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Chimeric antigen receptor T-cell therapy (CART) has extended survival of patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). However, limited durability of response and prevalent toxicities remain problematic. Identifying patients at high risk of disease progression, toxicity, and death would inform treatment decisions. Although the cumulative illness rating scale (CIRS) has been shown to correlate with survival in B-cell malignancies, no prognostic score has been independently validated in CART recipients. We retrospectively identified 577 patients with relapsed/refractory DLBCL indicated for CART at 9 academic centers to form a learning cohort (LC). Random survival forest modeling of overall survival (OS) and progression-free survival (PFS) was performed to determine the most influential CIRS organ systems and severity grades. The presence of a severe comorbidity (CIRS score ≥3) in the respiratory, upper gastrointestinal, hepatic, or renal system - herein termed "Severe4" - had the greatest impact on post-CART survival. Controlling for other prognostic factors (number of prior therapies, Eastern Cooperative Oncology Group performance status, BCL6 translocation, molecular subtype), Severe4 was strongly associated with shorter PFS and OS in the LC (hazards ratio [HR]=2.15 and 1.94, respectively; p

Introduction: CAR T-cell therapy (CART) has dramatically improved outcomes for patients (pts) with relapsed/refractory (r/r) DLBCL, but the majority of pts still have poor outcomes due to progressive disease and toxicities. Here we used a machine learning algorithm to rank the prognostic impact of specific comorbidities measured by the Cumulative Illness Rating Scale (CIRS) in DLBCL pts indicated for CART in a multicenter learning cohort (LC) and a separate validation cohort (VC). Methods: pts with r/r DLBCL included in RWE analysis underwent leukapheresis for CART at 10 academic centers. CIRS was assessed at the time of T-cell collection (Salvi et al, 2008). Progression-free survival (PFS) and overall survival (OS) were measured from T-cell collection. Random survival forest (RSF) modeling of PFS and OS was repeatedly applied to random subsets of the LC to determine the most important CIRS categories and comorbidity levels in the presence of known prognostic factors. Cox proportional hazards models of PFS and OS were fit to both cohorts. Associations between comorbidities and CART adverse events were evaluated with Fisher’s exact test. Results: The LC comprised 577 pts, median age of 63 (range, 19-90); 90% had ECOG 0-1. Median number of prior therapies was 3 (range, 1-11). GCB subtype was found in 54% of pts, with 38% non-GCB and 8% unknown. Twenty-seven pts (4.7%) died before CART infusion. Of the 550 pts who received CART, 71% got axicabtagene ciloleucel, 22% tisagenlecleucel, and 7% lisocabtagene maraleucel. The median CIRS score was 7 (range, 0-25) with 54% having CIRS ≥7. The median PFS was 11 months (95% CI: 8 – 15) and OS 30 months (95% CI: 23 – NA), with a median follow-up time of 20 months. Although CIRS ≥7 was significantly associated with PFS (HR=1.26) and OS (HR=1.35) in univariable analysis, it did not remain significant in multivariable models. According to a RSF tree depth-weighted nodal split score, severe comorbidities in the following CIRS categories had the greatest impact on PFS: respiratory, upper GI, renal, and hepatic (denoted Severe4, 9% of pts). When accounting for other significant variables, Severe4 was independently associated with inferior PFS (HR=2.45, p Citation Format: Geoffrey Shouse, Andy Kaempf, Max Gordon, David Yashar, Audrey M Sigmund, Gordon Smilnak, Steven M Bair, Agrima Mian, Lindsey Fitzgerald, Amneet Bajwa, Samantha Jaglowski, Neil Bailey, Mayzar Shadman, Krish Patel, Deborah M Stephens, Manali Kamdar, Brian T Hill, Jordon Gauthier, Reem Karmali, Loretta Nastoupil, Adam S Kittai, Alexey V Danilov. Impact of a validated composite comorbidity score on outcomes in patients treated with CAR T-cell therapy for diffuse large B cell lymphoma (DLBCL): A multicenter real-world evidence (RWE) study [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A27.

Background Previous epidemiologic studies have suggested an association between AMD and AD, and several therapeutic agents are being developed based on this principle. However, prior studies have provided conflicting results due in part to their reliance on clinical diagnoses that are not based on gold-standard histopathology. Objective To use histopathologic standards for diagnosis in order to determine the co-prevalence of AD among patients with and without AMD. Methods This is a cross-sectional study of 157 autopsy ocular specimens from patients with and without AMD that were greater than 75 years of age at death. Sarks staging was used to document the severity of AMD, and Braak and Braak staging was used to assess the severity of AD in corresponding brain specimens. The prevalence of AD within different severities of AMD was determined using univariable and multivariable logistic regression. Results 58% of autopsy eyes had AMD. The prevalence of AD was lower in AMD subjects (63%) compared to non-AMD subjects (73%), even when grouped by severity (all p > 0.15). The likelihood of AD was significantly less in AMD subjects, even after adjusting for age and sex in multivariable analysis (OR 0.47, p = 0.049). Conclusion Histopathologic diagnoses fail to support an increase in prevalence of AD among subjects with AMD, even when disease severity is considered.

BackgroundLeptomeningeal metastases (LM), late-stage cancer when malignant cells migrate to the subarachnoid space (SAS), have an extremely poor prognosis. Current treatment regimens fall short in effectively reducing SAS tumor burden. Neurapheresis therapy is a novel approach employing filtration and enhanced circulation of the cerebrospinal fluid (CSF). Here, we examine the in vitro use of neurapheresis therapy as a novel, adjunctive treatment option for LM by filtering cells and augmenting the distribution of drugs that may have the potential to enhance the current clinical approach.MethodsClinically relevant concentrations of VX2 carcinoma cells were suspended in artificial CSF. The neurapheresis system’s ability to clear VX2 carcinoma cells was tested with and without the chemotherapeutic presence (methotrexate [MTX]). The VX2 cell concentration following each filtration cycle and the number of cycles required to reach the limit of detection were calculated. The ability of neurapheresis therapy to circulate, distribute, and maintain therapeutic levels of MTX was assessed using a cranial–spinal model of the SAS. The distribution of a 6 mg dose was monitored for 48 h. An MTX-specific ELISA measured drug concentration at ventricular, cervical, and lumbar sites in the model over time.ResultsIn vitro filtration of VX2 cancer cells with neurapheresis therapy alone resulted in a 2.3-log reduction in cancer cell concentration in 7.5 h and a 2.4-log reduction in live-cancer cell concentration in 7.5 h when used with MTX. Cranial–spinal model experiments demonstrated the ability of neurapheresis therapy to enhance the circulation of MTX in CSF along the neuraxis.ConclusionNeurapheresis has the potential to act as an adjunct therapy for LM patients and significantly improve the standard of care.

Cryptococcal meningitis (CM) has emerged as the most common life-threatening fungal meningitis worldwide. Current management involves a sequential, longitudinal regimen of antifungals; despite a significant improvement in survival compared with uniform mortality without treatment, this drug paradigm has not led to a consistent cure. Neurapheresis therapy, extracorporeal filtration of yeasts from cerebrospinal fluid (CSF) in infected hosts, is presented here as a novel, one-time therapy for CM. In vitro filtration of CSF through this platform yielded a 5-log reduction in concentration of the yeast and a 1-log reduction in its polysaccharide antigen over 24 hours. Additionally, an analogous closed-loop system achieved 97% clearance of yeasts from the subarachnoid space in a rabbit model over 4–6 hours. This is the first publication demonstrating the direct ability to rapidly clear, both in vitro and in vivo, the otherwise slowly removed fungal pathogen that directly contributes to the morbidity and mortality seen in CM.

Introduction: CAR T-cell therapy has dramatically improved outcomes for patients (pts) with relapsed/refractory (r/r) DLBCL, with some achieving durable response. Still, the majority of pts have poor outcomes with CAR-T due to progressive disease, while inherent characteristics may predispose pts to CAR-T toxicities. Tools quantifying frailty and comorbidities have not been verified in large patient cohorts. The Cumulative Illness Rating Scale (CIRS) is a comprehensive tool that has been found to predict outcomes in various B cell malignancies. Here we use a machine learning algorithm to rank the prognostic impact of specific comorbidities, as measured by CIRS, and then assess survival and toxicities in pts treated with commercially available CAR T-cell products for DLBCL. Methods: We conducted a retrospective RWE analysis of pts with r/r DLBCL who underwent leukapheresis for CART at 9 academic centers. CIRS was assessed at the time of T-cell collection and calculated as in Salvi et al, 2008. High comorbidity burden was defined using a published cutoff of CIRS score ≥7. Progression-free survival (PFS) and overall survival (OS) were measured from T-cell collection. Repeated subsampling and random survival forest (RSF) modeling of PFS were used to determine the most prognostic CIRS categories in the presence of covariates. Cox proportional hazards models were fit to quantify the association between survival and the following patient features: IPI at diagnosis, concurrent indolent lymphoma, age, ECOG performance status, number of prior therapies, prior transplant, number of medications, cell of origin subtype, complex karyotype, MYC rearrangement by FISH, and MYC+BCL2/BCL6 rearrangement (double-hit). Associations between comorbidities and CAR-T adverse events were evaluated with Fisher's exact test. Results: We analyzed data from 577 pts, with a median age of 63 (range, 19-90); 90% had ECOG 0-1. Median number of prior therapies was 3 (range, 1-11) and 25% of pts (n=143) had prior autologous stem cell transplant. GCB subtype was found in 54% of pts (n=312), with 38% (n=218) non-GCB and 8% (n=47) unknown (Hahn's algorithm). MYC gene rearrangement was present in 21% and double-hit in 16% with 9% lacking FISH. Twenty-seven pts (4.7%) died before CAR-T infusion (progressive disease in 24 and infection in 3). Of the 550 pts who received CAR-T, 71% (n=393) got axicabtagene ciloleucel, 22% (n=120) tisagenlecleucel, and 7% (n=37) lisocabtagene maraleucel. The median CIRS score was 7 (range, 0-25) with 54% (n=309) having CIRS ≥7. The most frequent comorbidities were seen in the vascular (51%), endocrine (45%), and hypertension (43%) organ system categories. PFS event was observed in 56% of pts and 41% died, while survivors had a median follow-up time of 20 months. Median survival estimates were 11 months (95% CI: 8 - 15) for PFS and 30 months (95% CI: 23 - NA) for OS. CIRS ≥7 was significantly associated with PFS (HR=1.26, Fig 1A) and OS (HR=1.35, Fig 1B) in univariable analysis. According to RSF variable importance and node splits, key CIRS categories were respiratory, upper GI, renal, and hepatic (Fig 1C). Multivariable analysis showed higher ECOG (2/3 vs 1 vs 0) and 3 or more prior lines of treatment predicted shorter PFS and OS. Non-GCB subtype was related to reduced PFS but not OS, while double-hit status did not correlate with either outcome. Interestingly, CIRS ≥7 was not a significant predictor of outcomes in multivariable models. However, a severe comorbidity in any of the above four systems (denoted "Severe4", 9% of pts) was independently associated with inferior PFS (HR=2.45, Fig 1D) and OS (HR=2.30, Fig 1E). Although CIRS ≥7 was not associated with the development of CRS, pts with "Severe4" had a higher rate of grade ≥3 CRS (16% vs 6%; p=0.013). In addition, development of grade ≥3 ICANS was associated with CIRS ≥7 (26% vs 12%; p Conclusions: In this large RWE study, we demonstrate that CIRS is predictive of outcomes and identify a composite index comprising four CIRS organ systems (respiratory, upper GI, renal and hepatic; "Severe4") that had prognostic significance in CAR-T recipients for r/r DLBCL. "Severe4" is predictive of severe CRS and CIRS ≥7 is predictive of severe ICANS. The underlying mechanism leading to this observation is an area of active ongoing investigation. Given these results, CIRS evaluation and "Severe4" should be considered prior to CAR-T in DLBCL. GS & AK contributed equally Figure 1 Figure 1. Disclosures Shouse: Beigene Pharmaceuticals: Honoraria; Kite Pharmaceuticals: Speakers Bureau. Jaglowski: Novartis: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Juno: Consultancy; Takeda: Consultancy; CRISPR Therapeutics: Consultancy. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Patel: Kite Pharma: Consultancy, Speakers Bureau; Morphosys: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Bristol Myers Squibb: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy, Speakers Bureau; MEI Pharma: Consultancy; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy; Lilly: Consultancy. Stephens: CSL Behring: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Novartis: Research Funding; JUNO: Research Funding; Mingsight: Research Funding; Arqule: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kamdar: TG Therapeutics: Research Funding; Adaptive Biotechnologies: Consultancy; ADC Therapeutics: Consultancy; AstraZeneca: Consultancy; Genentech: Research Funding; Genetech: Other; Celgene: Other; SeaGen: Speakers Bureau; Celgene (BMS): Consultancy; Kite: Consultancy; KaryoPharm: Consultancy; AbbVie: Consultancy. Hill: Novartis: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Pfizer: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Gentenech: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding. Karmali: Genentech: Consultancy; BeiGene: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Karyopharm: Consultancy; Takeda: Research Funding; EUSA: Consultancy; Epizyme: Consultancy; Roche: Consultancy; Morphosys: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; Janssen/Pharmacyclics: Consultancy. Kittai: Abbvie: Consultancy; Bristol-Meyers Squibb: Consultancy; Janssen: Consultancy. Danilov: Abbvie: Consultancy, Honoraria; TG Therapeutics: Consultancy, Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Bayer Oncology: Consultancy, Honoraria, Research Funding; Gilead Sciences: Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Rigel Pharm: Honoraria; Astra Zeneca: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding.

IntroductionPrevious studies evaluating the association between clinically diagnosed Alzheimer's disease (AD) and age-related macular degeneration (AMD) have generated conflicting results. This study is the first to assess whether AMD prevalence is higher in AD patients than non-AD controls by using histopathology to definitively diagnose AD.MethodsThis was a retrospective case-control study utilizing diagnostic information extracted from autopsy reports of patients age 75 and above, including 115 with a neuropathological diagnosis of AD and 57 age-matched normal controls.ResultsThe rate of AMD was not significantly higher in AD cases (53.0%) than in controls (59.6%) (z = 0.820, p = 0.794). AMD severity as determined by Sarks score was similar between AD patients and controls (χ2 = 2.96, p = 0.706). There was also no significant association between Braak stage of AD severity and AMD (χ2 = 4.55, p = 0.602).DiscussionNo significant effect of AD diagnosis or pathologic severity on AMD comorbidity was found, suggesting that any shared mechanisms between AMD and AD may be nondeterministic.

Cryptococcus spp., important fungal pathogens, are the leading cause of fungus-related mortality in human immunodeficiency virus-infected patients, and new therapeutic options are desperately needed. Isavuconazonium sulfate, a newer triazole antifungal agent, was studied to characterize the exposure-response relationship in a rabbit model of cryptococcal meningoencephalitis. Rabbits treated with isavuconazonium sulfate were compared with those treated with fluconazole and untreated controls., Cryptococcus spp., important fungal pathogens, are the leading cause of fungus-related mortality in human immunodeficiency virus-infected patients, and new therapeutic options are desperately needed. Isavuconazonium sulfate, a newer triazole antifungal agent, was studied to characterize the exposure-response relationship in a rabbit model of cryptococcal meningoencephalitis. Rabbits treated with isavuconazonium sulfate were compared with those treated with fluconazole and untreated controls. The fungal burden in the cerebrospinal fluid was measured serially over time, while the yeast concentrations in the brain and the eye (aqueous humor) were determined at the end of therapy. The exposure impact of isavuconazonium sulfate dosing in the rabbit was linked using mathematical modeling. Similar significant reductions in the fungal burden in the brain and cerebrospinal fluid in rabbits treated with isavuconazonium sulfate and fluconazole compared with that in the untreated controls were observed. No dose-dependent response was demonstrated with isavuconazonium sulfate treatment in this study. The treatment of cryptococcal meningoencephalitis with isavuconazonium sulfate was similar to that with fluconazole. Dose-dependent reductions in yeast over time were not demonstrated, which limited our ability to estimate the pharmacodynamic target. Further nonclinical and clinical studies are needed in order to characterize the extent of the exposure-response relationship in cryptococcal meningoencephalitis. However, this study suggests that isavuconazonium sulfate, like fluconazole, could be beneficial in the setting of consolidation and maintenance therapy, rather than induction monotherapy, in high-burden cryptococcal meningoencephalitis.

e19504 Background: Cachexia is a known independent factor for negative outcomes in several cancer populations at early and late stages, but has not been in investigated in cancer patients receiving Chimeric Antigen Receptor T-cell therapy (CART). Our objective was to evaluate the relationship between cachexia and clinical and functional outcomes in patients with lymphoma receiving CART. Methods: Design: Retrospective cohort study including 70 adult patients with aggressive B-cell lymphomas (Diffuse Large B-cell or Mantle Cell Lymphoma) who received CART. Cachexia markers: body weight loss (BWL), BMI, albumin, creatinine, and neutrophil-to-lymphocyte ratio (NLR) – each captured at diagnosis, pre-collection, CART initiation, and through day 360 post-CART. Outcome measures: Primary outcomes: Disease relapse after CART and 90-day mortality. Secondary outcome: Need for rehabilitation services post-acute care (inpatient rehabilitation or home physical therapy). Statistical analyses: Linear regression modeling, area under the curve analysis, and multivariate modeling (any univariates with p < 0.25). Co-variates: age, ECOG PS, IPI, cell of origin, MYC status, number of prior cancer therapies, time from diagnosis to CART, and need for bridging / steroid pre-CART. Results: In longitudinal modeling from diagnosis to day 360, CART patients who relapsed had linear associations over time with BWL since diagnosis (p < 0.01), NLR (p < 0.0001), creatinine (p = 0.045), and albumin (p < 0.001). In univariate analyses (see table): at pre-collection, high NLR and BWL increased odds of relapse; at treatment, high NLR and CRP increased odds of mortality; and at D30, and BWL and high NLR increased odds of relapse and mortality, respectively. In multivariate analyses (see table, # = independent association), BWL and high NLR independently associated with relapse and mortality, respectively. Significant covariates included need for bridging (p = 0.02), steroid therapy pre-CART (p < 0.01), and time from diagnosis to CART (p = 0.02). Secondarily, BWL and low albumin pre-CART increased odds of needing rehabilitation services, with BWL independently associating in multivariate models (OR = infinity, p < 0.001). Conclusions: Cachexia markers, such as BWL from diagnosis and NLR, are candidate predictors of relapse and mortality after CART. Specific markers could also assign patients to neo/adjuvant rehabilitative and medical therapies targeted towards cachexia. Overall, this study suggests that cachexia may alter the clinical and functional trajectory of lymphoma patients receiving CART.[Table: see text]