HCA Midwest Division

To improve survival in patients with high-grade glioma, INC280 (capmatinib) a highly selective and potent oral inhibitor of the MET receptor with robust central nervous system (CNS) penetration, was evaluated in combination with bevacizumab (BEV). There were 2 phases, dose-escalation (3+3 design) and dose-expansion, which included patients (1) who progressed during or after first-line therapy (no prior BEV), (2) who progressed during or after second-line therapy with BEV, and (3) who had unresectable high-grade glioma (no prior BEV). Sixty-four patients with high-grade glioma were treated; 18 in escalation cohorts and 46 in expansion Cohorts A (21), B (15), and C (10). The maximum-tolerated dose (MTD) was not reached and the RP2D was 400 mg capmatinib PO BID (800 mg daily). Treatment continued for a median of 14 weeks and up to ~6 years in one patient. Common treatment-related adverse events (65% ≤ Grade 2) included fatigue, peripheral edema, nausea, diarrhea, ALT increased, and constipation. Headaches and seizures occurred in 11 patients; Grade 3+ events included Grade 3 headache (1) and Grade 3 seizures (4). There were no treatment-related deaths. The 12 responders to treatment (2 CRs [1 pt in escalation and 1 pt in Cohort A] and 10 PRs [2 pts in escalation and A = 6, B = 1, and C = 1]) had a median duration of response of 9.2 months. Two patients with durable responses (CR >5 years, PR >1 year) did not harbor baseline c-MET alterations. Capmatinib + BEV was well-tolerated but had no clear signal of activity in c-MET non-activated high-grade glioma.

Introduction: Ascites is typically caused by chronic liver disease (80%), malignancy (10%), and congestive heart failure (3%-5%). Rare causes include pancreatic, biliary, infectious, and others, each representing less than 1% of cases. Pancreatic ascites is secondary to continuous pancreatic secretion trickling into the peritoneum due to anterior pancreatic ductal disruption, secondary to leakage of a ruptured pseudocyst into the duct. Posterior ductal disruption causes pleural effusions. Ascitic fluid studies will reveal total protein > 3g/dL, amylase > 1,000u/l, and SAAG < 1.1. This case is unique as our patient presented with hemorrhagic ascites which was responsive to pancreatic duct stenting alone. Case Description/Methods: A 49 year-old male with history of alcohol abuse and chronic pancreatitis presents from an outside hospital with an acute flare of pancreatitis. He endorsed diffuse, crampy abdominal pain with distension. CT abdomen/pelvis with acute and chronic pancreatitis, large volume ascites with complex ascitic fluid, and bilateral pleural effusions (Figure 1). Paracentesis at the outside facility yielded grossly bloody ascitic fluid and he was transferred to our center to manage the hemorrhagic ascites. His hemoglobin on admission was 8.3, then 7.6 at discharge 2 weeks later without any blood product transfusions. He underwent a 2.9L paracentesis notable for lipase 19,800U/L, amylase 9,117U/L. MRCP with cystic lesions in pancreatic tail concerning for IPMNs and no pancreatic ductal dilation. He underwent an ERCP with pancreatic sphincterotomy and stent placement into the ventral pancreatic duct. Subsequent CTA abdomen/pelvis showed resolution of pleural effusions and decreased size of complex ascites (Figure 1). A repeat 1.2L paracentesis showed amylase 325U/L, total protein 3.2g/dL, >350,000/mm3 RBCs, 517 WBCs, 12% PMNs, LDH 205U/L, negative cytology and cultures. He underwent a repeat ERCP 2 months later with no pancreatic leak or fistula seen and removal of pancreatic stent with complete resolution of his symptoms (Figure 1). Discussion: Patients with pancreatic ascites are managed conservatively, endoscopically, or surgically. Our patient was unique with the grossly bloody ascites which did resolve with only pancreatic duct stenting and no surgical or interventional radiology intervention to control bleeding. While rare, pancreatic ascites is an important differential to keep in mind in an alcoholic patient who presents with abdominal ascites including hemorrhagic ascites.Figure 1.: Panel A - CT abdomen/pelvis with contrast demonstrating large volume ascites with Hounsfield units over 20 suggesting complex fluid within the ascites. Panel B - CT abdomen/pelvis angiogram with decreased size of small to moderate complex ascites. Panel C - ERCP with IV contrast demonstrating patency of the ventral pancreatic stent.

Abstract Infiltrative cardiomyopathies are a group of disorders characterized by the abnormal deposition of proteins and/or inflammatory cells leading to cardiac dysfunction and electrical disorders. This chapter will illustrate the role of PET/CT in cardiac sarcoidosis and amyloidosis, and the complementary role of PET/MR and 99mTc PYP SPECT.

Empirical pulmonary vein isolation (PVI) remains the cornerstone for catheter ablation of atrial fibrillation (AF). Various ablation strategies and modalities are continually tested with the aim of improving ablation outcomes. Although focal impulse and rotor modulation (FIRM)-guided ablation is currently used as an adjunct to PVI, evidence supporting this strategy is conflicting. We sought to examine whether the utilization of FIRM-guided ablation with or without PVI is associated with a decrease in all-atrial arrhythmia recurrence as compared to PVI alone. A systematic review of PubMed, Cochrane, and Embase was performed for head-to-head study designs comparing outcomes of patients who underwent FIRM-guided ablation with or without PVI to those who underwent PVI alone. The primary efficacy endpoint was all-atrial arrhythmia recurrence. The secondary endpoints were complications rates and procedural characteristics. Overall, six studies comprising 674 patients undergoing either FIRM-guided ablation ± PVI versus PVI were included (mean age 63.4 ± 9.2, male 74%, 9% paroxysmal AF, 91% nonparoxysmal AF). After a mean follow-up of 18.8 months, FIRM-guided ablation with or without PVI was not associated with improvement in all-atrial arrhythmia recurrence rate compared to PVI alone (43.4% vs. 45.9%, risk ratio [RR]: 1.06; 95% confidence interval [CI]: 0.77-1.47; p = .70). No statistically significant difference was noted in complication rates between the two groups (RR: 1.66; 95% CI: 0.08-34.54; p = .74). In this meta-analysis of head-to-head comparison studies, FIRM-guided ablation with or without PVI did not provide any benefit in improving all-atrial arrhythmia recurrence at follow-up when compared to PVI alone.

Background:Novel and effective therapies are needed in patients with myeloid malignancies. Hu5F9‐G4 (5F9) is a first‐in‐class antibody targeting CD47, a macrophage immune checkpoint and “don’t eat me” signal on cancers, that induces tumor cell phagocytosis. CD47 is also a leukemia stem cell (LSC) marker in AML. Pre‐clinically, CD47 blockade induces phagocytosis of AML cells and eliminates LSCs in animal models. Azacitidine (AZA) synergizes with 5F9 to eliminate AML by inducing pro‐phagocytic signals on AML, thus enhancing phagocytosis. This trial clinically investigated 5F9 alone or with AZA in AML/MDS patients and is the first report of a clinical study combining a CD47 targeting agent with a hypomethylating/cytotoxic agent.Aims:The primary objectives of this study were to evaluate the safety and efficacy of 5F9 treatment in relapsed/refractory (r/r) AML/MDS and 5F9 in combination with AZA in untreated AML and MDS patients.Methods:This Phase 1b trial enrolled: 1) relapsed/refractory (r/r) AML/MDS patients with 5F9 alone; and 2) untreated AML (induction ineligible) and intermediate‐very high risk MDS patients with 5F9+AZA. A 5F9 priming/intra‐patient dose escalation regimen (1–30 mg/kg weekly) was used to mitigate on‐target anemia. Standard AZA dosing was used.Results:10 (6 AML, 4 MDS) r/r pts received 5F9 (median 2 prior therapies (range 1–6). 24 untreated pts (15 AML, 9 MDS) received 5F9+AZA. In total, median age was 73, 62% of AML pts were intermediate or poor cytogenetic risk (38% unknown), all MDS pts were intermediate or high risk by IPSS‐R. 5F9 alone or with AZA was well‐tolerated with no MTD reached. 5F9 did not potentiate AZA toxicities. Treatment‐related AEs (&gt;10% of pts) for 5F9+AZA were anemia (25%), thrombocytopenia (20%), and infusion reactions (15%). In 25 efficacy evaluable pts, 8/15 (53%) untreated AML/MDS pts had a CR/CRi to 5F9+AZA (5/10 (50%) in AML, 3/5 (60%) in MDS). 1/10 (10%) r/r AML/MDS pts had a response (MLFS) to 5F9 alone. LSCs were reduced/eliminated in the majority of 5F9+AZA responders. 50% of all responders were minimal residual disease (MRD) negative by flow cytometry. 4/10 (40%) previously red cell dependent AML pts became RBC transfusion independent and 4/5 (80%) MDS pts had hematologic improvement. Time to response was more rapid (median 1.9 mos) than expected for AZA alone. As of Jan 2019, no responder has relapsed (median follow‐up of 3.4 mos (range 1.1 – 6.8 mos). 2 pts had successful allogeneic transplant. Additional patients and follow up will be reported.Summary/Conclusion:5F9+AZA is a novel immunotherapy blocking a key macrophage/cancer checkpoint. It is well tolerated with promising activity in AML/MDS patients including rapid CRs with MRD negativity. Adding 5F9 to cytotoxic agents may be a promising treatment strategy. An expansion cohort is ongoing (NCT03248479). Funded by Forty Seven and California Institute for Regenerative Medicine.