Cohort Of Pts Research Articles

Circulating Tumor Cells By Next Generation Flow Cytometry May be a New Prognostic Biomarkers Among Patients with Asymptomatic Monoclonal Gammopathies

Monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic (smoldering) multiple myeloma (sMM) precede symptomatic myeloma (MM) but are characterized by significant heterogeneity in terms of biological characteristics and clinical course. Currently no single molecular or clinical feature can identify patients (pts) who should be treated immediately or for which treatment should be prioritized over watchful wait. Circulating tumor cells (CTCs - clonal plasma cells) are frequent in pts with symptomatic MM and have prognostic significance, independently of other disease and patient characteristics. The use of next generation flow cytometry (NGF) is an accurate method to assess CTCs and provides a non-invasive tool to assess tumor cells. Few studies have addressed the prognostic significance of CTCs detected by NGF as a potential prognostic biomarker in SMM. Herein, we report our initial results from the prospective evaluation of pts with asymptomatic plasma cell dyscrasias with NGF to determine baseline CTC values. We prospectively analyzed the data and outcomes of 189 consecutive pts with asymptomatic monoclonal gammopathies (MGUS or SMM by IMWG criteria), diagnosed and followed in the Department of Clinical Therapeutics, Athens, which were evaluated prospectively for the detection of CTCs at the time of initial diagnosis. CTCs were assessed in peripheral blood (PB) according to the EuroFlow guidelines, using two independent 8-color panels, both containing CD19-PC7, CD27-BV510, CD38-FITC, CD45-PerCPCy5.5, CD56-PE, CD138-BV421, and additionally CD117-APC and CD81-APCC750 only in the surface tube or CyIgκ-APC and CyIgλ-APCC750 only in the intracytoplasmic tube. A median number of 5 million events (range 3.9x106-6.1x106) were acquired for each tube and median LOD was 2.3x10-6 (range 2x10-6- 3.1x10-6). The median age of the cohort's pts was 65 years (range 28-87) and 59% were females; 47% had non-IgM MGUS and 53% had a diagnosis of SMM. The isotype was IgG in 85% and 74%, IgA in 10% and 22% and light chain only in 2% and 4% in MGUS and SMM pts respectively. Among MGUS pts, 50% had abnormal FLC ratio and the median M-spike was 0.54 gr/dl (range: 0-1.96). For pts with SMM, 58% had abnormal FLC ratio, 16% had FLC ratio >20, 13% had M-spike >2 gr/dl and 31% had BM plasma cell infiltration >20%.Per IMWGs 20/2/20, 55% were low risk (no risk factors), 33% intermediate risk (one risk factor) and12% were high risk (2-3 risk factors). Cytogenetics were available in 60 pts (19 MGUS and 41 SMM): t(4;14) was present in 10% of SMM, t(11;14) in 22% of SMM and MGUS, t(14;16) in 8% if SMM, +1q21 in 31% of SMM and 6% of MGUS, del17p in 2% of SMM and 5% of MGUS (one patient each) and del13q in 29% of SMM and 17% of MGUS. Clonal plasma cells (CTCs) were detectable in 33% of patient in the cohort: in 17% of MGUS and in 42% of SMM pts. Among those with detectable CTCs, median level was 0.004% (range 0.0002% to 0.22%) and did not differ among MGUs and SMM pts. Among pts with low-risk SMM, 31% had detectable CTCs (median 0.0065%) vs 45% of pts with intermediate/high risk (median 0.0022%) (p=0.066). The median follow-up of the whole cohort is 18 months; until the data cutoff date 13pts have progressed (all with SMM); the 2-year progression rate 7%,29% and 46% for low, intermediate and high risk SMM (p=0.032) The presence of CTCs was associated with a higher risk of progression to symptomatic MM among all pts in the cohort (HR: 4; 95% CI 1.1-14.7, p=0.024); among SMM pts there was a trend for shorter time to progression but did not reach statistical significance probably due to relatively short follow up and small numbers. We also evaluated 0.015% as a CTCs cutoff(identified previously by Termini et al) but only 10pts had CTCs above this level and did not reach statistical significance. Adjusted for IMWG 20/2/20 risk score, the presence of CTCs was associated with a trend towards statistical significance (HR: 3, 95% 0.97-11.9, p=0.104). In conclusion, CTCs are detectable in about 33% of pts with asymptomatic monoclonal gammopathies, both in MGUS (in 17%) and more frequently in SMM (in 42%) pts. Their presence is associated with a trend towards increased risk of progression to symptomatic disease for SMM, but needs longer follow up to identify the role of CTCs in MGUS and the additive information over available risk stratification tools, which could provide an non-invasive, easy-to-follow longitudinally biomarker.

Age-Based Validation of the Advanced-Stage Hodgkin Lymphoma International Prognostic Index (A-HIPI) in a Real-World Danish Study: Suboptimal Performance in Older Patients

Purpose: Improved predictive tools are desired in classic Hodgkin lymphoma (cHL) to improve prognostication and to better risk stratify patients (pts) for clinical trials. In younger pts who tolerate intensive therapies, focus has been on limiting late treatment toxicity through risk-adapted, PET-guided treatment strategy. In older pts, acute treatment toxicities are limiting factors for optimal disease control. Due to these fundamental differences, predictive tools may perform differently in younger and older pts. In particular, tools developed in younger pts may be suboptimal in older populations and vice versa. The primary objective of this study was to assess the performance of the A-HIPI (development was limited to 18-65 years of age) against the international prognostic score (IPS) for modelling overall survival (OS) and progression-free survival (PFS) in younger and older pts with cHL. Methods: This study utilized data from the population-based, nationwide Danish National Lymphoma registry. Pts with advanced-stage cHL (Ann Arbor stage III-IV or IIB with extra nodal disease) were included and categorized by age in two groups: ages ≤65 years vs. >65 years. In the primary analysis, all pts regardless of therapy were included. A sensitivity analysis restricting to pts starting on BEACOPP or ABVD was performed (Only ABVD in the >65 cohort). Concordance index (C-index) and calibration were used to assess model performance and generalizability. Calibration was visualized using calibration plots and quantified by calibration in the large (CITL) and calibration slope (CS) at 5-years post diagnosis. Results: A total of 893 advanced-stage HL pts fulfilled the inclusion criteria (634 in the ≤65 cohort and 259 in the >65 cohort). The 5-year OS and PFS in the >65-year cohort were 44% (Confidence intervals (CI); 37-51%) and 35% (CI; 30-42%), respectively. Fifty-six pts in the >65 cohort were classified as low-intermediate-risk (IPS; 1-2), 128 intermediate-risk (IPS; 3-4), and 75 high-risk (IPS; 5-7). For the ≤65 cohort, the 5-year OS and PFS was 88% (CI; 85-90%) and 76% (CI; 73-80%), respectively. Twenty-three pts were classified as low-risk (IPS; 0), 244 low-intermediate-risk, 286 intermediate-risk, and 81 high-risk. The A-HIPI had a C-index of 0.74 and 0.63 for OS and PFS, respectively in the ≤65 years cohort vs. 0.65 and 0.64 for OS and PFS, respectively, in the >65 cohort. The IPS had a C-index in the ≤65 cohort of 0.66 and 0.60 for OS and PFS, respectively, vs. 0.58 and 0.59 for OS and PFS, respectively, in the >65 cohort (i.e., the IPS performed better in the ≤65 cohort in terms of OS and PFS but was inferior to the A-HIPI). When restricting to pts treated with ABVD or BEACOPP, the A-HIPI C-index in the >65 cohort (116 pts) were reduced to 0.55 for OS and 0.54 for PFS. For the ≤65 cohort (595 pts), the A-HIPI C-index was stable at 0.75 and 0.62 for OS and PFS, respectively. In terms of A-HIPI calibration in the >65 cohort, CITL and CS were -0.78 and 0.39 for OS vs. -0.98 and 0.80 for PFS. In the ≤65 cohort, CITL and CS were -0.06 and 0.99 for OS vs. 0.21 and 1.18 for PFS. Visual inspection of the calibration plot (Figure 1) for the >65 cohort showed that the A-HIPI underestimated the observed proportion for both OS and PFS (i.e., the observed events were higher than the predicted). Calibration plot for the ≤65 cohort (Figure 2) indicated that the A-HIPI accurately modelled the observed proportion for both OS and PFS (i.e., the predicted probability was consistent with the observed proportion). Conclusion: The newly developed A-HIPI was validated in a large population-based cohort of Danish pts with advanced-stage cHL. Performance of the A-HIPI was high in the ≤65 cohort and superior to the IPS for OS prediction. Calibration of A-HIPI was excellent in pts ages ≤65 years. However, A-HIPI performed significantly worse among pts >65 years and attained poor performance in pts receiving ABVD or BEACOPP, which is not surprising since patients older than 65 were not included in the development. This study emphasizes the importance of further efforts to develop or update models that apply specifically in older individuals. The inclusion of additional variables reflecting comorbidities and pts fitness into a prognostic model may be necessary to effectively deliver accurate prognoses and risk assessments for the older pt.

Real-World Experience with RTOG 0227 Induction for First Line Therapy of Primary CNS Lymphoma (PCNSL)

Introduction PCNSL is an aggressive and rare subtype of extranodal non-Hodgkin Lymphoma affecting the brain, spinal cord, cerebrospinal fluid (CSF), leptomeninges and/or vitreoretinal components. While there have been trials comparing outcomes of consolidation treatment with whole brain radiation therapy (WBRT) versus (vs) autologous hematopoietic cell transplantation (auto-HCT) following different induction regimens in PCNSL, the optimal induction regimen to pair with these forms of consolidation remains controversial. Our group adopted a modified version of the RTOG 0227 induction as our standard PCNSL induction in 2017. This regimen includes 5 cycles of Methotrexate (MTX) at 3.5 g/m 2 and Rituximab (R) at 375-500 mg/m 2, and Temozolomide (TMZ) on cycles 2 and 4. Based on the published phase 2 trial of 53 patients (pts), the regimen is significantly less toxic than more aggressive induction regimens such as MATRiX, especially in older pts or those with comorbidities. We evaluated our real-world outcomes in PCNSL pts treated with RTOG 0227 induction followed by consolidation with either WBRT/TMZ or auto-HCT, at a single academic university hospital. Methods We identified newly diagnosed PCNSL pts treated at a single academic university hospital between 2017 and 2023. Electronic medical records were retrospectively reviewed to collect data including demographics, clinicopathological features, treatment details, response rates, long-term follow up, disease recurrence, and survival. The IELSG prognostic index tool was used for risk assessment. All pts received induction regimen consisting of R (dose between 375- 500 mg/m 2) and 3.5 g/m 2 of MTX with leucovorin on weeks 1, 3, 5, 7 and 9 along with TMZ daily for 5 days on weeks 4 and 8, followed by consolidation with either WBRT/TMZ or auto-HCT. In WBRT cohort, maintenance TMZ was given at 200mg/m 2 daily for 5 days every 28 days, for total of 10 cycles, and dose was reduced if side effects developed. Objective response rate (ORR) and complete response rate (CRR) after induction chemotherapy were calculated. Overall survival (OS) and progression free survival (PFS) at 2 years were estimated with the Kaplan-Meir method (using GraphPad Prism 9.3.1) and compared between the WBRT and auto-HCT cohorts, using the log-rank test. Results A total of 29 PCNSL pts were included in the study. Patient and disease characteristics for the entire cohort, as well as pts treated with WBRT vs auto-HCT consolidation, are shown on the Table. On average (avg), pts received 4 cycles of MTX and 8 cycles of TMZ. Nine (31%) pts developed acute kidney injury and 1 (3.4%) developed transaminitis from MTX. The avg total cumulative TMZ dose was 5913 mg/m 2 and 8 (27.5%) pts required TMZ dose reduction. Treatment related mortality (TRM) following induction was 0%. Eight (27.5%) pts had complete response, 19 (65.5%) had partial response, 1 (3.5%) had stable disease and 1 (3.5%) had disease progression. ORR was 93.1% and CRR was 27.5%. Eighteen (62%) pts received WBRT/TMZ consolidation, while 11 (38%) received auto-HCT consolidation. Median dose of WBRT administered was 36 Gy (23.4 to 36 Gy). Thirteen (72.2%) pts received 36 Gy in 30 fractions (fx) of 1.2 Gy BID, 4 (22.2%) pts received 23.4 Gy in 13 fx of 1.8 Gy OD, and 1 (5.5%) pt received 30.6 Gy in 17 fx of 1.8 Gy OD. Most common conditioning regimen prior to auto-HCT was carmustine/thiotepa (BCNU/TT). With a median follow up of 36 months, 4 (22.2%) pts in WBRT cohort and 1 (9.1%) in auto-HCT cohort had disease recurrence. Two-year PFS was 83% overall, 81% for the WBRT pts and 87% for the auto-HCT pts, with a p value of 0.65 for log-rank comparison of PFS for the WBRT vs auto-HCT pts. Two-year OS was 96% for the entire cohort, 94% for the WBRT pts and 100% for the auto-HCT pts, with a p value of 0.27 for log-rank comparison of OS for the WBRT vs auto-HCT pts. Conclusion In this real-world cohort of PCNSL pts not treated as part of a clinical trial, we observed excellent outcomes using the modified RTOG 0227 induction regimen. PFS and OS at 2 yrs in our cohort exceeds those reported with any prospective clinical trial to date, and with zero TRM to date. This data indicates that the modified RTOG 0227 induction with either WBRT or auto-HCT consolidation represents a very tolerable and highly effective option for first line therapy of PCNSL, for both younger and older pts.

ELN Criteria for Cytoreduction Start Identify Patients with Polycythemia Vera at Higher Thrombotic Risk

Introduction Recently, the European Leukemia Net (ELN) recommended cytoreduction in patients (pts) with Polycythemia Vera (PV) at low risk (LR) (age <60 yrs & no previous thromboses) but carrying additional criteria for therapy start (CTS) ( Marchetti M et al, Lancet Haematol 2022). Little is known about: 1] efficacy of hydroxyurea (HU) in LR pts, high risk due to age >60 yrs (HR-AGE) or high risk due to previous thrombosis regardless of age (HR-THRO); 2] impact of CTS on thrombotic risk. Aims In a large cohort of HU-treated PV pts, we investigated if thrombotic risk was influenced by: 1] conventional risk factors for thrombosis; 2] ELN-defined complete response (CR) at 12 mos; 3] presence of CTS. Methods After IRB approval, data of 961 WHO2016-defined PV pts were retrospectively collected by 21 Hematology Centers. In April 2023, an update was performed in 10 participating Centers with specific focus on CTS at diagnosis and HU start; 504 HU-treated pts resulted eligible for this analysis. Therapy was at discretion of the treating hematologist. Pts were followed until death or data cut-off date. CTS evaluated for association with thrombosis included: persistent/progressive leukocytosis (100% increase if white blood cells (WBC) <10 x10 9/L or 50% increase if WBC>10 or WBC>15 at diagnosis and HU start); extreme persistent thrombocytosis (>1000 x10 9/L platelets (PLT) at diagnosis and HU start); progressive splenomegaly (increase of >5 cm from diagnosis); inadequate hematocrit (Hct) control (>6 PHL/yr; HCT >53% at diagnosis and HU start; PHL intolerance); uncontrolled cardiovascular risk factors (CVRF). Symptoms were present as the only ELN criterion in 40 patients, of whom none had thrombosis; therefore, they were not included in the analysis. Results 504 pts received HU: 81 pts were at LR and 423 (83.9%) were at HR (HR-AGE, no. 290, 57.5%; HR-THRO, no. 133, 26.4%). Median time on HU was 11.6 yrs (0.1-23.1). During HU, 53 pts had 69 thromboses (35 arterial) for an incidence rate of thrombosis (IR-thro) of 1.5 %p-y, comparably in LR and HR ( Table 1). Notably, IR-thro was equal in LR and HR-AGE (p=0.94), but significantly higher in HR-THRO pts (p=0.005 vs LR and p=0.009 vs HR-AGE). At 12 months, CR was achieved by 8.2%, 23% and 25% of LR, HR-AGE and HR-THRO pts, respectively (LR vs HR-AGE and HR-THRO, p<0.001 and p=0.003). Thrombosis-free survival (TFS) by landmark analysis at 12 months was significantly better in CR pts (p=0.01). Specifically, best TFS was observed in LR and HR-AGE pts with CR, while HR-THRO pts without CR had the worst TFR (p=0.009). CTS were observed in 255 (50.6%) pts: 48 LR (59.3%), 139 HR-AGE (47.9%) and 68 HR-THRO (51.1%). In the remaining LR pts, HU was triggered by mild thrombocytosis (<1000 x10 9/L) and/or mild leukocytosis (<15 x10 9/L) and/or mild splenomegaly (<5 cm from costal margin) and/or persistent systemic symptoms. CTS were associated to significantly increased of IR-thro in the overall cohort (p<0.001), in LR pts (p=0.04), in HR-AGE pts (p=0.02) and in HR-THRO pts (p=0.03) ( Table 1) . The impact of CTS was confirmed in the overall cohort both for arterial (1.30 vs 0.44 %p-y, p=0.01) and venous thrombosis (1.37 vs 0.44 %p-y, p=0.007). TFS at 5 yrs was 87% and 95% in pts with or without CTS (p<0.001) ( Fig.1a). In presence of CTS, TFS of LR and HR-AGE pts were comparable to HR-THRO pts without CTS ( Fig. 1b). In multivariate Cox analysis considering age>60 yrs, previous thrombosis, CTS, and CR to HU at 12 months, CTS and previous thrombosis remained associated with thrombotic risk (HR: 2.7, 95% CI: 1.4-5, p =0.002; HR: 2.4, 95% CI: 1.4-4.2, p =0.001). Finally, in 59 additional LR pts untreated with HU, IR-thro was 0.78 in absence of CTS, and 1.57 %p-y in presence of such criteria. Conclusions Albeit retrospective, this study shows for the first time that ELN criteria for therapy start including splenomegaly, leukocytosis, thrombocytosis, uncontrolled Hct and CVRF, identified an increased risk phenotype either in LR and HR pts treated with HU. This was confirmed also in HU-untreated pts. Also, lack of CR at 12 months was detrimental on TFS particularly in HR-THRO pts, and less significantly than CTS. These findings, that complement data from the Majic-PV trial ( Harrison CN et al, J Clin Oncol 2023), dictate better management of HU therapy, and call for greater attention to CTS and their integration into prognostic models that go beyond the two categories related only to age and thrombotic history.

Impact of Cytoreductive Drugs upon Outcomes in a Contemporary Cohort of Adolescent and Young Adults with Essential Thrombocythemia and Polycythemia Vera

Introduction Essential thrombocythemia (ET) and polycythemia vera (PV) are well described in adolescent and young adults (AYA) patients (pts); the most prevalent complications are thrombotic events, but progression to myelofibrosis (MF) is also associated with significant morbidity and mortality and this risk is time-dependent. Here we investigated the impact of cytoreductive drugs on outcomes in a well-defined cohort of AYA pts. Method and objectives Patients with a diagnosis (Dx) of ET or PV established at less than 25 years (yrs) of age and having known driver mutation status were included from a collaborative group of centers within the EHA MPN special working group. Patients were classified by the first cytoreductive treatment they received or no cytoreduction (NoCYTO). Main endpoints were thrombosis free survival (TFS) and, for those who received a minimum of 2 years of treatment, myelofibrosis free survival (MFS). Kaplan-Meier and log-rank tests were used to compare groups. Results Overall we included 348 pts (278 ET, 70 PV) with median age 20 yrs at Dx (IQR: 18-23). Median age at Dx for ET was 21 yrs (18-23) and for PV 20 yrs (16-23). 249 pts were female (216 ET, 33 PV). Median follow-up was 9 yrs (4-15). Overall, 237/348 (68%) started a cytoreductive therapy. First treatment was hydroxycarbamide (HU) in 126 pts (100 ET, 26 PV), IFN in 55 pts (33 ET, 22 PV), anagrelide (ANA) in 52 pts (51 ET, 1 PV) and other in 4 pts (1 ET, 3 PV). 111 pts (32 %) did not receive cytoreduction (93 ET, 18 PV) deemed NoCYTO. According to ELN risk group at Dx, 39/43 pts (26 ET, 13 PV) receiving a cytoreductive drug were high-risk and 197/304 pts (159 ET, 38 PV) were low-risk. Reason for treatment initiation was thrombotic event in 32 pts (24 ET, 8 PV), platelets >1000x10 9/L in 96 pts (87 ET, 9 PV), MPN-related symptoms 12 pts (7 ET, 5 PV), and other/unknown for 97 pts (67 ET, 30 PV). Ten year TFS was 87% (95%CI: 82-91%) overall, 87% (82-92%) for ET and 86% (77-96%) for PV. In multivariate analysis, elevated WBC (>11x10 9/L) was associated with higher thrombosis risk (HR: 2.8, 95%CI: 1.2-6.2, p=0.01) and splenomegaly with a lower risk (HR: 0.2, 95%CI: 0.1-0.9, p=0.04). In the ELN low-risk group, 10yrs TFS was 82% (73-90%) for HU, 84% (70-98%) for IFN, 93% (84-100%) for ANA and 94% (88-100%) for noCYTO, suggesting no benefit for cytoreduction, p=0.04. For high-risk patients, 10yrs TFS was 78% (56-100%) for HU, 67% (35-98%) for IFN, and 86% (59-100%) for ANA, p=0.689 (Fig 1A). Ten year MFS was 95% (92-98%) overall, 95% (91-98%) for ET, 93% (85-100%) for PV. On multivariate analysis, CALR mutation (HR: 6.0, 95%CI: 2.3-16.1, p<0.05) and interestingly thrombotic history at Dx (HR 3.8, 95%CI: 1.3-11, p=0.02) were associated with increased risk of MF progression overall. For ET: CALR mutation (HR 4.1, 95%CI: 1.6-10.5, p <0.05) and splenomegaly (HR: 2.9, 95% CI: 1.1-7.7, p=0.03) were associated with MF progression, but only CALR mutation was significant on multivariate analysis (HR: 4.2, 95% CI: 1.6-11.6, p<0.05). For PV, we did not identify risk factors associated with MF progression. Finally, we investigated the impact of cytoreductive therapy on MF progression. Overall, 10yrs and 20yrs MFS for IFN was 100%, for HU 10yrs and 20yrs MFS were 93% (86-99%) and 74% (57-92%), for ANA 10yrs and 20yrs MFS were 92% (82-100%) and 73% (40-100%), and for NoCYTO patients 10yrs and 20yrs MFS were 94% (88-100%) and 74% (47-100%), respectively (Fig 1b). Log-rank test comparing IFN vs. other management (HU, ANA or NoCYTO) was significantly in favour of IFN (p=0.046). Finally, during the follow-up there was only one MDS-progression and four deaths (1 of GVHD following HSCT 34 yrs after Dx, 1 of CMV disease 15 yrs after Dx, 2 of unknown cause, 4 yrs and 41 yrs after Dx). Discussion This study is the largest of its kind in contemporary young ET and PV patients focusing on specifically upon the impact of treatment. We demonstrate that early initiation of cytoreduction in low-risk patients does not impact TFS and that the choice of drug does not impact TFS in high-risk patients. In addition, importantly our data demonstrate that IFN specifically compared to other cytoreductive agents yields significantly better MFS compared to other treatments. These results support the use of IFN as a currently available disease-modifying agent to improve long-term MFS and also warrant reconsideration of earlier treatment in patients with ET and PV with IFN to improve MFS potentially as a primary aim.

The Genomic Landscape and Its Clinical Implication in NPM1-Mutated AML Patients: A Study within the AMLSG 09-09 Clinical Trial

Background: Mutations in the Nucleophosmin 1 gene ( NPM1 mut ) represent one of the most common genetic lesions in acute myeloid leukemia (AML).Based on its characteristic clinico-pathologic features, NPM1 mutAML has been recognized as a distinct entity among the category “AML with recurrent genetic abnormalities”. According to the ELN 2022 genetic risk-stratification, NPM1 mut AML, in the absence of FLT3-ITD mutation, is associated with a favorable prognosis. However, a significant proportion of these patients (pts) relapse after intensive therapy suggesting that other co-mutations may have an impact on outcome. Aims: To comprehensively characterize the genomic landscape and leukemogenic trajectoriesin a large cohort of NPM1 mut AML pts and to investigate its prognostic and predictive impact on outcome. Methods: Targeted DNA sequencing (mean read depth: 1817) on the entire coding region of 263 genes was performed in 568 NPM1 mut AML pts (median age: 58.7 years; 18-60 years, n=317; >60 years, n=251). All pts were enrolled in the randomized open-label Phase 3 AMLSG 09-09 trial [NCT00893399; Döhner H et al. Lancet Haematol 2023]. In this trial, pts were assigned to intensive chemotherapy plus all- trans retinoic acid with or without gemtuzumab ozogamicin; none of the pts received midostaurin. Results: In total n=3,058 variants (variant allele frequency of ≥1%) were identified in 195/263 genes. The median number of co-mutations was 3 (range 0-11). The most common co-mutated genes were DNMT3A (49.5%), FLT3-TKD (42.8%) PTPN11 (24.8%), NRAS (22.7%) TET2 (21.7%), IDH2 (21.3%), IDH1 (18%), and FLT3-ITD (17.3%). DNMT3AR882 hotspot mutations occurred more frequently in younger pts (36.6% vs 17.1%), while there was no difference for DNMT3AnonR882 mutations between the two age groups (21.8% and 21.9%). An age-dependent difference was also identified for mutations in myelodysplasia-related genes ( ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2) as defined by the ICC, occurring with a higher incidence in older pts (30.3% vs 12.3% in younger pts). Analyzing the mutational pattern of co-mutations, we found statistically significant tertiary gene-gene interactions: e.g., NPM1- NFE2- STAG2 (p<.001), NPM1- IDH2- SRSF2 (p<.001), NPM1- CEBPA- TET2 (p<.001), NPM1- DNMT3AR882- NRAS (p=.002), and NPM1- ASXL1- SRSF2 (p=.004); mutual exclusivities were identified for NPM1- DNMT3AR882- DNMT3AnonR882 (p<.001), NPM1- IDH2- TET2 (p<.001), NPM1- DNMT3AR882- SRSF2 (p<.001), NPM1- IDH1- TET2 (p<.001), and NPM1- FLT3-ITD- KRAS (p<.002). Correlating co-mutation data with outcome, we found that DNMT3AR882 hotspot mutations confer inferior event-free (EFS) and overall survival (OS) only in younger pts (EFS, p<.001 vs p=.11, Figure 1a; OS, p=.003 vs p=.8), whereas DNMT3AnonR882 mutations did not impact prognosis within the two age groups. We also found a negative prognostic impact of IDH1 mutations which was restricted to younger pts (EFS, p=.05), whereas IDH2 mutations were associated with superior EFS in older pts (p=.04) and superior OS in both groups (p=.05 and p=.03). Of note, co-mutations occurring in one or more of the myelodysplasia-related genes did not impact EFS or OS (Figure 1b). In multivariable analysis (all pts) including age, WBC, LDH, allogeneic transplantation in CR1, and mutations with an incidence of at least 3% as covariables, age (HR,1.03; p<.001), DNMT3AR882 (HR, 1.86; p<.001), FLT3-ITD (HR, 1.54; p=.012), IDH1 (HR, 1.48; p=.009), MYC (HR, 1.83; p=.032), and WT1 (HR, 1.73; p=.012), were associated with an inferior EFS, while SMC3 mutation showed favorable EFS (HR, 0.44; p=.019). To further study the leukemogenic trajectories, we used an oncogenetic tree modeling algorithm, which yielded a tree with several main branches including DNMT3AR882, DNMT3AnonR882, FLT3-TKD , IDH1, IDH2, PTPN11, and TET2. These mutations might represent initiating events which predispose to additional events with further distinct branches. Conclusions: Our study provides comprehensive data on the genomic landscape and its clinical impact in pts with NPM1mut AML fit for intensive chemotherapy. The co-mutational pattern clearly differs between younger and older NPM1 mutAML pts. Using this large dataset allowed the identification of secondary and tertiary gene-gene interactions with significant impact on outcome. Further data analysis is ongoing and will be presented at the meeting.

Engraftment Syndrome during Autologous Stem Cell Transplant in Hodgkin Lymphoma Patients Treated with Checkpoint Inhibitors: A Multi-Center Retrospective Analysis

Background: Engraftment Syndrome (ES) has traditionally been considered a rare complication of autologous stem cell transplant (ASCT) in patients (pts) with relapsed/refractory Hodgkin lymphoma (HL). There have been several attempts to define ES, but diagnostic criteria have not been unified. Diagnosis of ES is considered in pts developing non-infectious fever coinciding with neutrophil recovery, typically with at least one other inflammatory finding such as pulmonary infiltrates, diarrhea, rash, or transaminitis. The proposed pathogenesis of ES involves production of inflammatory cytokines by activated leukocytes, which may ultimately be suppressed by treatment with systemic corticosteroids. Recent clinical trials in HL have suggested that exposure to immune checkpoint inhibitors (ICI) before ASCT may increase the risk of developing ES. Methods: We conducted a retrospective study at several U.S. academic institutions to better characterize ES in HL pts undergoing ASCT in the era of ICIs. Eligibility criteria included age > 18, diagnosis with relapsed/refractory HL, treatment with an ICI as part of pre-transplant salvage therapy, and ASCT between January 1, 2015 and February 1, 2023. Inflammatory symptoms and timing of symptom onset were assessed by medical record review. ES was defined by Maiolino criteria (Maiolino et al. Bone Marrow Transpl, 2003) as at least two symptoms within 48 hours of engraftment not attributable to other causes, including fever in combination with diarrhea, rash, or pulmonary infiltrates. We assessed the incidence of inflammatory symptoms and ES, and evaluated potential risk factors associated with developing these symptoms. Results: A total of 53 pts with HL were identified. Pts had a median age of 33 (range 19-72), 49% were female, 75% White, and 11% Black. The majority (87%) had the nodular sclerosis subtype and were treated with ABVD (68%) or BV-AVD (23%) in the frontline setting, with a majority achieving CR (53%) or PR (15%). At relapse, 57% received BV-nivolumab and 13% received pembrolizumab-GVD. Overall, 70% received nivolumab prior to ASCT, and 30% received pembrolizumab. None of the pts in this reported cohort were treated on a clinical trial. On pre-ASCT PET, 77% achieved CR, after which all were mobilized with GCSF, with 42% also receiving plerixafor. An average of 9.57 million CD34+ cells/kg (median 7.28) were infused on day 0. Pts were hospitalized for an average of 20 days (range 2-99). All pts successfully engrafted, with a median time-to-engraftment (ANC 500) and time-to-platelet-recovery of 10 days. A majority of pts (70%) experienced at least one non-infectious inflammatory finding at engraftment, but only 21% met Maiolino criteria for ES. The frequency of non-infectious inflammatory findings is described in Figure 1. Of the 11 pts clinically diagnosed with ES by the treating physician, 7 received high-dose steroids for treatment, for a median of 8 days. There were no deaths attributed to ES. Following transplant, 91% achieved CR, with 5 pts experiencing progressive disease. Over a median follow-up of 15 months (range 1-57 months), 5 pts relapsed and 4 died. The outcomes of the entire cohort were excellent, with 2-year PFS of 78% (95% CI: 67-90%) and 2-year OS of 90% (95% CI 81-100%). There were no differences in survival based on ES status. We explored potential risk factors for developing ES, including number of cells infused, duration of ICI exposure/timing in relation to ASCT, and plerixafor use, but none achieved statistical significance. Conclusions: In this non-trial cohort of HL pts receiving ICI-based salvage before transplant, a minority of patients (21%) developed ES by traditional diagnostic criteria, but the majority of pts (70%) developed non-infectious inflammatory findings in the peri-engraftment period. Most pts experiencing ES were treated with steroids and had favorable outcomes similar to those without ES. With increasing use of ICI-based regimens in the pre-transplant setting, further studies with larger patient cohorts are needed to better characterize this entity, develop unified reporting and diagnostic criteria, identify pts at high risk for severe ES, and develop effective prophylactic and therapeutic strategies.

Biochemical and Metabolomic Analysis of Glycolytic Activity in Red Blood Cells from Low-Risk Myelodysplastic Syndromes (LR-MDS) Patients and in-Vitro Effect of the Pyruvate Kinase Activator AG-946

Background: Anemia is the most common cytopenia occurring in 80%-85% of patients (pts) with LR-MDS and therapeutic strategies remain limited. Beyond defective maturation, preliminary data has shown decreased glycolytic activity in MDS-RBCs. Glycolytic pathway is the prominent metabolic cascade in RBCs and is currently targeted with PK activators in clinical trials of congenital anaemias which are also marked by ineffective erythropoiesis like MDS. AG946 is an investigational, potent activator of PK with potential to enhance RBC functionality and survival by increasing glycolysis. Aim: Evaluate enzymatic activity of the glycolytic pathway in pts with anemia due to LR-MDS and in-vitro effect of pyruvate kinase (PK) activator (AG946) in RBCs cultures of LR-MDS pts. Methods In part A, 66 anemic pts (i.e., Hb<11 g/dL) diagnosed with MDS according to WHO 2022 were enrolled in the study and sampled for peripheral blood >4 weeks after the last RBC unit to reduce blood donor contamination. The determination of activities of RBC enzymes hexokinase (HK) and PK (the initial and terminal steps of glycolytic pathway), and of ATP levels was performed by standard spectrophotometric method according to Beutler et al, 1984. 2,3DPG levels were tested by (2,3-BPG) ELISA kit (ElisaGenie, IE). In part B, purified RBC or whole blood of 10 LRMDS pts and 5 healthy controls (HC) were incubated for 6 and 24 h at 37°C in presence or absence of AG946 in phosphate-buffered saline containing 1% glucose, 170 mg/L adenine, and 5.25 g/L mannitol (AGAM, pH 7.40). RBC were incubated with 1, 5 and 50 uM of AG946 for up to 24 h, at 37°C. After 6 and 24 h, enzymatic activities (HK, PK) and ATP levels were measured. Additionally, metabolomic analysis was performed by LC-MS on extracts from blood samples for each condition. Results Part A: Pts were mainly elderly males (median age 80yr, range 58-92), and mostly belonged to IPSS-R low (78%) and very low/low groups (85%). PK activity (median 13.7 IU/gHb, 7.5-35.9) was reduced in 35% of cases and HK activity (median 2.3 IU/gHb, 0.8-8.1) was increased in 91%, resulting in an abnormally reduced PK/HK ratio in majority of pts (95%). Notably, ATP levels (median 3.4 umol/gHb, 1.3-6.5) were also reduced in 33/56 tested patients (59%), whilst 2,3DPG levels were close to the upper limit of the normal range (median 389 nmol/gHb, 318-639). Conclusions: Our data demonstrates decreased glycolytic activity in a large cohort of anemic pts with LR-MDS versus HC, with reduced PK activity in 1/3 of cases, decreased PK/HK ratio in nearly all subjects, and reduced ATP in 2/3 of pts. Furthermore, in vitro incubation with AG946 led to an increase in PK activity and PK/HK ratio and stable ATP levels in RBCs of LR-MDS pts across all WHO classifications. Metabolomic analysis confirmed an altered RBC-metabolic status of MDS versus HC at baseline with possible modulation of glycolysis by AG946, further supporting a potential therapeutic role of PK Activation with AG946 in LR-MDS.

Comparisons of telemedicine and in-person visits: Utilization, oncology services and satisfaction among patients with breast cancer.

517 Background: Since the COVID-19 pandemic, telemedicine utilization has expanded in oncology settings and helps facilitate access to oncology services for breast cancer patients (pts). However, it remains unclear what types of oncology services are received via telemedicine and whether receipts of these services differ between telemedicine and in-person visits. Methods: We conducted a cross-sectional study surveying breast cancer pts in the Chicago Multiethnic Epidemiologic Breast Cancer Cohort from July-September 2022. Telemedicine (i.e., audio call [AC], video conference [VC], and both) and in-person visits were measured as having had a telemedicine and in-person visit with a provider in the past 12 months. Types of oncology services included treatment consultation, management of side effects/symptoms, review of lab, screening or pathology results, cancer genetic counseling, and clinical trial follow-up. We assessed common side effects/symptoms discussed during telemedicine or in-person visits. Satisfaction was assessed using a 5-point Likert scale. McNemar’s test was used to evaluate paired data on types of oncology services between telemedicine and in-person visits. Results: Of 1,160 pts (mean age 61.8 years, SD 12.0), 72.8% were White, followed by 19.7% Black, 4.5% Asian, and 3.0% Hispanic; 70.8% were privately insured and 23.0% on Medicaid/Medicare; 81.0% had stage I-III disease. Overall, 36.0% used telemedicine (of these, 65.0% VC, 22.7% AC, and 12.2% both) and 92.4% had in-person visits. Telemedicine users reported 93.9% and 95.5% of somewhat-to-extreme satisfaction with AC and VC, respectively, and 61.8% were likely or very likely to continue using telemedicine. In pts having both telemedicine and in-person visits, we observed differences between these visits in management of side effects/symptoms (15 vs. 54, p<.001), review of lab, screening or pathology results (26 vs. 90, p<.001), or trial follow-up (4 vs. 12, p=.046). However, there were no differences in treatment consultation (45 vs. 55, p=.317) or cancer genetic counseling (11 vs. 19, p=.144). Furthermore, BC pts who had in-person visits reported higher percentages of discussion of fatigue (50.3% vs. 41.1%), hot flashes (45.6% vs. 33.9%), lymphedema (26.0% vs. 19.6%), chemotherapy-induced neuropathy (24.9% vs. 19.5%), or nausea/vomiting (16.0% vs. 8.9%) than those used telemedicine; whereas a higher proportion of pts having discussed depressive symptoms via telemedicine than in-person visits (37.5% vs. 29.6%). Conclusions: In this multiethnic cohort of breast cancer pts, telemedicine use was prevalent and achieved high-level satisfaction. Our findings also suggest that both telemedicine and in-person visits are equally likely to include treatment consultation and genetic counseling, and telemedicine may be in greater need among breast cancer pts with mental health challenges.

Prompt Pain Relief: Advanced Practice Provider Led Rapid Access Palliative Radiotherapy Clinic

Patients (pts) commonly present to radiation oncology with painful bone metastases requiring urgent palliative radiotherapy (RT). Unfortunately, the pre-existing scheduling workflow for palliative referrals can be inefficient, causing significant delays before pts are seen by a radiation oncologist (RO). Our institution implemented an alternative workflow, which led to the creation of an advanced practice provider (APP) led Rapid Access Palliative RT Clinic (PRC). We investigated the impact of the PRC in reducing time from referral to consultation for pts in need of palliative RT. In March 2022, we initiated an outpatient APP led PRC focused on the APP driving consultations supervised by the weekly on-call RO. Pts are offered a variety of options for consultation such as virtual, in clinic with reserved simulation time, and when appropriate virtual simulation, using diagnostic imaging for RT planning, and same day treatment requiring only one visit to the department. The clinic provides a point of contact that fosters multidisciplinary interaction and proactive continuity of care and follow up. Following institutional review board approval, pts who received palliative RT for painful bone metastases from June 2021 to December 2022 were retrospectively reviewed. Data was collected with respect to when the referral was placed for palliative RT and when the pts was seen for consultation by a provider. The cohort of pts seen between June 2022 and December 2022 represented the PRC cohort. A comparison cohort of pts treated between June 2021 and December 2021 represented the pre-PRC cohort. Unpaired T-test was used to analyze time from referral to consultation (TTC) between groups. P value < 0.05 was considered statistically significant. During the pre-PRC period, 91 patients were treated, including 12 inpatients and 79 outpatients, while during the PRC period, 101 pts were treated, including 7 inpatients and 94 outpatients. The median dose was 8 Gy in 1 fraction for both cohorts. During the PRC period, there was a 19% increase in outpatients treated for bone metastases. Restricted to just outpatients, the average TTC was 10.4 days (SD 10.2) for pre-PRC cohort versus 6.3 days (SD 6.6) for the PRC cohort, which was statistically significant (p = 0.003). This was a 39% reduction in TTC. During the PRC period, 17 pts were not seen in the APP led PRC while 77 were seen in the PRC. The most common reason was an erroneous referral for curative intent treatment instead of palliative bone treatment. During the PRC period, those pts seen in the APP led PRC had an average TTC of 5.1 days (SD 4.6) versus 11.5 days (SD 10.64) for those not seen in the PRC (p = 0.03) with a 56% reduction in TTC. The APP led PRC clinic significantly decreased time from referral to consultation for pts requiring urgent palliative RT for painful bone metastases. Further research is underway to determine if the PRC increases referrals, patients treated, patient satisfaction, and the impact on staffing RO.

Abstract PR05: Changing the radiation and immune-oncology paradigm in patients with head and neck squamous cell carcinoma (HNSCC) with the radioenhancer NBTXR3: From bench to bedside

Abstract Purpose/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, yet most patients (pts) ultimately develop ICI resistance. Overcoming this resistance is a major clinical challenge. Radiation therapy (RT) has emerged as a promising combination with ICIs since in some settings it may produce an immunomodulatory effect. NBTXR3, a novel radioenhancer composed of functionalized hafnium oxide nanoparticles, is administered by a single intratumoral injection. NBTXR3 increases RT energy deposition inside tumor cells, subsequent tumor cell death, and tumor antigen release and thus in combination with ICI may overcome resistance. Materials/Methods: Pre-Clinical: Abscopal assays were conducted in immunocompetent mice. Anti-PD-1 sensitive or resistant lung tumor cell lines were injected in both legs. Intratumoral NBTXR3 injection (or vehicle) followed by RT was performed in right leg (primary) tumors only. Some mice also received anti-PD-1 injections alone or in combination with anti-LAG3 and anti-TIGIT. Tumor growth was monitored, and immune cell infiltrates analyzed by IHC. Clinical: A multicenter phase I trial [NCT01946867] is evaluating NBTXR3/RT in pts with AJCC 8th stage III-IVA or T3, T4 SCC of the oral cavity or oropharynx ineligible to cisplatin. Pts received NBTXR3 at the recommended dose (22% of baseline tumor volume) followed by RT (IMRT 70 Gy in 35 fractions). A multicenter phase I trial [NCT03589339] is evaluating NBTXR3/RT/anti-PD-1 in 3 cohorts of pts with advanced solid tumors eligible for anti-PD-1: 1) Locoregional recurrent or recurrent and metastatic HNSCC, 2) Lung metastases, or 3) Liver metastases. NBTXR3 was administered by intratumoral injection. Stereotactic Body RT (SBRT) was delivered at tumor site-specific doses per standard practice. Results: Pre-clinical studies demonstrated that NBTXR3/RT induces an immune response not observed with RT alone and enhances systemic control. IHC showed significant increase of CD8+ T-cell infiltrates in both NBTXR3/RT-treated and untreated tumors. NBTXR3/RT/anti-PD-1 improved local and systemic control in mice bearing anti-PD-1 resistant tumors, produced long-term memory, and reduced spontaneous lung metastases. NBTXR3/RT/anti-PD-1/anti-LAG3/anti-TIGIT improved tumor control, extended survival and produced a robust long-term memory anti-tumor immune response. Clinically, NBTXR3 intratumoral injection was feasible and safe. Preliminary signs of efficacy observed in pts with locally advanced HNSCC treated with NBTXR3/RT will be presented. Preliminary signs of efficacy were observed in pts treated with NBTXR3/RT/anti-PD-1 including in pts resistant to anti-PD-1, as well as in remote non-irradiated lesions. Responses in pts with HNSCC will be presented. Conclusions: With demonstrated radioenhancement as well as immune system priming, NBTXR3 positions itself to be a paradigm shift catalyst in the treatment of pts with head and neck cancers. These data support further development of NBTXR3/RT alone as well as in combination with anti-PD-1 and/or other ICIs. Citation Format: Colette J. Shen, Christophe Le Tourneau, Zoltán Takacsi-Nagy, Xavier Liem, Jessica Frakes, Jiaxin Niu, Jared Weiss, Jimmy Caudell, Yun Hu, James W. Welsh, Sebastien Paris, Anais Debard, Patricia Said, Pavel Tyan, Tanguy Y. Seiwert, Zsuzsanna Papai, Omar I. Vivar, Leonard A. Farber, Ari Rosenberg. Changing the radiation and immune-oncology paradigm in patients with head and neck squamous cell carcinoma (HNSCC) with the radioenhancer NBTXR3: From bench to bedside [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Innovating through Basic, Clinical, and Translational Research; 2023 Jul 7-8; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2023;29(18_Suppl):Abstract nr PR05.

Neoplasia detection via colonoscopic surveillance among young patients with MSH6 and PMS2-associated Lynch syndrome.

10516 Background: Lynch syndrome (LS) is the most common colorectal cancer (CRC) predisposition syndrome. While patients (pts) with MLH1/ MSH2-associated LS are recommended to start colonoscopy between age 20-25, recent guidelines recommend delaying initiation in pts with MSH6/ PMS2-associated LS to age 30-35. However, data on findings from colonic surveillance in young MSH6/ PMS2-LS pts are limited. Methods: We performed a retrospective review of a multi-institutional cohort of pts with MSH6/ PMS2-associated LS who underwent any colonic surveillance prior to age 50, and assessed corresponding pathology results. Neoplastic lesions were defined as a CRC, adenomas, or non-hyperplastic serrated lesions. Clinicopathologic variables were reported with summary statistics and compared using non-parametric tests at the patient level and among pooled procedures. Results: We identified 285 pts [161(56%) MSH6; 124(44%) PMS2] with history of colonic surveillance prior to age 50. 190 (67%) pts were female, with similar sex distribution among the MSH6 and PMS2 groups. 107 (38%) pts had personal history (hx) of any cancer, 67 (42%) MSH6 and 40 (32%) PMS2, including 58 (20%) with CRC [35(22%) MSH6; 23 (19%) PMS2]. Median age at CRC diagnosis (dx) was 39 and did not differ between groups (41 MSH6 vs. 37 PMS2, p = 0.47) with 16 (5.6%) pts dx prior to age 35. 157 (57%) pts had a family hx of CRC, and there was no difference in the rate of CRC between pts with or without family hx of CRC [50%(n = 25) vs 60%(n = 31), p = 0.33]. Pts underwent a median of 2 colonic surveillance procedures (range 1-12) with 824 total procedures, 806 (98%) colonoscopies and 18 (2%) sigmoidoscopies, with 691 (85%) occurring at an academic/tertiary center. Among the 824 pooled procedures, there were 194 (24%) procedures with neoplastic lesions identified, including 19 (2.3%) with advanced adenomas or advanced serrated lesions and 34 (4.1%) with CRC. Among 247 procedures completed at age &lt; 35, 43 (18%) detected neoplastic lesions, including 4 (1.6%) with advanced adenomas or advanced serrated lesions and 9 (3.6%) with CRCs. Notably, in 123 procedures performed prior to LS diagnosis, 43 (35%) had a neoplastic finding with 28 (23%) showing CRC. These findings did not differ between the MSH6 and PMS2 groups. Conclusions: Among this large, multi-institutional cohort of pts with MSH6/ PMS2-associated LS with history of colonic surveillance performed prior to age 50, colonic neoplasia was found at similar rates in both MSH6 and PMS2-associated LS. 20% of overall pts had CRC, with 48% presenting prior to LS dx. In surveillance procedures performed &lt; age 35, the upper threshold of initiation of colonic surveillance as per NCCN, 18% found a neoplastic finding with 3.6% finding CRC, highlighting the need to optimize the age of colonic surveillance initiation in MSH6/ PMS2-associated LS.

Tebentafusp (tebe) in a real-world cohort of 72 French metastatic uveal melanoma (UM) patients (pts).

e21583 Background: Up to 50% of UM pts will develop metastases with poor overall survival (OS) and limited treatment options. Tebe, a bispecific T-cell engager binding CD3 and the gp100 protein presented by the HLA A*02-01, recently showed a benefit in overall response rate (ORR), progression-free survival (PFS) and OS in HLA A*02-01pos metastatic UM (mUM) pts in the IMCgp100-202 phase III trial. Prior to the EMA approval, French Health Authorities allowed an early access to tebe in May 2021 to UM metastatic pts. We here report our real-world experience with tebe in metastatic UM pts. Methods: Ongoing ambispective cohort of mUM pts treated with tebe in France. Metastases are evaluated according to RECIST 1.1 with assessments every 12 weeks (liver MRI +/- CT-scan). ORR, PFS, OS and toxicities are retrieved. Results: 72 pts started tebe between May 26th 2021 and December 12th 2022 (29 men and 43 women). Median age was 61 yo (32-78). Thirty, 34 and 7 patients underwent enucleation proton beam therapy or brachytherapy, respectively (one pt did not receive local treatment). The median time to first metastasis was 24 months (0-276). Tebe was prescribed in first-line in 46 patients, in second-line or more in 26 patients. Metastatic sites at tebe initiation were liver, lung, skin, bone and muscle in 71, 4, 2, 3 and 2 patients, respectively. Liver was the sole metastatic site in 63/72 patients (87.5%). With a median follow-up of 44 weeks, patients received a median of 36 weeks of tebe. Thirty patients discontinued tebe because of disease progression, two because of poor health status and none for toxicity. Of 60 assessable pts, 33 (55%) pts showed stable disease and 5 (8%) showed partial response as best response according to RECIST 1.1. Median PFS was 28 weeks (confidence interval 95% [CI95%]: 8-56) in the global cohort. OS at 12 months was 74% ([CI95%] = 0.62-0.89) in the global cohort, 73% ([CI95%] = 0.55-0.99) and 74% ([CI95%] = 0.57-0.97) in 1st and 2nd line and more, respectively. To date, 13 pts died. Circulating tumor DNA analyses and monitoring of peripheral blood leukocytes are ongoing and will be available by June 2023. Conclusions: In this ongoing, real-world, cohort of metastatic UM pts, tebe is associated with similar clinical outcomes as in the IMCgp100-202, phase III trial. Translational studies on blood and tumor samples are ongoing to identify predictive biomarkers of clinical benefit to this drug.

Adverse events in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who received FOLFIRINOX in the first line.

e16295 Background: Quality of life is particularly important for patients (pts) with short life expectancy, such as those with metastatic pancreatic ductal adenocarcinoma (mPDAC). While first line (1L) FOLFIRINOX (FFX) is recommended by treatment guidelines for pts with mPDAC and good performance status, the regimen is known to be associated with significant toxicity that impacts quality of life. More than half of pts experience adverse (AEs)—such as nausea and vomiting, diarrhea, fatigue, neuropathy, anemia, thrombocytopenia, and neutropenia—during treatment with FFX. Efforts to reduce AEs have led to the use of modified FFX (mFFX) regimens that utilize lower doses of components of the regimen. Additional evidence on AEs associated with FFX and mFFX in the real world (RW) is needed. We assessed AEs in a RW cohort of mPDAC pts treated with FFX or mFFX in 1L. Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between January 2015 and November 2022 who initiated treatment with FFX or mFFX within 90 days of their diagnosis for metastatic disease (1L) were included in the study. Pts were required to have an available body surface area measurement within 7 days of the index date. mFFX was defined as administration of (i) &lt; 150mg/m2 of irinotecan, or (ii) &lt; 2,720mg/m2 5-FU total during cycle 1. Diarrhea, fatigue, nausea and vomiting, and neuropathy were available in the data as ungraded AEs abstracted from clinician notes. Assessment of hematologic and hepatic AEs were based on observed lab values and were graded according to the Common Terminology Criteria for Adverse Events version 5. Results: Of the 1,326 pts meeting study inclusion criteria and receiving 1L treatment with FFX or mFFX, 1,325 received mFFX and 1 received FFX. The median age at 1L initiation was 65yr (IQR: 58–70), 57% (754 pts) were male, 69% (916 pts) were white, 15% (197 pts) had an ECOG score of 0, 42% (550 pts) had an ECOG score of 1, and 78% (1028 pts) were stage IV at diagnosis. The median number of cycles was 5 (IQR: 3–10) and the median dose intensity per week was 940 mg/m2 for 5-FU, 179 mg/m2 for leucovorin, 38 mg/m2 for oxaliplatin, and 73 mg/m2 for irinotecan. Notable grade 3/4 AEs were: 16.4% neutropenia, 4.4% thrombocytopenia, 5.7% anemia, 4.7% elevated ALT, 4.9% elevated AST, and 10.6% elevated ALP. Of the ungraded AEs reported in clinician notes, 17.3% of pts experienced diarrhea, 10.9% fatigue, 10.9% nausea and vomiting, and 11.9% neuropathy. Conclusions: In a RW cohort of mPDAC pts treated with 1L FFX or mFFX, nearly all were treated with mFFX. The burden of serious AEs for mPDAC pts during 1L treatment with FFX or mFFX was high, with 30% (403 pts) experiencing at least one grade 3/4 AE.

Talazoparib (Tala) in patients (pts) with solid tumors with BRCA1/2 mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

3115 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with solid tumors with BRCA1/2 mut treated with Tala are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 1 mg of Tala orally daily until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response or stable disease (SD) of at least 16+ weeks (wks) duration (SD16+) per RECIST v1.1. The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (alpha 0.10; 82% power). Secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DOR) and SD, and safety. DOR is defined as time from pt’s first documented objective response (OR) to progressive disease (PD). Duration of SD is defined as time from tx start to PD. Results: 28 pts with 16 solid tumors (6/28 pts had lung cancer) with BRCA1 (n=9) , BRCA2 (n=16) , or BRCA1/2 (n=3) mut were enrolled from Dec 2019 to Sept 2021. All pts were included in efficacy analyses. Demographics and outcomes are shown. 1 CR, 9 PR and 6 SD16+ were observed for a DC rate of 57% (1-sided 90% CI: 43% to 100%) and an OR rate of 36% (95% CI: 19% to 56%); the null hypothesis of a 15% DC rate was rejected (p&lt;0.001). 11/16 pts with OR or SD16+ had a BRCA2 mut, 4 had BRCA1 mut, and 1 had both. The pt with a CR (duration of 93 wks) had non-melanoma skin cancer, with BRCA2 and ATM muts, and was microsatellite instability high with 41 muts per megabase. Pts with PR had various solid tumors; 6/9 pts had BRCA2 mut, 2 had BRCA1 mut , 1 had both. Of pts with DC, 11 had tumor types for which PARP inhibitors are not yet FDA approved. Median duration of PR was 20 wks (range, 11-80). 10/16 pts with DC had a co-alteration in the 24 homologous recombination-related genes examined, mainly ATM (3) or ARID1A (2). 13 pts had ≥1 grade 3 tx-related adverse or serious adverse events including: anemia, AST or bilirubin increase, hyponatremia, nausea, vomiting, neutrophil, platelet, or white blood cell decrease. Conclusions: Tala demonstrated antitumor activity in heavily pretreated pts with advanced solid tumors with BRCA1/2 mut. Additional study is warranted to confirm the efficacy of Tala in non-breast, non-ovarian cancer pts with BRCA1/2 mut. Clinical trial information: NCT02693535 . [Table: see text]

Nivolumab plus ipilimumab (N+I) in patients (pts) with ovarian cancer (OC) with BRCA1/2 mutation (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

5548 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with OC with BRCA1/2 mut treated with N+I are reported. Methods: Eligible pts had advanced OC, measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was done in CLIA-certified, CAP-accredited labs. PD-L1 status was not routinely reported. Pts received I at 3 mg/kg every 3 wks for 4 doses with N at 1 mg/kg IV every 3 weeks (wks) for 4 doses. N alone was then continued at 240 mg every 2 wks or 480 mg every 4 wks until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete or partial (PR) response per RECIST v. 1.1, or stable disease of at least 16+ wks duration (SD16+). CA-125 levels were not routinely reported. Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled; otherwise, the cohort is closed. If ≥7 of 28 pts have DC, the null DC rate is rejected. P-value calculated based on 2-stage design. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results: 33 pts with OC and BRCA1 (n=20), BRCA2 (n=10), or both mut (n=3) were enrolled from Sept 2017 to Oct 2019. 6 pts were not evaluable for efficacy analysis; 1 pt was found to be ineligible after enrolling, 5 pts discontinued tx before the post-baseline tumor evaluation due to an adverse or serious adverse event (SAE). Table shows demographics and efficacy outcomes. 6 pts with PR were observed for an OR rate of 22% (95% CI: 9% to 42%) and a DC rate of 27% (90% CI: 13% to 36%); the null hypothesis of a 15% DC rate was not rejected (p=0.17). 3 pts with PR had BRCA1 mut only, 2 pts had BRCA2 mut only and 1 pt had both BRCA1 and BRCA2 mut. Of the 6 pts with PR, 4 had microsatellite (MS) stable (MSS) tumors and MS status was not reported in 2. Of the 4 with MSS, 3 had a tumor mutational burden (TMB) ≤ 10 mutations per megabase and 1 had TMB of 11. 11 pts had at least 1 tx-related SAE, including acute kidney injury, ALT/AST increase, colitis, dehydration, diarrhea, E. coli, electrolyte disorder, fever, nausea/vomiting and pneumonitis. Conclusions: N+I did not meet prespecified criteria to declare a signal of activity in pts with OC and BRCA1/2 mut. However, given 22% of pts had PR (2 with &gt;1 year duration) in this heavily pretreated cohort, additional study may be warranted to further evaluate efficacy. Clinical trial information: NCT02693535 . [Table: see text]

Activity of cabozantinib (CABO) plus durvalumab (DURVA) in patients (pts) with advanced urothelial carcinoma (UC) or non-UC variant histologies (VH) after platinum chemotherapy: Interim results from the phase 2 ARCADIA trial.

4578 Background: Combining multitargeted receptor tyrosine kinase inhibitor (TKI) with checkpoint inhibitors has shown synergistic effect in pts with UC due to the immunomodulatory propriety of VEGFR inhibitors. We investigated if the combination of CABO and DURVA in pts with advanced UC and non-UC histology (VHs) in a phase II study (NCT03824691). Herein the preliminary results of the interim analysis. Methods: Patients affected by UC and VHs recurred or progressed after failure of at least one line of platinum-based chemotherapy for metastatic disease have been treated with CABO 40 mg daily, orally, and are administered DURVA 1500 mg IV, q28 days, until disease progression (PD, by RECIST 1.1) or onset of unacceptable toxicity. Key inclusion criteria were ECOG-PS 0-1 and adequate organ function. Response was evaluated by RECIST criteria v.1.1 every 8 wks. The primary endpoint of the study was OS. Secondary endpoints included safety (CTCAE v.4.03), objective response-rate (ORR), duration of response (DoR), progression-free survival (PFS). The assumption was to detect an improvement in the median OS from ≤6 months (H0) to ≥9 months (H1). Results: Between September 2019 and February 10, 2023, the ARCADIA study enrolled 63 pts: this interim analysis was performed after obtaining at least one post-baseline tumor assessment data from 58 pts. The median follow-up was 23.5 mos (interquartile [IQ] range: 7.7-27.7mos): 27% were female, the median age was 64 yrs (range: 42-81), 20 pts (34%) had a pure/predominant non-UC VH: 9 (45%) a squamous differentiation/sarcomatoid tumor, 5 (25%) an adenocarcinoma, 4 (20%) a small-cell neuroendocrine tumor, 1 (5%) a clear-cell tumor, and 1 a nested VH (5%). Eleven pts (19%) had received ≥2 prior systemic anticancer therapies. In 58 response-evaluable pts, 12 (20%) complete responses (CR) and 11 partial responses (PR) were obtained, the ORR being 39.7% (95%CI: 27.1-53.4) and disease control rate was 69% (95%CI: 55.5-80.5). In the cohort of pts with VH, the ORR was 45% (95%CI: 23.1-68.5). Median PFS was 7.6 mos (95%CI: 4.6-13-6 mos) and median OS was 11.6 (95% CI 6.8-20.3 months). Median exposure of treatment was 4.8 mos; 35 pts (55.5%) of 63 pts had all-grade treatment-related adverse events (AE) and 4 pts (6.3%) reported grade 3 (treatment related) AE with no grade 3-5 events. Dose-reductions of CABO were needed in 25 pts (39%). No treatment-related deaths were reported. Conclusions: CABO in combination with DURVA showed promising preliminary activity with a manageable safety profile in pts with advanced UC and in non-UC VH after previous chemotherapy exposure, deserving further evaluation of the combination that is ongoing with ARCADIA and other clinical trials. More mature results with longer follow-up will be presented. Clinical trial information: NCT03824691 .

Blood eosinophils as prognostic biomarkers for advanced urothelial carcinoma in patients treated with avelumab: First results of the MALVA study (Meet-URO 25).

e16570 Background: Platinum-based chemotherapies (CTs) represent the standard first-line treatment of advanced urothelial carcinoma (aUC). However, the development of resistance and toxicities to these regimens is responsible for poor progression-free survival (PFS) and overall survival (OS). Maintenance treatment with the programmed death-ligand 1 (PD-L1) inhibitor avelumab after initial response to CT improved significantly OS. Despite the survival advantage, only a limited percentage of patients (pts) benefits from immunotherapy. Therefore, prognostic/predictive factors for immunotherapy are needed. Studies carried out on small cohorts of pts with melanoma, renal cell cancer or lung carcinoma proved that eosinophil count or variations could be used as prognostic factors during immunotherapy. Thus, the aim of the present study is to evaluate eosinophil levels as potential biomarker for outcome among aUC pts enrolled in the MALVA (Maintenance with AVeLumAb in advanced urothelial neoplasms in response to first-line CT: an observational retrospective and prospective study) ongoing study (Meet-URO 25). Methods: The MALVA study is an ongoing real-life multicentric retro-/prospective observational study on aUC pts receiving avelumab maintenance after response to platinum-based first-line CT. The co-primary endpoints are OS and PFS. We present here data of the first 100 enrolled aUC pts who received avelumab as maintenance therapy after response to platinum-based CT between January 2021 and January 2023. Absolute Eosinophil Counts (AEC) were registered at baseline (week 0) and at time of the first tumor assessment (week 12). This study aims to evaluate whether the AEC could be a predictive biomarker of efficacy in pts with aUC treated with avelumab. Results: One-hundred pts (median age, 72 years), 71.4% of whom were men, were enrolled (data cut off, January 2, 2023). Median follow-up time was 8.5 months. Median duration of avelumab treatment was 5.9 months. Median PFS for the entire population was 8.7 months (95% CI; 5.7 months-not reached). Predefined subgroup analyses showed PFS and OS improvement (5.1 months vs NR, p = 0.0031; 12.9 months vs NR, p = 0.056 respectively) in pts with high AEC at week 0 vs low AEC pts. Additionally, a pilot analysis was conducted for 34 pts, for whom PFS and OS were stratified by AEC at first tumor assessment (week 12). PFS was longer (6.4 months vs NR, p = 0.045) for pts with high AEC vs low AEC pts. Conclusions: In order to optimize treatment efficacy in aUC, reliable biomarkers are required. In this study, we provide data from a homogeneous cohort investigating the relevance of eosinophils in aUC pts receiving avelumab, suggesting that AEC could be an easily accessible and reproducible prognostic biomarker that warrants further studies.

Clinical, pathologic, and genomic hallmarks of KRAS-amplified non-small cell lung cancer.

9118 Background: KRAS-mutant non-small cell lung cancers (NSCLCs) have unique clinicopathologic and genomic features, and novel therapies are in development to target many KRAS-mutant tumor types. Whether KRAS amplification also defines a unique, potentially targetable, molecular subset of NSCLC is currently unknown. Methods: Clinicopathologic and genomic data were abstracted from multiple independent cohorts of pts whose cancers underwent tumor genomic profiling at the Dana-Farber Cancer Institute (Cohort 1), AACR Project GENIE v.13, The Cancer Genome Atlas (TCGA), and 212 other studies (Cohort 2). Patient (pt) outcomes were examined according to KRAS amplification status ( KRAS amplified vs KRAS non-amplified). Whole transcriptome sequencing and quantitative proteomics data from TCGA and the Cancer Cell Line Encyclopedia (CCLE) were used to correlate KRAS amplification with KRAS RNA levels and protein expression. Results: Among 15,341 pts with NSCLC, KRAS amplification was identified in 355 (2.3%) cases (median number of copies [range]: 11 [7-87]); the prevalence was similar in adenocarcinomas and squamous cell carcinomas. Compared to KRAS non-amplified cases, pts with KRAS-amplified NSCLC were more likely to be men (52.4% vs 45.6%, p = 0.01), have a history of smoking (82.1% vs 64.2%, p &lt; 0.01), and higher median pack-years (35 vs 23.5, p &lt; 0.01). However, median age was similar between the two groups (66 vs 66, p = 0.88). KRAS amplification was also associated with higher aneuploidy (median fraction of genome altered 30.4% vs 14.3%, p &lt; 0.01), tumor mutational burden (p &lt; 0.01 across different platforms), and increased median PD-L1 expression (20% vs 5%, p = 0.01). Of the 355 NSCLC samples with KRAS amplification, 152 (43%) had no concurrent oncogene driver mutations. In unbiased mutation enrichment analyses, KRAS-amplified tumors were enriched in concurrent mutations in KRAS, PALB2, POLE, and SLC34A2 (q &lt; 0.1), while KRAS non-amplified tumors were enriched for oncogenic EGFR mutations (q &lt; 0.1). Transcriptomic and proteomic profiling from the TCGA and CCLE cohorts demonstrated that KRAS amplification was associated with significantly increased KRAS mRNA (p &lt; 0.01) and protein expression (p &lt; 0.01), compared to KRAS non-amplified samples. In pts with available clinical outcomes data in the combined cohort (N = 9,335), the median overall survival (OS) from the date of diagnosis was significantly shorter in KRAS-amplified vs KRAS non-amplified cases (adjusted HR: 1.40, p &lt; 0.01). KRAS amplification was confirmed to confer significantly worse survival outcomes in pts with both KRAS wild-type (N = 6,695, adjusted HR 1.37, p = 0.02) and KRAS-mutant (N = 2,640, adjusted HR 1.34, p = 0.02) NSCLC. These results were independently replicated in Cohort 1 and Cohort 2. Conclusions: KRAS amplification defines a novel molecular subset of NSCLC characterized by distinct clinicopathologic and genomic features and worse survival.

Association of frailty and high-risk immuno-nutritional score with outcomes in patients with relapsed and refractory multiple myeloma treated with chimeric antigen receptor T-cells.

12052 Background: Multiple myeloma is a disease of older adults with a median age at diagnosis of 68 years (y). Patients (pts) receiving chimeric antigen receptor T-cell (CAR-T) therapy for relapsed/refractory MM (RRMM) often experience detrimental effects due to frailty, comorbidity, and cumulative toxicities. In this study, we evaluated the prevalence and impact of frailty, defined by the simplified frailty score, (SFS; Facon et al, Leukemia 2020), and immuno-nutritional status, using Glasgow-prognostic score (GPS; Proctor et al, Br J Cancer 2011) in a real-world cohort of pts receiving CAR-T therapy for RRMM. Methods: We included all pts treated with commercial CAR-T therapy for RRMM between 2021 - 2023 at Moffitt Cancer Center. The SFS and GPS (CRP &gt; 10 mg/dL, 1 point; albumin &lt; 3.5, 1 point) were calculated for all pts at lymphodepletion. Primary endpoints included overall survival (OS) and progression free survival (PFS). Pearson’s chi-squared tests or Fisher’s exact tests were used to compare association between categorical variables. OS and PFS were estimated used using Kaplan-Meier methods; the log-rank test was used to compare OS and PFS, and a cox-proportional model was used for multivariable analysis (MVA). Results: A total of 139 pts were included, with a median follow up of 6.3 months (m; range, 0.2 to 20.3 m). Median age was 66 y (IQR, 58-72 y); 38% were ≥70 y. Pts were treated with either idecabtagene vicleucel (83%) or ciltacabtagene autoleucel (17%). Around 1/3rd of pts had features of high-risk disease [high disease burden, 30%; high-risk cytogenetics (HR-Cyto), 37%; extramedullary disease (EMD), 37%]. Overall, 30% of pts were categorized as frail and 14% were classified as high-risk GPS (score = 2). There were no significant differences in GPS between older (≥70 y) and younger pts ( &lt; 70 y; p= 0.8). Median OS in the cohort was not reached (NR) and median PFS was 11.7 m. Both frailty and high-risk GPS were associated with inferior PFS (frail vs non-frail, HR 2.0, p= 0.03, high GPS vs low/int, HR 1.7 p = 0.009) and OS (frail vs non-frail, HR 3.0, p = 0.006, high GPS vs low/intermediate, HR 2.1 p = &lt; 0.001). The association of GPS with OS remained significant in a MVA, even after adjusting for high-risk disease factors (high disease burden, HR-Cyto and EMD) and frailty. Pts categorized as frail had a lower median PFS of 5.4 m (vs 12.7m non-frail group, p= 0.025), and inferior median OS of 9.7 m (vs NR in non-frail, p= 0.0039). Conclusions: In a real-world setting, frailty affects almost a third of pts with RRMM receiving CAR-T therapy and is associated with inferior PFS and OS. The GPS, a simple immuno-nutritional score, is highly predictive of survival even after adjusting for the presence of high-risk disease. Studies looking at role of pre-habilitation and other modalities to reduce inflammatory burden prior to CAR-T therapy are warranted.