Central Nervous System Penetration Research Articles

Comprehensive Review on the Virulence Factors and Therapeutic Strategies with the Aid of Artificial Intelligence against Mucormycosis.

Mucormycosis, a rare but deadly fungal infection, was an epidemic during the COVID-19 pandemic. The rise in cases (COVID-19-associated mucormycosis, CAM) is attributed to excessive steroid and antibiotic use, poor hospital hygiene, and crowded settings. Major contributing factors include diabetes and weakened immune systems. The main manifesting forms of CAM─cutaneous, pulmonary, and the deadliest, rhinocerebral─and disseminated infections elevated mortality rates to 85%. Recent focus lies on small-molecule inhibitors due to their advantages over standard treatments like surgery and liposomal amphotericin B (which carry several long-term adverse effects), offering potential central nervous system penetration, diverse targets, and simpler dosing owing to their small size, rendering the ability to traverse the blood-brain barrier via passive diffusion facilitated by the phospholipid membrane. Adaptation and versatility in mucormycosis are facilitated by a multitude of virulence factors, enabling the pathogen to dynamically respond to various environmental stressors. A comprehensive understanding of these virulence mechanisms is imperative for devising effective therapeutic interventions against this highly opportunistic pathogen that thrives in immunocompromised individuals through its angio-invasive nature. Hence, this Review delineates the principal virulence factors of mucormycosis, the mechanisms it employs to persist in challenging host environments, and the current progress in developing small-molecule inhibitors against them.

Abstract 6472: Response to PARP inhibitors in patients with breast cancer metastatic to the central nervous system

Abstract Background: Central nervous system (CNS) metastasis from breast cancer can be challenging to treat due to the limited blood brain barrier penetration of many systemic therapies. PARP inhibitors (PARPi) block single-strand DNA break repairs and have activity in cancers with homologous recombination repair deficiency; they are FDA approved for patients with metastatic HER2 negative breast cancer with germline BRCA1/2 mutations. While preclinical studies suggest that PARPi have CNS penetration, clinical data is limited. The goal of our study is to describe the clinical benefit of PARPi in patients with breast cancer CNS metastasis. Methods: This retrospective case series was conducted at three academic cancer centers (Johns Hopkins, Dana-Farber, and Duke) and included patients with the following criteria: (1) age≥18 years with a breast cancer diagnosis (any subtype); (2) diagnosis of parenchymal brain metastasis or leptomeningeal disease (LMD); and (3) received PARPi (olaparib, talazoparib) for CNS metastasis. Clinical and pathologic information were analyzed with descriptive statistics (median, range) and Kruskal-Wallis rank sum tests. Survival analysis was performed using Kaplan-Meier curves with log-rank p-values. Results: Although this analysis includes one center’s experience, we will present a combined dataset (N = 45) at the main conference. 11 patients were identified at Johns Hopkins. 4 (36.4%) were Black and 6 (54.5%) were White; 6 (54.5%) had ER+HER2- disease and 5 (45.5%) had TNBC at time of brain metastasis; 5 (45.5%) had BRCA1 mutations, 5 (45.5%) had a BRCA2 mutations, and 1 patient (9%) had a BARD1 mutation; 7 (63.6%) had brain metastasis and 4 (36.4%) had LMD. Median lines of therapy prior to PARPi was 6 [1 - 11]; 8 patients (72.7%) had previous CNS radiation (5 SRS and 3 WBRT) and 3 (27.3%) had previous CNS surgery. On average, patients remained on PARPi for 5 months [0.5 - 66], and overall survival (OS) time from PARPi to death was 16 months [2 - 66]. Time on PARPi was 5 months [2 - 66] for patients with brain metastasis and 3 months [0.5 - 10] for those with LMD (p=0.22). Duration of PARPi and OS did not differ significantly between ER+HER2- and TNBC (p=0.74 and 0.69, respectively), BRCA 1 and 2 (p=0.78 and 0.72, respectively), or brain and LMD metastasis (p=0.22 and 0.91, respectively). Black patients had significantly shorter PARPi duration and survival than White patients (PARPi 2 vs. 8 months, p=0.028 and OS 4 vs 18 months, p=0.028). Prior CNS radiation was significantly associated with longer PARPi duration and survival (PARPi 5 vs 1 month, p=0.02 and OS 17 vs. 3 months, p=0.032). Prior CNS surgery was significantly associated with longer PARPi duration, but not overall survival (PARPi 18 vs 3 months, p=0.05 and OS 28 vs. 7 months, p=0.14). Conclusions: PARPi are associated with significant clinical benefit in patients with breast cancer CNS metastasis. Larger data series will help confirm these observations. Citation Format: Seoho Lee, Rani Bansal, Melissa E. Hughes, Amanda E. Van Swearingen, Heather N. Moore, David O. Kamson, Solmaz Sahebjam, Greg Kirkner, Anna Gorfinkel, Sarah Sammons, Nancy U. Lin, Carey Anders, Cesar A. Santa-Maria. Response to PARP inhibitors in patients with breast cancer metastatic to the central nervous system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6472.

Experimental and Computational Methods to Assess Central Nervous System Penetration of Small Molecules.

In CNS drug discovery, the estimation of brain exposure to lead compounds is critical for their optimization. Compounds need to cross the blood-brain barrier (BBB) to reach the pharmacological targets in the CNS. The BBB is a complex system involving passive and active mechanisms of transport and efflux transporters such as P-glycoproteins (P-gp) and breast cancer resistance protein (BCRP), which play an essential role in CNS penetration of small molecules. Several in vivo, in vitro, and in silico methods are available to estimate human brain penetration. Preclinical species are used as in vivo models to understand unbound brain exposure by deriving the Kp,uu parameter and the brain/plasma ratio of exposure corrected with the plasma and brain free fraction. The MDCK-mdr1 (Madin Darby canine kidney cells transfected with the MDR1 gene encoding for the human P-gp) assay is the commonly used in vitro assay to estimate compound permeability and human efflux. The in silico methods to predict brain exposure, such as CNS MPO, CNS BBB scores, and various machine learning models, help save costs and speed up compound discovery and optimization at all stages. These methods enable the screening of virtual compounds, building of a CNS penetrable compounds library, and optimization of lead molecules for CNS penetration. Therefore, it is crucial to understand the reliability and ability of these methods to predict CNS penetration. We review the in silico, in vitro, and in vivo data and their correlation with each other, as well as assess published experimental and computational approaches to predict the BBB penetrability of compounds.

Ceftaroline for Central Nervous System Infections: Case Report of a Young Infant, and Scoping Review.

Managing health care acquired and device-associated intracranial infections in young children can be challenging given adverse antibiotic side effects and difficulties in achieving adequate central nervous system (CNS) antibiotic concentrations. Ceftaroline is a cephalosporin with a favorable safety profile and activity against methicillin-resistant Staphylococci and several Gram-negative organisms. Published data on the use of ceftaroline for CNS infections in children and adults are limited. We describe a 2-month-old infant with ventriculo-subgaleal shunt-associated methicillin-resistant Staphylococcus epidermidis ventriculitis, which was successfully treated with ceftaroline, in addition to vancomycin and rifampin. We conducted a scoping review of English-language literature retrieved from PubMed, EMBASE and Web of Science that assessed the use of ceftaroline for CNS infections. We identified 22 articles for inclusion in our review, which described 92 unique patients, of whom 2 were <21 years old. Ceftaroline was commonly used in conjunction with other antibiotics to treat infections caused by Staphylococcus aureus, coagulase-negative Staphylococci and Streptococcus pneumoniae. Most case reports described clinical success with ceftaroline, though small case series and cohort studies yielded mixed efficacy assessments. Adverse effects attributed to ceftaroline were rare and included reversible myelosuppression, eosinophilia, hepatotoxicity and nephrotoxicity. Pharmacokinetic/pharmacodynamic studies suggested similar CNS penetration through inflamed meninges as other beta lactam antibiotics. We identified a growing body of published evidence supporting the use of ceftaroline in combination with other agents for the treatment of CNS infections. In absence of clinical trials, additional real-world data are needed to define the efficacy and safety of ceftaroline for children and adults with CNS infections.

Phase 1 Healthy Volunteer Study of AL01211, an Oral, Non-brain Penetrant Glucosylceramide Synthase Inhibitor, to Treat Fabry Disease and Type 1 Gaucher Disease.

Glycosphingolipid (GSL) storage diseases are caused by deficiencies in the enzymes that metabolize different GSLs in the lysosome. Glucosylceramide synthase (GCS) inhibitors reduce GSL production and have potential to treat multiple GSL storage diseases. AL01211 is a potent, oral GCS inhibitor being developed for the treatment of Type 1 Gaucher disease and Fabry disease. AL01211 has minimal central nervous system penetration, allowing for treatment of peripheral organs without risking CNS-associated adverse effects. AL01211 was evaluated in a Phase 1 healthy volunteer study with single ascending dose (SAD) and multiple ascending dose (MAD) arms, to determine safety, pharmacokinetics including food effect, and pharmacodynamic effects on associated GSLs. In the SAD arm, AL01211 showed a Tmaxof approximately 3.5 hours, mean clearance (CL/F) of 130.1 L/h, and t1/2 of 39.3 hours. Consuming a high-fat meal prior to dose administration reduced exposures 3.5-5.5-fold, indicating a food effect. In the MAD arm, AL01211 had an approximately 2-fold accumulation, reaching steady-state levels by 10 days. Increasing exposure inversely correlated with a decrease in GSL with plasma glucosylceramide and globotriacylceramide reduction from baseline levels, reaching 78% and 52% by day 14, respectively. AL01211 was generally well-tolerated with no AL01211 associated serious adverse events, thus supporting its further clinical development.

Durable response to first-line treatment with AZD3759 (zorifertinib) in a patient with epithelial growth factor receptor mutated non-small cell lung cancer and untreated multiple brain metastasis

Central nervous system (CNS) metastases, including brain and leptomeningeal metastasis, are associated with poor prognosis in epidermal growth factor receptor (&lt;i&gt;EGFR&lt;/i&gt;)-mutated non-small cell lung cancer (NSCLC) patients. CNS metastasis occurs in more than 50% of &lt;i&gt;EGFR&lt;/i&gt;-mutated NSCLC cases during the treatment course. The treatment options for CNS metastases in these patients are limited, and there have been ongoing efforts to develop targeted agents with enhanced CNS penetration. AZD3759 (zorifertinib) is a novel &lt;i&gt;EGFR&lt;/i&gt; tyrosine kinase inhibitor with a high capability of CNS penetration and proven efficacy with tolerable safety profiles. In this report, we describe a case of a patient with &lt;i&gt;EGFR&lt;/i&gt;-mutant NSCLC that was initially diagnosed with multiple brain metastasis who demonstrated prolonged response of both intra- and extracranial lesions over 7 years with AZD3759 as first-line treatment.

Series of (([1,1'-Biphenyl]-2-yl)methyl)sulfinylalkyl Alicyclic Amines as Novel and High Affinity Atypical Dopamine Transporter Inhibitors with Reduced hERG Activity.

Currently, there are no FDA-approved medications for the treatment of psychostimulant use disorders (PSUD). We have previously discovered "atypical" dopamine transporter (DAT) inhibitors that do not display psychostimulant-like behaviors and may be useful as medications to treat PSUD. Lead candidates (e.g., JJC8-091, 1) have shown promising in vivo profiles in rodents; however, reducing hERG (human ether-à-go-go-related gene) activity, a predictor of cardiotoxicity, has remained a challenge. Herein, a series of 30 (([1,1'-biphenyl]-2-yl)methyl)sulfinylalkyl alicyclic amines was synthesized and evaluated for DAT and serotonin transporter (SERT) binding affinities. A subset of analogues was tested for hERG activity, and the IC50 values were compared to those predicted by our hERG QSAR models, which showed robust predictive power. Multiparameter optimization scores (MPO > 3) indicated central nervous system (CNS) penetrability. Finally, comparison of affinities in human DAT and its Y156F and Y335A mutants suggested that several compounds prefer an inward facing conformation indicating an atypical DAT inhibitor profile.

Palliative radiotherapy for leptomeningeal metastases after photon-based intensity-modulated radiotherapy in a nasopharyngeal cancer patient.

Leptomeningeal metastasis is a rare in nasopharyngeal carcinoma, affecting less than 5% of patients with a poor prognosis. The aim of this case report was to present management of palliative radiotherapy in leptomeningeal metastasis of nasopharyngeal carcinoma patient. A 33-year-old female presented with nasopharyngeal carcinoma with stage III, T3N3M0, WHO type III. The patient has received chemoradiation with photon-based intensity-modulated radiotherapy (IMRT) technique at the dose of 70 Gy in 33 fractions and showed a satisfactory outcome in 12 months follow-up. Later, at 18 months after chemoradiation completion, the patient complained of worsening bilateral sciatic pain, particularly during coughing, with slight limitations in bilateral hip flexion observed during straight leg raises. The whole spine contrast-enhanced magnetic resonance imaging (MRI) examination showed nodular enhancement of leptomeningeal thickening at the T4 level of the spinal cord lower than S3. Palliative radiation therapy utilized a three-dimensional conformal radiation therapy (3D-CRT) technique producing 35 Gy in 14 fractions placed in a field spanning the T4-S3 vertebral bodies. Methotrexate was administered intravenously every two weeks for three cycles to ensure central nervous system penetration. After four months of follow-up, no evidence of disease was found at the primary site and metastatic areas on subsequent physical examination or imaging with MRI and there was satisfactory improvement in neurologic symptoms. In conclusion, leptomeningeal metastases with primary nasopharyngeal carcinoma are rare and typically cause neurological impairments in patients. Hematogenous or cerebrospinal fluid-mediated spread of the cancer is considered the most likely pathway for leptomeningeal dissemination. Strategic modalities, such as radiotherapy with chemotherapy, may improve outcomes in symptoms and quality of life.

Abstract B157: Preclinical evaluation of the blood-brain barrier permeability and intracranial efficacy of the next-generation RET inhibitor Vepafestinib

Abstract Background. Drug resistance and central nervous system (CNS) metastasis often hampers response to precision therapy for RET-rearranged solid tumors. Vepafestinib (Vepa) is a clinical-stage, potent and selective RET tyrosine-kinase inhibitor (TKI) with proven activity against on-target resistance mutations that arise post first-generation RET TKI. Here, we utilized an array of structural and pharmacokinetic methods to determine blood-brain barrier (BBB) permeability of vepa compared with other RET TKIs. Furthermore, we correlate BBB penetrability of RET inhibitors with in vivo efficacy in preclinical models of RET-rearranged intracranial solid tumors. Methods. RET inhibitors were generated by rational chemical design to identify agents which penetrate BBB more effectively than currently approved RET TKIs, and with reduced efflux transporter susceptibility. Transcellular transport assays were conducted in LLC-PK1 and MDCK II cells expressing P-gp and BCRP, respectively. Brain penetrability was assessed by total (Kp) and unbound (Kp,uu) brain:plasma concentration ratios in male Balb/c mice and microdialysis studies in freely-moving male Wistar rats. Models of CNS metastasis were generated by implanting cells labelled with luciferase into the cerebellum of mice. Studies were conducted in comparison with selpercatinib (Selp), pralsetinib (Pral) and TPX-0046. Results. Assessment of Kp and Kp,uu parameters of analogs revealed an excellent structure-activity relationship where modification at the 6-position of the pyrrolopyrimidine core resulted in improved BBB penetrability. The analog with the most favorable physiochemical and biological properties was Vepa. Vepa showed poor susceptibility to P-gp and BCRP-mediated efflux and better CNS penetrability (Kp,uu: 1.3) and retention than Sel, Pral and TPX-0046. The ratio of the observed concentrations of Vepa in microdialysates from the prefrontal cortex, cerebrospinal fluid (CSF) and plasma free fraction was approximately 1:1:1; these ratios were maintained from 2h to 6.5h after Vepaadministration (up to 8h for CSF). Importantly, Vepa was more effective than Selp at causing regression of intracranial xenograft tumors of RET fusion-driven malignancies (lung adenocarcinoma and sarcoma), thus extending survival of tumor-bearing animals. Common first-generation RET TKI resistance mutations at the solvent front (G810A/C/S/R), gatekeeper (V804L/M), hinge (Y806C) and roof (L730Q/R) regions remained sensitive to Vepa. Vepa was more selective than Selp, Pral and TPX-0046, inhibiting only RET when profiled against a panel of 256 kinases. In contrast, Selp, Pral and TPX-0045 also inhibited VEGFR2, and 4, 11 and 39 additional kinases, respectively. Conclusions. Vepafestinib is a structurally distinct and specific RET inhibitor, with superior brain penetration and retention kinetics. It is more effective than selpercatinib in controlling CNS disease. Vepafestinib is currently undergoing phase 1 and 2 clinical trial for patients with advanced solid tumors with RET alterations (margaRET, NCT04683250). Citation Format: Igor Odintsov, Kentaro Wakayama, Tom Zhang, Satoru Iguchi, Masanori Kato, Allan JW Lui, Inna Khodos, Morana Vojnic, Claudio Giuliano, Annalisa Bonifacio, Monika A Davare, Elisa de Stanchina, Emanuela Lovati, Marc Ladanyi, Isao Miyazaki, Romel Somwar. Preclinical evaluation of the blood-brain barrier permeability and intracranial efficacy of the next-generation RET inhibitor Vepafestinib [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B157.

Abstract C151: BLU-451 is a CNS-penetrant, wild-type-sparing EGFR inhibitor with broad coverage of uncommon EGFR mutations across structure-based subsets

Abstract Introduction: Uncommon EGFR mutations in non-small cell lung cancer (NSCLC), including exon 20 insertion and atypical mutations, are generally associated with poorer clinical outcomes than common EGFR mutations. Patients (pts) with these mutations have limited effective therapeutic options. Afatinib is the only approved agent for uncommon mutations but is associated with high rates of toxicity and limited central nervous system (CNS) penetration. Amivantamab and mobocertinib are approved for patients with relapsed EGFR exon 20 insertion NSCLC but are associated with limitations in efficacy and CNS activity. BLU-451 is an investigational, CNS-penetrant, EGFR-wild-type (WT)–sparing, selective inhibitor against exon 20 insertion and uncommon EGFR mutations that is currently being evaluated in the phase 1/2 CONCERTO study (NCT05241873). Here, we report on the prevalence of uncommon EGFR mutations from a single center, real-world data set (MD Anderson Cancer Center [MDACC]), and report preclinical activity of BLU-451 on a broad spectrum of uncommon EGFR mutations by structure classification. Methods: BLU-451 cellular activity was evaluated in engineered BaF3 cell lines expressing 62 EGFR kinase domain mutations as well as in cell lines dependent on WT EGFR, using the CellTiter-Glo® Luminescent Cell Viability Assay and a phosphorylation-specific EGFR AlphaLISA® assay. The MDACC Moon Shot™ Genomic Marker-Guided Therapy Initiative (GEMINI) database was searched for pts with NSCLC whose tumors harbored EGFR kinase domain mutations. Results: In the MDACC GEMINI database, a total of 1495 unique patients with NSCLC harboring EGFR mutations were identified, including 1025 with classical mutations (exon 19 deletion and L858R) with or without T790M, 223 with exon 20 insertion mutations, and 247 with only atypical mutations. In BaF3 cells, BLU-451 demonstrated nanomolar potency in multiple atypical and exon 20 insertion mutation cell lines with selectivity against WT EGFR. Conclusion: Atypical EGFR mutations represent a sizable NSCLC pt population, of similar magnitude to that of EGFR exon 20 insertion mutations. BLU-451 preclinical data in EGFR atypical and exon 20 insertion mutations showed broad, potent, and selective activity, supporting continued evaluation of BLU-451 in the phase 1/2 CONCERTO study in pts with advanced or metastatic NSCLC harboring uncommon EGFR mutations. Citation Format: Xiuning Le, Yves Millet, Monique Nilsson, Aditya Dhande, Jeffrey Keats, Holly Ponichtera, Joseph Kim, Junqin He, Yasir Y. Elamin, John V. Heymach, Chiara Conti, Stephanie Lee. BLU-451 is a CNS-penetrant, wild-type-sparing EGFR inhibitor with broad coverage of uncommon EGFR mutations across structure-based subsets [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C151.

PRX005, a novel anti‐MTBR tau monoclonal antibody: results from a first‐in‐human double‐blind, placebo‐controlled, single ascending dose phase 1 study

AbstractBackgroundMultiple lines of evidence indicate that tau protein spreads throughout the brain via synaptically connected pathways and that this propagation could be mediated by tau “seeds” containing the microtubule binding region (MTBR) of tau. In addition, cerebrospinal fluid (CSF) MTBR‐tau levels correlate with tau tangles and clinical stages of Alzheimer’s disease. To block the spread of tau pathology, we developed PRX005, a humanized monoclonal tri‐epitopic antibody that binds with high affinity to the R1, R2, and R3 repeats in the MTBR region of tau, and targets both 3R and 4R tau isoforms.MethodHealthy volunteers were randomly assigned to three dose cohorts and randomized in a 3:1 manner to receive either PRX005 or placebo. Primary endpoint was safety and tolerability with up to 2 months of follow‐up. Secondary endpoints included PRX005 pharmacokinetic parameters in plasma and CSF penetrance.ResultA total of 19 healthy volunteer participants received study drug or placebo. PRX005 was well tolerated and had a pharmacokinetic profile typical of IgG1 antibodies, with dose‐proportional increase in plasma concentration and central nervous system (CNS) penetrance. No persistent drug‐induced anti‐drug antibodies were observed following treatment with PRX005. Additional results from this Phase 1 will be presented.ConclusionIn this first‐in‐human, single ascending dose study, PRX005 was well tolerated and achieved CNS concentrations for pharmacological targeting of MTBR‐tau. Our results support the progression of the clinical development of PRX005 in an ongoing, multiple ascending dose study in patients with Alzheimer’s disease.

Measurement of ThioTEPA and Its Metabolite TEPA in Plasma and Cerebrospinal Fluid by Turbulent Flow Chromatography-Tandem Mass Spectrometry.

N,N',N''-Triethylenethiophosphoramide (thioTEPA) is a polyfunctional, organophosphorus alkylating agent that has been a primary treatment of multiple solid malignancies for many years and more recently as part of conditioning regimens prior to hematopoietic stem cell transplantation for a variety of hematologic malignancies. In vivo, thioTEPA is quickly metabolized to N,N',N″-triethylenephosphoramide (TEPA). ThioTEPA and TEPA have similar alkylating activity and both exhibit outstanding central nervous system penetration. Therefore, it is possible and desirable to monitor both compounds in plasma and cerebrospinal fluid (CSF).This chapter describes a method to measure both compounds simultaneously. ThioTEPA and TEPA are extracted with solvent from plasma and CSF by the addition of deuterated internal standards prepared in methanol. Chromatographic separation is attained using a C18 column and mass spectrometry which is performed in the positive ion mode. Herein, we describe a fast, accurate, and sensitive assay to quantify both compounds in plasma and CSF by turbulent flow LC-MS/MS which allows for fast and accurate therapeutic drug monitoring and timely dose modifications.

Multicenter Pilot Trial of Intrathecal Liposomal Cytarabine Combined with FAB Chemoimmunotherapy with Reduced Doxorubicin in CAYA with Mature De-Novo B-NHL

Background: Children, adolescents, and young adults (C-AYA) with newly diagnosed advanced Mature B Non-Hodgkin Lymphoma (MB-NHL), specifically Burkitt Lymphoma (BL) and Diffuse Large B Cell Lymphoma (DLBCL), have achieved ≥ 90% overall survival with multi-agent chemotherapy and intrathecal chemotherapy (IT) without central nervous system (CNS) radiation (Cairo et al., Blood 2007; Goldman/Cairo et al., BJH 2014; Frazier/Cairo, et al., BJH 2014; Minard-Colin, et al., NEJM 2020). Standard therapy includes short but intensive courses of multiagent chemotherapy including CNS-penetrating high dose methotrexate and cytarabine for CNS penetration as well as vincristine, prednisone, doxorubicin, and cyclophosphamide with or without etoposide. Patients also receive 9, 10 and 13 IT doses of intrathecal chemotherapy when treated according to FAB Group B, FAB Group C (CNS -) and FAB Group C (CNS +) protocols, respectively. While this approach has effectively eliminated need for CNS radiation for disease control, the need for sedation of patients during these procedures results in the need for repeated episodes of patient fasting, increased healthcare costs, and most importantly, general anesthesia is associated with long-term late effects in cognitive development (Banerjee et al., JAMA Oncol, 2019). Liposomal cytarabine (LC) is a formulation of cytarabine encapsulated in spherical multivesicular, biodegradable particles known as DepoCyt® which has a maximum-tolerated intrathecal dose of 35 mg in patients between the ages of 3 and 21 years (Bomgaars et al., JCO, 2004). This liposomal formulation has a half-life of 100-263 hours compared with only 3.4 hours of standard cytarabine. As an s-phase specific agent, prolonged exposure may increase its efficacy in controlling CNS disease while decreasing the total number of intraventricular doses required for treatment. Objective: To determine the safety and efficacy of reduction of IT therapy and substitution of LC within modified FAB group B and C backbones of systemic immunochemotherapy. Methods: LC was incorporated into the multiagent chemotherapy regimen in a unique manner to mitigate the risk of possible CNS toxicity. A total of 2 doses of LC were administered as part of the prophylaxis IT therapy for Group B and CNS negative group C patients. A total of 4 doses of LC were administered as part of the treatment of Group C CNS + patients (Table 1). The LC was given only in phases of therapy in which no systemic cytarabine was administered. When Methotrexate was given, the LC was only given after clearance. Dexamethasone replaced prednisone for all patients to mitigate potential CNS toxicities from LC. Results: This trial enrolled 33 patients with newly diagnosed MB-NHL (25 Group B, 8 Group C with 7 CNS+). Median age was 12 (Range 3-25). Males comprised 64% of patients and 52% had Burkitt Lymphoma/Leukemia. The CNS was involved in 21% of patients, and a total of 78 doses of LC was given. Twenty-six patients received 2 prophylactic doses (25 Group B and 1 Group C CNS negative). Six of seven CNS + patients received all 4 planned doses of LC. The median days from the start of the induction cycles until LC administration (post methotrexate clearance) was 3 days. Of the 33 patients, only 1 (3%) had a transient Grade 3 adverse event (facial nerve palsy). With dexamethasone prophylaxis, there were minimal adverse events and no toxic deaths reported. There were no other serious adverse events, such as seizure, headaches, nausea, vomiting, fever, somnolence, confusion, or asthenia that have been previously reported. The 2-year EFS and OS of LC when added to an FAB backbone for MB-NHL, was 94.5% and 97.2%, respectively (Figure 1). Conclusions: By utilizing dexamethasone prophylaxis and waiting for systemic methotrexate clearance, we were able to demonstrate that IT LC in C-AYAs with MB-NHL who received FAB chemoimmunotherapy with HD MTX was feasible, safe, and did not compromise event free and overall survival. We were also able to reduce the total number of IT injections without apparent compromise to CNS prophylaxis and treatment.

Efficacy and Safety of Selinexor-Based Combination Therapy in CNS Lymphoma: A Retrospective Experience

Introduction ： Primary central nervous system lymphoma (PCNSL) is a rare diffuse large B-cell lymphoma (DLBCL) with distinct clinical and biological features, characterized by an aggressive course and poor prognosis. Patients with relapsed/refractory (R/R) disease have an unmet medical need due to a median overall survival (OS) of only 6.8 months. Novel therapies are urgently required for patients with R/R CNSL. In June 2020, the U.S. Food and Drug Administration granted accelerated approval to selinexor for the treatment of adult patients with R/R DLBCL. Selinexor has demonstrated central nervous system (CNS) penetration and activity in secondary CNS lymphoma (SCNSL) patients. Thus, we conducted a retrospective review of PCNSL/SCNSL cases treated with a selinexor-based regimen to preliminarily evaluate its effectiveness and safety. Methods: We retrospectively analyzed the medical records of 13 patients with CNSL who received selinexor-based combination therapy between June 2021 and June 2023 at three research centers in China. Among these cases, 2 were previously untreated, and 11 were relapsed or refractory patients. All patients had histopathologically confirmed DLBCL at the time of initial diagnosis. Data collection included baseline characteristics, treatment efficacy and safety evaluation. Results: A total of 13 patients (10 PCNSL and 3 SCNSL) were included in the study, with a median age of 62 years (range, 28-73), including three male patients. The median international extranodal lymphoma study group (IELSG) score for PCNSL cases was 3 (range, 1-3). The median International Prognosis Index (IPI) score for the three systemic DLBCL cases was 5 (range, 3-5), and three cases were at Ann Arbor stage IV. Among the patients, 11 had relapsed or refractory disease with a median of 2 prior treatments (range, 1-4), and 10 of them were refractory to previous treatments. The main patient characteristics, responses, and toxicities of the selinexor-based combination regimen are summarized in Table 1. Figure 1 presents the response of all evaluable patients. The overall response rate (ORR) of the patients was 84.6% (11 /13), with a complete response (CR) rate of 76.9% (10/13). Both treatment-naïve patients achieved CR after four and six cycles of the selinexor-containing first-line regimen, respectively. They are currently experiencing sustained remission, with the longest duration reaching 13 months. For relapsed/refractory CNSL, the ORR and CR rate were 81.8% (9/11) and 72.7% (8/11), respectively. Two patients had stable disease (SD). Among the 9 patients who achieved remission, 4 patients are still in remission, with the longest duration reaching 20 months, 2 patients received CART bridging therapy, one received radiation therapy, and 2 patients experienced disease progression after 5 months, but all are currently still alive. These patients are currently under continuous observation. Due to the heterogeneity of the selinexor-based regimens, the categories and severity of adverse events (AEs) varied greatly among the different regimens. The median treatment cycle number was six (range, 2-22). One patient died due to pneumonia infection, one patient was lost to follow-up, three patients successfully bridged to CART/RT, and eight patients completed the treatment as planned. The common AEs included thrombocytopenia, infection, nausea, vomiting, and gastrointestinal bleeding(Table 1). Conclusion: This report provides encouraging evidence of the efficacy and tolerable safety of the selinexor-based regimen in the treatment of CNSL. However, further prospective studies with a larger sample size are needed to provide more comprehensive evidence regarding the efficacy of selinexor in central nervous system lymphoma and to determine the appropriate dosage and optimal combination strategies.v

Simvastatin with Intrathecal Dexamethasone Reduces Neurotoxicity in Adults Receiving Chimeric Antigen Receptor (CAR) T-Cells Treatment

Background Chimeric antigen receptor (CAR) T-celltherapy has become the standard of care for many relapsed/refractory hematological malignancies. There are significant associated side effects, most importantly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) that can limit its use in older and vulnerable populations. The rate of ICANS with axicabtagene ciloleucel (axi-cel) in the pivotal studies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) was approximately 60% with grade 3 or higher (≥ G3) in the range of 19-28%. Similarly, with brexucabtagene autoleucel (brexu-cel), ICANS also occurred in approximately 60% with ≥ G3 occurring in 26-31% of patients. The mechanism underlying ICANS remains unclear. The current hypothesis is that endothelial injury caused by systemic immune activation leads to the breakdown of the blood-brain barrier with the influx of pro-inflammatory cytokines into the CSF and subsequent activation of resident immune cells and neuroglial cells leading to local production of cytokines and the clinical syndrome observed. ICANS is treated with systemic steroids that have good central nervous system (CNS) penetration. Statins have been shown to stabilize the endothelium and have anti-inflammatory effects. We are currently evaluating the safety and feasibility of administering simvastatin in addition to intrathecal dexamethasone to decrease the incidence and/or severity of neurotoxicity in CAR-T recipients and we are herein reporting preliminary results. Methods This is a feasibility study (NCT04514029) combining simvastatin 40 mg daily, starting 5 days prior to apheresis and continuing through day +30 with dexamethasone (8 mg) delivered intrathecally (IT) on days -1 and +6 in relation to CAR T-cell infusion. Adult patients (age ≥18 years) receiving axi-cel or brexu-cel for FDA-approved indications are included. The primary endpoint is the percentage of patients who complete 80% of this therapy (pills and intrathecal). Secondary endpoints include the incidence of CRS and ICANS as well as overall response rates (ORR). Results At the time of data cutoff, a total of 15 patients who received treatment with axi-cel or brexu-cel and completed follow-up were enrolled. Baseline demographics and clinical characteristics are summarized in Table 1. Among patients who received axi-cel, 10 patients had DLBCL and 1 patient had FL. For brexu-cel, 2 patients had mantle cell lymphoma (MCL) and 2 had B-acute lymphoblastic leukemia (B-ALL). Median prior lines of treatment was 3 (range 2 to 7) and 11 patients (46.7%) had progressive disease at the time of the treatment. Analysis of baseline inflammatory markers prior to the cell infusion showed that 2 patients (13.3%) had elevated lactate dehydrogenase (LDH; upper limit normal 250 U/L; median 180, range 100 to 279). Eight patients (53.3%) had elevated C-reactive protein (CRP; median 9.24 mg/L, range &amp;lt;3 to 67.8). Ferritin was elevated in 6 patients (40%) (median 382, range 34 to 1749). All patients received &amp;gt; 80% of the total assigned doses. One patient was unable to receive intrathecal therapy due to thrombocytopenia with platelet transfusion refractoriness. All evaluable patients completed oral simvastatin with no patients requiring dose reductions. CRS occurred in 13 patients (86.7%), with ≥ G3 occurring in 1 patient (6.7%). Tocilizumab (8 mg/kg) was administered to 11 patients (73.3%) with the median number of doses being 1 (range 1 to 4). ICANS occurred in 4 patients (26.7%), with ≥ G3 occurring in 2 patients (13.3%) - one G3 and one G4 in the patient who was unable to receive IT therapy. Glucocorticoids were used in 3 patients (20%) for the management of ICANS. There were no grade 4 CRS events and no deaths related to CRS or ICANS. One patient had a vasovagal syncopal episode prior to the beginning of a lumbar puncture. There were no other ≥ G3 AEs associated with the administration of simvastatin or IT dexamethasone. One patient with Richter's had progressive disease at day 30, 4 patients had partial remission, and 10 patients had a complete remission for an ORR of 93%. Conclusions Preliminary results show that simvastatin and intrathecal dexamethasone appear to be feasible, safe, and effective in reducing the incidence and severity of ICANS in patients receiving axi-cel and brexu-cel.

Elenestinib, an Investigational, Next Generation KIT D816V Inhibitor, Reduces Mast Cell Burden, Improves Symptoms, and Has a Favorable Safety Profile in Patients with Indolent Systemic Mastocytosis: Analysis of the Harbor Trial

Introduction Indolent systemic mastocytosis (ISM) is a rare clonal mast cell disease driven by the KIT D816V mutation in nearly all patients. Patients with ISM can present with debilitating acute and chronic cutaneous, gastrointestinal, neurocognitive, and systemic symptoms caused by the release of inflammatory mediators from abnormal mast cells. In some patients, symptoms are not adequately controlled with best supportive care (BSC) medications. Elenestinib (BLU-263) is a novel, investigational, oral, next-generation tyrosine kinase inhibitor that potently and selectively inhibits KIT D816V with limited central nervous system penetration and pharmacokinetics (PK) that support once daily dosing. HARBOR (NCT04910685) is a randomized, double-blind, placebo-controlled, phase 2/3 study assessing efficacy and safety of elenestinib in patients with ISM. Methods Eligible adult patients with ISM, confirmed following central review of bone marrow (BM) pathology, clinical, and laboratory findings per World Health Organization criteria and a moderate-to-severe symptom score based on minimum mean total symptom score (TSS) of the ISM-Symptom Assessment Form (ISM-SAF©2018), were stratified by baseline serum tryptase (&amp;lt;20 ng/mL vs ≥20 ng/mL) and randomly assigned 3:1 to elenestinib 25 mg, 50 mg, or 100 mg once daily + BSC (“elenestinib”) or placebo + BSC (“placebo”). The primary objective of Part 1 was to determine the recommended dose based on safety, PK, and pharmacodynamics. Secondary endpoints included changes in biomarkers of disease burden (serum tryptase, KIT D816V variant allele fraction [VAF], and BM mast cells) and ISM-SAF TSS. Three additional open-label PK groups enrolled patients at 50 mg, 75 mg, and 100 mg to further characterize PK and safety. Results As of data cutoff on July 3, 2023, a total of 122 patients with ISM have received their assigned treatment in Part 1 of the study; 39 were blinded and randomized to elenestinib or placebo, and 83 were treated with open-label elenestinib in the PK groups (21 patients at 50 mg, 34 patients at 75 mg, and 28 patients at 100 mg). Baseline demographics were similar to those reported for the general ISM population. After 12 weeks of therapy, symptom improvement was observed for all dose cohorts, and symptom reduction by TSS was greater for patients on elenestinib versus placebo in the blinded portion of Part 1. Patients receiving elenestinib at 25 mg, 50 mg, and 100 mg doses showed reduction (mean percent) from baseline for tryptase (-15.4%, -50.9%, and -68.4% vs 3.3%, respectively) and KIT D816VVAF (-37.5%, -70.3%, and -77.0% vs -2.5%, respectively) as compared to placebo. Similar reductions in TSS and disease-related biomarkers were observed in the open-label PK cohorts. After a median treatment duration of 35.3 weeks, elenestinib was well-tolerated at all dose levels. There were no treatment-related serious adverse events and no treatment-related adverse events that led to drug discontinuation. Conclusion Elenestinib at all tested doses demonstrated beneficial effects on disease-related symptoms and biomarkers of mast cell burden in this large and maturing cohort of patients with ISM with a moderate-to-severe symptom burden. Elenestinib was well tolerated across all dose levels with a promising early benefit-risk profile in ISM. These preliminary findings will inform dosing for the planned Part 2 of HARBOR, which will examine elenestinib versus placebo in a randomized, blinded, placebo-controlled setting.

819. Experience with Isavuconazole Use for Treatment of Invasive Fungal Infections

Abstract Background The treatment of invasive fungal infections (IFI) is often complicated by drug-drug interactions, toxicities, and host comorbidities. Isavuconazole (ISA) has a favorable side effect profile and has FDA approval for invasive aspergillosis and mucormycosis, but there are fewer data on its efficacy for other microbes and non-pulmonary infections. We report our experience of ISA in IFI treatment, with a particular focus on non-pulmonary sites and other microbial etiologies. Methods We identified patients who received ISA as part of IFI treatment from 1/1/2015–4/1/2020 at Mayo Clinic. We categorized them by organ involvement and by pathogens, and identified patterns of ISA use and clinical outcomes. Results A total of 131 patients were identified. Similar to the existing literature, the majority were pulmonary infections (60%), with 12% invasive sinus infection, 12% central nervous system (CNS) infection, and 7% fungemia. Aspergillus was the most common pathogen (39%), yeast comprised 19%, dimorphic fungi 15%, Mucormycosis 12%, phaeohyphomycosis 5%, and other molds 3%. ISA was used as secondary/salvage therapy in 89% of cases. The response rate varied by organ involvement and pathogen. ISA had complete/partial resolution or achieved stability in 57% of fungemia cases, 63% of invasive sinus infections, 64% of pulmonary infections, and 73% of CNS infections. Aspergillus species had a 67% response rate, with 72% response in yeast infections, 65% rate in dimorphic fungi, 53% for mucormycosis, and 86% in dematiaceous molds. Conclusion Although limited by a small sample size, the subgroup review based on organ site and microbial etiology did seem to show roughly similar results to approved uses. The CNS infections treated with ISA were particularly of interest, given the limited options available with reliable CNS penetration. The current available literature has little to say on the efficacy of ISA in these off-label uses, with the majority being similar case series. This report highlights the importance of prospective trials comparing ISA to other antifungals in a greater variety of indications to better identify when this better-tolerated agent can be safely used. Disclosures Courtney E. Harris, MD, Dynamed: Advisor/Consultant

Leptomeningeal Carcinomatosis from Solid Tumor Malignancies: Treatment Strategies and Biomarkers.

Leptomeningeal metastases/diseases (LMDs) are a late-stage complication of solid tumor or hematologic malignancies. LMD is spread of cancer cells to the layers of the leptomeninges (pia and arachnoid maters) and subarachnoid space seen in 3 to 5% of cancer patients. It is a disseminated disease which carries with it significant neurologic morbidity and mortality. Our understanding of disease pathophysiology is currently lacking; however, advances are being made. As our knowledge of disease pathogenesis has improved, treatment strategies have evolved. Mainstays of treatment such as radiotherapy have changed from involved-field radiotherapy strategies to proton craniospinal irradiation which has demonstrated promising results in recent clinical trials. Systemic treatment strategies have also improved from more traditional chemotherapeutics with limited central nervous system (CNS) penetration to more targeted therapies with better CNS tumor response. Many challenges remain from earlier clinical detection of disease through improvement of active treatment options, but we are getting closer to meaningful treatment.

Preclinical Characterization of AZD9574, a Blood-Brain Barrier Penetrant Inhibitor of PARP1.

We evaluated the properties and activity of AZD9574, a blood-brain barrier (BBB) penetrant selective inhibitor of PARP1, and assessed its efficacy and safety alone and in combination with temozolomide (TMZ) in preclinical models. AZD9574 was interrogated in vitro for selectivity, PARylation inhibition, PARP-DNA trapping, the ability to cross the BBB, and the potential to inhibit cancer cell proliferation. In vivo efficacy was determined using subcutaneous as well as intracranial mouse xenograft models. Mouse, rat, and monkey were used to assess AZD9574 BBB penetration and rat models were used to evaluate potential hematotoxicity for AZD9574 monotherapy and the TMZ combination. AZD9574 demonstrated PARP1-selectivity in fluorescence anisotropy, PARylation, and PARP-DNA trapping assays and in vivo experiments demonstrated BBB penetration. AZD9574 showed potent single agent efficacy in preclinical models with homologous recombination repair deficiency in vitro and in vivo. In an O6-methylguanine-DNA methyltransferase (MGMT)-methylated orthotopic glioma model, AZD9574 in combination with TMZ was superior in extending the survival of tumor-bearing mice compared with TMZ alone. The combination of three key features-PARP1 selectivity, PARP1 trapping profile, and high central nervous system penetration in a single molecule-supports the development of AZD9574 as the best-in-class PARP inhibitor for the treatment of primary and secondary brain tumors. As documented by in vitro and in vivo studies, AZD9574 shows robust anticancer efficacy as a single agent as well as in combination with TMZ. AZD9574 is currently in a phase I trial (NCT05417594). See related commentary by Lynce and Lin, p. 1217.

INNV-40. DURABLE 10-YEAR RESPONSE TO VEMURAFENIB IN A PATIENT WITH CNS HAIRY CELL LEUKEMIA

Abstract Hairy cell leukemia (HCL) is an uncommon form of chronic B-cell lymphoproliferative disease, accounting for approximately 2% of all cases of leukemias. Although there have been rare instances of HCL affecting the central nervous system (CNS), these cases usually involve highly fatal leptomeningeal disease or direct leukemic infiltration into the brain. The BRAF V600E mutation, leading to the constitutive activation of the MAPK/ERK signaling pathway, is recognized as a key activating mutation in HCL and is present in almost all HCL patients. First-line treatment for HCL remains purine analogs; however, up to 20% of patients only achieve a partial response. Vemurafenib, an oral inhibitor of BRAF V600E, has demonstrated strong anti-tumor activity in patients with systemic relapsed/refractory HCL and has good CNS penetration. In this case study, we present a 67-year-old patient with HCL who initially presented with multifocal cranial neuropathies In August of 2013. His brain MRIs demonstrated multiple enhancing leptomeningeal foci. While a combination of cytarabine, methotrexate, and rituximab initially prevented disease progression, he experienced multiple relapses over the course of 2 years and eventually became refractory to treatment. Subsequently, the patient was started on vemurafenib, which resulted in the complete resolution of all lesions observed on MRIs. This response has persisted for 10 years since starting the medication. We suggest that besides its high response rate in systemic relapsed/refractory HCL, vemurafenib may offer benefits for patients with CNS involvement who are refractory to conventional chemotherapies and can achieve a durable response. Further investigation is needed to potentially establish vemurafenib as a first-line treatment option for HCL patients with CNS involvement.