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NPM1 mutations (NPM1+) are found in about 30% of adult AML. While NPM1+ are generally associated with favorable risk, prior studies have shown that NPM1+ older patients, defined as ≥ 65 years, have significantly worse outcomes. The updated European Leukemia Net 2022 (ELN22) now classifies NPM1+ AML patients with FLT3-ITD (ITD+) and MDS-associated mutations (MDSm+) as adverse-risk, while NPM1+/ITD-/MDSm+ patients remain favorable-risk unless they have an adverse-risk karyotype. A recent report (Chan et al., Blood Adv 2024) found MDSm+ conferred worse OS only in patients ≥ 60 years; however another report (Othman et al., Blood 2024) did not find MDSm+ were significantly associated with adverse outcomes in a larger cohort of NPM1+ patients. To further assess this question, we examined the mutational landscape in a large cohort of pre-treatment, diagnostic specimens from 456 patients enrolled in SWOG clinical trials (SWOG-9031, SWOG-9333, S0106, and S0112) and 126 patients from the UW/FHCC Hematopoietic Repository (Total N=582). Patients were treated with curative intent as per standard practice or clinical trials. Out of the 582 patients, 191 were NPM1+ (33%), of which 148 patients had cytogenetic and long-term outcome data. Kaplan-Meier and cumulative incidence estimates were estimated. C-statistics and AUC for Cox, cause-specific and logistic regression models for overall survival (OS), event-free survival (EFS), time to relapse (TTR, calculated in n=106 who achieved complete remission [CR], death in remission analyzed as a competing risk) and CR were calculated for age, ELN17, and ELN22, as well as ELN17 and ELN22 adjusting for age. ELN17 favorable-risk patients reclassified as adverse-risk (N=5 of 108) demonstrated significantly shorter EFS (HR=2.50, p=0.05) and CR rate (OR=0.20, p=0.024), although with similar OS (HR 1.30, p=0.66) and TTR (HR=1.20, p=0.86). ELN17 favorable-risk patients reclassified as ELN22 intermediate-risk (N=23 of 108) did not show a significant difference in OS (HR 1.47, p=0.20), EFS (HR 1.35, p=0.12), CR rate (OR 0.75, p=0.46), or TTR (HR=1.64, p=0.11) compared to ELN22 favorable-risk. For ELN17 intermediate-risk (N=40), 5 patients were reclassified as ELN22 adverse-risk (12.5%) and had significantly shorter EFS (HR 2.89, p=0.037) compared to ELN22 intermediate risk, although there was not a significant difference in CR rate (OR 0.31, p=0.23) or OS (HR 0.81, p=0.67). We next compared the prognostic significance of age relative to ELN risk classification. Age was associated with higher C-statistics (OS=0.65, TTR=0.57 and EFS=0.60) and AUC (CR=0.64) compared to both ELN17 (OS=0.56, TTR=0.54, EFS=0.54, CR=0.54) or ELN22 (OS=0.57, TTR=0.57, EFS=0.57, CR=0.58). The combination of age and ELN22 resulted in the highest C-statistics for OS, TTR, and EFS (OS=0.68, TTR=0.60, EFS=0.64). To further assess the impact of MDSm on risk-stratification of NPM1+ AML, we performed multivariable analyses adjusting for FLT3-ITD, MDSm, and age in patients without adverse-risk disease. These analyses showed MDSm did not have a significant association with OS when controlling for age or FLT3-ITD. We also compared ELN22 favorable-risk patients with and without MDSm (MDSm+ N=18; MDSm- N=61). Compared with the MDSm-, there was a trend toward an inferior OS (HR 1.85, p=0.054) for MDSm+ patients but not EFS (HR 1.38, p=0.3) or TTR (HR 1.2, p=0.64). When stratified by age (<65, N=53 vs. ≥65, N=26), MDSm+ in younger patients did not show a difference for OS (HR 0.96, p=0.96), EFS (HR 0.63, p=0.53) or TTR (HR 0.4, p=0.37). Older ELN22 favorable-risk patients (≥65) had similarly poor OS (MDSm- HR 3.33 and MDSm+ 3.27, respectively, p=0.001 for both) and EFS (MDSm- HR 3.11 and MDSm+ 2.39, p=0.001 and 0.01) compared to younger MDSm- patients. In our study, the ELN22 guidelines incrementally improve risk stratification for EFS in NPM1+ patients. However, age remains the most prognostic factor, and patients ≥ 65 years have similar adverse clinical outcomes, whether classified as favorable risk by ELN17, ELN22, or incorporating MDSm. Moreover, MDSm do not confer a worse prognosis in NPM1+ patients when accounting for age or FLT3-ITD status. These findings differ from a recent report by Chan et al. and are in keeping with the report by Othman et al. Therefore, further understanding of the underlying biology of age and its effect on NPM1+ AML is needed to improve outcomes for older patients.

Introduction: Brexucabtagene autoleucel (brexu cel) is a CD19-targeted chimeric antigen receptor (CAR) T cell therapy approved for the treatment of adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). Some patients (pts) proceed with a consolidative allogeneic hematopoietic cell transplant (HCT) after breux cel. We do not know which pts can safely avoid a consolidative HCT and its associated morbidity. Methods: We conducted a retrospective cohort study utilizing the Real-World Outcomes Collaborative of CAR-T in Adult ALL (ROCCA) dataset. ROCCA is a registry of brexu cel pts in 32 centers in North America. We defined complete remission (CR) as < 5% blasts in the bone marrow and no central nervous system (CNS) or extramedullary (EM) disease on or around D28 after brexu cel. We defined measurable residual disease negative (MRD-) CR as CR and no abnormal blasts in the bone marrow by multiparameter flow cytometry, quantitative polymerase chain reaction, ClonoSeq next generation sequencing (NGS), or other sequencing modalities with lower sensitivity. ClonoSeq NGS has a sensitivity of 10-6, while the other modalities have a sensitivity of at least 10-4. We defined progression free survival (PFS) as the time from CAR-T infusion to relapse or death, censored at the date of last follow-up. Statistical analyses were performed in R. Univariable Cox proportional hazards regression analyses were performed to determine the association of pre-specified variables with PFS. Variables known to be associated with CAR T outcomes in ALL were entered into a multivariable model. HCT was incorporated as a time-varying covariate. Results: During the study period, 281 pts were infused with brexu cel. We focused our analysis on 172 (61%) pts with confirmed MRD- CR on D28, as that is the group with clinical equipoise regarding maintenance strategy. 38 (22%) of those pts received a consolidative HCT, 30 (17%) received another form of maintenance therapy (primarily tyrosine kinase inhibitors for Philadelphia (Ph)-chromosome positive ALL), and 104 (60%) pts received no maintenance therapy. Pts who underwent consolidative HCT were younger (median age 35 years) than those who received no maintenance (42y) (p = 0.023) and were less likely to have a history of prior HCT (13% vs. 47%, p < 0.001). No differences were observed with respect to sex, TP53 mutation status, prior inotuzumab (ino) or blinatumomab (blina) exposure, disease burden prior to CAR, or development of any cytokine release syndrome (CRS) or any neurotoxicity with brexu cel. We performed univariable Cox proportional hazard regression analyses among pts in MRD- CR on D28, excluding those who received other maintenance therapy besides HCT; the median follow up was 8.1 months. In univariable analyses, D28 MRD negativity by ClonoSeq NGS (versus MRD negativity by other, less sensitive methods), development of CRS, and pre-CAR BM blasts < 5% were associated with improved PFS; prior ino exposure was negatively associated with PFS (p < 0.05). Age, sex, Ph status, TP53 status, and neurotoxicity development were not associated with PFS. In a multivariable model incorporating ALL type, prior HCT, prior ino/blina, and pre-CAR blast burden, as well as consolidative HCT as a time-varying covariate, only MRD negativity by ClonoSeq NGS with at least 10-6 sensitivity retained statistical significance (PFS hazard ratio 0.34, 95% confidence interval (CI) 0.15-0.77, p = 0.005). Pts who were MRD- by ClonoSeq NGS on D28 and received no maintenance had favorable 6m PFS of 76% (95% CI: 59-98%) and OS of 100% with a median follow up of 6.3 months in this subgroup. Among those in MRD- CR by NGS, HCT as a time-varying covariate was not associated with improved PFS (HR 0.6, p = 0.6). Conclusions: In a large real-world cohort of adults with R/R B-ALL infused with brexu cel, we identified practice variation regarding the use of consolidative HCT. Among brexu cel recipients who entered an MRD- CR, we identified ClonoSeq NGS MRD negativity as a novel predictive factor of favorable oncologic outcomes, even without a consolidative HCT. Similar results have been obtained in pediatric ALL patietns ftreated with 41BB-based tisagenleucleucel (Pulsipher et al., Blood Cancer Discovery 2022). Longer follow-up is needed to validate the safety of omitting consolidative HCT in such pts, but these results encourage the potential for definitive therapy with brexu cel when D28 ClonoSeq NGS MRD is negative.

Introduction: Despite advent of multiple tyrosine kinase inhibitors (TKIs) and newer treatment methods for both AML and ALL, the outcomes of patients (pts) with chronic myeloid leukemia in blast phase (CML-BP) remain poor. Consensus guidelines on treatment of CML-BP are scarce. A recent study from the European leukemia network (ELN) blast phase registry reported outcomes of 240 CML-BP pts. They also reported marked heterogeneity in treatment patterns and lack of an accepted standard. Hence, we are undertaking this study through the H Jean Khoury Cure CML Consortium (HJKC3) to study the treatment patterns and outcomes of pts with CML-BP in the US. Methods: This is a multi-institution, retrospective study. IRB approval was obtained at each institution separately and data sharing agreements were executed. All pts diagnosed with CML-BP based on modified MD Anderson Criteria (≥30% blasts in the blood or bone marrow or extramedullary (EM) disease) from 2010 to 2024 were included. Categorical variables were compared using the Chi-square test. Overall survival (OS) was calculated from the time of diagnosis to death from any cause. Survival probabilities were computed using the Kaplan-Meier method and compared with the log-rank test. Results: Of the 72 pts with CML-BP included in this analysis, 29 (40.3%) were female and 43 (59.7%) were males. At the time of diagnosis, 36 (50%) had CML-CP (chronic myeloid leukemia in chronic phase), 11 (15.3%) pts were diagnosed with CML-AP (accelerated phase CML) and 25 (34.7%) pts with de-novo CML-BP. For the 47 pts that were initially diagnosed with CML-CP or CML-AP, the median time to progression to CML-BP was 26 months (1-207 months). Median age at diagnosis of CML-BP was 54 years (range 21-86 years). EM disease was present in 17 (23.6%) pts (7 myeloid sarcoma, 5 central nervous system and 5 skin) with 3 pts presenting with EM disease only. Blasts were of myeloid phenotype in 41 (56.9%), lymphoid in 29 (40.3%) and mixed in 2 (2.8%) pts. The bcr-abl protein was p210 in 59 (81.9%), p190 in 5 (6.9%) and p230 in 1 (1.4%) pt. Four pts had prior allogeneic stem cell transplant (alloSCT) for CML-CP. Of the pts who had an ABL kinase domain mutation tested, 42.9% (18/42) pts were found to have an ABL kinase domain mutation. The most common TKD mutation was T315I (n=6). Next generation sequencing was performed in 32 pts. The most common mutations were ASXL1 (n=10), RUNX1 (n=4), BCOR (n=2), BCORL1 (n=2), DNMT3A (n=2) and 1 each in CSF3R, KMT2A, EZH2, NF1 and TP53. Of the 72 pts, 68 underwent CML-BP directed therapy. While only 9 (13.2%) pts were treated with TKI alone (4 dasatinib, 2 imatinib, 2 ponatinib and 1 asciminib), 54 (79.4%) pts were treated with a combination of chemotherapy with TKI (24 dasatinib, 13 ponatinib, 9 imatinib, 6 nilotinib, 1 bosutinib and 1 asciminib), and 5 (7.4%) pts were treated with chemotherapy alone. The response rate after CML-BP directed therapy was 72.1% (n=49). Best response was return to CML-CP in 17 pts, CHR with PCyR in 1 pt, CCyR in 11 pts, MMR in 5 pts, MR4 in 4 pts, MR4.5 in 5 pts and MR5 in 6 pts. Rate of response with third and second generation TKI was significantly better than first generation TKI (80% and 77.1% vs 36.3%; p=0.02287). 30 (44.1%) pts proceeded to alloSCT. Of the 49 pts that responded, 16 (32.6%) relapsed. The median time to relapse was 5 months (range 1-46 months). At a median follow up of 57 months, the median OS for all pts was 18 months. There was no difference in OS based on blast phenotype (14 months for myeloid, 21 for lymphoid and 7.5 for mixed; p=0.1185), initial diagnosis (38 months CP-CML, 13 for CML-AP and 16 for de-novo BP pts; p=0.6380), or TKI (13 months for first generation, 20 for second and not reached for third generation TKI; p=0.1729). The OS of pts that were treated with a combination of TKI and chemotherapy was significantly longer compared to pts treated with TKI or chemo alone (28 vs 13 or 4.5 months; p=0.0003). Of the 32 pts that responded, OS for pts that underwent alloSCT was significantly longer compared to pts that did not (not reached vs 14 months; p= 0.0022). Conclusion: CML-BP continues to have a dismal prognosis. Treatment is heterogenous involving various combinations of TKI and chemotherapy. In our analysis, treatment with second or third generation TKI led to better responses. In addition, treatment with chemotherapy in combination with TKI and alloSCT led to improved OS. Updated results from further multi-institution analysis will be presented at the meeting.

Introduction: Brexucabtagene Autoleucel (brexu-cel) is the first CD19-targeting chimeric antigen receptor (CD19.CAR) T-cell therapy approved for the treatment of relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) in adult (≥18 yo) patients (pts) based on results from the ZUMA-3 trial. However, data on the safety and efficacy of CAR-T cells in older pts (≥60 yo) remains limited, with only 8 pts >65 yo enrolled in the ZUMA-3 trial. We evaluated the treatment characteristics and outcomes with use of brexu-cel amongst patients ≥60 yo in the Real-World Outcomes Collaborative for CAR-T in ALL (ROCCA) consortium database. Methodology: ROCCA is a consortium of over 30 U.S.-based institutions with a database of adult pts with B-ALL who received brexu-cel as standard of care therapy. We identified pts ≥60 yo and further stratified them into two cohorts: 60-69 yo and ≥70 yo. Outcomes of interest included OS, PFS, ORR, and toxicities (CRS and ICANS). Both OS and PFS were calculated from the day of brexu-cel infusion. Response assessment occurred on day +28, and MRD evaluation was per institutional practices. CRS and ICANS were graded according to the American Society for Transplantation and Cellular Therapy criteria. Results: Of 280 brexu-cel recipients in the ROCCA database, 73 (26%) were ≥60 yo, of which 58 (79%) were between 60-69 yo and 15 (21%) were ≥70 yo. Among pts ≥60 yo, the median age at infusion was 65 (range 60-81). Pts were heavily pretreated with a median of 3 prior lines of therapy (range 2-9). Prior therapies included: allogeneic HSCT (38%), inotuzumab ozogamicin (41%), and blinatumomab (62%). Forty pts (55%) had Ph-negative B-ALL, 24 (33%) had Ph+ B-ALL and 9 (12%) had Ph-like B-ALL. When grouped by HCT-CI equal to 0, 1-2 or ≥3, a higher proportion of pts ≥60 yo had HCT-CI ≥3 (19% vs. 7% in <60 yo; p=0.004). Pre-apheresis, 33 pts (45%) had active disease (>5% marrow blasts or extramedullary disease), 34 (47%) were in CR (of whom 14 were MRD-negative) and 6 had unknown disease status. Following brexu-cel, 43 (59%) achieved MRD-negative CR, 20 (27%) had MRD + or CR with unknown MRD status, 6 (8%) had refractory disease and 5 had no disease evaluation available. The ORR was similar between pts 60-69 and ≥70 yo (MRD-negative CR rate: 58% vs 61%, r/r to brexu-cel: 9% vs 6%) and was comparable to pts <60 yo (MRD-negative CR 66%; r/r disease of 9%). The rate of all grade ICANS was higher in pts ≥70 (77%) than in pts 60-69 (47%) or pts <60 (49%), with grade 1-2 ICANS occurring at a significantly higher rate in pts ≥70 (44% vs. 20% in 60-69 and 20% in <60, p=0.049). Grade 3-4 ICANS were similar between the groups: 33%, 27% and 29% in the ≥70, 60-69, and <60 groups, respectively. Conversely, rates of CRS were similar across age groups (80-84%). There was no statistically significant difference in the rate of grade 3-4 CRS which was 17% in pts ≥70, 4% in pts 60-69, and 11% in pts <60 yo. With a median follow-up of 332 days (range 8-936 days) from infusion, pts ≥60 yo had a median PFS of 395 days compared to 547 days in pts <60 yo. Median PFS was lower in the ³70 yo (231 days) compared to 677 in the 60-69 yo cohort. No statistically significant difference was found between the <60 and ≥60groups in 6- and 12-month PFS rates (6 months PFS: 66% vs 64%, p=0.77 and 12 months PFS: 57% vs 57%, p=1.00). When pts ≥60 yo were stratified by age, pts ≥70 yo had similar 6-month PFS compared to other age groups but significantly lower 12-month PFS (38%; vs. 64% in pts 60-69and 57% in pts <60, p=0.001). Median OS was not reached in any of the age groups, and there was no statistically significant difference in 6-month OS (72% in ≥ 70 vs. 82% in the 60-69 vs. 82% in <60, p=0.14) or 12-months OS (61% in ≥ 70 vs. 69% in 60-69 vs. 73% in <60, p=0.18). Conclusion: This is the largest study to date of older B-ALL pts receiving CAR-T cells. We observed that older pts, particularly those aged 60-69, have similar outcomes to younger pts. However, pts ≥70 yo had lower median and 12-month PFS when compared to younger patients. Additionally, pts ≥70 yo had higher rates of grades 1-2 ICANS. An important limitation of this analysis is the potential selection bias among clinicians when selecting older patients for this treatment. Longer follow-up, including inclusion of additional pts ≥70 yo is needed to confirm these results, and further studies are needed to identify the optimal approach for use of CAR T-cell therapy in patients in this age group.

AbstractIntroductionAcute myeloid leukemia (AML) remains one of the deadliest hematopoietic malignancies. A better understanding of the molecular biology governing AML may lead to improved risk stratification and facilitate the development of novel therapies. Proteins are responsible for much of the biology of cells. Several studies have examined the global proteome in bulk mononuclear cells (MNCs) from AML specimens, which are comprised a heterogenous population of cells at various stages of differentiation.MethodsGiven the potential impact of the nonleukemic cells on protein expression profiles, we applied an integrative proteogenomic approach utilizing next‐generation sequencing and mass spectrometry‐based proteomics to identify novel protein biomarkers in unsorted MNCs and viable leukemic blasts (VLBs) isolated from blood and bone marrow specimens obtained at the time of AML diagnosis.ResultsWe identified significant differences in protein expression between VLBs and MNCs. Subsequent studies (N = 27) focused on proteomic profiling of VLBs that identified novel candidate biomarkers associated with mutational genotypes and clinical outcome, some of which were recapitulated in an independent cohort of patients. Using mass spectrometry, we also detected mutated protein products, some of which were predicted via in silico analyses to be potential neoantigens amenable to adoptive immunotherapy. As previously described, analyses comparing transcript and protein expression showed an overall modest correlation between mRNA and protein dataset, but enriching for genes associated with mutations significantly improved the protein–RNA correlation.ConclusionTogether, the results provide insight into the biology of VLBs and demonstrate the gains derived from examining the proteome in addition to genome and transcriptome.

OBJECTIVE Some patients treated surgically for grade 1 spondylolisthesis require revision surgery. Outcomes after revision surgery are not well studied. The objective of this study was to determine how revision surgery impacts patient-reported outcomes (PROs) in patients undergoing decompression only or decompression and fusion (D+F) for grade 1 spondylolisthesis within 5 years of the index surgery. METHODS Patients in the 12 highest Quality Outcomes Database (QOD) enrolling sites with a diagnosis of grade 1 spondylolisthesis were identified and the incidence of revision surgery between the decompression-only and D+F patients were compared. PROs were compared between cohorts requiring revision surgery versus a single index procedure. RESULTS Of 608 patients enrolled, 409 had complete 5-year data available for this study. Eleven (13.3%) of 83 patients underwent revision in the decompression-only group as well as 32 (9.8%) of 326 in the D+F group. For the entire cohort, patients requiring revision had significantly worse PROs at 5 years: Oswestry Disability Index (ODI) 27.4 versus 19.4, p = 0.008; numeric rating scale for back pain (NRS-BP) 4.1 versus 3.0, p = 0.013; and NRS for leg pain (NRS-LP) 3.4 versus 2.1, p = 0.029. In the decompression-only group, the change in 5-year PROs was not impacted by revision status: ODI 31.9 versus 24.2, p = 0.287; NRS-BP 1.9 versus 2.9, p = 0.325; and NRS-LP 6.2 versus 3.7, p = 0.011. In the D+F group, the change in 5-year PROs was diminished if patients required revision: ODI 19.1 versus 29.1, p = 0.001; NRS-BP 3.0 versus 4.0, p = 0.170; and NRS-LP 2.3 versus 4.6, p = 0.001. CONCLUSIONS The most common reasons for reoperation within 5 years in the decompression-only group were repeat decompression and instability, whereas in the D+F group the most common reason was adjacent-segment disease. The need for revision resulted in modestly diminished benefit compared with patients with no revisions. These differences were greater in the fusion cohort compared with the decompression-only cohort. The mean PRO improvement still far exceeded minimal clinically important difference thresholds for all measures for patients who underwent a revision surgery.

Abstract Disclosure: R.J. Auchus: Consulting Fee; Self; Neurocrine Biosciences, Inc., Crinetics Pharmaceuticals, OMass Therapeutics, H Lundbeck A/S, Adrenas Therapeutics. Research Investigator; Self; Neurocrine Biosciences, Inc., Diurnal, Crinetics Pharmaceuticals, Spruce Biosciences. O. Hamidi: Advisory Board Member; Self; Corcept Therapeutics, Recordati Rare Diseases, Amryt Pharma, Neurocrine Biosciences, Inc., Xeris, Lantheus. R. Pivonello: Advisory Board Member; Self; Corcept Therapeutics, Recordati AG, Crinetics Pharmaceuticals, H. Lundbeck A/S. Research Investigator; Self; Corcept Therapeutics, Recordati AG, Strongbridge Biopharma, Neurocrine Biosciences, Inc. I. Bancos: Consulting Fee; Self; Corcept Therapeutics, Recordati Rare Diseases, HRA Pharmaceuticals, Neurocrine Biosciences, Inc., Diurnal, Spruce Biosciences, Sparrow Pharmaceuticals, Adrenas Therapeutics. Research Investigator; Self; Recordati Rare Diseases. G. Russo: Advisory Board Member; Self; Novartis Pharmaceuticals, Sandoz, Diurnal. Speaker; Self; Novartis Pharmaceuticals, Sandoz, Diurnal. S.F. Witchel: Research Investigator; Self; Neurocrine Biosciences, Inc. A.M. Isidori: Research Investigator; Self; Pfizer, Inc., Merck Serono, HRA Pharmaceuticals, Recordati AG, Corcept. P. Rodien: Consulting Fee; Self; Pfizer, Inc., Novo Nordisk, Lilly USA, LLC, Ipsen, HRA Pharmaceuticals, IBSA Pharma, Recordati Rare Diseases. U. Srirangalingam: Advisory Board Member; Self; Diurnal. Speaker; Self; Diurnal. F.W. Kiefer: Advisory Board Member; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. Speaker; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. H. Falhammar: Consulting Fee; Self; Diurnal, Roche Diagnostics, Neurocrine Biosciences, Inc., H Lundbeck A/S, Adrenas Therapeutics. D.P. Merke: Research Investigator; Self; Diurnal, Adrenas Therapeutics, Neurocrine Biosciences, Inc. N. Reisch: Consulting Fee; Self; Diurnal, Crinetics Pharmaceuticals, Neurocrine Biosciences, Inc., Spruce Biosciences, H Lundbeck A/S. J. Sturgeon: Employee; Self; Neurocrine Biosciences, Inc. E. Roberts: Employee; Self; Neurocrine Biosciences, Inc. V.H. Lin: Employee; Self; Neurocrine Biosciences, Inc. J.L. Chan: Employee; Self; Neurocrine Biosciences, Inc. R. Farber: Employee; Self; Neurocrine Biosciences, Inc.. Introduction: Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD), a genetic disorder characterized by cortisol deficiency and excess adrenal androgens, typically requires management with supraphysiological glucocorticoid (GC) doses. Crinecerfont is a novel oral CRF1 antagonist that reduced elevated adrenocorticotropic hormone and adrenal androgens in patients with 21OHD in 14-day open-label Phase 2 studies. This Phase 3 study (CAHtalyst: NCT04490915) evaluated whether crinecerfont can reduce daily GC dose while maintaining androgen control in adults with 21OHD. Methods: Adults (≥18 years) with 21OHD, stable GC regimens at doses >13 mg/m2/d in hydrocortisone equivalents (HCe), and normal or elevated androstenedione (A4) were randomized (2:1) to crinecerfont 100 mg BID or placebo for 24 weeks. GC dosing was maintained stable for 4 weeks, followed by a planned GC down-titration over 8 weeks to achieve a GC dose of 8-10 mg/m2/d. GC doses were adjusted as needed during the last 12 weeks to maintain A4 control (≤120% of baseline or ≤upper limit of normal [ULN]) by week 24. Results: In the 182 randomized participants (51% male, mean age 31 years), demographics and baseline characteristics were similar between treatment arms (122 crinecerfont, 60 placebo). Mean GC dose at baseline was 17.6 mg/m2/d HCe (32 mg/d), with 58% on HC alone, 29% taking predniso[lo]ne, and 13% taking dexamethasone; mean pre-GC A4 (620 ng/dL) was elevated >2-3-fold the ULN. Over 95% of participants completed the double-blind treatment period. At week 24, the crinecerfont arm had a significantly greater percent reduction in GC dose while maintaining A4 control vs placebo (-27% vs -10%; least squares mean difference [LSMD]: -17%; p<0.0001) (primary endpoint). At week 4 (end of GC-stable period), a greater reduction in A4 prior to the morning GC dose was observed with crinecerfont vs placebo (LSMD: -345 ng/dL; p<0.0001) (key secondary endpoint). At week 24, a higher percentage of participants reached a protocol-defined physiological GC dose (≤11 mg/m2/d) while maintaining A4 control with crinecerfont (63% vs 18% for placebo; p<0.0001) (key secondary endpoint). The most common treatment-emergent adverse events (AEs) in the crinecerfont arm were fatigue (25% vs 15% for placebo), headache (16% vs 15%), and COVID-19 (14% vs 9%). There were few serious AEs (3% overall), with none assessed as related to the study drug. Conclusions: Crinecerfont, an oral CRF1 antagonist, represents a novel treatment option to improve androgen control for patients with 21OHD. In the largest interventional Phase 3 study conducted to date in adults with 21OHD, crinecerfont led to a significant reduction in A4 while GC dose was stable, enabling a significant percent reduction in GC dose while maintaining A4 control at 24 weeks. Crinecerfont was overall well tolerated. Presentation: 6/1/2024

OBJECTIVE The long-term effects of increased body mass index (BMI) on surgical outcomes are unknown for patients who undergo surgery for low-grade lumbar spondylolisthesis. The goal of this study was to assess long-term outcomes in obese versus nonobese patients after surgery for grade 1 spondylolisthesis. METHODS Patients who underwent surgery for grade 1 spondylolisthesis at the Quality Outcomes Database’s 12 highest enrolling sites (SpineCORe group) were identified. Long-term (5-year) outcomes were compared for patients with BMI ≥ 35 versus BMI < 35. RESULTS In total, 608 patients (57.6% female) were included. Follow-up was 81% (excluding patients who had died) at 5 years. The BMI ≥ 35 cohort (130 patients, 21.4%) was compared to the BMI < 35 cohort (478 patients, 78.6%). At baseline, patients with BMI ≥ 35 were more likely to be younger (58.5 ± 11.4 vs 63.2 ± 12.0 years old, p < 0.001), to present with both back and leg pain (53.8% vs 37.0%, p = 0.002), and to require ambulation assistance (20.8% vs 9.2%, p < 0.001). Furthermore, the cohort with BMI ≥ 35 had worse baseline patient-reported outcomes including visual analog scale (VAS) back (7.6 ± 2.3 vs 6.5 ± 2.8, p < 0.001) and leg (7.1 ± 2.6 vs 6.4 ± 2.9, p = 0.031) pain, disability measured by the Oswestry Disability Index (ODI) (53.7 ± 15.7 vs 44.8 ± 17.0, p < 0.001), and quality of life on EuroQol-5D (EQ-5D) questionnaire (0.47 ± 0.22 vs 0.56 ± 0.22, p < 0.001). Patients with BMI ≥ 35 were more likely to undergo fusion (85.4% vs 74.7%, p = 0.01). There were no significant differences in 30- and 90-day readmission rates (p > 0.05). Five years postoperatively, there were no differences in reoperation rates or the development of adjacent-segment disease for patients in either BMI < 35 or ≥ 35 cohorts who underwent fusion (p > 0.05). On multivariate analysis, BMI ≥ 35 was a significant risk factor for not achieving minimal clinically important differences (MCIDs) for VAS leg pain (OR 0.429, 95% CI 0.209–0.876, p = 0.020), but BMI ≥ 35 was not a predictor for achieving MCID for VAS back pain, ODI, or EQ-5D at 5 years postoperatively. CONCLUSIONS Both obese and nonobese patients benefit from surgery for grade 1 spondylolisthesis. At the 5-year time point, patients with BMI ≥ 35 have similarly low reoperation rates and achieve rates of satisfaction and MCID for back pain (but not leg pain), disability (ODI), and quality of life (EQ-5D) that are similar to those in patients with a BMI < 35.