Chimeric antigen receptor T-cells (CAR-T) are improving outcomes in pediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukemias and subtypes of non-Hodgkin Lymphoma. As this treatment is being increasingly utilized, a better understanding of the unique toxicities associated with this therapy is warranted. While there is growing knowledge on the diagnosis and treatment of cytokine release syndrome (CRS), relatively little is known about the associated cardiac events that occur with CRS that may result in prolonged length of hospital stay, admission to the intensive care unit for pressor support, or cardiac death. This review focuses on the various manifestations of cardiotoxicity, potential risk factors, real world and clinical trial data on prevalence of reported cardiotoxicity events, and treatment recommendations.

BackgroundImmune checkpoint inhibitors that block programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have improved outcomes for many cancer subtypes but do exhibit toxicity, in the form of immune-related adverse events.ObjectiveThe aim of this study was to investigate the emerging toxicities of PD-1 and PD-L1 inhibitors including acute or reactivation of tuberculosis (TB) and atypical mycobacterial infection (AMI).MethodsThis study was completed as a retrospective review using the US Food and Drug Administration Adverse Events Reporting System (FAERS) for incidence of TB and AMI due to PD-1 and PD-L1 inhibitors compared with other FDA (Food and Drug Administration) approved drugs. The statistical methods included disproportionality signal analysis using the reporting OR (ROR) to compare cases. The 95% Wald CI was reported to assess the precision of the ROR.ResultsOut of the 10 146 481 adverse events (AEs) reported to FAERS for all drugs between 1 January 2015 and 31 March 2020, 73 886 AEs were due to the five FDA approved PD-1/PD-L1 inhibitors. Seventy-two cases of TB were due to PD-1/PD-L1 inhibitors. Specifically, 45 cases (62.5%) due to nivolumab, 18 (25%) due to pembrolizumab, 5 (7%) due to atezolizumab and 4 (5.5%) due to durvalumab. There were 13 cases of AMI: 9 (69.3%) due to nivolumab, 2 (15.3%) due to pembrolizumab and 1 (7.7%) each due to durvalumab and atezolizumab. Avelumab was not attributed to any AE of TB or AMI. From analysis of the FAERS database, the calculated ROR for TB due to PD-1/PD-L1 inhibitors was 1.79 (95% CI, 1.42 to 2.26) (p<0.0001) and for AMI was 5.49 (95% CI, 3.15 to 9.55) (p<0.0001).ConclusionPD-1/PD-L1 inhibitors used in the treatment of cancer subtypes is associated with increased TB and AMI risk. Although this complication is rare, clinicians using PD-1/PD-L1 inhibitors should be aware of the risks.

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Herpes simplex virus (HSV) is a rare cause of hepatitis in pregnancy and the chronically immunosuppressed, with a high propensity to progress to acute liver failure (ALF) and death. Patients typically present with a nonspecific clinical picture that often delays diagnosis and treatment, contributing to the high mortality rate. We present a case of a young female on chronic prednisone and hydroxychloroquine for systemic lupus erythematosus (SLE) who was diagnosed with HSV-2 hepatitis after presenting with right-sided chest and abdominal discomfort. Despite early clinical deterioration, prompt initiation of therapy with intravenous acyclovir and methylprednisolone led to rapid improvement.

Background: There is a large unmet need for relapsed/refractory T cell lymphoma. For patients (pts) with recurrent disease, the efficacy of salvage and autologous stem cell transplant (if feasible) is moderate and the 3-year overall survival is less than 30%. Romidepsin is a histone deacetylase inhibitor (HDACi) that is FDA approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma. Immune checkpoint blockade (CPB) of PD1/PDL-1 has been successful in many malignancies. In a recent report, PDL1 expression was observed 5-17% of tumor cells and 43%-57% in stromal histiocytes in PTCL-NOS or AITL. A phase II single agent study of the PD1 monoclonal antibody (mAB) pembrolizumab in PTCL demonstrated modest responses (Barta et.al). In addition, PTCL often carries multiple gene mutations in epigenetic modifier genes (TET2, IDH2, DNMT3A) and others (RHOA, FYN) that may impair immunogenicity and promote immune escape. This was the rationale for combining HDACi and CPB. We report this single center, single arm, nonrandomized trial of pembrolizumab in combination with romidepsin in subjects with relapsed or refractory PTCL that have failed to achieve a complete response or progressed after at least one systemic treatment regimen (NCT03278782). METHODS: This is a phase I/II study to examine the safety and efficacy of pembrolizumab 200 mg fixed dose administered every 3 weeks (Q3W) in combination with romidepsin. The safety of the combination was tested in the lead-in phase I study with a strategy of dose de-escalation, keeping the starting dose of romidepsin 14 mg/m2 on days 1 and 8. This eventually became the dosing for the phase II study. Adverse events were monitored throughout the trial and graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary objectives of the trial are to determine safety, tolerability, and overall response rate (ORR) of the combination. Secondary objectives include further analysis of various efficacy parameters [complete remission rate (CRR), progression free survival (PFS), overall survival(OS) and duration of response (DOR)]. Response assessment was performed utilizing Lugano Revised Response Criteria, and PD-L1 expression assessed by immunohistochemistry and exploratory analysis of targeted Next Generation Sequencing in the primary lymphoma tissue. Changes in peripheral blood T-cell repertoire were assessed primarily by flow cytometry. RESULTS: 15 pts were evaluable for the primary endpoint (demographics in figure 1). The phase I part was expanded from 3 to 6 pts, because of a dose limiting toxicity (DLT) of hypotension and renal insufficiency which resolved. The phase II is ongoing with 9 pts enrolled. The overall response rate was 44%; 3 pts. achieved a complete response and 2 achieved PR. The median follow-up was 6 months (3 weeks- 12 months). The 3 complete responders remain in remission &gt; 10 months. One patient with refractory ALCL who achieved CR after 3 cycles is now 6 months post Haplo-identical transplant. Nausea and vomiting was the most common adverse event (Grade 1/2-). The most common ≥ grade 3 treatment-emergent adverse events were Nausea/vomiting and fatigue ( n =1 and n= 2). Two patients experienced hyperprogression within the first 10 days after the treatment. Correlative studies including NGS, expression of PD-L1, CD4+ T lymphocytes counts are in progress. CONCLUSIONS: The combination of Romidepsin and Pembrolizumab has demonstrated acceptable safety and early encouraging results. Table. Disclosures Iyer: Spectrum: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Trillium Therapeutics: Research Funding; Rhizen: Research Funding. Neelapu:BMS: Research Funding; Allogene: Consultancy; Acerta: Research Funding; Incyte: Consultancy; Cell Medica: Consultancy; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Karus: Research Funding; Cellectis: Research Funding; Poseida: Research Funding. Nieto:Affimed: Research Funding; Novartis: Research Funding; Astra-Zeneca: Research Funding; Affimed: Consultancy. Westin:Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding; 47 Inc: Research Funding; Kite: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fowler:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nastoupil:Bayer: Honoraria; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Spectrum: Honoraria; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding. Duvic:Janssen Pharmaceuticals (div of Johnson & Johnson): Speakers Bureau; PleXus Communications: Speakers Bureau; Therakos: Speakers Bureau; Eisai: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Jonathan Wood & Assoc.: Speakers Bureau; Mallinckrodt Pharmaceuticals (formeraly Therakos, Inc): Research Funding; Soligenetics: Research Funding; Evidera, Inc.: Consultancy; Guidepoint Global: Consultancy; Cell Medica Inc.: Consultancy; UT MD Anderson Cancer Center: Employment; Shape: Research Funding; USCLC Registry: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Secretary/treasurer of Item h; Hawaiian Dermatology Society: Speakers Bureau; Hemedicus: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spatz Foundation: Research Funding; Oncoceuticals: Research Funding; Millennium (formerly Takeda): Research Funding; Allos: Research Funding; Rhizen Pharma: Research Funding; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees; Cell Medica Ltd.: Honoraria; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Tetralogic: Research Funding. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding. OffLabel Disclosure: Pembrolizumab in T cell lymphoma

BackgroundThe NAPOLI-1 trial demonstrated that liposomal irinotecan in combination with fluorouracil (5-FU) and leucovorin (LV) prolonged survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. Real-world data on clinical outcomes associated with liposomal irinotecan in NAPOLI-1-based regimens is needed to further substantiate this.MethodsThis real-world, retrospective chart review study included patients with mPDAC who received NAPOLI-1-based regimens from six academic centers in the United States. Liposomal irinotecan initiation defined the index date. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier methodology.ResultsThere were 374 patients evaluated; median age was 68 years, and 51% were female. Among 326 patients with baseline ECOG information, approximately 74% had ECOG score &lt;2. Liposomal irinotecan was administered as a doublet with 5-FU in a NAPOLI-1-based regimen in the first line (1L; 16%), 2L (42%), and 3L+ (42%) of the metastatic setting. For patients treated in 1L, 2L, and 3L+, median [95% confidence interval (CI)] OS was 8.0 [5.1, 11.2], 7.3 [5.3, 8.8], and 4.6 [4.0, 5.7] months, and median [95% CI] PFS was 4.2 [2.2, 6.6], 3.0 [2.6, 3.7], and 2.0 [1.7, 2.2] months, respectively.ConclusionsPatients in a real-world setting treated with NAPOLI-1-based liposomal irinotecan doublet regimens at academic centers were older with poorer performance status compared to trial patients yet had similar outcomes and efficacy. Furthermore, liposomal irinotecan was frequently used in the 3L+ setting where no treatment has been approved and provided clinical benefit.