Cancer therapies have undergone several recent advancements. Current cancer treatments include immune-based therapies comprised of checkpoint inhibitors, and adoptive immunotherapy; each treatment has the potential for complications that differ from chemotherapy and radiation. This review evaluates immune-based therapies and their complications for emergency clinicians. Therapy complications include immune-related adverse events (irAE), cytokine release syndrome (CRS), autoimmune toxicity, and chimeric antigen receptor (CAR) T-cell-related encephalopathy syndrome (CRES). Immune-related adverse events are most commonly encountered with checkpoint inhibitors and include dermatologic complications, pneumonitis, colitis/diarrhea, hepatitis, and endocrinopathies. Less common irAEs include nephritis, myocardial injury, neurologic toxicity, ocular diseases, and musculoskeletal complications. CRS and CRES are more commonly associated with CAR T-cell therapy. CRS commonly presents with flu-like illness and symptoms resembling sepsis, but severe myocardial and pulmonary disease may occur. Critically ill patients require resuscitation, broad-spectrum antibiotics, and hematology/oncology consultation.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper activation of the immune system. Rare cases associated with HELLP syndrome and other similar conditions in pregnancy have been reported. Despite the improved survival rates with etoposide and dexamethasone-based regimens, HLH remains a challenging disease. Experience in pregnant patients is exceedingly rare.

Objective

Sinonasal lymphomas are a rare entity that commonly present with nonspecific sinonasal symptoms and are often recognized immediately. Through this review, we aim to summarize important principles in diagnosis and treatment of sinonasal lymphomas, with the goal of disseminating the current knowledge of this under-recognized malignancy to otolaryngologists.

Methods

Systemic review using PRISMA guidelines of foundational scholarly articles, guidelines, and trials were reviewed focusing on clinical characteristics of key sinonasal lymphoma subtypes, along with available treatments in the otolaryngology, medical oncology, and radiation oncology literature.

Results

Sinonasal lymphoma are derived from clonal proliferation of lymphocytes at various stages of differentiation, of which diffuse large B-cell lymphoma (DLBCL) and extranodal natural killer/T-cell lymphoma (ENKTL) are the most common. Diagnosis and staging require biopsy with immunohistochemistry in conjunction with imaging and laboratory studies. Treatment is ever evolving and currently includes multi-agent chemotherapy and/or radiation therapy.

Conclusion

Otolaryngologists may be the first to recognize sinonasal lymphoma, which requires a comprehensive workup and a multidisciplinary team for treatment. Symptoms are nonspecific and similar to many sinonasal pathologies, and it is crucial for otolaryngologists to keep a broad differential.

Level of evidence

5.

INTRODUCTION: Blastoid variant-mantle cell lymphoma (BV-MCL) represents an aggressive subset of patients with no established standard of care treatment approach. METHODS: We performed a retrospective analysis of the clinical characteristics and outcomes of 17 de novo BV-MCL patients treated at our institution between May 2009 and September 2023. In addition, we reviewed the literature supporting 2nd/3rd generation Brutons Tyrosine-kinase (BTKi)-based therapies for upfront management. RESULTS: The complete response rate to frontline and salvage therapy was 66.7% and 25%, respectively. Two-year overall survival (OS) was low at 62.5% (95% CI, 34.7%-81.1%). Variables associated with higher OS included receipt of consolidative HSCT (p = 0.017), TP53-wild type (p = 0.031), intermediate- versus high-risk Mantle Cell Lymphoma Prognostic Index score (p = 0.026), and achieving complete response with induction therapy (p = 0.027). DISCUSSION: Treatment outcomes with chemo-immunotherapy in BV-MCL patients are poor, especially among TP53-mutated patients. Recent findings describing positive outcomes with novel BTKi-based therapies are encouraging and should be considered in this high-risk population.

Background

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hematologic disorder resulting from an ineffective and pathologic activation of the immune response system that may mimic common emergency department presentations, including sepsis, acute liver failure, disseminated intravascular coagulation, and flu-like illnesses such as coronavirus disease 2019 (COVID-19).

Objective

This narrative review provides a summary of the disease and recommendations for the recognition and diagnostic evaluation of HLH with a focus on the emergency clinician.

Discussion

Though the condition is rare, mortality rates are high, ranging from 20% to 80% and increasing with delays in treatment. Importantly, HLH has been recognized as a severe variation of the cytokine storm associated with COVID-19. Common features include a history of infection or malignancy, fever, splenomegaly or hepatomegaly, hyperferritinemia, cytopenias, coagulopathies, abnormal liver enzymes, and hypertriglyceridemia. Using specific features of the history, physical examination, laboratory studies, and tools such as the HScore, HLH-2004/2009, and hyperferritinemia thresholds, the emergency clinician can risk-stratify patients and admit for definitive testing. Once diagnosed, disease specific treatment can be initiated.

Conclusion

This review describes the relevant pathophysiology, common presentation findings, and a framework for risk stratification in the emergency department.

Objectives/hypothesis

This study utilizes a large population national database to comprehensively analyze prognosticators and overall survival (OS) outcomes of varying treatment modalities in a large cohort of sinonasal diffuse large B-cell lymphoma (SN-DLBCL) patients.

Study design

Retrospective database study.

Methods

The National Cancer Database was queried for all SN-DLBCL cases diagnosed from 2004 to 2015. Kaplan-Meier log-rank test determined differences in OS based on clinical covariates. Cox proportional-hazards analysis was used to determine clinical and sociodemographic covariates predictive of mortality.

Results

A total of 2,073 SN-DLBCL patients were included, consisting of 48% female with a mean age of 66.0 ± 16.2 years. Overall, 82% of patients were Caucasian, 74% had early-stage disease, and 49% had primary tumors in the paranasal sinuses. Early-stage patients were more likely to receive multi-agent chemoradiotherapy compared to multi-agent chemotherapy alone (P < .001). Multivariable Cox proportional-hazards analysis revealed chemoradiotherapy to confer significantly greater OS improvements than chemotherapy alone (hazard ratio [HR]: 0.61; P < .001). However, subset analysis of late-stage patients demonstrated no significant differences in OS between these treatment modalities (P = .245). On multivariable analysis of chemotherapy patients treated post-2012, immunotherapy (HR = 0.51; P = .024) demonstrated significant OS benefits. However, subset analysis showed no significant advantage in OS with administering immunotherapy for late-stage patients (P = .326). Lastly, for all patients treated post-2012, those receiving immunotherapy had significantly improved OS compared to those not receiving immunotherapy (P < .001).

Conclusions

Treatment protocol selection differs between early- and late-stage SN-DLBCL patients. Early-stage patients receiving chemotherapy may benefit from immunotherapy as part of their treatment paradigm.

Level of evidence

3 Laryngoscope, 131:E2727-E2735, 2021.

Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; angioimmunoblastic T-cell lymphoma-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For angioimmunoblastic T-cell lymphoma-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706.

Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy; however, cure is highly dependent on the ability to deliver intensive, anthracycline-based chemoimmunotherapy. Nearly one third of cases of DLBCL occur in patients over age 75 years, and advanced age is an important adverse feature in prognostic models. Despite this incidence in older patients, there is no clear accepted standard of care due to under-representation of this group in large randomized clinical trials. Furthermore, insufficient assessments of baseline frailty and prediction of toxicity hamper clinical decision-making. Here, we present an ongoing randomized study of R-miniCHOP chemoimmunotherapy with or without oral azacitidine (CC-486, Onureg) for patients age 75 and older with newly diagnosed DLBCL and associated aggressive lymphomas. The incorporation of an oral hypomethylating agent is based on increased tumor methylation as a biologic feature of older patients with DLBCL and a desire to minimize the injection burden for this population. This is the first randomized study in this population conducted in North America by the National Clinical Trials Network (NCTN) and will enroll up to 422 patients including 40 patients in a safety run-in phase. This study incorporates an objective assessment of baseline frailty (the FIL Tool) and a serial comprehensive geriatric assessment (CGA). Key correlative tests will include circulating tumor DNA (ctDNA) assays at pre-specified timepoints to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has the potential to impact future trial design and to change the standard of care for patients 75 years and older with aggressive lymphoma given its randomized design, prospective incorporation of geriatric assessments, and exploration of ctDNA correlatives. Trial registration: The trial is registered with ClinicalTrial.gov Identifier NCT04799275.