Citations

Abstract Abstract 3680 Background: Current NHL radioimmunotherapy is administered with unlabeled antibody targeting the same B-cell antigen. This decreases sequestration of the radiolabeled antibody by normal B-lymphocytes, but potentially blocks access of the radiolabeled antibody to the tumor sites. In clinical studies, yttrium-90 radiolabeled anti-CD22 epratuzumab (90Y-epratuzumab) has demonstrated therapeutic activity with acceptable toxicity when given weekly × 2 at doses up to 20 mCi/m2 (Morschhauser et al., J Clin Oncol. 2010;28:3709–16), while separate studies showed that a 200-mg/m2 dose of anti-CD20 veltuzumab given weekly × 4 readily depletes peripheral blood B-cells and is also therapeutically active (Morschhauser et al., J Clin Oncol, 2009;27:3346–53). In mice bearing human B-cell lymphoma xenografts, this non-competing combination showed improved therapeutic responses over either agent alone (Mattes et al., Clin Cancer Res. 2008;14:6154–60). As such, a multicenter, phase I/II study was undertaken to evaluate combination therapy with 90Y-epratuzumab and veltuzumab. Methods: Adult patients with aggressive NHL who failed ≥ 1 prior standard regimen (excluding autologous SCT) were eligible if they had measurable CT lesions, ECOG 0–1 performance status, <25% bone marrow involvement, hemoglobin ≥ 10 g/dL, ANC ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L and were >4 weeks beyond last treatment. All patients received a 4-week treatment regimen (weekly 200 mg/m2 veltuzumab, 3–5 mCi 111In-epratuzumab on week 2, 90Y-epratuzumab on weeks 3 and 4). Using NCI CTCAE v4.0 toxicity criteria, dose-limiting toxicity (DLT) was defined as Grade 4 hemoglobin, platelet or neutrophil levels >7 days or not recovered to Grade 1 by 12 weeks, or any non-hematologic Grade 3 or 4 events. Starting at 15 mCi/m2, a standard 3+3 dose escalation determined the MTD of 90Y-epratuzumab. Treatment response utilized CT-based 2007 IWG revised criteria. Serial 111In imaging and serum samples were used to assess biodistribution, tumor targeting and determine normal organ radiation dosimetry. ELISA-based assays were used to measure veltuzumab pharmacokinetics and any human anti-veltuzumab antibodies (HAHA). Results: Fifteen patients (10 male/5 female, 56 – 84 years old) with diffuse large B-cell lymphoma (DLBCL N=7), transformed follicular lymphoma (TFL, N=4) or mantle cell lymphoma (MCL, N=4) have now been enrolled. They had 3 median prior treatments (1 – 7) [RCHOP (N=15); bendamustine plus rituximab (N=5); ICE, lenalidomide, bortezomib (N=2 each); others (1 each)] and had low (N=3), low-intermediate (N=3), high-intermediate (N=7), or high (N=2) IPI risk scores. Treatment was well-tolerated with no infusion reactions. 111In-imaging showed normal biodistribution, with acceptable normal organ dosimetry for the scheduled 90Y dose, and tumor targeting occasionally visualized. There was no evidence of HAHA, and the serum clearance of veltuzumab and 111In-epratzumab in combination was comparable to that reported previously for these agents alone. The 90Y dose was repeatedly de-escalated from 15 (N=3) to 12 (N=3), 9 (N=6), and currently 6 (N=3) mCi/m2 due to 7 hematologic DLTs at ≥ 9 mCi/m2in 6 patients involving Grade 3-thrombocytopenia (N=5) or neutropenia (N=2). Clinically, there were 3 SAEs (pneumonia, non-infectious pneumonitis, fracture from fall), but no other major infections or bleeding. Of 11 patients who have now had treatment response assessments, 5 (45%) had objective responses, including one DLCBL patient with a complete response (CR) continuing 12 months later and 4 patients (1 DLBCL, 3 TFL) with partial responses (PRs), with one continuing at 4 weeks and 3 relapsed at 3 – 6 months. Four other patients (1 DLBCL, 3 MCL) achieved stable disease (SD) continuing up to 6 months as best response, resulting in a disease control rate of 82% (CR+PR+SD). Conclusions: Combination treatment was well-tolerated, with the PK behavior of the two agents substantially unchanged, and with initial evidence of therapeutic activity (including one durable CR) in these difficult-to-treat patients. Hematologic toxicity necessitated lowering the 90Y dose, most likely due to the prior aggressive chemotherapies or depletion of the normal sequestering B-cell pool by veltuzumab preceding 90Y-epratzumab. The trial is continuing to determine an acceptable 90Y dose and define the safety and efficacy profile of this combination approach. Disclosures: Sharkey: Immunomedics: Employment. Rojo:Immunomedics: Employment. Wegener:Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.

Abstract We previously identified five single nucleotide polymorphisms (SNPs) at four susceptibility loci for diffuse large B-cell lymphoma (DLBCL) in individuals of European ancestry through a large genome-wide association study (GWAS). To further elucidate genetic susceptibility to DLBCL, we sought to validate two loci at 3q13.33 and 3p24.1 that were suggestive in the original GWAS with additional genotyping. In the meta-analysis (5662 cases and 9237 controls) of the four original GWAS discovery scans and three replication studies, the 3q13.33 locus (rs9831894; minor allele frequency [MAF] = 0.40) was associated with DLBCL risk [odds ratio (OR) = 0.83, P = 3.62 × 10−13]. rs9831894 is in linkage disequilibrium (LD) with additional variants that are part of a super-enhancer that physically interacts with promoters of CD86 and ILDR1. In the meta-analysis (5510 cases and 12 817 controls) of the four GWAS discovery scans and four replication studies, the 3p24.1 locus (rs6773363; MAF = 0.45) was also associated with DLBCL risk (OR = 1.20, P = 2.31 × 10−12). This SNP is 29 426-bp upstream of the nearest gene EOMES and in LD with additional SNPs that are part of a highly lineage-specific and tumor-acquired super-enhancer that shows long-range interaction with AZI2 promoter. These loci provide additional evidence for the role of immune function in the etiology of DLBCL, the most common lymphoma subtype.

Glioblastoma (GBM; grade 4 glioma) is a highly aggressive and incurable tumor. GBM has recently been characterized as highly dependent on alternative splicing, a critical driver of tumor heterogeneity and plasticity. Estrogen‐related receptor β (ERR‐β) is an orphan nuclear receptor expressed in the brain, where alternative splicing of the 3' end of the pre‐mRNA leads to the production of 3 validated ERR‐β protein products: ERR‐β short form (ERR‐βsf), ERR‐β2, and ERR‐β exon 10 deleted. Our prior studies have shown the ERR‐β2 isoform to play a role in G 2 /M cell cycle arrest and induction of apoptosis, in contrast to the function of the shorter ERR‐βsf isoform in senescence and G 1 cell cycle arrest. In this study, we sought to better define the role of the proapoptotic ERR‐β2 isoform in GBM. We show that the ERR‐β2 isoform is located not only in the nucleus but also in the cytoplasm. ERR‐β2 suppresses GBM cell migration and interacts with the actin nucleation‐promoting factor cortactin, and an ERR‐β agonist is able to remodel the actin cytoskeleton and similarly suppress GBM cell migration. We further show that inhibition of the splicing regulatory cdc2‐like kinases in combination with an ERR‐β agonist shifts isoform expression in favor of ERR‐β2 and potentiates inhibition of growth and migration in GBM cells and intracranial tumors.—Tiek, D. M., Khatib, S. A., Trepicchio, C. J., Heckler, M. M., Divekar, S. D., Sarkaria, J. N., Glasgow, E., Riggins, R. B. Estrogen‐related receptor β activation and isoform shifting by cdc2‐like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma. FASEB J. 33, 13476–13491 (2019). www.fasebj.org

Background: Clinicians need to deliver prognostic information to surrogates of nondecisional, critically ill patients so that surrogates can make informed medical decisions that reflect the patient’s values. Our objective was to implement a new approach for communicating with surrogates of patients with chronic critical illness. Methods: Surrogate decision makers of patients who were difficult to liberate from mechanical ventilation were prospectively enrolled. Surrogates met with different members of the intensive care unit treatment team for sequential 15-minute appointments to receive patient-specific assessments and education on chronic critical illness. The feasibility and acceptability of this approach were determined. A 24-question comprehension instrument was developed to assess a participant’s understanding that a family member was displaying features of chronic critical illness. Each question was scored from 1 to 5, with larger scores indicating greater comprehension. Results: Over a 15-week period, educational sessions for 9 mechanically ventilated patients were conducted. On average, 2 surrogates per patient (range: 1-4) and 6 members of the interdisciplinary team (range: 4-6) were at each meeting. Surrogates and clinicians had very positive impressions of the communication intervention. The average preintervention comprehension score was 85 of 120 (standard deviation [SD]: 8, range: 71-101). The postintervention comprehension score was greater by 5 points on average (SD: 9, range: −11 to +20 points, P = .04). Conclusions: Surrogates of critically ill patients approved of this novel communication approach and had a greater understanding of the patient’s medical condition after the intervention.

Susceptibility testing of the polymyxins (colistin and polymyxin B) is challenging for clinical laboratories. The Clinical and Laboratory Standards Institute (CLSI) Antimicrobial Susceptibility Testing Subcommittee evaluated two methods to enable accurate testing of these agents. These methods were a colistin broth disk elution (CBDE) and a colistin agar test (CAT), the latter of which was evaluated using two inoculum volumes, 1 μl (CAT-1) and 10 μl (CAT-10).

Aims Limited data exist on atypical lipomatous tumour (ALT)/well‐differentiated liposarcoma (WDL) and de‐differentiated liposarcoma (DDLPS) in children and young adults. Methods and results Cases of ALT/WDL/DDLPS arising in patients aged ≤ 40 years were collected from multiple institutional and consultation archives. A total of 116 cases of ALT/WDL (75) and DDLPS (41) were identified, representing fewer than 5% of these tumours seen at our institutions during this time‐period. The patients (59 male/57 female) ranged in age from 8 to 40 years. Sites included deep central (abdomen/retroperitoneum/pelvis/groin) ( n = 60), extremity ( n = 42), trunk ( n = 5), head/neck ( n = 8) and mediastinum ( n = 1). De‐differentiated patterns included: high‐grade pleomorphic sarcoma, myxofibrosarcoma‐like, heterologous rhabdomyoblastic differentiation, low‐grade spindle cell sarcoma and homologous lipoblastic differentiation. Forty‐one patients experienced a local recurrence and 11 patients with DDLPS developed metastasis. ALT arising in the extremities had lower recurrence rates than deep central WDL (5‐year recurrence‐free survival 88.9% versus 59.0%; P = 0.002), while patients with deep central DDLPS experienced significantly more adverse events compared to WDL at this site (5‐year event‐free survival 11.9% versus 59.0%) ( P < 0.0001). Seven (of eight) head/neck tumours had follow‐up available; five recurred, and one patient (DDLPS) with recurrence also experienced a metastasis. The single mediastinal tumour (DDLPS) recurred and metastasised. Conclusion ALT/WDL and DDLPS occurring in patients aged ≤ 40 years is rare, but exhibits similar morphological features to its counterparts in older adults, including potential for heterologous and homologous de‐differentiation in the latter. Although case numbers are limited, tumours arising in the head and neck exhibit high rates of adverse events, suggesting that classification as WDL rather than ALT is more appropriate.