Citations

Vitamin B12 is critical for hematopoiesis and myelination. Deficiency can cause neurologic deficits including loss of coordination and cognitive decline. However, diagnosis relies on measurement of vitamin B12 in the blood, which may not accurately reflect the concentration in the brain. Using programmable phage display, we identified an autoantibody targeting the transcobalamin receptor (CD320) in a patient with progressive tremor, ataxia, and scanning speech. Anti-CD320 impaired cellular uptake of cobalamin (B12) in vitro by depleting its target from the cell surface. Despite a normal serum concentration, B12 was nearly undetectable in her cerebrospinal fluid (CSF). Immunosuppressive treatment and high-dose systemic B12 supplementation were associated with increased B12 in the CSF and clinical improvement. Optofluidic screening enabled isolation of a patient-derived monoclonal antibody that impaired B12 transport across an in vitro model of the blood-brain barrier (BBB). Autoantibodies targeting the same epitope of CD320 were identified in seven other patients with neurologic deficits of unknown etiology, 6% of healthy controls, and 21.4% of a cohort of patients with neuropsychiatric lupus. In 132 paired serum and CSF samples, detection of anti-CD320 in the blood predicted B12 deficiency in the brain. However, these individuals did not display any hematologic signs of B12 deficiency despite systemic CD320 impairment. Using a genome-wide CRISPR screen, we found that the low-density lipoprotein receptor serves as an alternative B12 uptake pathway in hematopoietic cells. These findings dissect the tissue specificity of B12 transport and elucidate an autoimmune neurologic condition that may be amenable to immunomodulatory treatment and nutritional supplementation.

ABSTRACT Endoscopic retrograde cholangiopancreatography–guided transpapillary gallbladder drainage has emerged as an effective alternative for management of acute cholecystitis in nonoperable candidates. Delayed acute pancreatitis has not been previously described as an adverse event with this procedure. In this article, we describe 3 patients who developed acute pancreatitis between 2 and 6 weeks after stent insertion with no alternative inciting cause. Delayed acute pancreatitis may represent a rare and previously uncharacterized adverse event related to transpapillary gallbladder drainage.

Abstract We evaluate the impact of donor types on outcomes of hematopoietic cell transplantation (HCT) in myelofibrosis, using the Center for International Blood and Marrow Transplant Research registry data for HCTs done between 2013 and 2019. In all 1597 patients, the use of haploidentical donors increased from 3% in 2013 to 19% in 2019. In study-eligible 1032 patients who received peripheral blood grafts for chronic-phase myelofibrosis, 38% of recipients of haploidentical HCT were non-White/Caucasian. Matched sibling donor (MSD)–HCTs were associated with superior overall survival (OS) in the first 3 months (haploidentical hazard ratio [HR], 5.80 [95% confidence interval (CI), 2.52-13.35]; matched unrelated (MUD) HR, 4.50 [95% CI, 2.24-9.03]; mismatched unrelated HR, 5.13 [95% CI, 1.44-18.31]; P < .001). This difference in OS aligns with lower graft failure with MSD (haploidentical HR, 6.11 [95% CI, 2.98-12.54]; matched unrelated HR, 2.33 [95% CI, 1.20-4.51]; mismatched unrelated HR, 1.82 [95% CI, 0.58-5.72]). There was no significant difference in OS among haploidentical, MUD, and mismatched unrelated donor HCTs in the first 3 months. Donor type was not associated with differences in OS beyond 3 months after HCT, relapse, disease-free survival, or OS among patients who underwent HCT within 24 months of diagnosis. Patients who experienced graft failure had more advanced disease and commonly used nonmyeloablative conditioning. Although MSD-HCTs were superior, there is no significant difference in HCT outcomes from haploidentical and MUDs. These results establish haploidentical HCT with posttransplantation cyclophosphamide as a viable option in myelofibrosis, especially for ethnic minorities underrepresented in the donor registries.

Abstract Alpha-tubulin 4A encoding gene (TUBA4A) has been associated with familial amyotrophic lateral sclerosis and frontotemporal dementia, based on identification of likely pathogenic variants in patients from distinct amyotrophic lateral sclerosis and frontotemporal dementia cohorts. By screening a multicentric French cohort of 448 unrelated probands presenting with cerebellar ataxia, we identified ultra-rare TUBA4A missense variants, all being absent from public databases and predicted pathogenic by multiple in silico tools. In addition, gene burden analyses in the 100 000 Genomes project (100KGP) showed enrichment of TUBA4A rare variants in the inherited ataxia group compared to controls [odds ratio: 57.0847 (10.2−576.7); P = 4.02 ×10−7]. Taken together, we report 12 patients presenting with spasticity and/or cerebellar ataxia and harbouring a predicted pathogenic TUBA4A missense mutation, including five confirmed de novo cases and a mutation previously reported in a large family presenting with spastic ataxia. Cultured fibroblasts from three patients harbouring distinct TUBA4A missense showed significant alterations in microtubule organization and dynamics, providing insight of TUBA4A variants pathogenicity. Our data confirm the identification of a hereditary spastic ataxia disease gene with variable age of onset, expanding the clinical spectrum of TUBA4A associated phenotypes.

2598 Background: GI-102 (CD80-IL2v3) is a novel immunocytokine designed to direct IL-2v3 to immune cells and tumor cells. IL-2v3 of GI-102 abolished affinity to IL-2Rα minimizing the impact of IL-2 on Treg cells. Preferential targeting of immune cells and further inhibition of CTLA-4 and PD-L1 via CD80 synergize with potent activity of IL-2v3, resulting in robust proliferation and activation of CD8+ T and NK cells. Here we report preliminary safety and efficacy data of GI-102 from a phase 1/2a trial in patients with metastatic solid tumors. Methods: NCT05824975 is an ongoing, dose escalation (3+3 design) and expansion study to evaluate safety, tolerability, PK, PD and anti-tumor activity of GI-102. Each dose level allows to enroll additional 7 patients to fully inform the safety, PK and PD at that dose level. GI-102 was administered intravenously every 3 weeks until disease progression or unacceptable toxicities. Disease was assessed every 6 weeks using RECIST v1.1. Results: As of 12 Jan 2024, 32 patients were treated in dose escalation: 8 at dose level 0.06 mg/kg, 10 at 0.12 mg/kg, 9 at 0.24 mg/kg and 5 at 0.45 mg/kg. Patients had received median of 3 [1-7] prior lines of therapy, including 25.0% (8/32) who had received ≥ 5 lines and 68.8% (22/32) had experienced immune checkpoint blockade (ICB). No dose-limiting toxicities (DLTs) were observed until the highest dose of 0.45 mg/kg Q3W. The most common treatment-related adverse events (TRAEs, ≥ 10%) were pyrexia [43.8%] and chills [34.4%]. 5 patients [15.6%] had ≥ Grade 3 TRAEs and no patient reported TRAEs leading to discontinuation of GI-102. In 23 patients (7 cutaneous melanoma, 4 non-small cell lung cancer, 3 ovarian cancer and others) who had at least 1 post-treatment tumor assessment, objective responses were observed in 17.4% (4/23). In patients with metastatic melanoma who previously experienced ICB, overall response rate (ORR) and disease control rate (DCR) was 42.9% (3/7) and 85.7% (6/7), respectively, including 3 confirmed partial responses (cPR). The median time to response (TTR) was 6 weeks and duration of response (DoR) was 6.0+, 2.4+ and 1.7+ month, respectively. In patients with metastatic ovarian cancer, ORR and DCR were 33.3% (1/3) and 66.7% (2/3), respectively, including 1 cPR [TTR of 6 weeks; DoR 1.9+ month]. Preliminary PK profile showed target-mediated drug disposition with a half-life of ~48 hours. 0.24 mg/kg of GI-102 resulted in a significant expansion of peripheral lymphocytes, CD8+ T cells (effector & memory) and NK cells, by 4.4 [2.1-9.6], 3.9 [2.0–5.7] and 20.4 [9.5–32.6]-fold change from baseline, respectively. There was no meaningful increase in Treg cells. Conclusions: GI-102 was well tolerated up to dose of 0.45 mg/kg Q3W with meaningful monotherapy activity, regardless of previous ICB experience, in patients who failed on standard of care. The dose-escalation is currently ongoing to identify RP2D. Clinical trial information: NCT05824975 .

11558 Background: Nirogacestat (niro) is a targeted and selective gamma secretase inhibitor approved in the US for adults with progressing desmoid tumors (DT). In the phase 3 DeFi study, niro demonstrated significant improvement vs placebo (pbo) in progression-free survival (PFS: HR, 0.29 [95% CI: 0.15-0.55]; P<.001), objective response rate (ORR: 41% vs 8%; P<.001); and patient-reported outcomes (PROs) of pain, DT-specific symptom burden, physical and role functioning, and overall quality of life ( P≤.01, all). DT are driven by Wnt/β-catenin signaling pathway alterations and about 10-20% of DT are associated with mutations in the APC tumor suppressor gene, which may confer more aggressive DT behavior. Because patients with APC mutations may do worse, regardless of specific therapy, a post hoc analysis was conducted to assess effects of niro in patients with progressing DT and APC mutations. Methods: DeFi was a global, double-blind study that evaluated the efficacy, safety, and tolerability of niro in adults with progressing DT. Patients were randomized to oral niro (150 mg) or pbo twice-daily in continuous 28-day cycles. Descriptive post hoc analyses were conducted to assess effects of niro in patients with somatic and/or germline APC mutations. Results: Among 29 patients in DeFi with APC mutations (niro=13; pbo=16), 19 (66%) were female, 16 (55%) were aged ≤30 years, and 22 (76%) were refractory to prior treatment (with a median of 3 prior lines of treatment). In patients with APC mutation, PFS was improved with niro vs pbo (HR, 0.21 [95% CI: 0.05-1.00], P=.016). Confirmed ORR was 38% (5/13) for niro vs 13% (2/16) for pbo. Niro-treated patients also had greater reduction in median best percent change from baseline compared with pbo-treated patients in target tumor size (-29.5 vs +2.2), volumetric MRI (-71.0 vs +5.4), and T2 hyperintensity (-74.1 vs -21.0). Across all PROs assessed — Brief Pain Inventory, GODDESS DT Symptom Scale and DT Impact Scale, and European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 — patients treated with niro had numerically greater improvement from baseline at cycle 10 than pbo. Analyses were limited due to the small sample size. Adverse events in >50% of niro-treated patients with APC mutation were diarrhea, nausea, rash maculopapular, and fatigue; ovarian toxicity occurred in 9 of 10 of females of reproductive potential (6 resolved, 2 lost to follow-up, 1 ongoing and receiving niro). Conclusions: Improvement in PFS, ORR, tumor imaging characteristics and PROs was observed with niro compared to pbo in patients with DT harboring APC mutations. Efficacy and safety of niro in patients with APC mutations were generally consistent with findings for the overall DeFi population, suggesting that niro can provide clinically meaningful benefit to patients with progressing DT and APCmutations. Clinical trial information: NCT03785964 .

e20012 Background: PM 2.5, particulate matter with a diameter of 2.5 micrometers or less, is a major contributor to lung cancer and associated mortality. Epidemiological studies reveal a concerning trend, with each 10 micrograms per cubic meter increase in PM 2.5 associated with a 15% higher risk of lung cancer and a 13% increase in mortality rates, underscoring the significant burden it imposes on public health systems globally. We aimed to evaluate the odds of association between environmental exposure to PM 2.5 and the risk of lung cancer and associated mortality. Methods: We performed a systematic review and umbrella meta-analysis using studies containing quantitative data on PM 2.5 and lung cancer. We used PRISMA guidelines and the MOOSE protocol using PubMed and MeSH terms like PM 2.5, non-small cell cancer, lung cancer, pollutants, particulate matter 2.5, and environmental factors. We had excluded non-full-length articles, non-meta-analysis studies, and non-human studies. RavMan 5.4 was used, and generic inverse variance methods with mixed effect models were applied to identify a pooled risk ratio with a 95% confidence interval. Forest plots were obtained, and sensitivity analysis was performed based on funnel plots and I2 (heterogeneity) values. Results: Of the 245,529 articles evaluated for the quality of the data, 99 met the inclusion and exclusion criteria. Out of 99, we used six articles to derive the quantitative data. In umbrella meta-analysis, PM 2.5 exposure was associated with a 1.16 times higher risk (95%CI: 1.1-1.22, p<0.00001, I2=0%) of lung cancer and a 1.22 times higher risk of non-lung cancers (95%CI: 1.15-1.30, p<0.00001, I2=0%). PM 2.5 was associated with non-significant higher mortality (RR: 1.06, 95%CI: 0.99-1.13, p=0.09, I2=97%) with leave-on-out analysis (excluding Chen et al.) significant association between mortality and PM 2.5 (RR: 1.08, 95%CI: 1.06-1.10, p<0.00001, I2=0%). Conclusions: Our umbrella meta-analysis shows a significant risk of lung cancer and mortality from PM 2.5 exposure. Further investigation and increased consciousness are necessary to mitigate the risk of lung cancer associated with this pollutant.

7558 Background: Survival in patients with multiple myeloma (MM) continues to improve with the newer therapies, but there is no clear evidence of a cure and patients continue to relapse. However, most patients have the most extended period without progression with their first-line therapy, and subsequent therapies often provide a shorter duration of response due to the use of drugs with overlapping mechanisms of action and, more importantly, a shorter first remission, pointing toward more aggressive disease biology. With newer immunotherapies being used at 1st relapse, this may change. We designed this study to explore the natural history of MM after the 1st relapse and define the predictors of outcome after the initial relapse. Methods: We identified all patients in the Mayo Clinic database diagnosed between Jan 2004-June 2019 who had had initial disease progression. The study cohort included 2005 patients. We explored the overall survival (OS) from the time of documented disease progression or the start of second-line treatment in patients who had not met IMWG criteria before second-line therapy. Front-line therapy was grouped into those with either an IMiD or PI, both IMiD and PI, daratumumab with IMiD and PI, and none of these agents. The IMiD and PI were always used with dexamethasone with or without an alkylator. Results: The median age was 63 (range 24-95) years and 60% were male. The median estimated follow-up from diagnosis for all patients was 86 mos. (95% CI; 82, 88) and the median time to progression from the start of therapy was 25 mos. (95% CI; 24, 26). The median OS from the first progression was 45 mos. (95% CI; 42, 50), 36 mos. for those diagnosed before 2009, and 52-53 mos. for those diagnosed later. On univariate analysis, age <70 at 1st relapse, RISS I, novel agents in initial therapy, CR in the first line, diagnosis after 2009, initial remission >18 mos, and initiation of therapy before IMWG progression were all associated with improved OS after 1st relapse (Table). On multivariate analysis, age <70, RISS I, initial remission >18 mos, and initiation of therapy before IMWG progression were all associated with improved OS after 1st relapse. Conclusions: The study provides an estimate of the outcomes and significant predictors of outcomes after 1st relapse in patients with MM. These factors should be taken into consideration when designing clinical trials in this patient population. In particular, these factors identify a high-risk group of patients not always identified by baseline characteristics and should be the focus of future trials. [Table: see text]

7078 Background: Lisaftoclax is a novel, oral, highly selective, potent BCL-2 inhibitor in development. In an ibrutinib-resistant patient-derived WM xenograft/preclinical model, lisaftoclax + ibrutinib has a strong synergistic effect. This report provides updated efficacy and safety data of lisaftoclax-based therapies (including combinations with ibrutinib) in pts with WM. Methods: In this global, open-label, phase 1b/2 multicenter study, pts with WM were enrolled in 3 arms: Arm A (lisaftoclax) included BTKi-resistant/intolerant pts; Arm B (lisaftoclax + ibrutinib), treatment-naïve pts; and Arm C (lisaftoclax + rituximab), BTKi-naïve relapsed/refractory pts. Lisaftoclax was escalated from 400 to 1,200 mg using a modified toxicity probability interval design. A 3-day ramp-up was used for pts at high risk of tumor lysis syndrome (TLS). Objectives were efficacy, safety, and pharmacokinetics (PK) assessments (responses assessed per IWWM criteria). Results: As of January 25, 2024, 46 pts were enrolled and treated at doses of up to 1,000 (Arm A), 1,200 (Arm B), and 800 mg (Arm C; Table). The median (range) treatment duration was 11 (1-28; Arm A), 23.5 (1-34; B), and 11.5 (5-33; C) months. Objective response rates (PR, VGFR, CR) were: 41.7% (Arm A), 90.9% (B), and 37.5% (C). In Arm A, pts with wild-type CXCR4 (n = 7) had better overall response to lisaftoclax than the CXCR4mut group (n = 3). No significant difference was observed between pts with/without CXCR4mut in Arms B and C. In Arm B, 1 DLT (grade 3 clinical TLS due to preexisting renal impairment) was reported at 1,200 mg; 1 grade 3 laboratory TLS, primarily attributed to dehydration and concomitant symptomatic therapies, occurred at 1,000 mg; abnormal electrolytes resolved after 1 day of drug interruption, without recurrence. Grade ≥ 3 lisaftoclax-related AEs included neutropenia (15.2%), thrombocytopenia (4.3%), decreased leukocytes (4.3%), TLS (4.3%), anemia (2.2%), weight loss (2.2%), and septic shock (2.2%). Ventricular arrhythmia was not observed. One pt required dose reduction because of neutropenia. The MTD was not reached. Lisaftoclax + ibrutinib showed a PK exposure comparable to lisaftoclax or ibrutinib alone, indicating no potential drug-drug interactions. Conclusions: Lisaftoclax alone and combined with ibrutinib or rituximab was well tolerated and demonstrated measurable effects in pts with naïve or BTKi-treatment-failed WM. (CT.gov: NCT04260217; Internal ID: APG2575WU101) *Co-first authors: ML and SA. Clinical trial information: NCT04260217 . [Table: see text]

ABSTRACT Background The aim of this study was to determine the long-term effect of increasing water intake in patients with autosomal dominant polycystic kidney disease (ADPKD) on longitudinal changes in health-related quality of life (HRQoL) in the setting of a clinical trial. Methods Self-completed HRQoL (using the KDQoL-SF, v.1.3 questionnaire) was assessed annually in participants of a 3-year randomized controlled clinical trial (n = 187), allocated (1:1) either to increase water intake to reduce urine osmolality to ≤270 mosmol/kg (implemented by dietetic coaching, self-monitoring tools, text messaging) or continue usual water intake. Results Overall, 96% and 81.8% of participants (n = 187) completed the questionnaire at the baseline and final study visits, respectively. At baseline, the physical component summary score (PCS) and mental component summary score (MCS) were similar in the two groups (P &gt; 0.05) and the five dimensions with the lowest scores in both groups were: energy and fatigue; general and overall health; sleep; emotional well-being; and pain. Within each group, there were no longitudinal changes over time. At the final visit, the PCS was higher in the increased water intake group (51.3 ± 7.6, mean ± standard deviation) compared to the usual water intake group 48.8 ± 9.3; P = 0.037) whereas the MCS was numerically similar. The improvement in the PCS was due to higher sub-scale values for physical functioning and pain (both P &lt; 0.05). By multivariate analysis, only baseline PCS and height-corrected total kidney volume were associated with the final PCS (P &lt; 0.05). Conclusion HRQoL scores remained stable over a 3 year period, and were not adversely affected by the intervention to increase water intake. Future studies should evaluate the clinical significance of the higher PCS in the increased water intake group.