Pts Age Research Articles

Intensive Induction Chemotherapy with or without Gemtuzumab Ozogamicin Among Patients with Core-Binding Factor Acute Myeloid Leukemia

Background: Core-binding factor acute myeloid leukemia (CBF-AML) is characterized by the presence of inv(16)/t(16;16) or t(8;21), and is classified as favorable risk by the 2022 European LeukemiaNet (ELN) guidelines. High remission rates are observed in the setting of cytarabine- or anthracycline-based induction regimens. The CD33-targeted antibody-drug conjugate gemtuzumab ozogamicin (GO) is FDA-approved for use in newly-diagnosed CD33+ AML; a meta-analysis of 5 prospective randomized studies investigating intensive chemotherapy (IC) +/- GO demonstrated an improved overall survival (OS) with the addition of GO to IC for favorable-risk AML (Hills et al, Lancet Oncol 2014). The trials included in the meta-analysis did not restrict inclusion criteria to CBF-AML alone and there remains variation amongst IC regimens utilized in CBF-AML treatment. In addition, IC combined with the KIT inhibitor dasatinib has shown remission rates and promising overall survival in prospective studies (Paschka et al, Leukemia 2018; Marcucci et al, Blood Adv 2020). We set out to investigate the outcomes of patients (pts) with CBF-AML treated with IC +/- targeted agents (GO or KIT inhibitor) across 5 institutions that are part of the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND). Methods: Retrospective chart review was done to identify pts who were treated with IC with AML harboring inv(16)/t(16;16) or t(8;21) identified on cytogenetics, from January 2010 through April 2023, and were treated across 5 geographically-diverse academic institutions. Pt clinical characteristics, cytogenetics, molecular mutations, treatment, relapse, and OS data were collected. Relapse-free survival (RFS) and OS were both analyzed using Kaplan-Meier analysis. Results: One-hundred forty-nine consecutive pts with CBF-AML were identified, 76 (51%) with inv(16) and 73 (49%) with t(8;21). Median age of pts was 47 years (yrs) (range 18-80yrs), with 64% male pts, and 106 (71%) pts had an ECOG performance status of 0-1. One-hundred seven (72%) pts identified as non-Hispanic White, 22 (15%) identified as non-Hispanic Black, and 12 (8%) identified as Hispanic. Molecular testing via next-generation sequencing was available for 124 pts (83%); 49 (33%) pts had adverse-risk ELN cytogenetics or mutations when excluding CBF status, and 27 (18%) pts harbored KIT mutations. Other baseline pt characteristics are listed in Table 1A. All pts underwent induction with IC; 44 (30%) pts received IC + GO, 21 (14%) received IC + KIT inhibitor (14 received dasatinib, 7 received midostaurin), and the remaining 84 (56%) received IC without a targeted agent. One-hundred fourteen (77%) pts achieved a complete response (CR) to induction therapy, and 1 pt experienced induction-related mortality. Fluorescence in-situ hybridization (FISH) data was available in 82 pts at end of induction with 83% achieving FISH negativity. Measurable residual disease (MRD) testing was done by polymerase chain reaction (PCR) in 62 pts with 76% achieving MRD-negativity. One-hundred forty pts underwent consolidation with a median of 3 cycles of chemotherapy; 21 (15%) pts received GO with consolidation and 17 (12%) received a KIT inhibitor with consolidation. Forty-four (30%) pts underwent allogeneic stem cell transplantation (alloSCT), with 17 in first CR, and 27 after second-line or beyond therapy. With a median follow-up of 22.5 months, the observed 3-yr RFS was 51% (95% CI: 43-61%) and the 3-yr OS was 69% (95% CI: 61-78%). Pts treated with IC + KIT inhibitor had significantly improved 3-yr RFS of 85% (95% CI: 70-100%) compared to other pts, including those who received IC + GO who had a 3-yr RFS of 51% (95% CI: 37-70%) and those who received IC without targeted therapy who had a 3-yr RFS of 45% (95% CI: 35-58%) ( p = 0.02) ( Figure 1). Full survival statistics are shown in Table 1B and Figure 1. Conclusions: In this multi-center retrospective study of pts with CBF-AML undergoing induction with IC regimens with diverse national treatment practices, we find that the addition of GO to IC is not associated with improved outcomes. Pts treated with IC + KIT inhibitor had significantly improved RFS; of note, pts receiving a KIT inhibitor oftentimes continued on maintenance even after consolidation. These data suggest that there may be a role for targeted therapies other than GO to be explored in randomized prospective studies of intensive induction chemotherapy for CBF-AML.

Characteristics and Outcomes of Patients with DDX41-Mutated Acute Myeloid Leukemia: A Single-Center Experience

Background: Acute myeloid leukemia (AML) with germline DDX41 mutation is implicated in 2-5% of AML patients (pts). Unlike other genetic predispositions in AML, germline DDX41 mutations are associated with later-onset myeloid malignancies (median age 69 years), making it difficult to distinguish clinically from sporadic AML. Data suggests that pts with germline DDX41-mutated AML have more favorable outcomes compared to sporadic AML. However, data regarding optimal treatment and long-term prognosis remains limited. Methods: Pts treated for AML at The University of Kansas Medical Center between 2015 and 2022 with at least one DDX41 variant were identified via retrospective search. Demographics, disease characteristics, treatments, and vital status were analyzed. DDX41 and other co-occurring mutations included for analysis were pathogenic, likely pathogenic, or variants of uncertain significance. Mutations were considered germline in origin if the variant allele frequency (VAF) exceeded 40% or via search of ClinVar repository in borderline cases (VAF 35-40%, n=2) or if VAF was not reported (n=3). Pts suspected to have germline DDX41 mutations were included in the primary analysis. Results: We identified 42 pts with AML with at least one DDX41 variant. Two cases had donor-derived leukemia after prior related donor allogeneic stem cell transplant (SCT) and two cases only had somatic DDX41 p.R525H mutations. These were excluded from primary analysis. 36 pts had suspected germline DDX41 mutations and were included for analysis. 28 (78%) had DDX41 mutations at diagnosis and 8 were found later with a broader next-generation sequencing (NGS) panel (in 6, after induction and in 2, after relapse). Average age of pts with germline DDX41-mutated AML was 67 years, with 3:1 male predominance. Most had preceding cytopenias, and 12 (33%) had antecedent myelodysplastic syndrome (MDS). Family history of malignancy was common (Table 1). 27 (77%) of the available 35 karyotypes at diagnosis were normal. One patient did not have an available karyotype due to lack of records. 28 pts had testing at diagnosis that included DDX41 in the NGS panel. Of these, 57% (n=16) had two DDX41 mutations, with one germline and one somatic mutation. The most common germline DDX41 mutations were p.M1I (14.3%) and p.D140fs*2 (10.7%), and the most common somatic mutation was p.R525H (39.3%). Other commonly concomitant mutations were in ASXL1 (36.1%), CUX1 (22.2%), and KMT2C (13.9%). Mutations such as NPM1 (5.6%), TP53 (5.6%), and FLT3 (2.8%) were uncommon. Germline testing was performed in 5 (13.9%) pts, confirming germline variants. 39% (n=14) were treated with a 7+3-based regimen (average age 60 years) with a 71% response rate. 36% (n=13) were treated with venetoclax/hypomethylating agent (Ven/HMA) (average age 72 years) with a 69% response rate (Figure 1). Two pts receiving Ven/HMA died during the first cycle (one from myocardial infarction, one from pneumonia). 18 pts (50%) received SCT, and 50% of those (n=9) had a related donor. 33% of related donors (n=3) were tested for a germline DDX41 mutation prior to transplant. At last follow-up, 44% were alive in CR (n=16), 5.5% alive with disease (n=2), 14% deceased in CR (n=5), 25% deceased with disease (n=9), and 11% deceased with unknown status (n=4). Median survival was 12.8 months (average 19.6 months in pts with SCT vs. 8.3 in those without, p = 0.012). 11 pts died from AML (33.3%) or complications (22% infection, 6% bleeding). Two pts with only somatic DDX41 mutations were adverse risk (with ASXL1 mutation) and intermediate risk per 2022 ELN risk stratification, both deceased but in CR at time of death. The adverse-risk patient underwent SCT with unrelated donor (survival 7.3 months). The intermediate-risk patient was re-induced after PIF and died from aortic stenosis (survival 2.2 months). Conclusions: In our cohort of germline DDX41-mutated AML, responses to a 7+3- or Ven/HMA-based regimen were similar. SCT evaluation remains crucial with improved overall survival in pts receiving SCT. Our study highlights the importance of comprehensive genetic testing that includes DDX41 at diagnosis, along with testing of related donors and children of pts with a germline DDX41 mutation due to the impact of positive testing on donor selection and to identify pts at risk of AML. The presence of only somatic DDX41 mutations was rare, and further research is needed on the impact of somatic DDX41 mutations alone.

Immunogenicity of Recombinant Erwinia asparaginase (JZP458) for Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LBL)

Introduction: L-asparaginase is important in multi-agent treatment regimens for pediatric and adult patients (pts) with ALL/LBL. However, hypersensitivity reactions (HSRs) to E. coli-derived asparaginases (ASP) often lead to treatment delay or discontinuation. JZP458, a recombinant Erwinia ASP derived from a Pseudomonas fluorescens expression platform, is indicated as part of multi-agent chemotherapy regimens for ALL/LBL in adult and pediatric pts ≥1 month old who developed HSRs to E. coli-derived ASP. Here we report the immunogenicity profile of JZP458 based on study AALL1931. Methods: AALL1931 was an open-label, 2-part, multicenter, phase 2/3 trial conducted with the Children's Oncology Group to investigate efficacy, safety, and pharmacokinetics (PK) of JZP458 in ALL/LBL (NCT04145531). Eligible pediatric and adult pts with ALL/LBL who developed HSRs (grade ≥3 allergic reaction or silent inactivation) to E. coli-derived ASP received JZP458 as part of their multi-agent treatment regimen. Each dose of E. coli-derived pegaspargase was substituted with 6 doses of JZP458 either intramuscularly (IM, Part A) or intravenously (IV, Part B) on Mon/Wed/Fri over 2 weeks, defined as 1 course. Efficacy endpoints were the proportion of pts maintaining therapeutic nadir serum ASP activity (SAA) ≥0.1 IU/mL at the last 72-hour (primary endpoint) or 48-hour (key secondary endpoint) time point during course 1. Other endpoints included safety and tolerability, PK, and antidrug antibody (ADA) formation. Immunogenicity samples were collected prior to dose 1 in each course, prior to dose 6 in course 1, and at end-of-study safety follow-up visit (30±3 days after last dose). For pts experiencing HSRs, additional samples were tested for ADAs. A multi-tiered approach was used to measure ADAs and neutralizing antibodies (NAbs) to evaluate immunogenicity of JZP458. First, samples were screened for ADAs that bind JZP458. Samples with potentially ADA-positive (+) results were retested for binding specificity confirmation. Samples confirmed as ADA+ were tested further for NAbs. For pts with ADA+ samples obtained prior to study end, follow-up ADA samples up to approximately 6 months after the last dose of the last course were collected. The ADA assay was a validated binding assay based on an electro-chemiluminescence immunosorbent assay technique and the NAb assay was a validated enzymatic activity assay. Results: The median (range) age of pts was 10 (1-25) years. Analysis of pts receiving IM JZP458 (n=167) showed that 82 (49%) pts had confirmed ADA toward JZP458; of these, 7 (4%) were ADA+ at pre-dose 1. Twenty-two pts (15% of 146 pts with samples) remained ADA+ at the end of study. Overall, 18 (11%) pts developed treatment-related HSRs after receiving IM JZP458. Among ADA+ pts (n=82), 11 (13%) experienced treatment-related HSR and 4 (5%) developed positive NAbs. Of ADA-negative (-) pts, 7/85 (8%) experienced treatment-related HSRs. Among pts receiving IV JZP458 (n=61), 34 (56%) had confirmed ADA toward JZP458; of these, 1 (2%) was ADA+ at pre-dose 1. Seventeen pts (34% of 50 pts with samples) remained ADA+ at the end of study. Overall, 16 (26%) pts developed treatment-related HSRs after receiving IV JZP458. Among ADA+ pts (n=34), 12 (35%) experienced treatment-related HSRs and 2 (6%) developed positive NAbs. Of ADA- pts, 4/27 (15%) experienced treatment-related HSRs. Anti-JZP458 antibody status was evaluated as a potential covariate for PK of IM or IV JZP458 within the population PK analysis and it was not found to be a significant covariate. SAA levels were similar between ADA+ and ADA- pts. Overall treatment-related adverse events (TRAEs) in ADA+ and ADA- pts were similar and consistent with the most common TRAEs expected with ASP-containing chemotherapy for ALL (Table). TRAEs led to JZP458 discontinuation for 14 pts with ADA+ status in Part A (8%) and 13 in Part B (21%). Conclusions: The majority of pts who developed ADAs did not develop HSRs or NAbs. The overall rate of HSRs was similar to literature-reported rates for ASP and appeared to be higher with IV vs IM JZP458. ADA status did not appear to impact PK and other AEs for JZP458. Based on these results, no specific immunological concerns were identified with JZP458 beyond known immunogenicity risks associated with ASP and no specific clinical decisions are recommended based on immunogenicity testing.

Clinical and Prognostic Implications of WT1 Mutations in De Novo and Relapsed Acute Myeloid Leukemia

Introduction Wilms Tumor 1 ( WT1) is integral to cell proliferation and survival and is mutated in up to 10-15% of patients (pts) with acute myeloid leukemia (AML). WT1 mutated ( WT1 m) AML frequently co-occurs with fms-like tyrosine kinase 3 ( FLT3) and nucleophosmin 1 ( NPM1) mutations, and is generally thought to impart poorer outcomes, however the impact of WT1 m remains incompletely understood. Methods We analyzed 307 pts with WT1 m AML, identified through next generation sequencing panels of recurrently mutated myeloid genes performed at two large academic cancer centers between 2015 - 2022. Of the 307 pts, 161 (52%) had WT1 m at AML diagnosis (ND) and 146 (48%) were identified at relapse (RR). Here we describe the baseline characteristics and outcomes in pts with WT1 m AML with emphasis on co-mutated FLT3 and NPM1. Results In pts with ND WT1 m AML, the median age was 59 years (range,22-87). Pts most commonly had intermediate (41%) or adverse (43%) risk disease by ELN 2022 criteria. 51% (n=82) had co-mutated FLT3 (ITD or TKD). Among pts with FLT3 mutated AML, 30% (37%) also had co-mutated NPM1. 10 (7%) pts had co-mutant NPM1 m without FLT3 m. Median OS in the ND cohort was 19.8 months. Variant allele frequency (VAF) ranges of WT1 m were 1-98 (median 27) and 1-97 (median 13) in the ND and RR cohorts respectively. OS was affected by mutational profile (table 1) with triple mutated NPM1/FLT3/WT1 exhibiting worse OS compared to others. 68% of ND pts received intensive chemotherapy (+/- venetoclax (VEN)) at time of diagnosis with mOS of 26.5 mos vs. 11.1 mos (p = <0.0001) for pts treated with lower intensity therapy (+/- VEN). Improved OS was observed in pts with ELN2022 favorable risk disease (mOS not reached (NR)) and in pts receiving an allogeneic hematopoietic stem cell transplant (SCT). Pts with ND AML and ELN2022 intermediate-risk disease who underwent SCT had significantly longer OS of 47.9 mos vs. 11.8 mos (p<0.0001, figure 1). In the ND cohort, pts had significantly improved OS if they underwent SCT after achievement of CR1 compared to SCT after first relapse, mOS NR vs. 38 months (p=0.00039), respectively. Notably, the median age of pts who received SCT was 50 (22-74) with 16% having secondary (s-AML) or therapy related (t-AML). Of those who did not undergo SCT median age was 63 (23-87) and had with 28% of pts with (s- or t-AML). Within the RR cohort, 44 (30%) pts acquired WT1 mutation post SCT. 56 (38%) were FLT3 m (25 pts with co-mutated NPM1) and 10 (7%) NPM1 m mutated (without FLT3 m). The mOS in the RR cohort (from time of WT1 m acquisition) was shorter in pts with co-mutated FLT3/WT1 without NPM1 (table 1). Pts who underwent SCT after WT1 macquisition had mOS of 25.7 mos (95% CI 23.8-38.7) compared to 18.3 mos (95% CI 13.2-21.2) (p=0.001) in those who did not undergo SCT. 28% of pts received intensive therapy (+/- VEN) as salvage after acquisition of WT1 mwithout difference in OS compared to those receiving low intensity therapy (66% with VEN). mOS (11.1 vs. 7.8 mos, p=0.12) . In pts ND AML and co-mutant NPM1/WT1, WT1 m was frequently (75%) subclonal to NPM1 m with a mOS NR. However, in pts who initially had NPM1 m disease and acquired a WT1 m at relapse, WT1 m was more clonally co-dominant with NPM1 mwith a mOS of 15.9 mos (p=0.11). Amongst both cohorts, there was no difference in survival based on sex. Conclusion WT1 mutations are enriched in intermediate and adverse risk AML, frequently acquired at relapse, and are associated with overall poor OS in the absence of SCT. Our data suggests that pts with WT1m AML benefit from high intensity induction regimens and SCT at CR1 should be considered in all WT1 m pts with ELN2022 intermediate or adverse risk disease. WT1 mutations should also be considered for inclusion into ELN risk stratification given poor overall survival without SCT.

Treatment Patterns Among Patients with Relapsed/Refractory Core-Binding Factor Acute Myeloid Leukemia after Intensive Induction Chemotherapy

Background: Core-binding factor acute myeloid leukemia (CBF-AML) is characterized by the presence of inv(16)/t(16;16) or t(8;21), and is classified as favorable risk by the 2022 European LeukemiaNet (ELN) guidelines. High remission rates are observed in the setting of cytarabine- or anthracycline-based induction regimens. However, for the subset of patients (pts) who relapse, outcomes after relapse were poor in prior single-center analysis with median survival of less than 1.5 years (Khan et al. Clin Leuk Lymph Myeloma 2017). There remains a need to better understand outcomes of pts who experience relapse after initial complete remission (CR), particularly after diverse intensive chemotherapy (IC) induction regimens, where variable practices show differential induction outcomes. We set out to investigate the outcomes of pts with CBF-AML in first relapse or with disease refractory to initial therapy, across 5 institutions that are part of the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND). Methods: Retrospective chart review was done to identify pts who were treated with intensive IC with inv(16)/t(16;16) or t(8;21) identified on cytogenetics, from January 2010 through April 2023, with disease in first relapse after initial CR or refractory to primary induction. Pts were treated across 5 geographically-diverse, academic institutions. Pt clinical characteristics, cytogenetics, molecular testing via next-generation sequencing (NGS), treatment, relapse, and overall survival (OS) data were collected. OS since time of disease relapse was analyzed using Kaplan-Meier analysis. Results: Fifty-four consecutive pts with relapsed/refractory (R/R) CBF-AML were identified, 24 (44%) with inv(16) and 30 (56%) with t(8;21). Median age of pts at initial diagnosis was 50 years (yrs) (range 20-80yrs), with 61% male pts. Molecular testing and/or NGS was available at initial diagnosis for 41 pts (76%); 12 (22%) pts had adverse-risk ELN cytogenetics or mutations when excluding CBF status, and 8/41 (20%) pts harbored KIT mutations. Other baseline pt characteristics are listed in Table 1. All pts underwent induction with IC; 14 (26%) pts received intensive induction with gemtuzumab ogozamicin (GO), 3 (6%) received intensive induction with a KIT inhibitor (dasatinib or midostaurin), and the remaining 37 (68%) received IC induction without a targeted agent. Forty-one (76%) pts achieved a CR to induction therapy. Measurable residual disease (MRD) testing by polymerase chain reaction (PCR) and/or fluorescence in situ hybridization (FISH) for CBF protein was available in 30 (56%) pts, with 16/21 (76%) achieving MRD-negativity by PCR and 20/26 (77%) by FISH. Forty-six pts underwent consolidation with a median of 4 cycles of chemotherapy (IQR 3-4), with 9 (17%) pts receiving GO with consolidation and 4 (7%) receiving a KIT inhibitor with consolidation. Median time to relapse was 10.1 months (IQR 8.0-13.6 months), and median OS after relapse was 9.2 months (IQR 4.4-22.1 months) for the whole cohort. Second line treatment data was available for 44 pts, with 29 (66%) receiving intensive 2nd line therapy vs 15 (34%) receiving lower intensity 2nd line therapy; 14 (32%) pts received venetoclax as part of their 2nd line therapy. There was no significant difference in 2-yr OS after relapse for those who received IC (50%, 95% CI: 34-72%) vs lower intensity therapy (24%, 95% CI: 8-72%) ( p=0.28) (Figure 1A). Twenty-eight (52%) pts who received 2nd line therapy for R/R disease proceeded to allogeneic stem cell transplantation (alloSCT), with a 2-yr OS of 57% (95%CI: 40-80%) for this group after time of relapse, compared to 15% (95% CI: 5-42%) for those who did not achieve CR after 2ndline therapy and/or proceed to transplant ( p<0.01) (Figure 1B). Conclusions: In this multi-center retrospective study of pts with R/R CBF-AML, we describe patterns of relapse after intensive induction chemotherapy, and do not observe a statistically difference in outcomes based on intensity of 2nd line therapy among pts with available treatment information. Median OS in the entire cohort was 9.2 months from diagnosis of R/R disease. Pts who proceeded to alloSCT after receiving 2nd line therapy had significantly improved long-term outcomes compared to those who did not proceed to alloSCT, highlighting the need for better therapies in the 2nd line and beyond to improve longer term outcomes for pts with CBF-AML.

Course of uveitis in patients with ankylosing spondylitis during the interleukin 17 inhibitors therapy

Background. Biological disease-modifying antirheumatic drugs (bDMARDs) can have different effects on various clinical manifestations of ankylosing spondylitis (AS). Data on the effects of interleukin 17 inhibitors (iIL17) on uveitis in AS continue to accumulate. Objective – to evaluate the effect of iIL17 therapy on the course of uveitis in AS. Material and methods. 73 patients (pts) with AS (New York criteria, 1984), who received iIL17 (57 – secukinumab (SEC), 22 – netakimab (NTK)) for at least 1 year were included in the study. The average age of pts at the time of inclusion in the study was 41.93±8.95 years, the average duration of AS was 10.75±6.22 years. There were 40 (56.7%) men and 33 (43.3%) women among the pts. HLA-B27 was detected in 62/73 (85%), coxitis in 58 (79%), enthesitis in 63 (86.3%), peripheral arthritis in 57 (78%), psoriasis in 7 (9.5%), inflammatory bowel disease (IBD) in 3 (4.1%); in 6 (8.2%) the disease started before the age of 16; 19 (26%) pts had at least 1 episode of uveitis during the course of the disease. The rates of uveitis was estimated by comparing the number of incidences per 100 patient-years before the start of bDMARDs therapy and during iIL17 using. Result. The incidence rate of uveitis before the start of bDMARDs therapy for all pts was 8.3 per 100 pt-years (95% CI: 0.065–0.107), during iIL17 therapy – 9.2 per 100 pt-years (95% CI: 0.06–0.15; p=0.72). The incidence rate of uveitis among pts used SEC was 10.1 per 100 patient-years (95% CI: 0.079–0.13) before the start of bDMARDs therapy, during SEC using – 9.4 per 100 pt-years (95% CI: 0.05–0.15; p=0.74). The incidence rate of uveitis among pts used NTK was 4.8 per 100 pt-years (95% CI: 0.028–0.08) before the start of bDMARDs therapy, during the NTK using – 7.1 per 100 pt-years (95% CI: 0.019–0,22; p=0.3). For patients with a history of uveitis, the incidence rate of uveitis before the start of therapy with bDMARDs was 22.5 per 100 pt-years (95% CI: 0.18–0.28), during iIL17 therapy – 29.1 per 100 pt-years (95% CI: 0.18–0.43; p=0.29). Occurrences of uveitis were observed in 4 of 57 pts (7%) during the using of SEC, and in 1 of 25 pts (4%) – during the NTK therapy. 1 case of new-onset uveitis was recorded during the using of SEC. Conclusion. There were no significant differences in the incidence rates of uveitis during iIL17 using compared with non-biological therapy. iIL17 have not demonstrated a significant effect on the course of uveitis in AS in the study group.

Brachial Plexus Tolerance to Standard Fractionation Re-Irradiation: The Ohio State University Experience

Factors contributing to brachial plexopathy (BPP) in the re-irradiation setting need further assessment. Preliminary work revealed that higher the doses and the use of concurrent cisplatin were associated with higher risk of BPP. Here, we expand our cohort and increase our follow-up duration, given the late nature of BPP development. Sixty-two BP sites with 41 patients (pts), treated between 2015 and 2020 for recurrent H&N cancer, were assessed. Contours and plans were reviewed via a prospective multidisciplinary chart rounds prior to treatment delivery and re-verified by two authors prior to this analysis. Kaplan-Meier and logistic regression were used to test the correlation between variables and outcomes. ROC was used to evaluate the cutoff values. Common terminology criteria of adverse events were used to define BPP. The median age of pts was 63 (29-78) and 65% were males. Median prescription dose was 70 Gy (60-70) for the 1st course and 66 Gy (44-70) for the 2nd course. 13% received intraoperative radiotherapy (IORT) during salvage treatment ranging from 10-15 Gy. 30% of pts in the 1st course and 80% in the 2nd course of pts had surgery. Concurrent chemotherapy was delivered to 71% of pts in the 1st course (Cisplatin 34%, Cetuximab 22%, Carboplatin +/- Paclitaxel 15%) and 76% in the 2nd course (Carboplatin/Paclitaxel 41%, Cisplatin 19%, Cetuximab 12%, Nivolumab 4%). The median interval between courses was 26.5 months (8-221). The median cumulative Dmax (0.03cc) and mean dose to the BP were 96.5 Gy (51-144) and 61.5 Gy (15-110), respectively. The median V60, V70, V80, V90, and V100 were 3.6cc (0.03-10.4), 2.4cc (0-9.9), 1.3cc (0-9.3), 0.6cc (0-8.4), and 0.0015cc (0-7.2), respectively. The median follow-up after the completion of the 2nd RT course was 19 months (1.4-71.5). The 1-yr incidence of BPP was 17%, with a median time to onset of 8.9 months (1-16.6). Factors associated with development of BPP were cumulative Dmax > 100 Gy (HR 1.06, [CI 1.014-1.1], p = 0.009), cumulative mean dose >70 Gy (HR 1.05, [CI 1.01-1.09], p = 0.03), V80 > 1.6cc (HR 1.2. [CI 0.99- 1.52], p = 0.06), V90 > 1cc (HR 1.3, [CI 1.013-1.58], p = 0.038), V100 > 0.3cc (HR 1.33, [1.044-1.69], p = 0.021) and the usage of concurrent cisplatin during the 2nd course (HR 8.9, [CI 2.36-33.75], p = 0.001). Other factors including gender, age, surgery, treatment interval between the two courses, IORT, V60, and V70 were not associated with increased risk of BPP. The incidence of grade 1, grade 2, and grade 3 BPP were 9.6%, 3% and 2.4%, respectively. The 1-yr OS was 70% and LC was 60%. At a median follow up of 19 months, the 1-yr incidence of grade 2 and 3 BPP was approximately 5%. Cisplatin during the 2nd course, cumulative metrics of Dmax 100 Gy, mean 70 Gy, V80 1.6cc, V90 1cc and V100 0.3cc were associated with development of BPP. Prospective study, longer follow up, and higher numbers are warranted. To our knowledge, this represents the largest cohort and longest follow up yet reported for BPP in the re-irradiation setting.

Stereotactic Radiosurgery (SRS) for Brain Metastasis in the Era of Evolving Systemic Treatment (Immunotherapy or Targeted Therapy) in Patients with Non-Small Cell Lung Cancer (NSCLC)

With evolving role for targeted and immunomodulatory agents, the survival rate of NSCLC has been improved even with brain metastasis. This study analyzed the outcome of brain metastasis treated with SRS in conjunction with immunotherapy and target therapy as well as chemotherapy. After obtaining institutional review board (IRB) approval, 229 patients with NSCLC with brain metastasis treated with SRS at our institution were retrospectively reviewed from 2008-2021. Demographic information (e.g., age, sex, race), performance status (PS), extracranial metastasis (ECM), sequence of systemic therapy (SST) and surgery for BM (SBM) were reviewed and collected. Overall survival (OS) and intracranial recurrence free survival (ICRFS) were analyzed using the Kaplan-Meier method/Cox regression, and time to each event were measured from the date of the first SRS treatment. All statistical analyses were performed using SAS version 9.4 (Carey, NC). Of the 229 pts, the median age of pts at first SRS was 64.1 (range, 34.8- 83.0 years). 38.6% were biomarker (EGFR/ALK/ROS/PDL1) positive, and 30% were PDL1 positive. 28.8 % had surgery before SRS. The median number of SRS was 1 (range, 1 - 6), and 10 patients received salvage whole brain radiation therapy (WBRT) after SRS. With a median follow-up of 9.6 months (mo), median OS and ICRFS were 14.0 mo and 8.1 mo respectively. On univariate outcome analysis, PS, ECM, SBM and PDL1 were associated with OS while biomarker, SBM and SST were closely related to ICRFS. Pts with poor PS had worse median OS of 8.3 mo compared to 29.1 mo with good PS (p = 0.001). Median OS for no ECM vs. ECM were 20.7 mo vs. 9.6 mo respectively (p = 0.002). Patients who underwent SBM initially had better median OS of 28.7 mo compared to 9.9 mo without SBM (p<0.001). There was a trend of significant impact of positive PDL1 on median OS (21.1 mo vs. 11.7 mo, p = 0.06). Similarly, SBM was found closely related to ICRFS with median ICRFS of 8.1 mo vs. 4.9 mo for those with and without SBM respectively. Both positive biomarker (13.1 mo vs. 6.4 mo, P = 0.17) and SRS first SST (8.1 mo vs. 4.9 mo, p = 0.11) demonstrated a trend of increased median ICRFS. On multivariable analyses, no SBM was linked with worse OS (HR: 1.85; 95% CI:1.15 - 2.97; p = 0.01) and decreased ICRFS (HR: 1.65; 95% CI: 1.09 - 2.51; p = 0.02). Of 31 pts with information on cause of death, 3.2% died from brain metastasis related cause. This study demonstrated effective treatment of brain metastasis in NSCLC with multiple SRSs, especially for patients with favorable prognosis. Of noticed there was only a small number of patients received salvage WBRT and most patients didn't die from brain metastasis related progression.

The Effects of Adjuvant Chemoradiotherapy (CRT) on Myeloid-Derived Suppressor Cell (MDSC) Subsets in Glioblastoma (GBM)

GBM continues to be a diagnosis with an exceedingly low survival rate despite standard therapy of resection followed by concurrent CRT. MDSC, immunosuppressive myeloid cells that aid immune system evasion by the tumor, expand during fractionated RT. To date, little is known about the effects of CRT on MDSC subsets. The goal of our pilot study is to compare peripheral blood MDSC subset frequency in patients (pts) undergoing CRT. We hypothesize that the pro-tumor, monocytic MDSC (M-MDSC) subset increases following CRT. Pts over the age of 18 yo with a new diagnosis of GBM from a single institution participated in the study between 7/2022 -1/2023. Exclusion criteria included prior history of brain RT. Baseline peripheral blood samples were collected within one week prior to CRT start and post-CRT samples were collected within the last week of CRT. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood and freshly stained for intracellular flow cytometric analyses. Total MDSC (singlet, viable, non-lymphocyte, CD11b+CD33+ HLA-DR- cells) and subsets (M-MDSC, granulocytic (G-MDSC), and early MDSC (eMDSC)) were identified. Percent frequency (%fx) of total and MDSC subsets as well as MDSC activation status (n = 3) (interleukin (IL)-10, transforming growth factor-β (TGF-β), interferon gamma (IFNγ)) was compared before and after CRT. The average age of pts receiving CRT (n = 4) was 70 yo. Fractionated RT consisted of CF RT (n = 2), 6000 cGy in 30 fractions, and HF RT (n = 2), 4005 cGy in 15 fractions. All pts received concurrent chemotherapy with temozolomide. The %fx of MDSC of non-lymphocytes started at 29.2% prior to CRT and decreased to 9.9% at the end of CRT. The fold change of %fx of total MDSC in CF RT and HF RT was 0.39 and 0.29, respectively. The mean change in %fx of MDSC subsets before and after CRT are shown in Table 1. The mean %fx of TGF-β-expressing MDSC in all GBM pts increased by 3.5% after CRT. The mean IFNγ+ MDSC %fx for all GBM pts decreased after CRT from 24.2% to 16.2% with a corresponding decrease in geometric mean fluorescence intensity (GMFI). The mean %fx of IL-10+ MDSC decreased by 1.5% at the end of CRT with a decrease in GMFI from 5550 to 1806. In this limited dataset of pts with GBM receiving standard of care adjuvant therapy, we identified an expansion in the eMDSC and decrease in the M-MDSC subsets. These early results suggest HF RT may promote immunity that is more supportive of anti-tumor function, with a lesser increase in fold change of total MDSC after CRT. A more detailed understanding of the effect of RT on myeloid subpopulations is essential to addressing immune suppression in pts with GBM.

#4879 PREDICTORS OF KIDNEY DISEASE PROGRESSION IN MALES WITH X-LINKED ALPORT SYNDROME

Abstract Background and Aims Alport's syndrome is the second most common monogenic cause of end-stage renal disease (ESRD). Males with X-linked Alport's syndrome (XLAS) have a high risk of early ESRD development. The aim of study was to determine the predictors of unfavorable renal prognosis in boys with XLAS. Method The children with genetically confirmed XLAS (n = 84, age 8.7±4.3 yrs, eGFR 102±16.2 ml/min/1.73 m2, 59 pts with missense COL4A5 mutations) were included in observation single center study (FU 6.9±2.4 yrs). Seventy three pts (q = 0.87) were treated with ACEi (age of start 7.6±3.3 yrs, dose for Ramipril 2.7±0.8 mg/m2/day). Arterial blood pressure (BP), proteinuria (Pr, mg/m2/day), eGFR (Schwartz equation, ml/min/1,73m2), gene mutation type and ACEi-treatment data (age of pts and disease stage at the therapy start, ACEi dosage, dynamics of Pr and eGFR) were obtained and updated for each patients. BP &amp;gt;90 perc for gender, age and height was defined as uncontrolled (uBP); Pr was categorised according to its level as a low (100-&amp;lt;250 mg/m2/day), moderate (≥250-500 mg/m2/day), high (≥500-1000 mg/m2/day) and nephrotic (≥1000 mg/m2/day). Gene mutations were divided into severe (nonsense, deletion, splicing) and less severe (missense) mutations. The eGFR&amp;lt;60 ml/min/1,73m2 was defined as primary outcome. Results Twenty pts (q = 0.24, age 13.5±2.96 yrs) reached the end point during observation period. Non-missense COL4A5 mutations (HR = 4.28, 95% CI 1.47-12.4, p = 0.007), uBP (HR = 20, 95% CI 4.68-29.6, p&amp;lt;0.001), persistent Pr &amp;gt;250 mg/m2/day (HR = 20, 95% CI 3.36-21, p&amp;lt;0.001), absence of ACEi treatment (HR = 10.7, 95% CI 2.45-14.7, p = 0.02) or start therapy at proteinuric stage of disease (HR = 20, 95% CI 2.2-13.8, p&amp;lt;0.001) were the risk factors of disease progression. Multiple regression analysis adjusted for age, initial eGFR revealed that late start of ACEi treatment (β = 0.23, p = 0.036), persistence of uBP (β = 0.26, p = 0.008) and Pr &amp;gt;250 mg/m2/day (β = 0.17, p = 0.04) had independent significance and predict unfavorable renal prognosis (R = 0.76, R2 = 0.57, p&amp;lt;0.000). Conclusion Persistent proteinuria and uncontrolled blood pressure, initiation of ACEi treatment at the proteinuric stage of glomerulopathy are the factors of unfavorable prognosis in male with XLAS.

Modeling genetic testing (GT) attitudes in a socio-demographically diverse cohort of patients (pts) with cancer: The importance of race/ethnicity and medical mistrust (MM).

10562 Background: Germline GT and tumor genomics are relevant to the care of nearly every cancer pt. These tests inform treatment planning by NGS-based tumor genomic profiling (TGP) and hereditary risk assessment. Socioeconomic and race-based disparities in GT are well-known, but the impact of growing MM, fueled by political polarization and social unrest due to overt and institutional racism, has been less studied. In previous research of African American (AA) cancer pts, we identified a consistent association of high levels of MM with negative attitudes toward GT. To inform development of an intervention to support informed decisions about GT in cancer pts, we further characterized the relationship of MM to GT attitudes. Methods: Pts from two Fox Chase Cancer Center (FCCC) sites were recruited (6/2022-12/2022) to complete a cross-sectional survey (n=105, Burholme campus; n=95, Temple University Hospital). A stratified purposive sampling method was employed. Data on pt demographics and disease factors were collected. MM was queried with two validated measures: LaVeist MM Index (MMI: range 0-10, measures healthcare/institution MM) and Thompson Group Based MM Scale (GBMMS: range 1-5, measures race/ethnicity specific MM; suspicion, discrimination, and lack of support subscales). Attitudes toward GT (GTpros=6 items/GTcons=11 items) were measured w/a validated scale (Morren: range 0-10) plus 4 items developed by our team. The study was approved by the FCCC IRB 22-8003. Results: Median age of pts was 62 yrs (range 25-91); 62% were female, 47% AA, 15% Hispanic, 42% married, 47% ≤high school grad, 52% had household income ≤$50K/yr. Mean GBMMS was 2.11 (SD 0.80) and mean MMI was 4.63 (SD 1.54). Mean of GTpros was 8.77 (SD 1.68); GTcons 4.16 (SD 2.32). MM was associated with race/ethnicity by GBMMS (p&lt;0.001) and MMI (p&lt;0.04), as were GBMMS subscales (suspicion, discrimination, lack of support, all p&lt;0.001). Race/ethnicity was not associated w/GTpros (p=0.59) but was w/GTcons (p&lt;0.001). In univariate models both GTpros and GTcons were associated with GBMMS (p=0.005 and p&lt;0.001, respectively) and MMI (p=0.002 and p&lt;0.001, respectively). In a multivariable model examining GTcons, GBMMS score remained significant (p&lt;0.001) even when controlling for race (p&lt;0.01) and an interaction btw race*mistrust. A similar model showed MMI score also remained significant (p=0.04) when controlling for race and interaction effects. Only the GBMMS suspicion subscale remained significant (p&lt;0.02) in a model with both race and an interaction term. Conclusions: MM is markedly more common among racial/ethnic minority cancer pts, but the relationship btw MM and GT attitudes is only partially rooted in race/ethnicity. Oncologists considering germline GT or tumor genomics for pts, and efforts to support informed decision-making, must consider the pervasiveness of MM.

First in human phase Ⅰ study of BMS-986299 as monotherapy and combined with nivolumab and ipilimumab in advanced solid tumors.

e14584 Background: Immune checkpoint inhibitors (ICIs) face hurdles in overcoming the immunosuppressive tumor microenvironment. BMS-986299 is first-in-class, NOD-, LRR-, and pyrin domain containing 3 (NLRP3) inflammasome agonist enhancing adaptive immune and T cell memory responses. In-vivo studies demonstrated BMS-986299 synergy with ICIs and induction of durable immunological memory. Methods: This multicenter, open-label, phase I [NCT03444753] study assessed safety and tolerability of intra-tumoral (IT) BMS-986299 monotherapy (Part 1A) and in combination (Part 1B) with the programmed death 1 receptor antibody nivolumab (N), and the anti-cytotoxic T lymphocyte associated protein 4 antibody ipilimumab (I) in advanced solid tumors. Eligible patients (pts) regardless of prior ICI with accessible solid tumors (≥ 2 lesions) received IT BMS-986299 administered on day 1, 8, 15, 22, 29 for Cycle 1 (C1) and on days 1, 29 until C2, 8 weeks apart across 7 dose escalation cohorts in Part 1A (75μg-4000μg; Bayesian Logistic Regression Model (BLRM). In Part 1B, BMS-986299 was given across 3 dose escalation cohorts (75μg-2000μg; BLRM Copula) with nivolumab 480 mg q4weeks and ipilimumab 1 mg/kg q8weeks (fixed dosing) from day 1 up to 24 months (m). Cross-over (CS) was allowed from Part 1A to Part 1B. Results: The study was terminated early, unrelated to safety, due to the COVID-19 pandemic and did not complete enrollment. From April 2018 to February 2022, 50 pts were treated (33; Part 1A and 17; Part 1B). Eleven pts crossed over to Part 1B. Median age of pts enrolled was 59 years and with preponderance in female gender (58.0%) and white (80.0%) pt. participation. Forty-two pts (70%) had treatment related adverse events (TRAEs). Grade (G)3/G4 TRAEs included tubulointerstitial nephritis (1; Part 1A), hepatitis (1; CS), colitis, diabetic ketoacidosis, elevated liver enzymes (1 each; Part 1B). No G5 TRAEs or dose limiting toxicities were seen. In Part 1A, 3 pts (melanoma; bladder; anal) achieved stable disease (SD). In CS cohort, 1 triple negative breast cancer (BC) pt had partial response (PR; -60%) for 27.4 m and 3 had SD (breast; cSCC, squamous oropharynx). In Part 1B, 3 pts had PR including 2 pts with hormone positive BC (1 pt with -86%; 3.2m and 1 pt with -39%; 2m) and 1 pt with cutaneous squamous cell cancer (cSCC) (-43%; 1m). Four pts in part 1B had SD (2 breast, 1 lung, 1 chondrosarcoma). All 4 responders received the combination of BMS-986299 with N + I with 3 responders receiving BMS-986299 at 2000μg and one at 300μg. 3 responders (2 breast; 1 cSCC) had prior ICI therapy. Conclusions: BMS-986299 in combination with ICI resulted in modest clinical activity in select tumor types and carried a manageable toxicity profile. However, definitive conclusions could not be drawn as the study was not powered for inference testing. Further exploration is warranted to define the role of this novel agent in the ICI refractory population. Clinical trial information: NCT03444753 .

Final results of a phase II trial of prolgolimab with platinum-based therapy and bevacizumab in patients with advanced cervical cancer.

5536 Background: Here we present the final results of single-arm phase II CAESURA (NCT03912402) study of prolgolimab (anti-PD-1 antibody) with platinum doublet and bevacizumab in subjects with advanced cervical cancer (CC). Methods: 58 patients (pts) with metastatic or recurrent/persistent CC with measurable disease received prolgolimab (3 mg/kg) Q3W together with paclitaxel, platinum drug (cis- or carboplatin) and bevacizumab for 6 cycles and then therapy with prolgolimab and bevacizumab until disease progression or toxicity. Objective response rate (ORR) was assessed by central radiology review per RECIST 1.1 (primary endpoint) and iRECIST criteria. CT scans were performed after 9 and 18 weeks of treatment and in case of suspicion on disease progression. Results: Distant metastases at screening had 42 pts, 16 had recurrent or persistent CC. The median age of pts was 48 [38; 58] years old. Squamous cell carcinoma was diagnosed in 50 of 58 subjects. PD-L1 CPS ≥ 1 (22C3) was found in 45 pts, CPS &lt; 1 in 6 cases. ORR per RECIST 1.1 was 63.8% (37 of 58 pts) and included 2 complete, 35 partial responses. ORR per iRECIST was 70.7% (41 of 58 pts) with 2 complete and 39 partial responses. At the cut-off date (12 months) PFS (secondary endpoint) per RECIST 1.1 criteria counted 8.5 (95% CI 5.7; 10.9) months, per iRECIST criteria it reached 13.1 (95% CI 8.1; 13.6) months. Median overall survival was not reached. Any grade adverse events (AEs) occurred in 98% (57/58) of pts, of them in 69% (40/58) they were related to study treatment, including 12 cases of severe events (gr. 3 or higher). Immune-related AEs (irAEs) occurred in 38% (22/58) of pts. The most common irAEs were gr. 1–2 endocrine disorders (26%), including thyroid disorders and one case of gr. 2 adrenal insufficiency. Other important irAEs included 2 cases of enterocolitis (gr. 3 and 4), 1 case of dermatitis (gr. 3), several cases of gr. 2–3 transaminase elevation (9%). In 15 pts at least one component of study treatment was discontinued due to AE, of them 4 events were related to study treatment (including immune-related enterocolitis and adrenal insufficiency). Conclusions: Prolgolimab in combination with chemotherapy and bevacizumab demonstrated promising efficacy, known and acceptable safety profile in pts with advanced CC. Phase III placebo-controlled trial evaluating prolgolimab with chemotherapy and bevacizumab (NCT03912415) as first-line therapy option in subjects with CC is ongoing. Clinical trial information: NCT03912402 .

Use of PARPi among patients with HER2+ve MBC: Results from a real world dataset.

e13044 Background: Among individuals with germline mutations in BRCA1/ BRCA2 genes, life-time risk of developing breast cancer is approximately 50%. The majority of these cancers are HER2-ve with a low frequency of HER2+ve breast cancer (2.1%-10% in pts with BRCA1 mutations and 6.8%-13% of pts with BRCA2 mutations) with co-occurrence of BRCA mutation and HER2+ve status being a poor prognostic factor. PARPi have been shown in phase III trials to be effective in HER2-ve BRCA mutation MBC. The objective of this retrospective analysis was to look at the prognostic outcome associated with use of PARPi among pts with HER2 +ve BRCA mutated MBC in the real-world setting. Methods: We utilized a federated network of de-identified health data representing approximately 107 million pt lives available through the TriNetX Research Network. We identified patients with MBC who were treated with PARPi, and pts were assumed to have BRCA mutated MBC if they were recorded with a PARPi. Overall survival (OS) was computed using the Kaplan Meier product limit method. Pts with MBC were defined as having HER2+ve status if they received an anti-HER2 therapy after metastasis, HR+ve if they received endocrine therapy after metatstasis, and triple negative (TNBC) if they did not receive anti-HER2 therapy or endocrine therapy. Results: 1369pts with MBC were treated with PARPi, of whom 77.9%received olaparib. Mean age of pts was 57ys. 546(39.9%), 521(38.1%) and 73(5.3%) pts had TNBC, HR+ve/HER2-ve, and HER2+ve MBC, respectively. Among pts with HER2+ve disease, 35.2% and 74.0% had HR-ve and HR+ve MBC, respectively. Median time to use of PARPi was 7.1m, 15.1m, and 24.0m among pts with TNBC, HR+ve/HER2-ve, and HER2 +ve MBC respectively. Median OS was 44.4m, 47.0m, and 46.7m among pts with TNBC, HR+ve/HER2-ve and HER2+ve MBC respectively. Among pts with HER2+ve disease, median OS was 74.5m and 31.5m among pts with HR+ve and HER-ve disease, respectively (HR=0.27, p=0.0001). 321(23.4%) pts had brain metastases of whom 36.8%, 36.4% and 8.1% had TNBC, HR+ve/HER2-ve and HER2+ve MBC respectively. Among pts with HER2+ve MBC,38.3% received anti HER2 therapy before PARPi, 24.7% received anti HER2 therapy after PARPi and 37.0% received PARPi and anti HER2 therapy concurrently. Among pts with HER2+ve disease, median OS was 44.4m among those who received anti -HER2 therapy on or before PARPi and 93.8m among those who received anti-HER2 therapy after PARPi (HR 0.83, p=0.64).Among pts with brain metastases, median OS was 23.9m, 40.0m and 40.2m among pts with TNBC, HR+ve/HER-ve and HER2+ve MBC respectively. Conclusions: To our knowledge this is the first real world data set to report on the prognostic outcome of pts with HER2+ve BRCA mutated MBC. When PARPi inhibitors are given median OS is similar among the three subtypes of breast cancer. Although not significant, there appears to be a trend towards improved OS with earlier use of PARPi among patients with HER2+ve BRCA mutated MBC.

Real-world baseline characteristics and first-line (1L) treatment (Tx) in patients (pts) with de novo metastatic castration-sensitive prostate cancer (mCSPC) by disease volume.

e17081 Background: Intensification of androgen deprivation therapy (ADT) using novel hormonal therapies (NHT) has been established as a new standard of care for pts with mCSPC. Tx intensification still remains suboptimal, and data in de novo mCSPC pts is limited. Moreover, prior studies utilized claims data and so could not assess the impact of disease burden on Tx intensification. This study assessed baseline characteristics and 1L Tx patterns in pts with high-volume (HV) vs low-volume (LV) de novo mCSPC. Methods: This retrospective study used the Veterans Affairs Informatics and Computing Infrastructure to identify adult men who had ≥1 ICD code for prostate cancer and de novo mCSPC diagnosed between February 2018 and June 2020 confirmed by clinical chart review and initiated either ADT alone, ADT + first-generation non-steroidal anti-androgens [NSAA], or ADT+NHT. Index date was defined as ADT initiation date. The volume of disease was defined as HV or LV per the CHAARTED trial criteria (presence of visceral metastasis and/or ≥4 bone metastases, with ≥1 metastasis beyond the pelvis and vertebral column). Clinical data was hand abstracted from the medical record. Baseline characteristics and 1L Tx were analyzed descriptively. Results: Of the 380 de novo mCSPC pts reviewed, 57% had HV and 43% had LV disease. Mean age of pts was similar between HV and LV cohorts, 74.5 vs 75.2 years, respectively. In addition, the proportion of Black vs White pts in the HV and LV cohorts was similar, 34% and 35% were Black, and 66% and 65% were White, respectively. At index date, HV pts had higher median prostate-specific antigen (153.1 ng/mL vs 73.8 ng/mL) and alkaline phosphatase (192.0 IU/L vs 106.0 IU/L) vs LV pts. HV pts were less likely to have diabetes and cardiovascular comorbidities than LV pts (Table); however, the distribution of Charlson Comorbidity Index score was similar between cohorts (mean [SD]: 4.4 [3.1] vs 4.2 [3.1]). Among the pts with bone metastases only, HV pts had higher proportion (65%) of “too numerous to count” bone metastases vs LV pts (9%). While ADT+NHT use was slightly more common among HV pts (35%) vs LV pts (27%), in both HV and LV cohorts, ADT±NSAA was the most common 1L Tx (Table). The median 1L Tx duration was shorter in the HV pts compared with the LV pts (286 vs 358 days). Conclusions: The results showed that Tx intensification was underutilized in de novo mCSPC pts, even among those with HV, pointing toward an unmet need among pts with de novo mCSPC regardless of disease burden. [Table: see text]

Comparison of peripheral blood markers in predicting the occurrence of immune-related adverse events in patients with metastatic genitourinary cancer treated with cabozantinib + nivolumab +/- ipilimumab.

e16506 Background: Peripheral blood markers (PBM) have been demonstrated to be prognostic and/or predictive for cancer patients (pts) treated with immune checkpoint inhibitors (ICI). Initial evidence has shown their potential role in predicting the occurrence of immune-related adverse events (IrAE) in pts treated with single-agent ICI. We explored the potential role of different PBM in predicting IrAE in metastatic genitourinary cancer (mGU) pts treated with an ICI-based combination. Methods: We retrospectively evaluated 60 mGU pts treated with Cabozantinib + Nivolumab +/- Ipilimumab (CaboNivo +/- Ipi) in a phase I study at the National Cancer Institute. We retrieved their demographics, the occurrence of IrAE, and the baseline values of different PBM (neutrophil/lymphocyte ratio [NLR], neutrophil/eosinophil ratio [NER], lymphocyte/monocyte ratio [LMR], monocyte/lymphocyte ratio [MLR], platelet/lymphocyte ratio [PLR], systemic immune-inflammation index [SII] [N/L*P], and HALP score [albumin*hemoglobin*L/P]). We evaluated PBM based on the presence or absence of IrAE using the Wilcoxon rank sum test followed by multivariable logistic regression analysis. Receiver operating characteristic (ROC) curve analyses were used to investigate an optimal cut-off for PBM suitable for prediction. Results: The median age of pts was 58.5 years (interquartile range [IQR] 46 - 67), and 13 (21.7%) were female. Twenty (33.3%) pts developed at least one IrAE. Baseline median values of PMB are summarized in the Table. A multivariable logistic regression model showed after backward elimination that only NER had the potential to predict IrAE (p = 0.033; Odds Ratio = 0.989 per unit [95% Confidence Interval 0.979 - 0.999]) and thus, we further investigated the predictive potential of NER for the development of IrAE following CaboNivo +/- Ipi. The ROC curve suggested that an optimal cut-off value for NER was 30.647 (area under the ROC = 0.6351). Accordingly, we classified pts with high NER ( &gt; 30.647) as not having IrAE vs low NER (≤ 30.647) as having IrAE. Using this classification, 24/37 (64.9%) of those without (w/o) IrAE and 14/20 (80%) of those with an IrAE could simultaneously be correctly predicted by NER alone. Conclusions: A baseline low NER value was an independent factor associated with a higher probability of developing IrAE in mGU pts treated with CaboNivo +/- Ipi. Prospective validation on a larger cohort of pts is needed. [Table: see text]

Superior outcomes after allogeneic stem cell transplantation (SCT) among patients (Pts) ≥ 60 years (yrs) treated with cladribine (CLAD), low dose cytarabine (LDAC) plus venetoclax (Ven) for newly diagnosed acute myeloid leukemia (AML).

7047 Background: CLAD/LDAC/VEN alternating with AZA-VEN has shown promising outcomes in older pts with AML ( Kadia, JCO Nov 2022). Improved disease control and preserved performance status achieved with CLAD/LDAC/VEN treatment, may translate into superior post-SCT outcomes. Methods: We compared outcomes of pts ≥ 60 yrs of age treated on the phase II study of CLAD-LDAC-VEN who underwent SCT in 1st remission (CR1) to a retrospective cohort of pts ≥ 60 yrs treated with hypomethylating agent (HMA)-VEN based or intensive (INT) therapy who underwent SCT in CR1 between 2013-2022. Relapse free survival (RFS) was from response to relapse/death &amp; overall survival (OS) from start of therapy to death. Results: 35 pts treated with CLAD-LDAC-VEN were compared to 42 pts treated with INT &amp; 40 pts with HMA-VEN therapy for remission induction prior to SCT at our center (Table). The median age of pts in the low-intensity arms were similar (68 yrs), but lower on the INT arm (62 yrs). More pts post INT therapy received a myeloablative conditioning (MAC). At a median follow up of 17+ months (m) for CLAD-LDAC-VEN arm, 59 m for INT arm, and 30 m for HMA arm, the median RFS (NR vs. 50 m vs. 20 m respectively, p &lt;0.01) and OS (NR vs. 58 m vs. 32 m respectively, p &lt; 0.01) was superior for the CLAD-LDAC-VEN arm. 3-yr cumulative incidence of relapse &amp; NRM (as competing events) were both significantly lower with CLAD-LDAC-VEN (4% and 7%) compared to INT (17% and 23%) or HMA-VEN (41% and 27%) therapy. Conclusions: Older pts with AML proceeding to SCT after CLAD-LDAC-VEN therapy had significantly improved survival, characterized by significantly lower rates of NRM and relapse compared to HMA-VEN or INT therapies. Larger studies and longer follow up is needed to confirm its benefit. [Table: see text]

The effect of antibiotic (Abx) use on immune checkpoint inhibitor (ICI) efficacy in patients (pts) with metastatic urothelial carcinoma (mUC) in a real-world setting.

4580 Background: Use of Abx may negatively affect outcomes with ICI, possibly due to negative impact on gut microbiota. We previously showed that in our real world cohort of 138 mUC pts, Abx use within 30 or 60 days (d) of ICI initiation did not impact overall survival (OS). We now report updated follow-up (fu) and results from our expanded cohort of 310 mUC pts who received ICI. Methods: We performed a retrospective analysis of adult pts with mUC treated at the Cleveland Clinic between 2015 and 2022 who received 2 or more cycles of ICI with pembrolizumab (P), atezolizumab (A) or avelumab (Av). Effect of Abx use within 30 and 60 (d) of ICI initiation was correlated with progression free survival (PFS) and OS. OS and PFS were estimated using Kaplan-Meier method and compared using log rank test. Results: Median age of pts was 71 years (41-90) and 75% pts were males. 224 pts (72.3%) received P, 82 (26.4%) A and 4 (1.3%) Av. Fluoroquinolones (31.1%), penicillins (29.6%) and cephalosporins (19.7%) were most commonly used Abx. With a median fu of 47 weeks (3.86- 325.3), median OS in pts who received Abx within 60 (d) prior to ICI was 11.79 months (mos) vs 14.55 mos in those who did not receive Abx (p=0.007) and median PFS was 3.68 mos vs 5.29 mos respectively (p=0.038). Median OS in pts who received Abx within 30 days prior ICI was 10.41 mos vs 14.46 mos in those who did not receive Abx (p=0.037). There was a non-significant trend for worse PFS in pts who received Abx within 30 (d) prior to ICI (3.06 mos vs 5.03 mos, p=0.238). There was no effect on OS or PFS with Abx use 30 or 60 (d) after ICI initiation. Conclusions: In our real-world cohort of mUC pts receiving ICI, Abx use 60 and 30 (d)prior to ICI initiation was associated with significant worse OS and worse PFS for the former group but Abx use after ICI initiation did not have an effect on OS or PFS. These findings have the potential to influence clinical practice, including a higher threshold for giving Abx to mUC pts starting ICI. Further prospective studies are warranted. [Table: see text]

Safety and effectiveness of continuous denosumab for unresectable or advanced giant cell tumor

Introduction. Giant cell tumor of bone is a relatively rare, locally aggressive osteolytic skeletal neoplasm with uncertain behavior: recurrence rates up to 70 % and distant metastases occur 2–6 % of cases. Nowadays denosumab is the choice of therapy for patients with unresectable or advanced disease. However, the efficiency, duration or administration and most of all safety of continuous denosumab are not established.Materials and methods. Fourty advanced or unresectable giant cell tumor cases were observed from 2005 till 2020 in N.N. Blokhin National Medical Research Center of Oncology. The average age of pts was 33,6 ± 13,1 years (18–64), and the women and men ratio was about 2,1 : 1. The most commonly affected sites were long bones of the lower extremities (22,5 %), sacrum (22,5 %), long bones of the upper extremities (17,5 %), spine (17,5 %), pelvis (10 %) and others. 70 % of cases were anatomically compounded due to tumor localization and 27,5 % of cases were primary disease. 37,5 % of cases were with pulmonary metastases. Patients underwent computed tomography / magnetic resonance imaging every 3 months during the first three years and then once every six months. Patient received subcutaneous denosumab 120 mg every 4 weeks with a loading dose of 120 mg subcutaneous on study days 8 and 15. After 2 years monthly therapy and confirmed stabilization effect patient then received maintenance therapy: once in three months injection. All patients received daily calcium and vitamin D supplement.Results. Median follow-up was 52,8 ± 41,3 months (3–219 months). The average denosumab injections were 25 ± 16 (4–85). Clinical and radiographically stabilization of the effect occurred on average at 12 ± 8 (4–32) injections. Hypocalcemia was registered in one case (2.5 %). There was significant improvement of Karnofsky scale, Visual analogue scale (VAS) and Watkins scale (p &lt;0.001). 5-year progression-free survival for was 70.1 % (95 % confidence interval 55.7–88.0), the median was not reached. Progression of disease was observed only in subgroup with violations in denosumab administration or its cancellation (32,5 %). 3-year progression-free survival in subgroup with violations in denosumab administration or its cancellation was 10 % (95 % confidence interval 15.5–64.1). In subgroup with continuous denosumab and once in three months injection after 2 years monthly therapy there was no signs of progression.Conclusions. In this study we showed evidence of safety and effectiveness of continuous denosumab for unresectable or advanced giant cell tumor even with once in three months injection therapy. Denosumab for advanced giant cell tumor of bone became a choice of treatment, but we need further investigation for observation long term denosumab effectiveness and complications.

Profile and outcome of cancer patients enrolled in contemporary phase I trials

BackgroundPhase I trials historically involved heavily pretreated patients (pts) with no more effective therapeutic options available and with poor expected outcomes. There are scare data regarding profile and outcomes of pts enrolled into modern phase I trials. Here, we sought to provide an overview of pts’ profile and outcome into phase I trials at Gustave Roussy (GR). MethodsThis is a monocentric retrospective study, including all pts enrolled into phase I trials at GR from 2017 to 2021. Data regarding pts’ demographics, tumour types, investigational treatments and survival outcomes were collected. ResultsIn total, 9482 pts were referred for early phase trials; 2478 pts were screened, among which 449 (18.1%) failed screening; 1693 pts finally received at least one treatment dose as part of a phase I trial. Median age of pts was 59 years old (range, 18–88) and most common tumour types included gastrointestinal (25.3%), haematological (15%), lung (13.6%), genitourinary (10.5%) and gynaecologic cancers (9.4%). Amongst all pts treated and evaluable for response (1634 pts), objective response rate was 15.9% and disease control rate was 45.4%. Median progression-free survival and overall survival were, respectively, 2.6 months (95% confidence interval [95% CI], 2.3; 2.8) and 12.4 months (95% CI, 11.7; 13.6). ConclusionAs compared with historical data, our study shows that outcomes of pts included into modern phase I trials have improved and that these trials constitute nowadays a valid and safe therapeutic option. These updated data provide facts for adapting the methodology, role and place of phase I trials over the next years.