PurposeMalnutrition severely impacts tolerance to anticancer therapies, but any relationship with overall survival (OS) at the time of solid tumour diagnosis in outpatients in the USA remains unclear.MethodsThis retrospective study evaluated 3562 patients who completed the Malnutrition Screening Tool (MST) at diagnosis, identifying the relationship between MST risk, a validated tool evaluating anorexia and weight loss, and OS. MST score of ≥2 of 5 was classified as high malnutrition risk (H-MST). Kaplan-Meier techniques and Cox proportional hazards models were used to analyse OS in H-MST versus low malnutrition risk (L-MST).ResultsIn the unadjusted models, MST risk was individually associated with OS. Multivariable regression confirmed that MST risk remained independently prognostic for OS after controlling for key confounding variables, HR=1.51 (95% CI: 1.33 to 1.72). The H-MST group had shorter OS (50-month survival rates: 69% L-MST vs 60% H-MST).ConclusionMST risk at diagnosis is an independent prognostic factor for OS. H-MST risk is associated with shorter survival in a broad cohort of solid tumour oncology outpatients.

INTRODUCTION Distress negatively affects cancer outcomes. The National Comprehensive Cancer Network (NCCN) recommends screening patients for distress by a self-reported scale (0-10) and to refer those with scores ≥ 4 to supportive services (SS). Little is known about the prevalence of distress and healthcare utilization in classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs): polycythemia vera (PV), essential thrombocythemia (ET), myelofibrosis (MF). METHODS We retrospectively identified MPN patients at our center to measure the proportions of patients with distress ≥ 4 evaluated by a SS [chaplaincy, integrative oncology, palliative medicine, psychiatry, psychology, and social work (SW)] or had acute care utilization (ACU; ≥ 1 ED visit or hospitalization) within six months of electronic distress screening (EDS). We also obtained sociodemographic, disease characteristics, and symptom score data to stratify variables associated with distress. RESULTS Among 141 patients (44 PV, 49 ET, 48 MF), the median age was 63 years (range, 25-89). Most patients identified as female (62%), White (77%), and completed EDS within three months of diagnosis (55%). Of 75/141 (53%) who reported distress ≥ 4, only 25/75 (33%) were evaluated by SS, and 23/75 (31%) had ACU within six months of EDS. Patients with distress ≥ 4 evaluated by SS had significantly higher ACU (48% vs. 14%; p=0.009). Distress was associated with higher symptom scores and more ED visits but not gender, race, ethnicity, diagnosis, relationship status, or insurance. CONCLUSION Despite consensus recommendations, most patients with distress ≥ 4 were not evaluated by SS. Future work should identify ways to better use patient-reported outcomes to promote early intervention.

Introduction Racial disparities exist in the treatment of prostate cancer in the US, and robust data for African American (AA) vs Caucasian (CAU) patients with metastatic castration-resistant prostate cancer (mCRPC) are scarce. This study explored characteristics, treatment patterns, and outcomes of AA vs CAU patients with mCRPC in the real-world setting. Methods TRUMPET, a prospective, observational, multicenter study, enrolled 1028 patients who initiated CRPC treatment at 147 urology and oncology sites in the US (20152019). The post hoc analysis included patients with mCRPC who identified as AA or CAU. Patients were enrolled within 90 days of the decision to treat or treatment initiation. Characteristics and treatment patterns were analyzed descriptively; radiographic progression-free survival (rPFS), prostate-specific antigen PFS (PSA-PFS), overall survival (OS), and time to skeletal-related events (SREs) were analyzed using Kaplan–Meier methods and adjusted Cox proportional hazards models. An exploratory sub-analysis compared outcomes by race in patients initially treated with androgen receptor pathway inhibitors (ARPIs). Results In total, 133 AA vs 661 CAU patients with M1 CRPC at baseline were included: median age, 69.0 vs 74.0 years; hypertension, 72% vs 66%; diabetes, 32% vs 23%; osteoporosis, 5% vs 12%; other cancers, 6% vs 24%; PSA at diagnosis, 48.8 vs 13.9 ng/mL; N1 tumors, 17% vs 11%; M1 tumors, 29% vs 23%. Primary treatment before CRPC diagnosis (AA vs CAU patients): surveillance, 12% vs 19%; radical prostatectomy, 18% vs 36%; radiation, 48% vs 41%. Initial mCRPC treatment: chemotherapy, 12% vs 6%; ARPI, 62% vs 57%; immunotherapy, 29% vs 41%. After treatment initiation, a trend toward improved clinical outcomes was seen in AA vs CAU patients (Table). In the exploratory analysis, AA patients initiating ARPIs showed a trend toward improved OS vs CAU patients (adjusted median time to death [95% CI]: 41.86 [33.25, not estimable] vs 32.30 [28.62, 40.08] months; adjusted HR [95% CI]: 0.71 [0.45–1.14]). Conclusions AA patients were younger, had higher rates of some comorbidities and more severe disease, and were more likely to receive ARPIs or chemotherapy. Despite our initial hypothesis predicting differences favoring CAU patients, we observed generally similar treatment patterns and a trend toward better outcomes in AA patients. Further research is needed to better understand the outcomes of AA patients with mCRPC.

3097 Background: Patients with certain DPYD variants are at increased risk of fluoropyrimidine (FP) related adverse events (AEs) and mortality at standard doses. We previously showed pre-treatment DPYD testing and genotype-guided FP dosing reduced severe AEs and hospitalizations in variant carriers (PMID 38935897), but testing cost remains a barrier to widespread adoption in the U.S. Herein, we performed a cost analysis of pre-treatment DPYD genotyping. Methods: Variant carrier rates, hospitalization rates, and AEs were derived retrospectively from our institutional cohort (n=442) of patients with no observed variant, dose reduced variant carriers, and standard dose variant carriers (identified reactively) receiving FP primarily for gastrointestinal cancers. All patients were genotyped and followed for three months for FP-related AEs and hospitalizations. Hospitalization cost was the weighted average cost of treating the most expensive AE experienced by the hospitalized patient. Input parameters (Table 1) were modeled using a decision tree to compare the cost of pre-treatment testing (no variant and dose reduced variant carriers) to no pre-treatment testing (no variant and standard dose variant carriers) from a health-system perspective with a three-month time horizon. The model accounted for hospitalization and genotype test costs only. Results: Pre-treatment testing resulted in a cost savings of $36.98 per patient compared to no pre-treatment testing (average per patient cost = $1,655.81 and $1,692.79, respectively). Cost savings increase to $124.39 per patient if half of those tested have insurance that reimburses the test cost. Additional savings are expected if costs for outpatient management of AEs and use of uridine triacetate in the inpatient setting are included in the model. Conclusions: Pre-treatment DPYD genotyping led to cost savings by reducing AE related hospitalizations among variant carriers. Cancer centers should adopt pre-treatment DPYD genotyping to reduce severe AEs, hospitalizations, and costs. Model inputs. Parameter Value Source No variant population prevalence 94% Institutional cohort Variant carrier population prevalence 6% Institutional cohort No variant hospitalization rate 11% Institutional cohort Dose reduced variant carrier hospitalization rate 25% Institutional cohort Standard dose variant carrier hospitalization rate 64% Institutional cohort No variant hospitalization cost $12930.67 HCUP NC Inpatient Database 2021 Dose reduced variant carrier hospitalization cost $8858 HCUP NC Inpatient Database 2021 Standard dose variant carrier hospitalization cost $8928.29 HCUP NC Inpatient Database 2021 Genotype test cost $174.81 CMS clinical laboratory fee schedule 2023 HCUP; Healthcare Cost and Utilization Project, NC, North Carolina; CMS, Centers for Medicare and Medicaid Services.

We evaluated the prognostic value of circulating tumor cell (CTC) counts and androgen receptor splice variant 7 (AR-V7) status at baseline and after docetaxel in the previously published ENZADA trial. We analyzed data for 35 participants with both baseline and postdocetaxel CTC counts. CTC count status at two thresholds (≥2 vs <2 cells/μl; ≥3 vs <3 cells/μl) was not prognostic for a 26-wk or 52-wk prostate-specific antigen (PSA) complete response (CR), overall survival (OS), or time to castration resistance (TTCR). CTC count status (>0 vs 0 cells/μl) after docetaxel was not associated with 26-wk PSA CR, OS, or TTCR. However, there was a trend towards a higher 52-wk PSA CR rate among those with detectable CTCs after docetaxel (92% vs 52%; p = 0.03). A binary variable indicating the change in CTC level (increased or remained stable/decreased) from baseline after docetaxel was also not associated with OS, TTCR, or landmark 26-wk or 52-wk PSA CR rates. However, in the group with 52-wk PSA CR data, a rise in postdocetaxel CTC level was associated with shorter TTCR (hazard ratio [HR] 9.8, 95% confidence interval [CI] 1.1–88.1) and a trend towards shorter OS (HR 7.3, 95% CI 0.76–70.6). AR-V7 was only detected in one patient at each time point. The CTC count was not prognostic for patients with metastatic hormone-sensitive prostate cancer treated with chemohormonal therapy in this small cohort, although a rise in CTC count after docetaxel may identify patients at high risk of progression among those with a PSA CR. Patient summary: For men with metastatic prostate cancer treated with hormone therapies and chemotherapy, we looked at whether the level of tumor cells circulating in the blood (CTCs) was associated with the PSA (prostate-specific antigen) response and survival time. The CTC level was checked before treatment and after six doses of chemotherapy. We found no association with prostate cancer outcomes. However, in the group of patients whose PSA became undetectable after treatment, a CTC increase after chemotherapy identified men with a higher risk of cancer progression and death.

Background Patients with locally advanced non-small-cell lung cancer (NSCLC) who undergo concurrent chemotherapy and radiotherapy often experience synergistic toxicity, and local regional control rates remain poor. We assessed the activity and safety outcomes of primary tumour stereotactic body radiotherapy (SBRT) followed by conventional chemoradiotherapy to the lymph nodes and consolidation immunotherapy in patients with unresectable locally advanced NSCLC. Methods In this multicentre, single-arm, phase 2 trial, patients aged 18 years and older were enrolled at eight regional cancer centres in North Carolina and South Carolina, USA. Patients were eligible if they had stage II-III, unresectable, locally advanced NSCLC (any histology), with peripheral or central primary tumours that were 7 cm or smaller, excluding central tumours within 2 cm of involved nodal disease, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients who had previously received systemic therapy or radiotherapy were excluded. Participants received SBRT to the primary tumour (50-54 Gy in three to five fractions) followed by standard radiotherapy (planned up to 60 Gy in 30 2 Gy fractions) to the involved lymph nodes with concurrent platinum doublet chemotherapy (either paclitaxel 50 mg/m2 intravenously plus carboplatin area under the curve mg/mL per min every 7 days for a total of six 1-week cycles or etoposide 50 mg/m2 intravenously on days 1-5 and days 29-33 plus cisplatin 50 mg/m2 intravenously on days 1, 8, 29, and 36 for two cycles of 4 weeks). An amendment to the protocol (Dec 11, 2017) permitted the administration of consolidation durvalumab at the discretion of the treating investigator. An additional protocol amendment on Jan 13, 2021, directed patients without disease progression after chemoradiotherapy to receive consolidation durvalumab (10 mg/kg intravenously on day 1 and day 15 of a 4-week cycle for up to 12 cycles or 1500 mg intravenously on day 1 of a 4-week cycle for up to 12 cycles). The primary endpoint was 1-year progression-free survival (per Response Evaluation Criteria in Solid Tumours version 1.1), assessed in all participants who received at least one fraction of SBRT and had radiological follow-up data up to 1 year. A 1-year progression-free survival rate of greater than 60% was required to reject the null hypothesis and show significant improvement in 1-year progression-free survival. One-sided exact binomial tests were used to compare the primary endpoint versus the historical control 1-year progression-free survival rate used to determine the sample size. Safety was assessed in all patients who received at least one fraction of SBRT. This study is registered with ClinicalTrials.gov, NCT03141359, and is closed to accrual. Findings Between May 11, 2017, and June 27, 2022, 61 patients were enrolled and received at least one dose of fractionated SBRT, of whom 59 were evaluable for the primary endpoint. Median age was 67 years (IQR 61-72), 28 (46%) of 61 were female, 33 (54%) were male, 51 (84%) were White, seven (11%) were Black, and three (5%) were of other or unknown race. Of the 61 patients enrolled, 47 received at least one dose of consolidation durvalumab. As of data cutoff (July 12, 2023), median follow-up was 295 months (IQR 149-471). 1-year progression-free survival was 627% (90% CI 512-732; one-sided p=039, compared with the historical control rate), with 37 of 59 evaluable participants progression free and alive 1 year after enrolment (n=14 progressed, n=8 died). The most common grade 3-4 treatment-related adverse events were decreased neutrophil count (nine [15%] of 61 patients), decreased white blood cell count (five [8%]), and anaemia (four [7%]). Treatment-related serious adverse events occurred in 11 (18%) of 61 patients, which included lung infection (three [5%]), pneumonitis (two [3%]), decreased neutrophil count (two [3%]), febrile neutropenia (two [3%]), and dyspnoea, hypoxia, respiratory failure, sinus tachycardia, bronchial infection, and acute kidney injury (each in one [2%] patient). Treatment-related deaths occurred in four (7%) of 61 patients (one each of respiratory failure, respiratory failure and dyspnoea, lung infection, and pneumonitis). Copyright (c) 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.

PURPOSE Alterations in human epidermal growth factor receptor 2 (HER2; ERBB2 gene) may be clinically relevant when considering HER2-targeted therapies. We have characterized the breadth of ERBB2 alterations (mutation, fusion, and copy number amplification) in breast cancer and explored the relationship between ERBB2 alterations and prognosis. METHODS DNA next-generation sequencing (592-gene panel and whole-exome sequencing) and RNA whole-transcriptome sequencing data from 12,153 breast samples were retrospectively reviewed for ERBB2 alterations. Clinicopathologic features were described, including breast cancer subtype, age, and biopsy site. HER2 status was determined according to ASCO guideline recommendations, including HER2-low. Overall survival (OS) data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank-sum tests. RESULTS Pathogenic ERBB2 mutations ( ERBB2- mut) were identified in 3.2% (N = 388) of tumors overall, most common in liver metastases (113/1,972, 5.7%). ERBB2- mut was more common among breast lobular than ductal (10% v 2.1%; P < .001) and HER2-positive (HER2+)/low tumors (≥3.8% v 1.5% TNBC; P < .05). The most common variant was ERBB2 -L755S (1.0% prevalence), enriched in metastatic tumors (1.2% v 0.6% in primary; P < .001). ERBB2 fusions were rare (0.3% prevalence). Coalterations associated with ERBB2 -mutated tumors compared with ERBB2 wildtype (WT) included CDH1 (40.0% v 10.2%; P < .001) and ERBB3 (10.6% v 0.8%; P < .001). Of the 10,115 tumor samples with outcome data, ERBB2- mut was associated with worse OS compared with WT. CONCLUSION ERBB2- mut and fusions were observed in all breast cancer subtypes—more commonly in HER2+/low, metastatic, and lobular histology tumors—and associated with poorer prognosis.

Abstract In newly diagnosed multiple myeloma (NDMM), measurable residual disease (MRD) status is prognostically important, but its role in treatment decisions remains unclear. In a phase 2 trial, we assessed daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) induction followed by a next-generation sequencing–based MRD-adapted strategy. The primary outcome was complete response (CR) and stringent CR (≥CR) after induction. Flow cytometry was used to profile T cells. Among 39 patients, 21 (54%) achieved ≥CR after induction (P = .375), with MRD-negative rates of 59% (10−5) and 41% (10−6). Patients who were MRD-negative (n = 24, group A) received lenalidomide maintenance, showing sustained MRD negativity in 14 of 18 (77.8%) for ≥12 cycles. MRD-positive transplant-eligible patients (n = 8, group B) underwent autologous stem cell transplantation, with 62.5% converting to MRD-negative at 10−5 (37.5% at 10−6) posttransplant. MRD-positive, transplant-ineligible patients (n = 4, group C) received KRd consolidation. Best MRD-negative rates improved to 77% (10−5) and 72% (10−6). No new safety concerns were identified for Dara-KRd. With a median follow-up of 30.1 months, 3, 2, and 1 patient(s) in groups A, B, and C, respectively, have progressed or died. We observed that Dara-KRd strongly activated memory T cells, which was associated with an MRD-negative state post induction. Although the primary outcome was not met, Dara-KRd induction in NDMM achieved high ≥CR and MRD-negative rates without new safety concerns. The post induction MRD-adapted strategy deepened responses in MRD-positive patients and maintained durable MRD control in MRD-negative patients. This trial was registered at www.clinicaltrials.gov as #NCT04113018.

PURPOSE Venetoclax has made a significant impact in the treatment of chronic lymphocytic leukemia (CLL) due to its ability to induce deep and durable remissions with a finite duration of oral therapy. However, it can lead to tumor lysis syndrome (TLS) which is mitigated with dose escalation strategies. Patients who initiate venetoclax need to follow rigorous, and potentially burdensome, TLS monitoring during dose ramp-up. The frequency with which this rigorous monitoring leads to therapeutic interventions in clinical practice has not been well described. We conducted a study to assess the incidence of TLS and interventions needed after initiation of venetoclax in patients with CLL. METHODS Adult patients with CLL who started treatment with venetoclax between July 2017 and March 2021 at Levine Cancer Institute were included in this study. Adherence to the venetoclax package insert (PI) for tumor lysis monitoring, incidence of laboratory as well as clinical TLS, and interventions resulting from the monitoring of TLS were collected. RESULTS We report outcomes on 73 consecutive patients with CLL who initiated venetoclax. The majority of patients had low (49%) or medium (44%) tumor burden. During venetoclax ramp-up, 66% of patients adhered strictly to TLS monitoring as per the venetoclax PI. One patient developed laboratory TLS, and no patients developed clinical TLS. Six patients received unplanned interventions to treat TLS; all had medium or high tumor burden. There were no unplanned interventions in patients with low tumor burden. CONCLUSION In patients with low and medium tumor burden CLL who start venetoclax, the incidence of TLS is very low, and interventions are uncommonly needed.

Maintenance therapy post-HCT for multiple myeloma is aimed to avoid relapse or delay disease progression. Immunizations are common practice to confer protection against vaccine-preventable infections during both early and late phases post-HCT. However, limited data on efficacy exist for patients undergoing maintenance therapy post-HCT.We performed this study to characterize the humoral and cellular responses to pneumococcal (PCV13) immunization post-HCT in patients undergoing maintenance therapy for multiple myeloma. Sixty patients, of which 52 received maintenance with an immunomodulatory (IMID) agent while 18 received a combination of an IMID and a proteasome inhibitor (PI), were immunized with PCV13 at 6, 8 and 12 months (mo.). Serotype-specific pneumococcal antibody concentrations as well as B- and T-cell distributions were determined pre-vaccination at 2, 6 mo. post-HCT and, 8, 12, and 14 mo. thereafter.Patients in both cohorts (IMID and IMID+PI) mounted a humoral response with a statistically significant difference between concentrations at 8, 12, and 14 mo. vs pre-vaccination baseline for all analyzed serotypes. No significant differences were observed in concentrations across all serotypes or in a time-dependent manner between the two cohorts. There were significant increases in concentrations over time from 8 to 14 mo. for serotypes 4, 23, and 26, while a significant decrease over time was observed for serotype 5. We did not observe a significant difference between arms at any time point in the proportion of patients protected against invasive or non-invasive pneumococcal disease. However, protective titers at 14 mo. were achieved in a significantly higher number of patients in the IMID cohort. No patients developed pneumococcal disease by 14 mo. after transplant. We observed no significant difference in the B effector and memory cell acquisition kinetics between treatment groups. Plasmablasts and activated memory B cell blood content peaked at 8 and 12 mo., respectively. Memory cell retention was the only marked difference between treatment arms with only IMID patients retaining circulating switched memory B cell (resting or activated) at 14 mo. (p=0.022). This suggests that while the type of maintenance therapy regimen might not affect acquisition of protective immunity in response to PCD13 vaccination, it may affect immunity retention. Immunization with PCV13 did not significantly alter effector and memory T cell compartments.Our study suggests that at both humoral and cellular levels, IMID +/- PI maintenance therapy post-HCT in multiple myeloma does not interfere with acquisition of protective immunity to PCV13. Past one year of maintenance though, doublet IMID+PI may limit retention of protective immunity to PCV13 compared to IMID only. This would need to be confirmed with a larger cohort of patients and potentially across other acellular vaccines.

639 Background: EOPC, defined as pancreatic cancer (PC) diagnosed at 60 years of age or younger, is associated with significant life years lost. Approximately 5-10% of average-onset PC have an underlying germline etiology. Currently NCCN & ASCO guidelines recommend germline testing in all pts w PC. However, there is limited data regarding to what extent pts with EOPC pursue recommended germline testing. We examined the findings from genetic evaluation in EOPC. Methods: A retrospective review of EOPC pts at the Levine Cancer Institute who underwent clinical genetic assessment between January 2019 and December 2021 was performed. Data on clinicodemographic, family history, and genetic testing results were obtained and analyzed descriptively. Results: We identified 69 EOPC pts who were evaluated by genetics. Baseline characteristics include median age of 55 years (range 25-60) with 52% male, 48% white, 23% black, and 52% with current or prior tobacco use. At presentation, 41% and 59% had metastatic and non-metastatic disease, respectively. Eight (12%) pts declined germline testing. Among the 61 who underwent germline testing, 30 (49%) pts had negative testing, 21 (34%) had only variants of uncertain significance, and 10 (16%) had pathogenic/likely pathogenic germline variants (PVs). The most frequently seen PVs were ATM (20%), BRCA1 (20%), BRCA2 (10%), MLH1 (10%), NTHL1 (10%), PTCH1 (10%), CFTR (10%) and one (10%) with multiple pathogenic germline findings including RAD51 and BRCA1. Among the 10 pts with PVs, only two reported any first or second-degree family members with cancer. Conclusions: In this cohort of EOPC at a large community multi-site cancer center, 16% of patients had germline PVs, higher than reported in older patients with PC. Only 20% of pts w PVs reported first or second-degree family members with cancer and highlights the importance to recommend germline testing independent of family history even among EOPC cohorts. Further investigation to clarify reasons for refusal of germline testing in EOPC should be evaluated.

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by unregulated red blood cell production resulting in elevated hemoglobin and/or hematocrit levels. Patients often have symptoms such as fatigue, pruritus, and painful splenomegaly, but are also at risk of thrombosis, both venous and arterial. Ruxolitinib, a selective Janus kinase inhibitor, is approved by the US Food and Drug Administration as second-line cytoreductive treatment after intolerance or inadequate response to hydroxyurea. Although ruxolitinib has been widely used in this setting, limited data exist in the literature on ruxolitinib treatment patterns and outcomes among patients with PV in routine clinical practice. We report a retrospective, observational, cohort study of patients treated for PV with ruxolitinib across three US centers (academic and regional practice) from December 2014-December 2019. The study included 69 patients, with a median follow-up duration of 3.7 years (95% CI, 2.9-4.4). Our data demonstrate very high rates of hematocrit control (88% of patients by three months and 89% by six months); few patients required dose adjustments or suspension. No arterial thromboses were observed; however, the follow-up duration does not allow for the generation of meaningful conclusions from this. Three patients had thrombotic events; one was in the setting of a second malignancy, one post-operative, and a third related to prolonged immobility. We also found that 28% of patients initiated ruxolitinib as a result of poorly controlled platelet counts, second only to hydroxyurea intolerance (46%) as a reason to start therapy. In clinical practice, ruxolitinib continues to be effective in controlling hematocrit levels after three and six months of treatment in patients and is associated with low thrombotic risk.

BACKGROUND:Young women with breast cancer (YWBC; ≤40 years) often have a poorer prognosis than older women with breast cancer (OWBC; ≥65 years). We explored molecular features of tumors from YWBC and OWBC to identify a biologic connection for these patterns. MATERIALS AND METHODS:We retrospectively analyzed the molecular profiles of 1879 breast tumors. Testing included immunohistochemistry (IHC), in situ hybridization (ISH), and next-generation sequencing. Statistical analyses included Pearson's chi2 test for comparisons, with significance defined as FDR (false discovery rate)-P < .05. RESULTS:TP53 and BRCA1 somatic mutations were more common in YWBC tumors than in OWBC tumors (53%, 42%; P = .0001, FDR-P = .0025 and 7%, 2%; P = .0001, FDR-P = .0025; respectively). Conversely, OWBC tumors had higher androgen receptor expression (55%, 45%; P = .0002, FDR-P = .0025) higher PD-L1 expression detected by IHC (8%, 5%; P = .0476, FDR-P = .2754), and more frequent PIK3CA mutations (33%, 17%; P = < .0001, FDR-P = < .0001). Among HR+/HER2- samples, YWBC had more gene amplifications in FGF3 (27%, 10%; P = .0353, FDR-P = .2462), FGF4 (27%, 9%; P = .0218, FDR-P = .1668), FGF19 (30%, 12%; P = .034, FDR-P = .2462) and CCND1 (37%, 18%; P = .0344, FDR-P = .2462) than OWBC. CONCLUSIONS:Our data suggest distinct molecular aberrations exist between YWBC and OWBC. Exploiting these molecular changes could refine our treatment strategies in YWBC and OWBC.

Introduction . We had previously reported that TLR 2 levels were significantly elevated in patients with polycythemia vera and MPN ( PV , ET, MF grouped together ) and TLR2 levels were related to JAK2 mutation and leukocytosis ( Blood (2022) 140 (Supplement 1): 12185-12186.). Since MPN has increased incidence of thrombosis in patients with JAK2V617F mutation and leukocytosis , therefore , current studies were done to test whether TLR-2 is related to thrombosis in MPN . In vitro platelet activation ( an pre-thrombotic marker) and clinical episodes of thrombosis were then investigated. . Material and Methods. 119 patients ( 51ET, 37 PV, 31MF, 21 CTR) were studied . 1) platelet activation. : The diluted blood was incubated with platelet agonists Pam3CSK4 (TLR2 agonist) or lipopolysaccharide (LPS) (TLR4 agonist) for 15 minutes at room temperature , then platelet activation was measured by Flow cytometry assaying CD40L, P-selectin, PAC-1 and LPI ( leukocyte-platelet-interaction). We obtained more consistent results from the LPI methods . Therefore, LPI methods were used to measure the platelet activation. LPI method was measured by CD45 and CD41 antibodies (Miltenyi Biotec, Auburn, CA), and platelet activation were measured as the percentage of CD45 cells with aggregated CD41. To test whether TLR2 or TLR4 were responsible for the LPI response ,TLR2 inhibitor C29 (InvivoGen, San Diego, CA) or the TLR4 inhibitor C34 ((Sigma-Aldrich, St. Louis, MO) were added to the LPI assay. Effects of inhibitions were measured by fold-changes which were calculated by dividing the LPI values after activation by either Pam3CSK4 (TLR2 agonist) or LPS (TLR4 agonist), with or without added inhibitors, by the LPI values before activation or inhibition. Results . 1) As shown in Fig A, a) un-activated MPN (U-MPN) patients had more LPI than un-activated controls (u-CTR), with mean ± SE of 13.01 ± 1.12 and 5.01 ± 0.97 in U-MPN and U-CTR, respectively (P<0.01). This is consistent with previous reports that un-activated MPN patients have more intrinsically activated platelets than un-activated controls .b) Greater LPI response by activation by Pam3CSK4, (TLR2 agonist ) than by LPS ( lipopolysaccharide)) (TLR4 agonist) . MPN and controls ( mean ± SE ) were of 22.25 ± 0.99 and 10.46 ± 0.44 ( by Pam3CSK4) and 12.12 ± 2.16 and 4.34 ± 0.32 ( by LPS) (P<0.0005) respectively . 2). Fig B showed the TLR2 inhibitor C29 significantly suppressed LPI ( measured by fold-changes ) , in un-activated MPN (0.38 ± 0.05), activated controls (0.42 ± 0.11), and activated MPN (0.42 ± 0.05). Conversely, the TLR4 inhibitor C34 had no inhibitory effect on un-activated MPN (0.98 ± 0.03), activated MPN (1.02 ± 0.02), or activated controls (0.84 ± 0.06) . 3) As shown in Table 2 , TLR 2 levels elevated Patients ( TLR2-E) ( defined as more than mean plus 2 standard deviation of controls (> 310 MFI) , have more thrombosis episode (29%) than TLR2 -normal patients (11%) . Conclusion . TLR2 likely plays a significant role in thrombosis in MPN patients on the basis : 1) JAK2 mutated patients have more TLR2 levels 2) TLR2-E patients have more leukocytosis than TLR-N patients 3) LPI was significantly elevated with TLR2 agonist ( Pam3SK4) but not by TLR4 agonist ( LPS) , and LPI was significantly decreased by TLR2 inhibitor and not by TLR4 inhibitor. 4) clinical evidence of more thrombosis in TLR -E patients than TLR-N patients.

Using haploidentical donors for allogeneic hematopoietic cell transplantation (HCT) broadens transplant accessibility to a growing number of patients with hematologic disorders. Moreover, haploidentical HCT with post-transplant cyclophosphamide (PTCy) has become widespread practice due to accumulating evidence demonstrating favorable rates of survival and graft-versus-host disease (GvHD). Most studies comparing outcomes by donor sources have been confounded by variability in conditioning regimens, graft type (peripheral blood [PB] or bone marrow), and post-transplant GvHD prophylaxis (PTCy or non-PTCy), making it difficult to define the effect of donor source on outcomes. Levine Cancer Institute started a transplant and cellular therapy program in 2014, with both haploidentical and matched related donor (MRD) transplants initially performed using a uniform reduced-intensity conditioning (RIC) regimen, PB grafts, and PTCy-based GvHD prophylaxis. This retrospective observational study was conducted to compare the clinical outcomes associated with RIC haploidentical HCT and MRD HCT in patients receiving identical conditioning regimens, graft types, and supportive care. Our transplant database was queried to evaluate demographic characteristics, clinical features, and outcomes of RIC HCT for consecutive patients with hematologic malignancies who received haploidentical or MRD grafts between March 2014 and December 2017. An MRD was the preferred donor source; when unavailable, a haploidentical donor was used. Sixty-seven patients underwent haploidentical HCT and 25 MRD HCT. Overall, characteristics of transplant recipients were similar for the haploidentical and MRD groups; however, haploidentical donors were younger than MRDs (median 36 yr versus 57 yr, P < .0001). Results of univariable analysis showed similar overall survival (OS) for haploidentical and MRD HCT (hazard ratio [HR], 1.15; 95% CI, 0.61 to 2.15; P = .669). One-year, 1-yr, and 5-yr OS were 80.2%, 54.7%, and 41.2% for haploidentical HCT and 76.0%, 55.7%, and 51.1% for MRD HCT, respectively. With a median follow-up of 81.90 months, results of multivariable analysis revealed that donor source (haploidentical versus MRD) was not significantly associated with OS (HR, 0.97; 95% CI, 0.51 to 1.87; P = .933), relapse-free survival (HR, 0.75; 95% CI, 0.42 to 1.35; P = .337), cumulative incidence of relapse (HR, 0.81; 95% CI, 0.39 to 1.70; P = .579), or non-relapse mortality (HR, 1.12; 95% CI, 0.40 to 3.14; P = .827). Cumulative incidences of acute GvHD (aGvHD) and chronic GvHD (cGvHD) were not significantly different for haploidentical and MRD HCT (grades II to IV aGvHD: HR, 1.78; 95% CI, 0.72 to 4.37; P = .210; grades III to IV aGvHD: HR, 2.84; 95% CI, 0.34 to 23.63; P = .335; cGvHD: HR, 1.00; 95% CI 0.36 to 2.76; P = .995). With care that was homogenous in terms of conditioning regimens, graft type, GvHD prophylaxis, and supportive care, 92 patients who were biologically randomized to either haploidentical HCT or MRD HCT after RIC with PTCy had comparable outcomes.

PURPOSE Fluoropyrimidine-related toxicity and mortality risk increases significantly in patients carrying certain DPYD genetic variants with standard dosing. We implemented DPYD genotyping at a multisite cancer center and evaluated its impact on dosing, toxicity, and hospitalization. METHODS In this prospective observational study, patients receiving (reactive) or planning to receive (pretreatment) fluoropyrimidine-based chemotherapy were genotyped for five DPYD variants as standard practice per provider discretion. The primary end point was the proportion of variant carriers receiving fluoropyrimidine modifications. Secondary end points included mean relative dose intensity, fluoropyrimidine-related grade 3+ toxicities, and hospitalizations. Fisher's exact test compared toxicity and hospitalization rates between pretreatment carriers, reactive carriers, and wild-type patients. Univariable and multivariable logistic regression identified factors associated with toxicity and hospitalization risk. Kaplan-Meier methods estimated time to event of first grade 3+ toxicity and hospitalization. RESULTS Of the 757 patients who received DPYD genotyping (median age 63, 54% male, 74% White, 19% Black, 88% GI malignancy), 45 (5.9%) were heterozygous carriers. Fluoropyrimidine was modified in 93% of carriers who started treatment. In 442 patients with 3-month follow-up, 64%, 31%, and 30% of reactive carriers, pretreatment carriers, and wild-type patients had grade 3+ toxicity, respectively ( P = .085); 64%, 25%, and 13% were hospitalized ( P < .001). Reactive carriers had 10-fold higher odds of hospitalization compared with wild-type patients ( P = .001), whereas no significant difference was noted between pretreatment carriers and wild-type patients. Time-to-event of toxicity and hospitalization were significantly different between genotype groups ( P < .001), with reactive carriers having the earliest onset and highest incidence. CONCLUSION DPYD genotyping prompted fluoropyrimidine modifications in most carriers. Pretreatment testing reduced toxicities and hospitalizations compared with reactive testing, thus normalizing the risk to that of wild-type patients, and should be considered standard practice.

Introduction/Background: In the pivotal DREAMM-2 study, belantamab mafodotin (Belamaf), an antibody-drug conjugate targeting BCMA, achieved an overall response rate (ORR) of 32% with a median response duration (DOR) of 11 months in relapsed or refractory multiple myeloma (RRMM). In the DREAMM-7 study, Belamaf showed superior efficacy outcomes compared to daratumumab when combined with bortezomib and dexamethasone. Moreover, in the DREAMM-8 trial, Belamaf outperformed bortezomib in combination with pomalidomide and dexamethasone. We, therefore, aimed to evaluate the safety and preliminary efficacy of adding Belamaf to carfilzomib, lenalidomide, and dexamethasone (KRd) for patients with RRMM who have received 1 - 3 prior lines of therapy. When Belamaf was administered at a dose of 2.5 mg/kg once every 3 weeks, it resulted in a 27% incidence of grade 3 keratopathy. We theorized that using lower doses of Belamaf every 8 weeks would improve tolerability without compromising efficacy. Here, we present the findings of the phase 1 portion of the trial. Methods: Pts with RRMM after 1-3 prior lines of therapy (LOT) were enrolled in the phase 1 component of the trial with a 3+3 dose escalation design followed by an expansion cohort to better inform the recommended phase II dose (RP2D). The primary objective for the phase 1 portion was to establish the maximum tolerated dose (MTD) of Belamaf when given with KRd as determined by dose-limiting toxicities (DLTs) in cycle 1 of therapy. Secondary objectives included ORR, response depth, DOR, progression-free survival, overall survival, and safety. Two doses of Belamaf were tested: 1.4 mg/kg and 1.9 mg/kg given intravenously over 30 - 60 minutes every 8 weeks with KRd (K 20/56 mg/m2 days 1,8,15; R 25 mg po days1-21; and d 20/40 mg po weekly) in 28-day cycles. In the absence of disease progression or the emergence of unacceptable toxicity, pts were treated for up to 18 cycles followed by lenalidomide maintenance. Results: With a data cutoff of June 10, 2024, 26 pts consented to phase 1, and 19 were enrolled; 6 pts at 1.4 mg/kg and 13 at 1.9 mg/kg (6 DLT evaluable pts in 1.4 mg/kg cohort and 12 DLT evaluable pts in the 1.9 mg/kg cohort). Median age was 63. Most pts were males 63%, 42% were black, and 53% had high-risk cytogenetics, including 1q gain and 1p deletion. 50% of pts with available ISS staging data at diagnosis had stage III, 42% were refractory to lenalidomide, 11% were bortezomib refractory, 26% were double refractory, and 26% were daratumumab refractory. The median lines of prior therapy was 1 (range 1- 3). At the 1.4 mg/kg dose level, one DLT of grade 4 thrombocytopenia was reported out of 6 pts. No DLTs were reported among the 12 DLT evaluable pts enrolled at the 1.9 mg/kg dose level (6 pts as part of the dose escalation portion and 6 pts for dose expansion). The most common adverse events were non-specified eye disorders (total; ≥G3) (94.7%; 31.6%), blurred vision (89.5%; 36.8%), fatigue (57.9%; 0%), hypokalemia (52.6%; 10.5%), cough (47.4%; 0%), diarrhea (47.4%; 0%), and pain (47.4%; 0%). 15 pts experienced G2(+) corneal events per KVA (26 total G2(+) events), and 15 pts experienced a decline of 2 or more lines on the Snellen Visual Acuity scale (25 events). After a median follow-up (IQR) of 16.1 months (11.4; 24.1), 3 pts progressed. The total and median number of cycles of belantamab were 73 and 5 cycles, respectively. All pts achieved a best response of at least a PR, the VGPR(+) rate was 73.7%, and the CR(+) rate was 52.6%, including 52.6% and 36.8% with MRD negativity 10^-5 and 10^-6 by flow cytometry, respectively. Out of 7 pts with R-ISS-III, 57.1% achieved VGPR(+). Out of 8 pts with IMWG high risk cytogenetics, 5 pts (62.5%) achieved a VGPR or better. Responses are expected to deepen with further follow-up. In total, 9 pts achieved sCR, which exceeds the protocol-directed criterion to proceed to Phase 2 at the RPD2 dose. 13 pts are off treatment due to consent withdrawal (n=4), investigator decision post 18 cycles (n=4), participant non-compliance (n=1), and toxicity (n=1). Conclusions: This phase 1 trial established the MTD of belantamab of 1.9 mg/kg every 8 weeks in combination with KRd. KRd-B is effective even in pts with high-risk MM. Despite the dosing schedule of every 8 week Belamaf dosing, clinically significant keratopathy was common. Pts with high-risk newly diagnosed MM will be enrolled in the phase 2 portion of this trial.