Tisagenlecleucel Outcomes in Relapsed/Refractory Extramedullary ALL: A Pediatric Real World CAR Consortium Report.

Chimeric antigen receptor (CAR) T-cells have transformed the therapeutic options for relapsed/refractory (R/R) B-cell ALL. Data for CAR therapy in extramedullary (EM) involvement is limited. Retrospective data was abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 US institutions. Response (CR) rate, overall survival (OS), relapse-free survival (RFS), and duration of B-cell aplasia (BCA) in patients referred for tisagenlecleucel with EM disease (both CNS3 and non-CNS EM) were compared to bone marrow (BM) only. Patients with CNS disease were further stratified for comparison. Outcomes are reported on 55 patients with EM disease prior to CAR (n=40 CNS3; n=15 non-CNS EM). The median age at infusion in CNS cohort was 10 years (range <1-25) and the non-CNS EM cohort was 13 years (2-26). In patients with CNS disease, 88% (35/40) achieved a CR, versus only 66% (10/15) with non-CNS EM disease. Patients with CNS disease (both with and without marrow involvement) had comparable 24-month OS outcomes to non-CNS EM or BM only (p=0.41). There was no difference in 12-month RFS between CNS, non-CNS EM, or BM only patients (p=0.92). No increased toxicity was seen with CNS or non-CNS EM disease (p=0.3). Active CNS disease at time of infusion did not impact outcomes. Isolated (iCNS) disease trended towards improved OS when compared to combined CNS and BM (p=0.12). R/R EM disease can be effectively treated with tisagenlecleucel with toxicity, relapse rates and survival rates comparable to patients with BM only. Outcomes for iCNS relapse are encouraging.

Microarray profiling predicts early neurological and immune phenotypic traits in advance of CNS disease during disease progression in Trypanosoma. b. brucei infected CD1 mouse brains

Human African trypanosomiasis (HAT), also known as sleeping sickness, is a major cause of mortality and morbidity in sub-Saharan Africa. We hypothesised that recent findings of neurological features and parasite brain infiltration occurring at much earlier stages in HAT than previously thought could be explained by early activation of host genetic programmes controlling CNS disease. Accordingly, a transcriptomal analysis was performed on brain tissue at 0, 7, 14, 21 and 28dpi from the HAT CD1/GVR35 mouse model. Up to 21dpi, most parasites are restricted to the blood and lymphatic system. Thereafter the trypanosomes enter the brain initiating the encephalitic stage. Analysis of ten different time point Comparison pairings, revealed a dynamic transcriptome comprising four message populations. All 7dpi Comparisons had by far more differentially expressed genes compared to all others. Prior to invasion of the parenchyma, by 7dpi, ~2,000 genes were up-regulated, denoted [7dpi↑] in contrast to a down regulated population [7dpi↓] also numbering ~2,000. However, by 14dpi both patterns had returned to around the pre-infected levels. The third, [28dpi↑] featured over three hundred transcripts which had increased modestly up to14dpi, thereafter were significantly up-regulated and peaked at 28dpi. The fourth, a minor population, [7dpi↑-28dpi↑], had similar elevated levels at 7dpi and 28dpi. KEGG and GO enrichment analysis predicted a diverse phenotype by 7dpi with changes to innate and adaptive immunity, a Type I interferon response, neurotransmission, synaptic plasticity, pleiotropic signalling, circadian activity and vascular permeability without disruption of the blood brain barrier. This key observation is consistent with recent rodent model neuroinvasion studies and clinical reports of Stage 1 HAT patients exhibiting CNS symptoms. Together, these findings challenge the strict Stage1/Stage2 phenotypic demarcation in HAT and show that that significant neurological, and immune changes can be detected prior to the onset of CNS disease.

Non–Multiple Sclerosis Central Nervous System Inflammatory Disease

Multiple sclerosis (MS) is the most common inflammatory central nervous system (CNS) disease. Yet, clinicians should be cognizant of other demyelinating and nondemyelinating CNS inflammatory diseases, some of which mimic MS. This chapter reviews the spectrum of non-MS CNS inflammatory diseases and MS mimics.

262. Epidemiology, Treatment, and Clinical Outcomes of Methicillin-Sensitive Staphylococcus aureus (MSSA) Bacteremia Complicated by Central Nervous System (CNS) Disease within the Veterans Affairs (VA) Healthcare System

Background The epidemiology of methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia (BSI) complicated by central nervous system (CNS) involvement is not well defined or described. We aimed to identify patients with MSSA BSI with CNS disease using imaging reports and define the epidemiology, characteristics, management, and associated clinical outcomes. Methods We conducted a retrospective study of inpatients (1/1/2014 to 10/31/2019) with MSSA BSI and head imaging (± 7 days of BSI). Imaging reports were categorized into probable, possible, or no CNS involvement. Charts were reviewed to assess source and metastatic sites of infection, severity of illness, and clinical course. Demographics, comorbidities, antibiotic use, and morbidity and mortality were electronically extracted from the corporate data warehouse. Primary antibiotic treatment was defined as the antibiotic received for the highest proportion of treatment course. Results 1852 patients had MSSA BSI and a head imagining performed. 151 (8%) had probable and 56 (3%) had possible CNS involvement. Embolic disease (n=167 [87%]) was the most common type of CNS disease (136 [83%] with probable CNS disease). Overall, high severity of illness defined by ICU admission (52%), vasopressor (7%), or mechanical ventilation (15%) was observed overall and was more common with probable CNS disease. Cefazolin was the most common primary antibiotic (71 [40%]), followed by nafcillin or oxacillin (51 [29%]). 16 (31%) patients had an adverse reaction to nafcillin. 69 (33%) patients died by day 30 and 88 (43%) by day 90. Recurrent CNS infections and bacteremia by day 90 was observed in 11 (6%) and 6 (3%). Conclusion We propose a definition of MSSA bacteremia complicated by CNS disease. CNS disease with MSSA bacteremia is infrequent with the most common manifestation being embolic disease. A significant number of patients with MSSA bacteremia were treated with cefazolin despite evidence of CNS disease. Overall mortality was high. Given higher rates of adverse drug events with nafcillin or oxacillin, comparative effectiveness studies are needed to further define the role of cefazolin for MSSA bacteremia with CNS disease. Disclosures All Authors: No reported disclosures

CNS Involvement in AML at Diagnosis is Rare and does not Affect Response or Survival: Data from 11 ECOG-ACRIN Trials

Central nervous system (CNS) involvement in newly diagnosed acute myeloid leukemia (AML) patients is rare and systematic data regarding outcome are scarce. This retrospective study summarized data from 11 consecutive ECOG-ACRIN clinical trials for newly diagnosed AML patients. 3240 patients with AML were analyzed and 36 (1.11%) were found to have CNS involvement at diagnosis. The incidence of CNS disease among the 5 studies with per protocol mandatory lumbar puncture (LP) was similar to the incidence among studies where LP was done at the discretion of the investigator (0.86% vs. 1.41%, p=0.18). There was no significant difference in the complete remission (CR) rate between patients with CNS involvement and those with other extramedullary disease (EMD) sites or those with no EMD (52.8% vs. 59.3-60%). The median overall survival (OS) of CNS-positive patients, other EMD or no EMD was 11.4, 11.3 and 12.7 months, respectively. There was no difference in OS between patients with CNS involvement and those with other EMD (HR 0.96, adjusted p=0.84) or no EMD (HR 1.19, adjusted p=0.44). In conclusion, the reported incidence of CNS involvement of newly diagnosed AML is low (1.1%), irrespective of whether an LP is mandatory or not. The presence of CNS disease at diagnosis does not appear, in and of itself, to portend for a poor prognosis for either achieving an initial CR or OS.

PGRMC1 Exerts Its Function of Anti-Influenza Virus in the Central Nervous System

Central nervous system (CNS) disease is one of the most common extra-respiratory tract complications of influenza A virus (IAV) infections. However, there is still little knowledge about IAV regulating host responses in brain.

Analysis of the pan-Asian subgroup of patients in the NALA Trial: a randomized phase III NALA Trial comparing neratinib+capecitabine (N+C) vs lapatinib+capecitabine (L+C) in patients with HER2+metastatic breast cancer (mBC) previously treated with two or more HER2-directed regimens

Purpose Neratinib, an irreversible pan-HER tyrosine kinase inhibitor, has demonstrated systemic efficacy and intracranial activity in various stages of HER2+breast cancer. NALA was a phase III randomized trial that assessed the efficacy and safety of neratinib+capecitabine (N+C) against lapatinib+capecitabine (L+C) in HER2+ metastatic breast cancer (mBC) patients who had received ≥ 2 HER2-directed regimens. Descriptive analysis results of the Asian subgroup in the NALA study are reported herein. Methods 621 centrally assessed HER2+ mBC patients were enrolled, 202 of whom were Asian. Those with stable, asymptomatic brain metastases (BM) were eligible for study entry. Patients were randomized 1:1 to N (240 mg qd) + C (750 mg/m2 bid, day 1–14) with loperamide prophylaxis or to L (1250 mg qd) + C (1000 mg/m2 bid, day 1–14) in 21-day cycles. Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints included time to intervention for central nervous system (CNS) disease, objective response rate, duration of response (DoR), clinical benefit rate, and safety. Results 104 and 98 Asian patients were randomly assigned to receive N+C or L+C, respectively. Median PFS of N+C and L+C was 7.0 and 5.4 months (P = 0.0011), respectively. Overall cumulative incidence of intervention for CNS disease was lower with N+C (27.9 versus 33.8%; P = 0.039). Both median OS (23.8 versus 18.7 months; P = 0.185) and DoR (11.1 versus 4.2 months; P < 0.0001) were extended with N+C, compared to L+C. The incidences of grade 3/4 treatment emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were mostly comparable between the two arms. Diarrhea and palmar-plantar erythrodysesthesia were the most frequent TEAEs in both arms, similar to the overall population in incidence and severity. Conclusion Consistent with the efficacy profile observed in the overall study population, Asian patients with HER2+ mBC, who had received ≥ 2 HER2-directed regimens, may also benefit from N+C. No new safety signals were noted. Clinical trial registration NCT01808573

The Impact of IgA and the Microbiota on CNS Disease

Although anatomically distant from the central nervous system (CNS), gut-derived signals can dynamically regulate both peripheral immune cells and CNS-resident glial cells to modulate disease. Recent discoveries of specific microbial taxa and microbial derived metabolites that modulate neuroinflammation and neurodegeneration have provided mechanistic insight into how the gut may modulate the CNS. Furthermore, the participation of the gut in regulation of peripheral and CNS immune activity introduces a potential therapeutic target. This review addresses emerging literature on how the microbiome can affect glia and circulating lymphocytes in preclinical models of human CNS disease. Critically, this review also discusses how the host may in turn influence the microbiome, and how this may impact CNS homeostasis and disease, potentially through the production of IgA.