Citations

Background: Diffuse large B-cell lymphoma (DLBCL) is frequently curable after frontline therapy, however, relapses can occur after achievement of a PET-negative complete remission (CR). Early detection of relapse may be associated with improved outcomes with second-line curative intent therapy or novel therapies. Controversy exists regarding the utility of post-therapy surveillance imaging which is associated with patient (pt) anxiety, radiation exposure, false-positive results, and cost. A retrospective study found that serial minimal residual disease (MRD) monitoring during DLBCL surveillance could identify pts at risk of relapse before clinical evidence of disease (Roschewski, Lancet Oncol, 2015). In this multicenter prospective study, we assessed whether a next-generation sequencing (NGS)-based MRD assay could be used for early detection of molecular relapse in DLBCL. Methods: Eligible pts with DLBCL or high-grade B-cell lymphoma (HGBCL) who received anthracycline-containing chemotherapy were enrolled across five cancer centers. In pts who achieved a PET-negative CR, serial peripheral blood samples were obtained every 3 months (mos) and CT scans every 6 mos for 2 years (yrs) post-treatment. The clonoSEQ® next generation sequencing (NGS) MRD assay (Adaptive Biotechnologies, Seattle, WA) that leverages multiplex PCR followed by NGS to identify and track rearrangements of IgH, V-J, D-J and IgK/L loci and translocations in Bcl1/2-IgH was used. MRD positive was defined as any detectable rearrangement and MRD negative as no evidence of rearrangement. We also reported MRD positivity above the limit of detection (LOD) (observations required to have 95% reproducibility). Interim futility analysis was performed after approximately 50% of anticipated relapses occurred to assess the preliminary sensitivity of the assay. Progression-free survival (PFS) was defined as time from treatment start date to relapse or death. Results: 501 pts were enrolled and 401 were evaluable (pre-treatment tumor pathology available, completed frontline treatment, and achieved PET-negative CR at end-of-treatment). Baseline characteristics were median age of 62 yrs (range 19-95), male sex 58%, advanced stage 61%, and poor-risk by R-IPI 40% (Table 1). Histologies included DLBCL, NOS (86%), primary mediastinal B-cell lymphoma (6%), HGBCL (5%), T-cell rich B-cell lymphoma (1%), and other (1%). Pts received regimens including RCHOP x 6 cycles (36%), REPOCH x 6 cycles (20%), clinical trial (15%), combined modality therapy (RCHOP+RT) (10%), and other RCHOP variations (19%). Among the 401 evaluable pts, 44 relapses have occurred as of June 1, 2020. In 47% of pts (18/38), clinical relapse was detected using surveillance imaging alone (typically CT CAP with IV contrast) in an otherwise asymptomatic pt with a normal physical exam and laboratory evaluation. Clinical relapse was detected by clinical symptoms alone in 11% (4/28), by the evaluation of an oncologist alone in 0%, and by imaging and clinical symptoms and/or evaluation by an oncologist in 42% (16/38) (missing data in 6 pts). With a median follow-up of 2.2 yrs, the 2-yr PFS was 88.1% (84.8, 91.4) (Figure 1). Advanced age, advanced stage, and poor-risk R-IPI were associated with inferior PFS. Of the 44 relapses, 43 pts were included in the interim analysis and tumor-specific clonotypes were identified in 39 pts (91%). In 56% (22/39), the MRD assay was positive at or before clinical relapse. In 38% (15/39), the MRD assay was positive above the limit of detection at or prior to clinical relapse, with only 10 relapses detected more than 3 mos prior to relapse, reflecting the poor clinical sensitivity of the assay. The NGS-MRD assay was more sensitive in the acellular (plasma cell-free DNA) than in the cellular (circulating leukocytes) compartment. Results: Overall outcomes are excellent for DLBCL and HGBCL pts who achieve PET-negative complete remission. In interim analysis, surveillance MRD assessment using the clonoSEQ® assay fails to consistently identify pts at risk of recurrence before clinical evidence of relapse in DLBCL. In a prospective analysis, a substantial proportion (47%) of clinical relapses are detected by imaging in asymptomatic pts, supporting the value of CT surveillance imaging in DLBCL, particularly for pts with advanced stage or high-risk disease. Additional analyses are forthcoming for MRD assessment in all pts, including those in remission. Disclosures Kumar: Celgene: Research Funding; Pharmacyclics: Research Funding; Adaptive Biotechnologies,: Research Funding; AbbVie: Research Funding; Seattle Genetics: Research Funding; Celgene: Honoraria, Other: Honoraria for Advisory Board; Astra Zeneca: Honoraria, Other: Honoraria for Advisory Board; Kite Pharmaceuticals: Honoraria, Other: Honoraria for Advisory Board. Westin:Kite: Consultancy, Research Funding; Curis: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Amgen: Consultancy; Astra Zeneca: Consultancy, Research Funding; Morphosys: Consultancy, Research Funding; 47: Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding. Nowakowski:Curis: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; MorphoSys: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Kite: Consultancy; Denovo: Consultancy; Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other. Lossos:Verastem: Consultancy, Honoraria; Seattle Genetics: Consultancy, Other; NCI: Research Funding; Stanford University: Patents & Royalties; Janssen Biotech: Honoraria; Janssen Scientific: Consultancy, Other. Batlevi:Life Sci, GLG, Juno/Celgene, Seattle Genetics, Kite: Consultancy; Janssen, Novartis, Epizyme, Xynomics, Bayer, Autolus, Roche/Genentech: Research Funding. Drullinsky:Roche: Research Funding; Novartis: Research Funding. Gerecitano:Janssen: Current Employment. Hamlin:Celgene: Consultancy; Karyopharm: Consultancy; Juno Therapeutics: Consultancy; Portola: Research Funding; Molecular Templates: Research Funding; Incyte: Research Funding; J&J Pharmaceuticals: Research Funding; Portola Pharmaceutics: Consultancy. Horwitz:ASTEX: Consultancy; Affirmed: Consultancy; Vividion Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Myeloid Therapeutics: Consultancy; Miragen: Consultancy; Kura Oncology: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Daiichi Sankyo: Research Funding; C4 Therapeutics: Consultancy; Beigene: Consultancy; Portola: Consultancy, Research Funding; Mundipharma: Consultancy; Innate Pharma: Consultancy; Corvus: Consultancy; Trillium: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding. Jacob:Adaptive Biotechnologies: Current Employment, Current equity holder in publicly-traded company. Joffe:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees. von Keudell:Bayer: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding. Lahoud:MorphoSys: Other: Advisory Board. Matasar:Bayer: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Rocket Medical: Consultancy, Research Funding; Teva: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Daiichi Sankyo: Consultancy; IGM Biosciences: Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Immunovaccine Technologies: Honoraria, Research Funding; Merck: Consultancy; Juno Therapeutics: Consultancy; Genentech, Inc.: Consultancy, Honoraria, Research Funding. Mullins:Adaptive Biotechnologies: Current Employment, Other: shareholder. Noy:Pharmacyclics: Research Funding; NIH: Research Funding; Rafael Pharma: Research Funding; Janssen: Consultancy; Pharmacyclics: Consultancy; Medscape: Consultancy; Targeted Oncology: Consultancy; Morphosys: Consultancy. Straus:Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; ASH: Other: Conference in December 2019 on HL to other physicians during ASH; Elsevier: Membership on an entity's Board of Directors or advisory committees, Other: CME writer; OncLive: Speakers Bureau; Takeda Pharmaceuticals: Research Funding, Speakers Bureau; NY Lymphoma Rounds: Consultancy; Targeted Oncology: Consultancy, Speakers Bureau; Imedex, Inc.: Speakers Bureau; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees. Younes:Takeda: Consultancy; HCM: Consultancy; AstraZeneca: Current Employment; Novartis: Consultancy; Daiichi Sankyo: Consultancy; Janssen: Consultancy; Epizyme: Consultancy; BMS: Consultancy; BioPath: Consultancy; Curis: Consultancy. Zelenetz:MEI Pharma: Research Funding; MorphoSys: Research Funding; Sandoz: Research Funding; Celgene: Research Funding; Roche: Research Funding; Gilead: Research Funding; Genentech/Roche: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Adaptive Biotechnology: Consultancy; BeiGene: Membership on an entity's Board of Directors or advisory committees.

Introduction Monoclonal gammopathy of undetermined significant (MGUS) is a premalignant plasma cell disorder that is common in individuals over age 50. MGUS prevalence estimates to date have generally been based on results of serum electrophoresis and immunofixation (for heavy chain [HC] MGUS) and additionally, free light chain (for light chain [LC] MGUS). Mass-spectrometry assays, however, can detect lower levels of monoclonal (M) proteins, identify the isotype and provide accurate quantification of the M-protein. Given the evidence that MGUS is likely present at least 10 years prior to its detection, mass spectrometry may provide more accurate estimates of underlying MGUS. We examined the prevalence of HC-MGUS using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry among three risk groups: European Americans (EA), African Americans (AA) and first-degree relatives (FDR) of patients with multiple myeloma (MM), MGUS, chronic lymphocytic leukemia (CLL) or non-Hodgkin's lymphoma (NHL). Methods We sampled all AA and a random sample of EA participants ages 50 and older enrolled in the Mayo Clinic Biobank. We also selected unaffected first-degree relatives (limiting to ages 50 and older) from our ongoing family study of hematological malignancies. We screened serum samples by the MALDI-TOF mass spectrometry assay, which is clinically used at Mayo Clinic (known as MASS-FIX) for detection and isotypes of M-proteins. The assay uses isotype-specific nanobody enrichment coupled to MALDI-TOF mass spectrometry. For each of the risk groups, HC- MGUS prevalence was estimated by age (50-59, 60-69, 70+). Age- and sex-adjusted prevalence rates were calculated by direct standardization to the 2010 US population. Ninety-five percent confidence intervals (95% CI) for the prevalence rates and comparisons across the three groups were based on the Poisson distribution. Because free LC information was unavailable, LC-MGUS was not estimated. Results A total 327 AA, 854 EA and 792 FDR were screened for M-proteins using the MASS-FIX assay. All three groups had similar sex (42-44% male) and age distributions (mean[SD] age was 64.5[9.5] yrs., 64.4[8.8] yrs. and 64.9[10.5] yrs. for AA, EA and FDR, respectively). As previously noted using conventional detection methods, the overall prevalence of HC-MGUS was higher in the AA population (16.5% [95%CI: 12.2%, 20.8%]) and FDR (21.5% [95%CI: 18.3%, 24.7%]) than in EA (11.2% [95%CI: 8.8%, 13.5%]), both p-values <0.0001. This pattern was generally seen across age groups (Table 1), with increasing prevalence with age. FDR of MM or MGUS cases had a higher prevalence (22.2% [95%CI: 18.4%, 26.0%]) than FDR of CLL or NHL cases (18.8% [95%CI: 13.3%, 24.4%]), although the difference was not statistically significant (p-value=0.82). Overall prevalence estimates of HC-MGUS using MASS-FIX were at least three-fold higher than estimates using conventional methods alone (i.e. age- and sex-adjusted prevalence in Olmsted County, MN, was 3.1% [95% CI: 2.9%-3.4%]). Conclusion We provided some of the first data on prevalence of HC-MGUS across three risk groups, using a sensitive method for detecting monoclonal proteins. The MASS-FIX assay resulted in substantially higher absolute rates of HC-MGUS (at least 3-fold higher) relative to conventional methods. Further, the prevalence of HC-MGUS among the AA and FDR was significantly higher than the EA population. Thus, the more sensitive assay identified greater absolute numbers of individuals with MGUS, but resulted in similar relationships as seen in prior studies across these risk groups. Our results have implications for future studies of the etiology of MGUS and its progression. Disclosures Dispenzieri: Janssen: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Intellia: Research Funding; Celgene: Research Funding; Takeda: Research Funding. Kumar:Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Karyopharm: Consultancy; Genecentrix: Consultancy; Cellectar: Other; Carsgen: Other, Research Funding; Merck: Consultancy, Research Funding; Dr. Reddy's Laboratories: Honoraria; Adaptive Biotechnologies: Consultancy; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Sanofi: Research Funding; MedImmune: Research Funding; Novartis: Research Funding. Murray:The Binding Site: Patents & Royalties: Patent Use of Mass Spec to identify monoclonal proteins licensed to The Binding Site.

Background: The prognosis for patients (pts) with relapsed T-ALL and T-LL is dismal; the primary goal of T-ALL/T-LL treatment is to prevent relapse. AALL1231 was a COG phase 3 clinical trial that randomized children and young adults (age 1-30 years) to a modified augmented BFM (aBFM) backbone +/- the proteasome inhibitor bortezomib during induction and delayed intensification (DI) (1.3mg/m2 x 4 doses per block). Bortezomib was tested in frontline therapy based on strong preclinical data and data in relapse on COG AALL07P1. Pts were stratified as standard (SR), intermediate (IR), or very high risk (VHR), primarily based on disease response: morphologic and minimal residual disease (MRD) at end induction and end consolidation (T-ALL) and radiographic response (T-LL). To eliminate cranial radiation (CXRT) in all pts, (except VHR: Day 29 M3 marrow or EOC MRD >0.1% or pts with overt CNS leukemia at diagnosis, CNS3), the aBFM backbone was modified to use dexamethasone (dex) as the sole corticosteroid and an extra pegaspargase dose was added in both induction and DI, following the MRC strategy. IR pts received a second interim maintenance (IM) phase (one Capizzi MTX; one HD-MTX). Following consolidation, VHR pts received 3 BFM high-risk intensification blocks in lieu of IM. Results: AALL1231 accrued 847 patients (824 eligible and evaluable) of 1400 anticipated from 2014 until early closure in 2017 when COG AALL0434 established that nelarabine (NEL) improved DFS in T-ALL (AALL1231 did not include NEL). The 3-year EFS for Arm A (no bortezomib) vs Arm B (bortezomib) were 81.7±2.4% and 85.1±2.2 % (HR=0.782, p=0.074) (3/31/20 data cut-off; see Table 1 for additional outcomes). SR and IR pts, who account for 95% of pts, had significantly improved EFS on Arm B as compared with Arm A. Yet, VHR patients had improved EFS on Arm A. Patients with T-LL had improved EFS and OS with bortezomib: 3-year EFS (76.5±5.9% vs 88.3±4.5%; p = 0.01); 3-year OS (78.0±5.8% vs 89.5±4.2%, p = 0.007). A similar improvement in EFS and OS was not seen in T-ALL; however, with longer follow-up this may change. No excess toxicity was seen on Arm B. A dex-based Induction did result in lower MRD rates; more T-ALL pts on AALL1231 had Day 29 MRD <0.1% as compared with AALL0434 which used a prednisone-based Induction (AALL1231 Arm A: 69.6%; Arm B: 72.2%; AALL0434: 64.6%; p = 0.02). However, this did not translate into improved survival. Indeed OS, but not EFS was worse on AALL1231 than AALL0434. On-going analyses are investigating the increased mortality on AALL1231, but preliminary analyses suggest a combination of increased toxic deaths and overall poor outcome in the VHR group. On AALL0434, 90.8% of T-ALL pts received CXRT. On AALL1231, 9.5% of subjects were scheduled to receive CXRT (CNS3 T-ALL/T-LL: 5.7%; VHR T-ALL: 4.1%). A comparison of AALL0434 pts that received CXRT with similar AALL1231 pts not receiving CXRT on AALL1231 demonstrated similar EFS (p = 0.14) and OS (p = 0.42) (Table 2). CNS relapse rates were higher in these pts on AALL1231 (4.5%) as compared with AALL0434 (1.7%), but overall relapse rates were the same (6.5% vs 6.4%). Notably the benefit of NEL in AALL0434 was due to reduction of CNS relapses. 128 AALL1231 pts came off protocol therapy after the study was closed for physician or patient/parent choice. Data collection is underway to understand the reasons for removal, including if it was to receive NEL. Conclusions: Outcomes for SR and IR pts with T-ALL and T-LL treated with bortezomib were excellent despite the elimination of prophylactic CXRT. Bortezomib significantly improved 3-year EFS for these groups, comprising ~95% of pts. Outcomes for VHR pts were dismal and worse on the bortezomib arm. T-LL pts had significantly improved EFS and OS with bortezomib on the AALL1231 backbone. This is the first trial to demonstrate an OS benefit for de novo pediatric T-LL with a new agent; however, longer follow-up is needed. Therapy intensification allowed elimination of CXRT in the majority of pts without excessive relapse. These results should be interpreted cautiously as the 3-yr OS on AALL1231 was inferior to AALL0434. Nevertheless, incorporating bortezomib into standard therapy for de novo T-LL appears advantageous. Future COG T-ALL/T-LLy trials will build on the positive findings from AALL0434 and AALL1231, balancing intensity while mitigating toxicity to maintain high cure rates without routine cranial radiation. (MLL, SPH, EAR contributed equally) Disclosures Teachey: Amgen: Consultancy; Janssen: Consultancy; La Roche: Consultancy; Sobi: Consultancy. Dunsmore:Dexcom: Current equity holder in publicly-traded company. Galardy:Abbott: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company. Harker-Murray:Regerenon Pharmaceuticals: Consultancy. Hermiston:Sobi: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Shimano:Novartis: Research Funding; Daiichi Sankyo: Research Funding; Pfizer: Research Funding; Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. McKay:Immunogen: Current Employment. Bollard:Mana Therapeutics: Other: IP. Loh:Medisix Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pfizer: Other: Institutional Research Funding. Hunger:Novartis: Consultancy; Amgen Inc.: Current equity holder in publicly-traded company, Honoraria. Raetz:Celgene/BMS: Other; Pfizer: Research Funding. OffLabel Disclosure: Bortezomib for the treatment of acute lymphoblastic leukemia under an IND

BACKGROUND Aneuploidy, defined by abnormal copy number changes of chromosomes, contributes to genome instability in multiple myeloma and has potential prognostic impact. Previous research has explored transcriptional pathways affected by aneuploidy. We aim to evaluate aneuploidy, clinical prognosis, and gene expression in RRMM patients (pts) who participated in MMRF (Multiple Myeloma Research Foundation) sequencing study at University of Michigan. We further used gene set analysis to identify enrichment and variation of genetic pathways associated with aneuploidy and overall survival (OS). This was a pilot study in view of applying similar methods to larger populations. METHODS DNA and RNA materials were obtained from 51 RRMM pts at the time of disease relapse. Targeted sequencing was performed with the Onco1700 panel and RNA sequencing was performed with a capture protocol using Agilent SureSelect All Exon V4, followed by paired end sequencing. Copy number variation (CNV) was estimated using an in-house pipeline using matched normal samples. Arm-level aneuploidy was defined as copy number status (gain, loss or neutral) with maximal proportion for each chromosomal arm. Aneuploidy score was determined by total number of arm-level CNV aberrations, with the median score defining high and low aneuploidy groups. Survival analysis was performed using Kaplan-Meier (KM) and Cox regression. RNA-seq libraries were aligned with STAR aligner to the hg38 reference and read quantification were performed with featureCounts. We used gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) to obtain genetic pathway-level summaries for 50 hallmark pathways representative of cancer from the GSEA Molecular Signatures Database (https://www.gsea-msigdb.org/). Supervised GSEA was performed, based on differential analyses comparing gene expression profiles between high versus low aneuploidy groups to identify the differences in genetic pathways in RRMM pts. Unsupervised GSVA was applied to RNAseq count data of RRMM and newly-diagnosed multiple myeloma (NDMM) pts from the MMRF CoMMpass study (797 pts). Univariate Cox proportional hazard model was used to identify pathways having significant association with OS. RESULTS Arm scale aneuploidy analysis revealed high frequency of gains and losses in multiple chromosomes (Figure 1). RRMM pts with high aneuploidy scores had worse OS (median 15.9 months since study enrollment) compared to those with low scores (median not reached, p=0.027). Multivariate analysis demonstrated that high aneuploidy score is persistently associated with poor OS (hazard ratio (HR): 3.9, p=0.006), adjusting for t(4;14) and t(11;14). Hyperdiploidy (any whole chromosome carrying >2 copies) was identified in chromosomes 3, 5, 7, 9, 11, 19, 21, with frequency >20%. Pts with hyperdiploidy had better OS via KM (p=0.04). Using RNAseq gene expression data and GSEA analysis, we found enrichment of gene markers involving the pathways for targets of E2F transcription factors (Normalized Enrichment Score (NES) = 2.07), G2-M checkpoint in the cell division cycle (NES = 1.87), MYC proto-oncogene (NES = 1.93 and 1.85), and DNA repair (NES = 1.68) in RRMM pts with high aneuploidy compared against those with low scores (Benjamini-Hochberg adjusted p-value <0.001 for all pathways, Figure 2). GSVA analysis revealed 21 genetic pathways associated with survival in NDMM and RRMM pts, with 8, 2, and 11 pathways associated with OS in NDMM only, RRMM only, and both, respectively (Figure 3). Enrichment of several biological pathways involved with cellular growth, cell cycle regulation, and stress response (E2F, G2-M, MYC, DNA repair, mTORC1 signaling, UV radiation, mitotic spindle assembly, unfolded protein response, and peroxisome) are associated with poor survival (HR>1) in both NDMM and RRMM pts. Downregulation of KRAS signaling pathway is associated with better survival (HR<1) in both groups. CONCLUSION Aneuploidy, adjusted for chromosomal translocations, is an independent adverse prognostic factor for RRMM. Aneuploidy is correlated with dysregulation of major biological pathways involving cell cycle regulation, cellular division, oncogenes, and DNA damage repair. The majority of common pathways shared between RRMM and NDMM are linked to or reflective of genomic instability, and may explain association with poor survival. Disclosures Talpaz: IMAGO: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Ye:Janssen: Research Funding; Portola: Research Funding; Millennium: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Nektar: Research Funding; AbbVie: Research Funding.

Introduction Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal disorder, which progresses at a rate of 1% per year to multiple myeloma (MM), or other plasma-cell or lymphoid disorders. MGUS is common and occurs in approximately 3% and 5% of persons 50 and 70 years of age or older, respectively. Clinical factors reported to be associated with MGUS progression include MGUS isotype, abnormal serum free light-chain ratio (FLCr), and high serum monoclonal protein (M protein) level (>=1.5 g per deciliter). Body mass index (BMI) has also been seen associated with MGUS progression, but has not been evaluated in context of established clinical prognostic factors. Here, we evaluate the contribution of BMI to MGUS progression beyond clinical prognostic factors in a population-based study and examine differential associations by sex. Methods We studied 594 patients residing in Olmsted County Minnesota, who were identified with MGUS in a screening study conducted between1995 through 2003. Patients with light-chain MGUS were not included. Patients were screened for M-protein [normal (<1.5 g/dl) or high (≥1.5 g/dl)], FLCr [normal (0.26-1.65) or abnormal (<0.26 and/or >1.65)], and isotype (IgG, IgM, IgA, bi-clonal). Follow-up time was calculated from date of MGUS screening to date of last follow-up, death, or progression to MM or another plasma-cell or lymphoid disorder. BMI (kg/m2) was calculated using height and weight values reported close to sample date (80% of patients within 2 years), and then categorized into BMI<25 and BMI≥25. We used Cox regression to estimate the association of BMI with risk of MGUS progression to MM or another plasma-cell or lymphoid disorder, univariately, and accounting for clinical factors. Analyses were also stratified by sex. We report hazard ratios (HR) and 95% confidence intervals (CI). Results Of the 594 patients, 51% were male, and the median age at screening date was 73 (range:50-98 years). The immunoglobulin type was IgG in 71% of patients, IgM in 17%, IgA in 10%, and bi-clonal in 2%. High M protein level was observed in 22% and abnormal FLCr in 28%. BMI≥25 was observed in 67% of patients. The median follow-up time was 10.5 years (range:0-25). Over a median of 6,846 person-years, 465 patients (78%) died and 57 patients progressed and developed MM (N=39), amyloidosis (N=8), lymphoma (N=5), or Waldenstrom macroglobulinemia (N=5). The overall rate of progression was 0.87 events (CI:0.67-1.12) per 100 person-years, and higher among males (1.01, CI:0.73-1.42) than in females (0.72, CI:0.48-1.08), however, the difference was not statistically significant (P=0.24). In univariate analyses, BMI≥25 (HR=2.14, CI:1.05-4.36, P=0.04), non-IgG isotype (HR=2.84, CI:1.68-4.80, P=0.0001), high M protein (HR=2.57, CI: 1.50-4.42, P=0.001), and abnormal FLCr (HR=3.39, CI:1.98-5.82, P<0.0001) were associated with increased risk of progression (Table 1.A). These four factors were independently associated with MGUS progression in a multivariable model, with a c-statistic=0.75 (CI:0.68-0.82). When stratifying by sex, associations of BMI with progression were stronger among females than males (Table 1.B) [c-statistic=0.81 (CI:0.72-0.90) vs 0.71 (CI:0.60-0.82) for females vs. males respectively], however, a test for interaction between BMI and sex was not statistically significant (P=0.15). Conclusions In this study we found evidence that high BMI is a prognostic factor independent of isotype, M protein, and FLC ratio in the full cohort, however, this was mainly driven by the effect in females rather than males. Future studies should further investigate sex differences in evaluating prognostic factors among MGUS patients. Disclosures Dispenzieri: Intellia: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Janssen: Research Funding. Kumar:Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; Kite Pharma: Consultancy, Research Funding; Tenebio: Other, Research Funding; BMS: Consultancy, Research Funding; Karyopharm: Consultancy; MedImmune: Research Funding; Sanofi: Research Funding; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Genecentrix: Consultancy; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding; Carsgen: Other, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member.

Background: Relapse is expected when treating patients with follicular lymphoma (FL) and marginal zone lymphoma (MZL), with a shortened response associated with each relapse. Lenalidomide combined with rituximab (R2) has shown enhanced activity, with a recently reported median progression free-survival (PFS) of 39.4 months in patients with relapsed/refractory (R/R) indolent non-Hodgkin lymphoma, including those with FL and MZL (AUGMENT; J Clin Oncol. 2019;37:1188). Methods: MAGNIFY is a multicenter, phase IIIb trial in patients with R/R FL grades 1-3b, transformed FL (tFL), MZL, or mantle cell lymphoma (MCL; NCT01996865) in which optimal lenalidomide duration is being explored. Patients received 12 cycles of R2 (lenalidomide 20 mg/d, d1-21/28 + rituximab 375 mg/m2 weekly in cycle 1 and then on day 1 of cycles 3, 5, 7, 9, and 11) followed by 1:1 randomization in patients with stable disease, partial response, or complete response/complete response unconfirmed (CR/CRu) to R2 versus rituximab maintenance for 18 months. Data presented here focus on induction R2 in efficacy-evaluable MZL patients compared with the overall population of FL grades 1-3a+MZL (not including FL grade 3b, tFL, or MCL) receiving ≥ 1 treatment with baseline/post-baseline assessments. The primary end point is progression-free survival (PFS) by 1999 International Working Group criteria. Results: As of November 30, 2019, 393 patients with FL grades 1-3a and MZL enrolled; 76 (19%) had MZL. The median age of MZL patients was 68 years (range, 46-90), 68 (89%) had stage III/IV disease, and 72 (95%) had prior rituximab-containing therapy. Overall response rate was 68% with 39% CR/CRu, and median duration of response was 38.6 months (95% CI, 29.4-not reached [NR]). The median PFS was 41.2 months (95% CI, 38.4-NR). Efficacy results for MZL subtypes and the overall population (FL grades 1-3a + MZL) are shown in the table. Forty-two patients (55%) have completed 12 cycles of R2, and 41 (54%) have been randomized and entered maintenance. Twenty-eight patients (37%) prematurely discontinued both lenalidomide and rituximab, primarily due to adverse events (AEs; n = 11; 14%) and progressive disease (n = 6; 8%). The most common (≥ 20%) all-grade AEs were neutropenia (49%), diarrhea (37%), anemia (25%), thrombocytopenia (24%), and constipation (24%). Most common (≥ 10%) grade 3/4 AEs were neutropenia (41%; 1 patient [1%] had febrile neutropenia), thrombocytopenia (13%), and leukopenia (11%). Conclusions: R2 is active with a tolerable safety profile in patients with R/R MZL. The efficacy and safety profile of R2 in MZL patients were similar to results observed in the overall MAGNIFY population. Disclosures Coleman: Seattle Genetics: Research Funding; EMD Serono Research and Development Institute Inc.: Research Funding; Innocare: Research Funding; ARCUS Biosciences: Research Funding; AstraZeneca Pharmaceuticals, LP (Acerta Pharma BV Trials): Research Funding; AstraZeneca Pharmaceuticals, LP: Research Funding; BMS (Celgene Corporation): Research Funding; Eli Lilly and Company: Research Funding; Genetech (F. Hoffman-LaRoche Ltd): Research Funding; Hutchinson MediPharma, LTD: Research Funding; Ipsen Group: Research Funding; Karyopharma Therapeutics, Inc.: Research Funding; Klus Pharma, Inc.: Research Funding; MeiPharma, Inc.: Research Funding; Merck Sharp & Dohme Corp.: Research Funding; Novartis Pharmaceuticals: Research Funding; Incyte Corporation: Research Funding; Boston BIoMedical, Inc.: Research Funding; BeiGene: Research Funding; Acerta: Research Funding. Andorsky:CTI: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Research Funding. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Dynavax: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau. Melear:Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau. Fanning:Takeda: Consultancy, Speakers Bureau; Bristol Myers Squibb: Consultancy, Speakers Bureau; TG Therapeautics: Consultancy; Abbvie: Consultancy; Prisma Health: Current Employment; Sanofi Aventis: Speakers Bureau. Kolibaba:Atara Biotech: Consultancy; Compass Oncology: Ended employment in the past 24 months; Verastem: Honoraria; Seattle Genetics: Research Funding; Pharmacyclics: Research Funding; Novartix: Research Funding; Janssen: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Acerta: Research Funding; AbbVie: Research Funding; Sumitomo Dainippon Pharma Oncology: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lansigan:BMS: Consultancy; Seattle Genetics: Consultancy; BMS Steering Committee for MAGNIFY Program: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharma: Consultancy, Research Funding. Reynolds:IHA Hematology/Oncology Consultants: Current Employment. Nowakowski:Kymera: Consultancy; Ryvu: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Curis: Consultancy; Kite: Consultancy; MorphoSys: Consultancy, Research Funding; Denovo: Consultancy; Seattle Genetics: Consultancy; Nanostrings: Research Funding; Celgene/BMS: Consultancy, Research Funding; Roche: Consultancy, Research Funding. Gharibo:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company; Bayer: Ended employment in the past 24 months. Ahn:BMS: Current Employment, Current equity holder in publicly-traded company. Li:BMS: Current Employment, Current equity holder in publicly-traded company. Rummel:Roche: Honoraria; Amgen GmbH: Honoraria; Celgene: Consultancy, Honoraria; Janssen: Honoraria; Novartis Pharma GmbH: Honoraria. Sharman:BeiGene: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Recent successes and FDA approvals of CD19 redirected chimeric antigen receptor T cell (CART19) therapy have been achieved in pivotal clinical trials in patients with B cell malignancies. However, durable response rates in non-Hodgkin B cell lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL) are low. Tumor-associated macrophages have emerged as key mediators of tumor-induced CART cell immunosuppression. Axl receptor tyrosine kinase (Axl-RTK) is overexpressed in various human cancers including B-NHL or CLL and correlates with poor overall survival. Thus, several Axl-RTK inhibitors are currently being investigated in clinical trials. We have previously reported that the Axl-RTK inhibitor TP-0903 modulates CART19 function by Th1 polarization. Moreover, we observed a significant reduction in myeloid-derived cytokines in preclinical models. This led us to hypothesize that Axl-RTK inhibition also modulates monocytes which in turn affects CART function. To test our hypothesis, we interrogated the interactions between Axl-RTK inhibition, monocytes, and CART. First, we isolated CD14+ monocytes from peripheral mononuclear cells (PBMCs) from healthy donors by magnetic negative selection. Flow cytometric analysis revealed a robust Axl expression on monocytes (Fig.1A). Monocytes were maintained in ImmunoCult Macrophage Medium (STEMCELL Technologies) and differentiated with lipopolysaccharide and interferon-γ for M1-type and interleukin (IL)-4 for M2-type macrophages. After confirming the macrophage phenotypes, cells were assessed for Axl expression. Flow cytometric analysis demonstrated that M2-type macrophages expressed higher Axl compared to M1 macrophages (Fig.1B). Then, we treated PBMCs from healthy donors with TP-0903 for 24 hours to determine the specific cell types affected by Axl-RTK inhibition. Flow cytometric analysis revealed that monocytes were significantly inhibited by TP-0903 compared to B cells or T cells (Fig.1C). Having demonstrated that TP-0903 strongly suppresses monocytes and that M2-type macrophages express Axl on their surface, we then performed a cytotoxicity assay against CD19+ mantle cell lymphoma cell line, JeKo-1, to study the impact of Axl-RTK inhibition on monocyte-induced CART suppression. We used CART19 generated in our laboratory (FMC63-41BBζ). CART19, JeKo-1, and M2-type macrophages were co-cultured at 1:2:1 ratio and incubated for 3 days. The data revealed that M2-type macrophages strongly suppress CART19 killing (Fig.1D) which could be overcome with TP-0903 (Fig.1E). Next we studied monocyte-induced CART19 suppression with antigen-specific proliferation. CART19, JeKo-1, and monocytes were co-cultured at 1:5:1 ratio and incubated for 5 days. Flow cytometric analysis revealed that in the presence of monocytes, antigen-specific proliferation of CART19 was significantly suppressed, which was reversed in the presence of TP-0903 (Fig.1F). To assess how Axl inhibition modulates myeloid cell-derived cytokines/chemokines, we performed Multiplex (Millipore-Sigma) with the supernatants obtained from these co-culture assays. The presence of monocytes resulted in a significant increase in IL-17a, IL-6, IL-1 receptor agonist, IL-1β, and soluble CD40 ligand. However, Axl-RTK inhibition resulted in selective reduction of those cytokines/chemokines (Fig.1G) while preserving other effector cytokines. Finally, we tested whether Axl-RTK inhibition with TP-0903 could overcome the negative effects of monocytes in vivo. Here, immunocompromised NSG mice were injected with 1x106 luciferase+ JeKo-1 cells intravenously. Ten days later, mice were injected with freshly isolated monocytes derived from a healthy donor. Two weeks after JeKo-1 inoculation, tumor burden was assessed with bioluminescence imaging. Mice were then randomized according to the tumor burden to receive 0.5x106 CART19 as a monotherapy or in combination with 20 mg/kg/day of oral TP-0903. The combination therapy resulted in superior anti-tumor effects and overall survival compared to CART19 monotherapy (Fig.1H-I). In summary, Axl-RTK inhibition with TP-0903 demonstrates a direct suppression of inhibitory monocytes, which in turn enhances CART cell function. Our findings support the strategy of further refining and testing the novel and potent combination of Axl-RTK inhibition and CART cell therapy for the treatment of B cell malignancies. Figure 1 Disclosures Sakemura: Humanigen: Patents & Royalties. Cox:Humanigen: Patents & Royalties. Mouritsen:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment. Foulks:Tolero Pharmaceuticals, Inc.: Current Employment. Warner:Tolero Pharmaceuticals, Inc.: Current Employment. Ding:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees. Parikh:GlaxoSmithKline: Honoraria; Verastem Oncology: Honoraria; Genentech: Honoraria; Ascentage Pharma: Research Funding; AbbVie: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; MorphoSys: Research Funding; Pharmacyclics: Honoraria, Research Funding. Kay:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Research Funding; Abbvie: Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Sunesis: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees. Kenderian:Mettaforge: Patents & Royalties; Lentigen: Research Funding; MorphoSys: Research Funding; Sunesis: Research Funding; Tolero: Research Funding; BMS: Research Funding; Juno: Research Funding; Gilead: Research Funding; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy; Humanigen: Consultancy, Patents & Royalties, Research Funding.

CT053 comprises autologous T cells genetically modified with a second-generation chimeric antigen receptor (CAR) incorporating a fully human B-cell maturation antigen (BCMA)-specific single-chain fragment variant (25C2) with high binding affinity. Twenty-four subjects have been treated in phase 1 studies with an 87.5% overall response rate (ORR), 79.2% complete response (CR), and a median duration of response of 21.8 months without inducing immunogenicity [Blood (2019) 134 (Supplement_1): 4435]. Here we present the ongoing phase 1b/2 study (LUMMICAR-2) conducted in North America (NCT03915184) to evaluate safety and clinical efficacy. Eligible subjects with relapsed/refractory multiple myeloma (RRMM) had received ≥3 prior lines of therapy including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 antibody, and had measurable disease per International Myeloma Working Group (IMWG) criteria. All subjects received a lymphodepletion regimen of cyclophosphamide (500 mg/m2/day ×2 days) and fludarabine (25 mg/m2/ day × 3 days). A single infusion of CT053 at the targeted 1.5-3.0×108 CAR+ T-cell dose was administered after lymphodepletion. Primary objectives for phase 1b were to evaluate the safety and tolerability of CT053 and to identify the recommended phase 2 dose. Adverse events (AEs) were graded using CTCAE, v5.0; cytokine release syndrome (CRS) and neurotoxicity were graded according to ASTCT CRS consensus grading system (Lee DW et al, 2019). The response was assessed per 2016 IMWG criteria, and minimal residual disease (MRD) was assessed by next generation flow cytometry or sequencing. As of July 28, 2020, 20 subjects have enrolled, and 14 subjects have received CT053 infusion in the phase 1b portion of the study, including 8 subjects who received 1.5-1.8×108 CAR+ T cells while 6 subjects received 2.5-3.0×108 CAR+ T cells. The treated subjects had a median age of 59 years (range 42-73), had received a median of 6 (range 3-11) prior lines of treatment, 93% were triple refractory to a PI, IMiD, and anti-CD38 antibody, and 64% were penta-refractory. In addition, 36% of the subjects had extramedullary disease at baseline, and 64% had high-risk cytogenetics. All subjects received bridging therapy. The most common ≥ grade 3 AE was hematological toxicity. All subjects experienced ≥ grade 3 neutropenia (100%) and leukopenia (100%), and 36% of subjects had ≥ grade 3 thrombocytopenia within 30 days of treatment. No grade 3 or higher CRS or neurotoxicity was observed. Twelve of 14 subjects (86%) experienced grade 1 or 2 CRS, including 2 subjects who experienced grade 2 CRS and 1 subject who had grade 2 neurotoxicity. CRS events had a generally predictable time to onset, occurring at a median of 2 days post infusion with a median duration of 4 days (range 1-6). Two subjects received tocilizumab, and one subject with grade 2 CRS received both tocilizumab and steroids. One subject experienced grade 2 neurotoxicity with complete resolution within 24 hours upon administration of dexamethasone. At the data cutoff, 10 subjects were evaluable for at least two months of efficacy assessment with a median follow-up of 4.5 months (range 2-8). A 100% ORR was observed, with 2 stringent complete responses, 2 CRs, 1 very good partial response, and 5 partial responses. Of the 12 subjects with evaluable bone marrow samples, 11 were MRD-negative at the 10-5 sensitivity level. Responses were independent of baseline bone marrow BCMA expression. CT053 transgene levels showed expansion and persistence in peripheral blood, with peak expansion at 7-14 days after infusion. All subjects showed similar kinetics of rapid declines in serum free light chains and soluble BCMA (sBCMA) levels within 1 month, and continued depletion in sBCMA suggests CT053-mediated pharmacodynamic activity. Serum C-reactive protein and cytokine levels (i.e., IL-6, IFNγ, IL-8, IL-10) increased post-infusion within 7 days and correlated with the onset of CRS symptoms. Collectively, these results demonstrate that CT053 at a target dose of 1.5-3.0×108 CAR+ T cells delivers early and deep responses, including MRD negativity, with an acceptable safety profile in subjects with heavily pretreated relapsed or refractory MM. The promising results from the ongoing LUMMICAR-2 study are consistent with the previous phase 1 studies and support the launch of a pivotal Phase 2 LUMMICAR-2 study. Updated results will be presented at the conference. Disclosures Kumar: Carsgen: Other, Research Funding; Kite Pharma: Consultancy, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Adaptive Biotechnologies: Consultancy; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Dr. Reddy's Laboratories: Honoraria; Tenebio: Other, Research Funding; Genecentrix: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; MedImmune: Research Funding; Cellectar: Other; Merck: Consultancy, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Sanofi: Research Funding; Novartis: Research Funding; Karyopharm: Consultancy. Baz:Sanofi, Karypharm, Janssen, Celgene: Other: Advisory board; Karyopharm, janssen, Bristol Myers Squibb, Celgene, Merck, Sanofi, Abbvie Inc.: Research Funding. Orlowski:Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding. Anderson:Amgen: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Ma:CARsgen Therapeutics Corp.: Current Employment. Bilgi:CARsgen Therapeutics Corp.: Other: Current shareholder in the company. Kansagra:Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics: Other: Advisory Board. Kapoor:Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Honoraria; Amgen: Research Funding; Sanofi: Consultancy, Research Funding. Li:CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in private company. Brayer:Bristol-Myers Squibb, WindMIL Therapeutics: Research Funding; Janssen: Consultancy; Bristol-Myers Squibb, Janssen, Amgen: Speakers Bureau.

Abstract The COVID-19 pandemic continues to overwhelm global healthcare systems. While the disease primarily causes pulmonary complications, reports of central nervous system (CNS) involvement have recently emerged ranging from encephalopathy to stroke. This raises a practical dilemma for clinicians as to when to pursue neuroimaging and lumbar tap with cerebrospinal fluid (CSF) analysis in COVID-19 patients with neurological symptoms. We present a case of an encephalopathic patient infected with SARS-CoV-2 with no pulmonary symptoms. We propose a three-tier risk stratification for CNS COVID-19 aiming to help clinicians to decide which patients should undergo CSF analysis. The neurological examination remains an integral component of screening and evaluating patients for COVID-19 considering the range of emerging CNS complications.

Abstract Background There has been increasing interest in the superficial circumflex iliac artery perforator (SCIP) flap as a source of thin, pliable soft tissue combined with a favorable donor site. Despite several clinical series from Asia, barriers to adoption include reluctance to perform submillimeter “supermicrosurgery” and the effect of body habitus on flap feasibility. The purpose of this study is to distinguish vascular anatomic characteristics of the SCIP flap in a North American population. Methods Computed tomography angiography was examined in 84 flaps in healthy prospective renal donor patients from a radiographic database. Descriptive statistics as well as linear regression comparing variables to body mass index (BMI) were performed. Results Mean BMI was 27.1 ± 3.5 kg/m2, while the mean patient age was 47.8 ± 11.4 years. The superficial circumflex iliac artery (SCIA) originated from the common femoral artery in 92% cases, with remainder originating from the profunda femoris. The mean vessel diameter was 1.85 mm at source vessel origin. Distance from skin to source vessel averaged 30.7 mm. Suprascarpal subcutaneous thickness averaged 16.5 mm. The mean distance from Scarpa's fascia to vessel origin was 14.1 mm. Direct three-dimensional distance from vessel origin to pubic tubercle was 50.2 mm. A medial and lateral perforator split off of the SCIA was observed in 38 cases (45%). Significant differences were shown when comparing BMI to skin to source vessel distance (p < 0.001), suprascarpal subcutaneous fat thickness (p < 0.001), and fascial distance to vessel origin (p < 0.001). BMI did not significantly affect vessel diameter. Conclusion Despite a significantly higher BMI than many previously published cohorts, the SCIP remains an excellent source of thin and pliable tissue. When dissected closer to the source vessel, a vessel caliber of nearly 2 mm can be achieved, which may obviate the need for “supermicrosurgery” in this population.