Citations

7575 Background: CA-4948 is a novel oral inhibitor of interleukin-1 receptor-associated kinase 4 (IRAK4), which is essential for toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) signaling in B cell proliferation. IRAK4 forms a Myddosome complex with MYD88 adaptor protein and drives overactivation of nuclear factor-kappa B (NF-κB), causing inflammation and tumor growth. CA-4948 has been reported to be well tolerated and active as monotherapy in heavily pretreated patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). Preclinical studies demonstrated that tumor resistance and survival via IRAK4 activation could be delayed or reversed. CA-4948 crossed the blood-brain barrier in a murine PDX model of pCNS lymphoma, resulting in tumor response and prolonged survival. In combination with Bruton tyrosine kinase (BTK) inhibitors, CA-4948 showed in vivo synergy in B-cell NHL. Here we will present an update on the preliminary efficacy data of CA-4948+ibrutinib in R/R hematologic malignancies. Methods: This is an ongoing open-label trial (NCT03328078) of CA-4948 as monotherapy and in combination with ibrutinib. Part A1 (completed) dose escalation of CA-4948 as monotherapy; the recommended phase 2 dose (RP2D) is 300 mg BID with continuous oral dosing. Part A2 (dose escalation in combination with ibrutinib), and Part B (a basket design of 4 expansion cohorts of CA-4948 and ibrutinib: BTK-naïve MZL, DLBCL, or PCNSL and NHL with adaptive resistance to ibrutinib). The primary endpoints of Parts A1 and A2 include safety, tolerability, and RP2D. The primary endpoints of Part B include CR or ORR, with key secondary endpoints of DOR, DCR, PFS and OS following treatment of CA-4948 at dose levels of 200 (DL1) or 300 mg BID (DL2) with ibrutinib at full prescribed dose. Results: As of December 7th, 2021, 35 heavily pretreated NHL patients have received CA-4948 monotherapy (median age 66 years, range 50-87), of which six patients have been on CA-4948 for approximately 1 year or longer, suggesting CA-4948 has a long-term acceptable safety and tolerability profile at RP2D (dose level of 300 mg BID). In Part A2, 10 patients are treated with CA-4948+ibrutinib (median age 65 years, range 56-82). Median number of prior lines of anti-cancer therapies is 3 (range 1-8). No DLTs were observed at 200 or 300 mg dose levels to date. The preliminary efficacy data of seven evaluable patients with combination therapy showed 1 CR (MCL), 2 PR (MCL and MZL), 3 SD, and 1 PD, 3 of whom had failed prior ibrutinib. The preliminary data indicate the combination therapy may overcome ibrutinib resistance. Conclusions: CA-4948 as a monotherapy and in combination with ibrutinib is well tolerated with an acceptable long term safety profile and promising efficacy. Part A2 is transitioning to Part B basket cohorts of MZL, ABC-DLBCL, PCNSL and NHL with adaptive resistance to ibrutinib. Clinical trial information: 03328078.

Introduction: Congenital bowel malrotation resulting in midgut volvulus is traditionally regarded as a diagnosis of infancy. Rarely, congenital bowel malrotation is diagnosed in adolescents or adults and requires a high index of suspicion. Presentations can be acute or chronic, and physical examination findings are nonspecific. Diagnosis is primarily achieved through abdominal computed tomography (CT) or during exploratory laparotomy. The pathophysiology in late-onset malrotation is similar to neonatal malrotation, with a division of Ladd’s bands – peritoneal fibrous bands that connect the cecum to the right lower quadrant retroperitoneum – as the definitive treatment. We present a case of congenital bowel malrotation in an adolescent with persistent and worsening migratory abdominal pain. Case Report: An 18-year-old female presented to the emergency department with two days of poorly localized abdominal pain and nausea. Initial evaluation was unremarkable and she was discharged home with a diagnosis of constipation. She returned two days later with worsening abdominal pain and new onset emesis. Given her persistent and worsening symptoms an abdominal CT was performed, which revealed malrotation of the bowel. Taken together, her CT findings and abdominal symptoms were concerning for symptomatic congenital bowel malrotation and she underwent a Ladd procedure. She remained asymptomatic both at discharge and at two-week postoperative follow-up. Conclusion: Symptomatic congenital bowel malrotation is more common in older children and adults than has traditionally been thought. Physicians must consider this diagnosis in their differential when working up a patient for acute or chronic intermittent abdominal pain to prevent potentially severe sequelae.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.

Abstract In Glioblastoma (GBM), tumor spreading is driven by tumor cells’ ability to infiltrate healthy brain parenchyma, which prevents complete surgical resection and contributes to tumor recurrence. GBM molecular subtypes, classical, proneural and mesenchymal, were shown to strongly correlate with specific genetic alterations (Mesenchymal: NF1; Classical: EGFRVIII; Proneural: PDGFRA). Here we tested the hypothesis that a key mechanistic difference between GBM molecular subtypes is that proneural cells are slow migrating and mesenchymal cells are fast migrating. Using Sleeping Beauty transposon system, immune-competent murine brain tumors were induced by SV40-LgT antigen in combination with either NRASG12V (NRAS) or PDGFB (PDGF) overexpression. Cross-species transcriptomic analysis revealed NRAS and PDGF-driven tumors correlate with human mesenchymal and proneural GBM, respectively. Similar to human GBM, CD44 expression was higher in NRAS tumors and, consistent with migration simulations of varying CD44 levels, ex vivo brain slice live imaging showed NRAS tumors cells migrate faster than PDGF tumors cells (random motility coefficient = 30µm2/hr vs. 2.5µm2/hr, p < 0.001). Consistent with CD44 function as an adhesion molecule, migration phenotype was independent of the tumor microenvironment. NRAS and human PDX/MES tumor cells were found to migrate faster and have larger cell spread area than PDGF and human PDX/PN tumors cells, respectively, in healthy mouse brain slices. Furthermore, traction force microscopy revealed NRAS tumor cells generate larger traction forces than PDGF tumors cells which further supports our theoretical mechanism driving glioma migration. Despite increased migration, NRAS cohort had better survival than PDGF which was attributed to enhanced antitumoral immune response in NRAS tumors, consistent with increased immune cell infiltration found in human mesenchymal GBM. Overall our work identified a potentially actionable difference in migration mechanics between GBM subtypes and establishes an integrated biophysical modeling and experimental approach to mechanically parameterize and simulate distinct molecular subtypes in preclinical models of cancer.

Introduction: Pectus excavatum is a common congenital anomaly in the pediatric population. During the postoperative period, pain control is one of the top priorities. As a result, multiple techniques for pain control have been developed, including thoracic epidural analgesia, multimodal analgesia (MM), and elastomeric pain pump (EPP) placement. The purpose of this study was to evaluate the effectiveness of pain control using EPP as an adjunct to MM after the minimally invasive repair of pectus excavatum (MIRPE). Methods: We identified all pediatric patients undergoing MIRPE from June 2017 to July 2018. MM was employed in all patients; some patients additionally received subpleural EPP as adjuncts to postoperative analgesia. We reviewed pain scores, length of stay, opioid use, and complications. Results: During the study period, a total of 62 patients were included. The study cohort was divided into 15 patients undergoing MM alone versus 47 patients undergoing subpleural EPP placement plus MM (EPP + MM). Median pain scores were lower in the EPP + MM group (2.9 versus 4.2, P < .05). There was a significant reduction of total inpatient opioid use in the EPP + MM group (357.6 mg versus 466.9 mg, P = .03). There was no difference in median length of stay or complications. We found no significant difference between subpleural versus subcutaneous placement of the infusion catheters. Conclusion: The use of subpleural EPP as an adjunct to MM is an effective way to reduce pain and opioid use after MIRPE without increased risk of complications. Type of Study: Retrospective study with comparison group.

Magnesium is an essential element that is involved in the regulation of cell growth, division and differentiation. Epidemiologic studies have demonstrated that a diet poor in magnesium is associated with an increased risk of developing cancer. There are few studies investigating whether magnesium deficiency is associated with a poor prognosis in lymphomas. The recent discovery of X-linked immunodeficiency with magnesium defect, Epstein-Barr virus, and neoplasia (XMEN) disease, suggests a role of magnesium in the development of hematologic malignancies and lymphocyte function. Furthermore, a recently published study found that hypomagnesemia prior to chemotherapy is associated with inferior overall survival (OS) in patients with Burkitt Lymphoma. We hypothesized that low magnesium levels prior to autologous hematopoietic stem cell transplant (AHSCT) may lead to inferior outcomes via impaired lymphocyte recovery. We evaluated whether low serum magnesium levels were associated with inferior survival in patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) who underwent autologous hematopoietic stem cell transplant (AHSCT) between January 1998 and May 2020 using a retrospective study design. We cross-referenced our search with patients who had a magnesium level as part of their pre-transplant workup between 7 and 28 days prior to their first transplant. Two-sided Wilcoxon rank sum test and Chi square/Fischer's exact test were used to compare the continuous and categorical variables, respectively. Kaplan-Meier and log-rank tests were used to perform all time to event analysis. Hazard ratios (HR) with confidence intervals (CI) were calculated using Cox-proportional hazards. Our study included 581 patients of which 82 (14.1%) had hypomagnesemia (magnesium &lt; 1.7 mg/dL) prior to AHSCT. Our study found that hypomagnesemia was associated with inferior OS and event-free survival (EFS) defined as re-transplant, relapse or death, compared to those with a normal magnesium level; median OS: 7.3 years (95% CI: 2.91 - upper limit not estimable) versus 9.7 years (95% CI: 6.92 - 12.3 years), p=0.0041; and median EFS: 3.9 years (95% CI: 1.63 - 8.98 years) versus 6.29 years (95% CI: 4.73 - 8.95 years), p = 0.016 respectively(B). Higher serum magnesium (HR 0.199 per doubling, 95% CI 0.078 - 0.503; p&lt;0.001) and higher albumin (HR 0.090 per doubling, 95% CI 0.021 - 0.394; p=0.001) were associated with lower mortality rates, and higher creatinine (HR 1.669 per doubling, 95% CI 1.03 - 2.52; p=0.04) was associated with greater mortality up to 1 year post-transplantation. In a multivariate Cox regression excluding albumin, hypomagnesemia (p &lt; 0.001) and elevated creatinine (p = 0.038) were independent predictors of poor overall survival(A). There was no significant difference between day 15 absolute lymphocyte count between patients with normal magnesium levels and low serum magnesium levels prior to their conditioning regimen. Although we hypothesized that we would find a significant difference between 15 day absolute lymphocyte count recovery and hypomagnesemia, this was not apparent. However, magnesium is an important nutrient for immune function and immune recovery is important after the bone marrow is restored post ablative therapy. Thus, low serum magnesium levels may lead to impaired OS and EFS via impaired lymphocyte function. In vitro studies will be necessary to understand this mechanism further. Magnesium may simply be a marker of illness and replacement of magnesium may not improve outcomes. However, further investigations are needed to determine whether outcomes would improve with replacement of magnesium in patients with hypomagnesemia, which our study did not address. Overall, our preliminary data suggests that hypomagnesemia is an independent prognostic factor and predictor of inferior OS and EFS in this cohort of patients. Figure Disclosures Ansell: ADC Therapeutics:Research Funding;AI Therapeutics:Research Funding;Trillium:Research Funding;Affimed:Research Funding;Regeneron:Research Funding;Seattle Genetics:Research Funding;Bristol Myers Squibb:Research Funding;Takeda:Research Funding.Witzig:Spectrum:Consultancy;Celgene:Consultancy, Research Funding;Immune Design:Research Funding;Karyopharm Therapeutics:Research Funding;Acerta:Research Funding;Incyte:Consultancy;AbbVie:Consultancy;MorphSys:Consultancy.

Abstract Background High–ω‐6 polyunsaturated fatty acids (PUFAs) are noted to contribute to development of intestinal failure–associated liver disease (IFALD) in home parenteral nutrition (HPN). Fish oil (FO) has been added to latest generation of lipid injectable emulsion (ILE) to increase ω‐3:ω‐6 PUFA ratio; however, appropriate dose of FO to treat IFALD is unknown. Methods After approval of exclusive FO ILE in the US for pediatric patients, we noted 2 adult patients with ongoing IFALD despite transition to mixed‐oil (MO) ILE. They were transitioned to off‐label FO ILE after review of literature regarding use of FO ILE in adult HPN patients was conducted to guide management. Results The first case involves a 40‐year‐old female receiving HPN with IFALD refractory to MO ILE. MO ILE (with 15% FO) was provided at 50 g/d for 3 d/wk and combined with FO ILE at 50 g/d for 4 d/wk. This combination resulted in improvement in liver studies and allowed for decrease in dextrose calories. The second case involves a 49‐year‐old male receiving HPN (secondary to complications of necrotizing pancreatitis) who developed IFALD. FO ILE was used as the sole source of lipids and led to improvement in liver function tests. No evidence of essential fatty acid deficiency was found in either case. Conclusions Current case presentations and review of literature support the use of FO ILE to increase ω‐3 PUFAs in patients with IFALD refractory to MO ILE. Additional research is necessary to delineate the dose of FO ILE necessary to achieve benefit.