Citations

Abstract Migraine attacks can be provoked in people with underlying primary headache disorders by multiple peripheral mechanisms suggesting the possible convergence of trigeminal nociceptive inputs onto a common, unknown central circuit. As calcitonin gene-related peptide (CGRP) expressing cells in the parabrachial nucleus (PBN) have been implicated in nociplastic pains, we hypothesized that (a) PBN CGRP-expressing neurons and their projections to the central amygdala (CeA) may be an essential central relay of multiple peripheral inputs promoting injury-free migraine headache and (b) this pathway may prioritize threat from activation of cranial afferents over other nociceptive inputs. Periorbital cutaneous allodynia (CA) was determined following supradural application of a cocktail of inflammatory mediators (IM), CGRP or pituitary adenylate cyclase-activating polypeptide (PACAP), or systemic administration of nitroglycerin (NTG) in CalcaCre or wild-type mice. Decreased rearing and photophobia were respectively evaluated as measures of ongoing headache and light-evoked migraine-like pain. Phosphorylation of extracellular signal-regulated kinases (pERK) was evaluated to assess regional neuronal activation. Compared with vehicle, supradural IM increased pERK in the trigeminal nucleus caudalis and PBN, but not in the paraventricular thalamus. Chemogenetic activation (Gq-DREADD) of PBN CGRP neurons elicited CA and photophobia while decreasing rearing. Lesioning of PBN neurons with ibotenic acid suppressed CA produced by supradural IM. Chemogenetic silencing (Gi-DREADD) or expression of tetanus toxin (TeNT) in PBN Calca neurons to prevent neurotransmitter release also inhibited CA elicited by supradural IM, CGRP, PACAP or systemic NTG. CRISPR/Cas9 editing of CeA receptor-associated membrane protein-1 (Ramp1) prevented IM-induced migraine-like symptoms revealing CGRP/CGRP-receptor activation from PBN→CeA projections. In contrast, PBN lesions, chemogenetic manipulation, and TeNT expression in PBN Calca cells and CeA Ramp1 CRISPR/Cas9 editing did not affect acute pain responses induced by hind paw IM injection, intraperitoneal acetic acid, or acute nociceptive behaviors from IM stimulation of the maxillary (V2) and mandibular (V3) branches of the trigeminal nerve. These data reveal a central pathway composed of PBN Calca neurons and CeA CGRP receptor signaling that is both sufficient to elicit migraine-like pain in naive mice and necessary to promote migraine-like pain following activation of the ophthalmic (V1) branch of the trigeminal nerve. Importantly, this pathway is essential for acute pain arising from V1 trigeminal, but dispensable for acute stimuli from other nociceptive afferents. The prioritization of V1 acute nociception suggests evolutionary importance for detecting threats to the head to promote survival through advantageous behaviors such as defensive coping observed in migraine.

ABSTRACT Prior surveys of chronic automated red blood cell exchange (RCE) for patients with sickle cell disease (SCD) have identified considerable procedural variability, especially with the use of isovolemic hemodilution red blood cell exchange (IHD‐RCE). We conducted a survey of chronic RCE practices among American Society for Apheresis (ASFA) members to identify opportunities for practice harmonization and future studies. The ASFA SCD Research Subcommittee developed a 72‐item survey of chronic RCE practices, with a focus on IHD‐RCE. The survey was validated internally and distributed by email to all ASFA members from September 2024 to February 2025. One survey response from each institution was retained for data analysis. Descriptive statistics were performed. Sixty‐two survey responses, including three from international institutions, were retained for analysis. Sixty‐one percent of respondents (38/62) reported using at least one fixed RCE target, with end hematocrit being the most common fixed parameter (40%, 25/62), followed by fraction of cells remaining (31%, 19/62) and hemoglobin S% (27%, 17/62). Most respondents (60%, 37/61) performed IHD‐RCE at their institution, though other details such as the minimum hematocrit, exclusion criteria, and response to adverse effects were variable. Consistent pre‐ and post‐RCE laboratory monitoring practices were reported. Consistent with earlier surveys, procedural variability in chronic RCE practices for patients with SCD is observed. This highlights opportunities to compare outcomes where practice variability exists. Consensus guidelines based on institutional practices with optimal outcomes should be developed.

Abstract Mild traumatic brain injury (mTBI) commonly induces transient acute (APTH) or persistent (PPTH) post-traumatic headache (PTH) that often resembles migraine. As orexin B sensitizes male but not female murine, nonhuman primate, and human dorsal root ganglion neurons and supradural orexin B/orexin receptor 2 (OX2R) signaling elicits migraine-like pain in naïve male, but not female, mice we explored possible sexually dimorphic contributions of orexin B/OX2R to PTH. In mice of both sexes, mTBI-induced transient cephalic allodynia, a surrogate measure of APTH. After APTH resolution, allodynia was reinstated by exposure to normally innocuous stress or by inhalational delivery of a subthreshold concentration of umbellulone, a TRPA1 agonist, suggesting the expression of PPTH. In contrast to these nonselective stimuli, subthreshold supradural orexin B induced PPTH only in male mTBI mice. Intranasal delivery of a CRISPR/Cas9 plasmid to edit trigeminal OX2R expression prevented APTH and development of PPTH selectively in male mTBI mice. Daily oral suvorexant, a dual orexin receptor antagonist (DORA), beginning immediately after mTBI, prevented APTH as well as PPTH. Critically, starting suvorexant treatment after resolution of APTH also prevented stress- or umbellulone-induced PPTH. EEG/EMG-defined sleep architecture or immobility-defined sleep was not disrupted in this mTBI model suggesting that suvorexant benefits are unlikely related to sleep modulation. Our findings reveal a male-specific mechanism of PTH maintained by orexin B/OX2R signaling and suggest that approved DORAs may be beneficial in treating APTH and preventing transition to PPTH in men. Importantly, DORAs may also be effective in men with established PPTH.

7028 Background: Axi-cel, autologous anti-CD19 CAR T-cell therapy, showed long-term survival and curative potential in R/R LBCL (ZUMA-1; Neelapu et al. Blood . 2023). Few studies have examined long-term outcomes beyond clinical trials. Here we report long-term real-world outcomes of axi-cel in R/R LBCL using large-sample CIBMTR data. Methods: A total of 1500 adults from 79 US centers receiving commercial axi-cel after ≥2 LOT for LBCL from Oct 2017-Aug 2020 were enrolled in a post-marketing requirement study. A protocol was developed prior to the study’s implementation, reviewed by Kite and CIBMTR. This is a secondary analysis of said study. Key outcomes were progression-free survival (PFS), overall survival (OS), time to next therapy (TTNT), disease-specific mortality (competing risks were non-relapse deaths), subsequent malignancies, and non-relapse mortality (NRM). Outcomes were analyzed descriptively. Cases with missing data were excluded separately for each endpoint. Results: As of Aug 2025, 1446 patients (pts) were included in the analysis. Median age at infusion was 62.2 y (range, 19.6-90.8: 38% of pts ≥65 y); 65% were male. Five percent of pts had ECOG PS ≥2 and 16% had high-grade lymphoma. Pts had a median of 3 (range, 2-4) prior LOT, 28% had prior autologous hematopoietic cell transplantation, and 50% received bridging therapy. At 59.7 mo median follow-up, median PFS (95% CI) was 7.9 mo (6.3-10.9) and 5-y PFS was 30% (27-32). The median OS was 25.7 mo (21.6-30.2); 5-y OS was 38% (35-41). The 5-y cumulative incidence of disease-specific mortality was 51%. Among pts who were progression-free at 2, 3, 4, or 5 y post-infusion, the OS at 6 y (95% CI) was 73% (68-78), 81% (76-86), 90% (84-94), and 94% (89-97), respectively. The median duration of response (DOR) was 25.3 mo (95% CI, 20.7-32.8) and 5-y DOR was 38% (35-41). The median TTNT was 12.2 mo and 30% did not need additional LOT at 5 y. Of pts who received subsequent salvage therapy, 12 (2%) received cell therapy, 39 (7%) received hematopoietic cell transplant, and 475 (90%) received other therapy. The 1, 2, 3, 4, and 5-y cumulative incidence of relapse (95% CI) was 49% (46-51), 52% (50-55), 54% (52-57), 55% (53-58), and 56% (53-59), respectively. No new safety signals were observed. The primary causes of death (n=864; 60%) were primary disease (540; 63%), infection (111; 13%), and organ failure (57; 7%). The 5-y cumulative incidence of NRM was 16% (95% CI, 14-18). At 5 y, 11% (95% CI, 10-13) had subsequent malignancies, mostly therapy-related myeloid neoplasms (6%) and non-melanoma skin cancer (3%); none were directly attributed to axi-cel. Conclusions: This real-world study showed sustained survival at 5 y among pts with R/R LBCL treated with axi-cel after ≥2 LOT, consistent with ZUMA-1. Infection and organ failure were common causes of NRM. These results continue to support the use of axi-cel with curative intent in R/R LBCL.

OBJECTIVE Overuse of broad-spectrum empiric antimicrobials remains common in children hospitalized with respiratory tract infections (RTI). A negative methicillin-resistant Staphylococcus aureus (MRSA) nasal swab (MNS) polymerase chain reaction (PCR) result has been shown to have a high negative predictive value for MRSA in RTI. In this quality improvement (QI) initiative, we developed a pharmacist-driven approach to reduce the duration of empiric vancomycin for RTI in children. The primary aim was the time to de-escalation of vancomycin, and the secondary aim was the reduction in vancomycin monitoring in patients hospitalized with RTI. METHODS Baseline duration of vancomycin therapy was assessed by conducting a retrospective chart review. After root cause analysis and engaging key stakeholders, an electronic health record OurPractice Advisory (OPA) was implemented, prompting pharmacists to order an MNS PCR during order verification for vancomycin with an RTI indication. RESULTS Preimplementation (01/01/2021 to 08/31/2023) included 89 patients, and 25 postimplementation (09/21/2023 to 05/31/2024). We found a 36% decrease in mean vancomycin duration from 53 to 34 hours after implementation of the pharmacist-driven OPA. Postimplementation, 24% of patients had a vancomycin concentration obtained, compared with 37% preimplementation. No patients were readmitted within 30 days postimplementation, compared with 1 patient preimplementation. CONCLUSIONS This QI initiative provides preliminary data that empiric vancomycin duration in pediatric patients with RTI may be impacted by pharmacist-facing OPA implementation, prompting ordering of MNS PCR at the time of vancomycin verification. This initiative could be replicated at other institutions seeking to reduce empiric vancomycin usage.

Abstract Introduction: Axi-cel, an autologous anti-CD19 CAR T-cell therapy has shown high and durable response rates and a manageable safety profile among R/R FL pts in the ZUMA-5 trial (Jacobson et al. 2022; Neelapu et al. 2024). Evidence from real-world data showed favorable early outcomes in a broader population using CIBMTR data, with comparable outcomes by ZUMA-5 eligibility, age, lines of therapy (LOT), and prior bendamustine (benda) use (Jacobson et al. 2023). This study investigated long-term outcomes and the association between age, performance status, comorbidities, and therapies given prior to infusion among R/R FL pts treated with axi-cel. Methods: Pts with R/R FL who received commercial axi-cel between 03/2021–10/2023 in the US were identified from the CIBMTR® registry; pts without consent, with prior non-transplant cellular therapy, and FL grade 3B or 3A/3B unspecified or unknown were excluded. Descriptive analyses were done among all pts and by age at infusion (<65 vs ≥65 y), Karnofsky performance score (KPS), presence of hepatic, cardiovascular (CV), or moderate to severe pulmonary comorbidities, prior treatments (benda pre-leukapheresis, autologous hematopoietic stem cell transplant [autoHSCT]), and lymphodepletion (LD) therapy. Multivariable (MV) Cox and logistic regression were used to adjust for confounders. Results: In total, 238 pts from 68 centers were included (data cut-off October 2024). Median age at infusion was 61 yr (range, 29-83; ≥65 yr, 38%), and 79% were non-Hispanic White. KPS of pts was ≤70% (11%), 80% (35%), or 90-100% (54%); 2% had ECOG ≥2. Most (75%) had ≥1 clinically significant comorbidity (hepatic, 6%; CV, 15%; pulmonary, 18%). Median (min, max) prior LOT was 4 (1,13); 74% received benda pre-leukapheresis, and 6% had benda LD therapy. At a median follow-up of 24.1 months, objective response rate (ORR) was 96% (complete response [CR] rate, 91%). The 2-yr (95% CI) DOR, PFS, and OS were 70% (63-77), 64% (57-71), and 84% (78-89) respectively. Grade ≥3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 4% and 18% of pts (any grade, 74% and 42%), respectively. Prolonged cytopenias by day 30 occurred in 14% of pts (neutropenia [10%] and thrombocytopenia [8%]) while 29% had clinically significant infections at 6 months. Second primary malignancies occurred in 16 pts (7%), with 7 (2%) being therapy-related myeloid neoplasm. The leading primary causes of death (n=34) were relapse/progression (10; 29%), organ failure (7; 21%), and infection 5 (15%). Cumulative incidence of non-relapse mortality at 2-yr was 9%. Outcomes were generally comparable among age, autoHSCT, and comorbidity subgroups. However, effectiveness outcomes differed by prior benda use (Yes vs No): ORR (95% vs 98%); CR (88% vs 98%); DOR (65% vs 89%), PFS (58% vs 84%), and OS (82% vs 91%) at 2 years. By LD therapy (single agent benda vs cyclophosphamide + fludarabine [Cy + Flu]): the ORR was 93% vs 96%; CR rate was 57% vs 93%. On MV analysis, prior benda use was associated with (OR/HR [95% CI]): worse CR (0.02 [<0.01-0.43]), DOR (3.69 [1.51-9.02], and PFS (2.21 [1.12-4.38]). Pts given benda LD therapy had (OR/HR [95% CI]): worse CR rate (0.02 [<0.01-0.16]), DOR (7.59 [2.33-24.72]), and PFS (4.89 [1.79-13.39]) compared to those who received Cy + Flu. CRS and ICANS were lower among those with prior benda use (Yes vs No): any-grade CRS (70% vs 87%); Grade ≥3 CRS (3% vs 8%); any-grade ICANS (36% vs 61%); and grade ≥3 ICANS (17% vs 25%). By LD therapy (single agent benda vs Cy + Flu): the Grade ≥3 CRS and ≥3 ICANS were 0% vs 5% and 7% vs 19% respectively. Any-grade ICANS was higher among those aged ≥ 65 yr vs <65 yr (53% vs 35%). On MV analysis, pts who had prior benda use were less likely to have any-grade CRS (0.30 [0.12-0.75]), and any-grade ICANS (0.23 [0.11-0.50]. Pts ≥ 65 yr had higher any-grade ICANS (2.31 [1.18 – 4.50]). Summary/Conclusion: This long-term follow up of axi-cel in R/R FL shows durable responses and manageable safety similar to ZUMA-5. Outcomes among the elderly and those with comorbidities were generally comparable to the overall R/R FL population. Although benda use pre-leukapheresis was associated with less durable responses, we were unable to determine whether this association is limited to use close to axi-cel infusion, as data on timing of use was unavailable. The associations for benda LD should be interpreted with caution given the small sample size.

OBJECTIVE The optimal dose for triazoles in pediatric patients may substantially vary given the dynamic changes in pharmacokinetics and pharmacodynamics, based on disease severity. Therapeutic drug monitoring has been a valuable tool to help guide management and avoid potential toxicities associated with treatment of invasive fungal infections (IFIs). Goal azole serum concentrations are based on specific drug, indication, and minimum inhibitory concentration when known. This study aimed to determine the optimal pediatric azole doses needed to achieve targeted serum concentrations of isavuconazole, itraconazole, posaconazole, and voriconazole. METHODS This is a single center, retrospective chart review of pediatric patients who received isavuconazole, itraconazole, posaconazole, or voriconazole between January 1, 2011, and August 31, 2021. RESULTS A total of 273 pediatric patients received isavuconazole, itraconazole, posaconazole, or voriconazole in the inpatient or outpatient setting during the study period. Of the 273 patients, only 122 met criteria for inclusion in the analysis. Eighty-three percent of patients reached a goal serum concentration. Patients younger than 12 years required a higher dose (mg/kg/day) to achieve goal serum concentrations. Patients who received an azole in the form of an oral tablet or intravenously were more likely to reach a goal concentration than those not receiving these formulations. Median time to goal concentration occurred at 20 days for isavuconazole, 34 days for itraconazole, 11 days for posaconazole, and 10 days for voriconazole. CONCLUSIONS Higher starting azole doses are needed to obtain goal concentrations quickly, especially for children younger than 12 years.

Abstract Background Pharmacokinetics of beta-lactams vary widely in neonatal and pediatric patients due to developmental biology and critical illness. Cefepime (FEP), meropenem (MEM), and piperacillin/tazobactam (TZP) are highly susceptible to pharmacokinetic changes as hydrophilic, small molecules with renal clearance. Subtherapeutic levels are associated with clinical and microbiologic failure, and supratherapeutic levels associated with toxicity. Beta-lactam therapeutic drug monitoring (TDM) may optimize the effectiveness and safety of these agents. The purpose of this investigation is to describe the % of pediatric and neonatal patients with beta-lactam serum levels within target range. Methods In August 2023, TDM launched at the Mayo Clinic Children’s Center for select patients treated with FEP, MEM, or TZP with expected durations ≥ 48 hours, or who were on kidney replacement therapy (KRT), extracorporeal membrane oxygenation (ECMO), weighed > 120 kg, had a BMI > 95th percentile, or at the discretion of pediatric ID team. Validated drug assays were performed daily, Monday through Friday. A two-level sampling strategy was preferred with a peak 1 hour after the end of the infusion and a trough 30 minutes before the next dose. Empiric trough target ranges were set at FEP 8-50 mg/L, MEM 2-30 mg/L, and piperacillin 16-150 mg/L. These target ranges were adjusted with confirmed microbiology to a time above the minimum inhibitory concentration of the organism for 100% of the dosing interval (100%T > MIC). Results From August 2023 to April 2024, 74 episodes of TDM were performed on 45 patients. Thirty-seven (82%) patients were in an intensive care unit (ICU) at the time of TDM, 8/45 (22%) of whom were in the neonatal ICU. Target range was achieved in 67% of patients on FEP, 50% on MEM, and 52% on TZP. Median (IQR) trough values were 22.1 (8.6, 44.2) mg/L for FEP, 0.6 (0, 4.1) mg/L for MEM, and 15.5 (3.8, 27.1) mg/L for TZP. Seven levels were above target for FEP and 0 for MEM and TZP. Seven levels were below target for FEP, 4 for MEM, and 11 for TZP. Conclusion Implementation of a TDM program for FEP, MEM and TZP in pediatric and neonatal patients revealed drug levels frequently outside target range. TDM may facilitate dose individualization to optimize medication efficacy and minimize toxicity. Disclosures Raymond Stetson, MD, MS, Moderna: Grant/Research Support Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Board Member Erin F. Barreto, PharmD, MSc, Baxter Health: Advisor/Consultant|Wolters Kluwer: Advisor/Consultant

Background Women with endometriosis are more likely to have migraine. The mechanisms underlying this co-morbidity are unknown. Prolactin, a neurohormone secreted and released into circulation from the anterior pituitary, can sensitize sensory neurons from female, but not male, rodents, monkeys and human donors. Methods We used a syngeneic model of endometriosis to determine whether elevated prolactin levels can sensitize trigeminal ganglion neurons and increase vulnerability to migraine pain. Results Mice with endometriotic lesions showed increased serum prolactin levels and developed persistent abdominal, but not cephalic, allodynia. However, inhalation of a transient receptor potential ankyrin 1 agonist, umbellulone, a known environmental trigger of headache in some patients, elicited cephalic allodynia in mice with endometriosis but not sham controls, suggesting that endometriosis can promote sensitization of trigeminal neurons and migraine attacks. Endometriosis dysregulated the expression of prolactin receptor isoforms in trigeminal neurons and increased their excitability measured by in vitro patch clamp electrophysiology. Inhibition of pituitary prolactin following a 2-week treatment with a dopamine receptor agonist, cabergoline, prevented cephalic allodynia elicited by activation of trigeminal afferents with umbellulone. Cabergoline treatment also normalized the expression of prolactin receptor isoforms in trigeminal ganglia and the hyperexcitability of trigeminal neurons. Conclusions These data demonstrate that circulating prolactin in endometriosis promotes vulnerability to migraine through sensitization of trigeminal afferents. Clinically available dopamine receptor agonists or novel monoclonal antibodies targeting prolactin signaling may be effective for migraine prevention in women with endometriosis.

Background We wished to explore possible sexual dimorphism in mechanisms sensitizing or activating meningeal nociceptors that can promote the headache phase of migraine. Methods Male and female C57BL6J mice received either supradural orexin B and an inflammatory mediator cocktail (IM) with migraine-like pain behaviors and photophobia recorded. Expression of orexin 2 receptor (OX2R) in trigeminal ganglion (TG) and phosphorylated extracellular signal-regulated kinases (ERK) levels in trigeminal nucleus caudalis (TNC) were evaluated. Orexin B-induced excitability of TG cells was assessed with patch-clamp electrophysiology. Intranasal delivery of CRISPR/Cas9 plasmids was used to edit the expression of OX2R in the TG. Results Supradural orexin B induced migraine-like pain behaviors, photophobia and increased TNC ERK phosphorylation exclusively in males. Blockade of orexin signaling with supradural suvorexant, a dual orexin receptor antagonist, prevented, but did not reverse, migraine-like pain in males induced by supradural IM cocktail. OX2R expression was higher in male TG and orexin B increased TG neuron excitability in males. Intranasal OX2R CRISPR/Cas9 reduced TG receptor expression and orexin B-induced TNC ERK phosphorylation and prevented migraine-like pain induced by supradural orexin B in males. Conclusions Our studies reveal a male-specific mechanism of TG nociceptor sensitization and migraine-like pain behavior mediated by orexin B/OX2R signaling. Sexually dimorphic mechanisms of trigeminal nociceptor sensitization and activation offer opportunities to improve patient outcomes by considering patient sex and may influence clinical trial design and interpretation.