPAR. Our results demonstrated that patients with a high NPAR (≥16.93) had worse overall survival (OS) and disease-free survival (DFS), and a high NPAR (≥16.93) was an independent risk factor for poor OS and DFS in multivariate analyses. The nomogram integrating independent clinicopathological variables and NPAR provides accurate OS prediction and feasible application to OSCC management. Given its high availability and cost-effectiveness, the NPAR has potential to serve as a promising prognostic biomarker in patients with OSCC after external validation in a larger cohort.This study investigated preoperative neutrophil percentage-to-albumin ratio (NPAR) for predicting oral cavity squamous cell carcinoma (OSCC) survival. We retrospectively analyzed 368 patients who received curative OSCC surgery between 2008 and 2017. Receiver operating characteristic curve analyses were employed to identify the optimal NPAR cutoff (16.93), and the patients were then separated into low-NPAR and high-NPAR groups. Intergroup differences in survival were determined through Kaplan–Meier analysis and log-rank tests. Disease-free survival (DFS) and overall survival (OS) predictors were identified using Cox proportional-hazards models. A nomogram integrating independent prognostic factors was proposed to increase the accuracy of OS prediction. A high NPAR (≥16.93) was associated with worse median OS and DFS than was a low NPAR (both p < 0.001); this finding was confirmed through multivariate analyses (hazard ratio (HR) for OS = 2.697, p < 0.001; and HR for DFS = 1.671, p = 0.008). The nomogram’s favorable predictive ability was confirmed by the calibration plots and concordance index (0.784). The preoperative NPAR is thus a promising prognostic biomarker in patients with OSCC after external validation in a larger cohort. Our nomogram can facilitate clinical use of the NPAR and provides accurate individualized OS predictions.

Inflammatory Prognostic Index in Metastatic Renal Carcinoma Treated with Nivolumab.

To evaluate the utility of inflammatory prognostic index (IPI), albumin, c-reactive protein (CRP), and lactate dehydrogenase (LDH) as predictive biomarkers of oncologic outcome in metastatic renal cell cancer (mRCC) patients treated with nivolumab. Descriptive study. Manisa Celal Bayar University, Aydın Adnan Menderes University, Bitlis Tatvan State Hospital and Private Hatay Defne Hospital Medical Oncology Clinics, Turkey, from January 2017 to June 2020. Seventy-five mRCC patients treated with nivolumab between January 2017 and June 2020 were enrolled. Several factors were retrospectively investigated, including IPI, CRP, LDH, and albumin level, for their association with progression-free survival (PFS) and overall survival (OS). The IPI was calculated as CRP × NLR/albumin. Univariate and multivariate analyses were performed to assess the prognostic value of relevant factors. When analysed according to the calculated IPI score, it is seen that the group with <2.153 has an OS duration of 96.3 months, while the group with ≥2.153 has a shorter time of 42.9 months (p=0.02). In the analysis performed according to albumin level, it was reported that those with low levels (22.8 months) had worse median OS than those with high levels (92.8 months) (p=0.004). According to the cox regression analysis results, it was determined that those with a high IPI score significantly increased the risk of death compared to those with a low score (HR:2.4, p=0.023). However, this significance could not be confirmed in the multivariate analysis. It was analysed that those with low albumin levels significantly increased the risk of death compared to both univariate analysis (HR:3.3, p=0.007) and multivariate analysis (HR:4.4, p=0.003). Those with high IPI scores and low albumin levels were associated with worse median OS. However, only the multivariate analysis analysed albumin level as an independent prognostic variable. Prospective and more extensive research is needed to consolidate the potential prognostic power of these markers. Albumin, Immune checkpoint inhibitor, IPI score, Metastatic renal cell carcinoma, Nivolumab, overall survival, Progression-free survival.

Impact on Outcome of Minimal Residual Disease after Hematopoietic Stem Cell Transplantation with Fludarabine, Amsacrine, and Cytosine Arabinoside-Busulfan Conditioning: A Retrospective Monocentric Study

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) after conditioning with a sequential association of fludarabine, amsacrine, and cytosine arabinoside (FLAMSA) followed by a reduced-intensity conditioning regimen has emerged for patients with high-risk acute myeloid leukemia (AML), especially in refractory or relapsing patients. Here we aimed to address retrospectively the impact of pretransplantation minimal residual disease (MRD) by flow cytometry on the outcomes of high-risk AML patients who underwent allo-HSCT after sequential FLAMSA-busulfan (FLAMSA-Bu)-based conditioning regimens. We included 165 high-risk AML patients who underwent transplantation after FLAMSA-BU in this retrospective single-center "real life" study. All patients received in vivo T cell depletion with antithymocyte globulin (5 mg/kg). MRD detection was based on a leukemia-associated immunophenotype using the European LeukemiaNet recommendations, with a threshold of .1%. Univariate and multivariate analyses were performed using R version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria). With a median follow-up of 4.0 years post-transplantation, the median overall survival (OS) was 54.9 months. Overall, 41 patients (24.8%) relapsed post-transplantation, with a resulting cumulative incidence of relapse (CIR) of 26.7% at 2 years and 34.0% at 5 years. Detectable MRD preceding allo-HSCT and refractory status were associated with worse median OS and CIR rates compared with patients without detectable MRD; however, OS was not significantly different between pre-HSCT MRD-positive and refractory patients (median, .7 year versus 2.0 years; P=.3). Conversely, pre-HSCT MRD negativity was associated with a reduced 2-year CIR. Neither European LeukemiaNet risk stratification nor age had a significant influence on OS. In the multivariate analysis, only pre-HSCT MRD positivity and lower conditioning regimen intensity were significantly associated with a poorer OS. The cumulative incidence of extensive chronic graft-versus-host disease at 2 years was 26.15%. The estimated nonrelapse mortality (NRM) of the entire cohort at 2 years was 23.1%, with age and unrelated donor identified as risk factors for higher NRM. Our data ahow that FLAMSA-Bu conditioning did not reverse the pejorative effect of detectable pre-HSCT MRD, suggesting that such patients should be offered alternative strategies before HSCT to reach deeper remission.

P1055: CLINICAL AND GENETIC RESULTS OF THE PHASE IB/II TRIAL MPNSG-0212: RUXOLITINIB PLUS POMALIDOMIDE IN MYELOFIBROSIS WITH ANEMIA

Background: Ruxolitinib (RUX) alleviates disease-associated symptoms including splenomegaly in patients (pts) with myelofibrosis (MF). However, management of cytopenia remains challenging. Aims: As single-agent pomalidomide (POM) improved cytopenia in 14-29% of MF pts in our previous MPNSG-0109 trial, we sought to investigate the combination of RUX plus POM in MF pts with anemia (Hb <10 g/dL and/or RBC transfusion dependency [RBC-TD]). Methods: MPNSG-0212 is a multicenter, open-label, phase-Ib/II trial (NCT01644110) comprising 39 pts in cohort 1 (co1, recruited 2013-2017) and 52 pts in co2 (2017-2021). Co1 pts received RUX 10 mg BID plus POM 0.5 mg QD, while POM was intended to be increased in co2 to 1 and 2 mg QD after 3 and 6 28-day-cycles, respectively. Primary endpoint was response according to IWG-MRT and RBC-TI criteria at end of cycle 12 (EOC12). In addition, genomic landscape was characterized in all pts using targeted NGS of 269 candidate genes (Illumina NextSeq550). Results: Co1 and co2 pts had similar characteristics: median age was 71 years (range 49-86), median Hb level 8.6 g/dL (5.4-11.7), and median spleen size 17.5 cm (11.4-36); 30% were RBC-TD, 66% intermediate-2, and 25% high-risk according to DIPSS; mutations (muts) in JAK2, CALR, or MPL were identified in 57%, 23%, and 20%, respectively; 55% had ≥1 high-molecular risk (HMR) mut, with ASXL1 being the most common (41%), followed by SRSF2 (24%), EZH2 (10%) and IDH2 (9%). Of note, pts in co2 were more frequently pre-treated with RUX compared to co1 (44% vs 15%; p=.006). Median treatment time at data cut-off was 12 cycles in co1 (2-98) and co2 (3-46); 3 pts of co2 have not yet reached EOC12. In co1, 8/39 pts (21%) achieved response at EOC12: partial remission (PR, n=1), clinical improvement (CI, n=6), or RBC-TI (n=1); 18/39 pts (46%) were treated for >12 cycles due to response (n=8), clinical benefit (CB, n=5) defined as Hb increase ≥1 g/dL or >50% improvement of ≥1 quality of life (QoL) symptom according to MPN-SAF, or stable disease (SD, n=5). Median Hb level at EOC12 was 9.3 g/dL; 15/39 pts (38%) were on treatment for >30 cycles, and 3 pts remained on long-term treatment (cycle 76, 97, and 98). In 73% and 40% of pts in co2, POM dose was increased to 1 mg and 2 mg QD after cycle 3 and 6, respectively. 5/49 pts (10%) showed response at EOC12 (CI, n=3 and RBC-TI, n=2), while 14 additional pts (29%) had CB; median Hb level at EOC12 was 8.6 g/dL; 22/49 pts (45%) were treated for >12 cycles; 3 pts were still on treatment (cycle 21, 36, and 46). Targeted NGS did not reveal a distinct mutational pattern associated with treatment response. Median overall survival (OS) of co1 and co2 was 3.6 and 2.6 years, respectively (p=.66). Among all, CALR, but not JAK2 or MPL muts were associated with better OS (p=.04), whereas HMR muts were in trend prognostically adverse (p=.057). Pts with more than 3 muts had a worse median OS (1.2 vs 4 years, p=.002). Combination therapy was well tolerated in both cohorts. Most common grade 1/2 adverse events (AE) were dyspnea (28%) and fatigue (23%), while the most frequent grade 3 AE was worsening of anemia (32%) in the first weeks of combination treatment not limiting therapy. Summary/Conclusion: Treatment with RUX and POM was safe and feasible in our study of advanced MF with an adverse genetic profile. Almost half of co1 and co2 pts were treated >12 cycles due to clinical benefit of the combination therapy with a subset of 38% of pts in co1 receiving treatment for >30 cycles. Dose increase of POM in co2 did not result into better anemia response or improvement of OS. Authors FS and EJ contributed equally.

Prognostic value of hPG80 (circulating progastrin) in IDH-wild type glioblastoma treated with radio-chemotherapy.

2049 Background: hPG80 (circulating progastrin) is a protein secreted by many cancer types, playing a role in tumorigenesis by regulating cancer stem cells, angiogenesis, proliferation/differentiation and decreasing apoptosis. hPG80 is detectable in plasma of cancer patients and previous studies have shown its prognostic role in various cancers. Given the lack of circulating biomarker in glioblastoma, we evaluated the prognostic value of plasma hPG80 in patients with IDH wild type glioblastoma Methods: This multicentric retrospective study included IDHwt glioblastoma patients treated with standard radio-chemotherapy. The ELISA DxPG80.lab kit (Biodena Care, Lausanne, Switzerland) was used to measure hPG80 levels after surgery with a detection threshold of 1 pM in all plasma EDTA samples according to the manufacturer’s instruction. The prognostic impact of hPG80 was evaluated on patient’s progression-free survival (PFS) and overall survival (OS). Results: We included 70 patients (38 males /32 women) with a median age of 64 years (Range 19 - 84). Karnofsky index was &gt; 70% in 52 (91%) of 57 evaluable patients. Tumor biopsy (B), partial resection (PR), complete resection (CR) were performed in 22, 25 and 23 patients respectively. MGMT promotor was methylated in 22 (40%) of the 55 evaluable patients. After surgery, hPG80 was detected in 48 (69%) patients (hPG80+) with a median concentration of 9.52 pM (IQR 5.21 - 21.20). Complete surgery was associated with undetectable levels of hPG80 (52% (CR) vs 28% (PR) vs 14% (B), p = 0.006) and lower concentration if hPG80+ (CR: 5.8 pM [IQR 1.92 - 11.38] vs PR: 12.84 pM [IQR 8.09 - 37.09]; p = 0.04 vs B: 9.86 pM [IQR 4.66 - 21.63]; p = 0.16). With a median follow-up of 39 months (22.4-NR), 86% of patients had progressed and 70% had died. In univariate analysis, hPG80 positivity was associated with PFS (5.6m vs 8.5m, p = 0.053) and OS (14.5 vs 22m, p = 0.04) in hPG80+ vs hPG80- patients respectively. hPG80+ patients with complete surgery had worse median OS than hPG80- patients (14.5 vs 22.0 m; p = 0.051 respectively. Cox proportional hazards model did not fit for covariate analysis. Conclusions: Our findings show that hPG80 could serve as a new circulating prognostic biomarker in IDHwt glioblastoma patients treated with radio-chemotherapy. Further explorations are ongoing in larger cohorts including longitudinal evaluation during the course of the disease.

Mismatch repair deficiency, chemotherapy and survival for resectable gastric cancer: an observational study from the German staR cohort and a meta-analysis

PurposeIn a post hoc analysis of the MAGIC trial, patients with curatively resected gastric cancer (GC) and mismatch repair (MMR) deficiency (MMRd) had better median overall survival (OS) when treated with surgery alone but worse median OS when treated with additional chemotherapy. Further data are required to corroborate these findings.MethodsBetween April 2013 and December 2018, 458 patients with curatively resected GC, including cancers of the esophagogastric junction Siewert type II and III, were identified in the German centers of the staR consortium. Tumor sections were assessed for expression of MLH1, MSH2, MSH6 and PMS2 by immunohistochemistry. The association between MMR status and survival was assessed. Similar studies published up to January 2021 were then identified in a MEDLINE search for a meta-analysis.ResultsMMR-status and survival data were available for 223 patients (median age 66 years, 62.8% male), 23 patients were MMRd (10.3%). After matching for baseline clinical characteristics, median OS was not reached in any subgroup. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd and MMRp had a HR of 0.67 (95% CI 0.13–3.37, P = 0.63) and 1.44 (95% CI 0.66–3.13, P = 0.36), respectively. The meta-analysis included pooled data from 385 patients. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd had an improved OS with a HR of 0.36 (95% CI 0.14–0.91, P = 0.03), whereas those with MMRp had a HR of 1.18 (95% CI 0.89–1.58, P = 0.26).ConclusionOur data support a positive prognostic effect for MMRd in GC patients treated with surgery only and a differentially negative prognostic effect in patients treated with perioperative chemotherapy. MMR status determined by preoperative biopsies may be used as a predictive biomarker to select patients for perioperative chemotherapy in curatively resectable GC.

A Prospective Multicenter Evaluation of Initial Treatment Choice in Metastatic Renal Cell Carcinoma Prior to the Immunotherapy Era: The MaRCC Registry Experience.

The Metastatic Renal Cell Carcinoma (MaRCC) Registry provides prospective data on real-world treatment patterns and outcomes in patients with metastatic renal cell carcinoma (mRCC). Patients with mRCC and no prior systemic therapy were enrolled at academic and community sites. End of study data collection was in March 2019. Outcomes included overall survival (OS). A survey of treating physicians assessed reasons for treatment initiations and discontinuations. Overall, 376 patients with mRCC initiated first-line therapy; 171 (45.5%) received pazopanib, 75 (19.9%) sunitinib, and 74 (19.7%) participated in a clinical trial. Median (95% confidence interval) OS was longest in the clinical trial group (50.3 [35.8-not reached] months) versus pazopanib (39.0 [29.7-50.9] months) and sunitinib 26.2 [19.9-61.5] months). Non-clear cell RCC (21.5% of patients) was associated with worse median OS than clear cell RCC (18.0 vs. 47.3 months). Differences in baseline characteristics, treatment starting dose, and relative dose exposure among treatment groups suggest selection bias. Survey results revealed a de-emphasis on quality of life, toxicity, and patient preference compared with efficacy in treatment selection. The MaRCC Registry gives insights into real-world first-line treatment selection, outcomes, and physician rationale regarding initial treatment selection prior to the immunotherapy era. Differences in outcomes between clinical trial and off-study patients reflect the difficulty in translating trial results to real-world patients, and emphasize the need to broaden clinical trial eligibility. Physician emphasis on efficacy over quality of life and toxicity suggests more data and education are needed regarding these endpoints.

Circulating Cell-Free Tumor DNA in Advanced Pancreatic Adenocarcinoma Identifies Patients With Worse Overall Survival.

BackgroundPlasma-based circulating cell-free tumor DNA (ctDNA) genomic profiling by next-generation sequencing (NGS)is an emerging diagnostic tool for pancreatic cancer (PC). The impact of detected genomic alterations and variant allele fraction (VAF) in tumor response to systemic treatments and outcomes is under investigation.MethodsPatients with advanced PC who had ctDNA profiled at time of initial diagnosis were retrospectively evaluated. We considered the somatic alteration with the highest VAF as the dominant clone allele frequency (DCAF). ctDNA NGS results were related to clinical demographics, progression-free survival (PFS) and overall survival (OS).ResultsA total of 104 patients were evaluated. Somatic alterations were detected in 84.6% of the patients. Patients with ≥ 2 detectable genomic alterations had worse median PFS (p < 0.001) and worse median OS (p = 0.001). KRAS was associated with disease progression to systemic treatments (80.4% vs 19.6%, p = 0.006), worse median PFS (p < 0.001) and worse median OS (p = 0.002). TP53 was associated with worse median PFS (p = 0.02) and worse median OS (p = 0.001). The median DCAF was 0.45% (range 0-55%). DCAF >0.45% was associated with worse median PFS (p<0.0001) and median OS (p=0.0003). Patients that achieved clearance of KRAS had better PFS (p=0.047), while patients that achieved clearance of TP53 had better PFS (p=0.0056) and OS (p=0.037).ConclusionsInitial detection of ctDNA in advanced PC can identify somatic alterations that may help predict clinical outcomes. The dynamics of ctDNA are prognostic of outcomes and should be evaluated in prospective studies.

Investigating early progression of Hodgkin lymphoma in a two-center analysis

The early progression of disease (POD) of Hodgkin lymphoma (HL) leads to a poor prognosis. To identify risk factors for early POD, this retrospective two-center cohort analysis was conducted. Medical records of HL patients between 1998 and 2020 from two referral centers were reviewed. Two-hundred and sixty-nine patients were analyzed. The distribution of early vs. advanced stages was 51.1 vs. 48.9%, respectively. The 5-year progression free survival (PFS) was 63%, and the overall survival (OS) was 87% with a median follow-up of 52.0 months. The complete remission (CR) rate was 85.7%. Disease progression or relapsed disease occurred in 33.9% (n=85) of patients while 17.0% of this cohort had early POD within 12 months of induction therapy. Patients with early POD had a worse median OS than those without (p<0.001). Failure to achieve post-induction CR and high international prognostic score (IPS, 3-7) were independent risk factors for early POD. Compared with chemotherapy alone, consolidative radiotherapy after induction chemotherapy was associated with a lower risk of early POD (21.3% vs. 6.2%, p=0.006). High IPS was an independent risk factor for early POD, which was less observed in those with consolidative radiotherapy.