Targeted therapy in Burkitt lymphoma: Small molecule inhibitors under investigation.

Multiagent chemoimmunotherapy remains the standard of care treatment for Burkitt lymphoma leading to a cure in the majority of cases. However, frontline treatment regimens are associated with a significant risk of treatment related toxicity especially in elderly and immunocompromised patients. Additionally, prognosis remains dismal in refractory/relapsed Burkitt lymphoma. Thus, novel therapies are required to not only improve outcomes in relapsed/refractory Burkitt lymphoma but also minimize frontline treatment related toxicities. Recurrent genomic changes and signalling pathway alterations that have been implicated in the Burkitt lymphomagenesis include cell cycle dysregulation, cell proliferation, inhibition of apoptosis, epigenetic dysregulation and tonic B-cell receptor-phosphatidylinositol 3-kinase (BCR-PI3K) signalling. Here, we will discuss novel targeted therapy approaches using small molecule inhibitors that could pave the way to the future treatment landscape based on the understanding of recurrent genomic changes and signalling pathway alterations in the lymphomagenesis of adult Burkitt lymphoma.

Challenges identifying DLBCL patients with poor outcomes to upfront chemoimmunotherapy and its impact on frontline clinical trials.

Diffuse large B cell lymphoma (DLBCL) has a variable course of disease among patients as it consists of subgroups that are clinically, biologically and molecularly heterogeneous. In this review, we will discuss how this heterogeneity has likely hindered the ability of traditional prognostic models to identify DLBCL patients at high risk of having poor outcomes with conventional upfront chemoimmunotherapy. We will highlight the challenges and downsides of using these models for risk stratification in clinical trials. Also, we present some of the novel prognosticators that have shown a prognostic value independently or when incorporated into existing prognostic models. Additionally, since the failure of frontline clinical trials to improve outcomes beyond R-CHOP chemoimmunotherapy may be at least partially explained by the restrictive eligibility criteria, risk stratification methods and the selection bias encountered due to the complexed logistics of clinical trials; we will discuss strategies to refine and modernize clinical trial design.

Post-transplant lymphoproliferative disorder: Update on treatment and novel therapies.

Post-transplant lymphoproliferative disorder (PTLD) is rare and heterogeneous lymphoid proliferations that occur as a result of immunosuppression following solid organ transplant (SOT) and haematopoietic stem cell transplant (HSCT) with the majority being driven by EBV. Although some histologies are similar to lymphoid neoplasms seen in immunocompetent patients, treatment of PTLD may be different due to difference in pathobiology and higher risk of treatment complications. The most common treatment approach in SOT PTLD after failing immunosuppression reduction (RIS) takes into consideration a risk-stratified sequential algorithm with rituximab +/- chemotherapy based on phase 2 studies. In HSCT PTLD, RIS alone and chemotherapy are usually ineffective making rituximab +/- RIS as the gold standard of frontline treatment. In this review, we give an update on the treatment of PTLD beyond RIS. We highlight the most recent studies that attempted to incorporate more aggressive chemotherapy regimens and novel treatments into the traditional risk-stratified sequential approach. We also discuss the role of EBV-cytotoxic T lymphocytes in treatment of EBV-driven PTLD. Other novel agents with potential role in PTLD will be discussed in addition to the challenges that could arise with chimeric antigen receptor T-cell therapy and immune checkpoint inhibitors in this population.

Novel Immune-Based treatments for Diffuse Large B-Cell Lymphoma: The Post-CAR T Cell Era.

Prognosis for patients with refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL) is poor. Immune-based therapeutic treatments such as CD19 Chimeric Antigen Receptor (CAR) T cell therapies have dramatically changed the treatment landscape for R/R DLBCL leading to durable remissions in ~ 50% of patients. However, there remains an unmet need for developing novel therapies to improve clinical outcomes of patients not responding or relapsing after CAR T cell therapies. Lack of suitable immunotherapeutic targets and disease heterogeneity represent the foremost challenges in this emerging field. In this review, we discuss the recently approved and emerging novel immunotherapies for patients with R/R DLBCL in the post-CAR T era and the cell surface targets currently used.

Epigenetic Aberrations and Targets in Peripheral T-Cell Lymphoma.

Peripheral T cell lymphomas (PTCL) comprise a diverse group of aggressive T-cell and NK-cell lymphomas with many subtypes sharing same treatment algorithms despite having different pathobiology and responses to treatment. The molecular advances made in discovery of genetic mutations that disrupt epigenetic modulation in some subtypes of PTCL such as angioimmunoblastic T cell lymphoma and PTCL-not otherwise specified (NOS) may explain the poor outcomes and unsatisfactory responses to frontline line CHOP and CHOP-like therapy seen in this group of lymphomas. In this article, we address the main genetic mutations such as IDH2, TET2 and DNMT3A seen in PTCL and that disrupt the epigenetic modulation pathways, focusing on acetylation, deacetylation and methylation. Since therapeutic agents that target the disrupted epigenetic modulation pathways in PTCL may change treatment landscape in the near future, we will highlight the ones approved for treatment of refractory and/or relapsed PTCL and also the pivotal regimens being evaluated in clinical trials for treatment of frontline and refractory relapsed disease. We stress the importance of determining whether there is an association between the discussed genetic mutations and responses to the highlighted therapeutic agents such that treatments could be better tailored in patients with this kind of lymphoma with unmet needs.

Cytokine Based Immunotherapy for Cancer and Lymphoma: Biology, Challenges and Future Perspectives.

Cytokines regulate both the innate and adaptive immune responses to cancer. Although antitumor activity has been seen for several cytokines in preclinical models, they have had limited success as single therapeutic agents in clinical trials of cancer immunotherapy. However, the possible combinations of cytokines with other immune therapeutics and the advancement in genetic engineering, synthetic biology and cellular and immune therapy has led to the revival of interest in cytokines as anticancer agents. This article will review several immunostimulatory cytokines with anticancer activity, focusing on the those that have been studied in treatment of lymphoma and highlighting recent advances of potential clinical relevance.

Current and emerging monoclonal antibodies, antibody-drug conjugates, and bispecific antibodies in treatment of lymphoma.

The improvement in outcomes seen with the introduction of rituximab, a CD20 monoclonal antibody in combination with chemotherapy or as a single agent in the treatment of indolent non-Hodgkin lymphomas has paved the way for development of various forms of monoclonal antibodies that act in different ways against non-Hodgkin lymphoma tumor cells. These could directly target a single surface antigen resulting in various ways of tumor cells toxicity and killing. Other forms of monoclonal antibodies include antibody-drug conjugates and bispecific antibodies. The role of therapeutic monoclonal antibodies in the treatment of lymphoma will be reviewed, highlighting their mode of action, clinical efficacy, and side effects.

Impact of cardiovascular comorbidities on inpatient mortality in patients hospitalized with neutropenic fever.

INTRODUCTION: Concomitant cardiovascular comorbidities in patients with cancer are not uncommon. There is limited data on the impact of cardiovascular comorbidities on in-hospital mortality in patients admitted with neutropenic fever. METHODS: This is a retrospective cohort study using the 2016 NIS database of adults (> 18 years old) hospitalized for neutropenic fever as the primary diagnosis. The primary outcome studied is all-cause mortality in patients with neutropenic fever. ICD-10-CM codes were used to identify cardiovascular risk factors including smoking; hyperlipidemia; peripheral vascular diseases; hypertension; history of cerebrovascular disease or transient ischemic attack; and cardiovascular morbidities including atrial fibrillation, coronary artery disease, and congestive heart failure. Multivariate linear regression analysis was used to adjust for cofounders. RESULTS: A total of 28,060 patients were admitted with neutropenic fever in 2016. Average age was 43.9 ± 1.7 years, and 49.3% were females. Among the cases identified, 205 patients died during hospitalization with an overall in-hospital mortality of 0.7%. Atrial fibrillation was independently associated with higher in-hospital mortality (odds ratio [OR] 3.01; CI 1.38 to 6.57; p = 0.005) as was congestive heart failure (OR 3.15; CI 1.08 to 10.14; p = 0.049). CONCLUSION: Atrial fibrillation and congestive heart failure were associated with higher inpatient mortality in patients with neutropenic fever. Identifying the risk factors for increased mortality in patients with neutropenic fever is important for risk stratification and guiding clinicians in taking therapeutic decisions in this set of patients.

HIV-associated Burkitt lymphoma.

Burkitt lymphoma is a rare and aggressive non-Hodgkin lymphoma with three classifications: endemic, sporadic, and immunodeficiency-related. High-intensity chemotherapeutic regimens have considerably improved overall survival for patients with Burkitt lymphoma. In this Review of HIV-associated Burkitt lymphoma, we summarise expert opinion and provide general recommendations for the treatment of Burkitt lymphoma in patients with HIV on the basis of retrospective and prospective studies, taking into consideration immune status, CD4 cell counts, the presence of systemic disease, and the risk of CNS involvement or relapse. We also discuss the role of rituximab and antiretroviral therapy. We highlight the reasons behind the possible different mechanisms of lymphomagenesis in HIV-associated Burkitt lymphoma and endemic Burkitt lymphoma, which indicate that HIV might have either a direct or indirect oncogenic role in Burkitt lymphoma. We discuss the possible mechanisms by which HIV and HIV proteins could directly contribute to lymphomagenesis. Identifying these mechanisms might lead to the development of therapies that have fewer toxic effects than high-intensity chemotherapeutic regimens.

Plasmablastic lymphoma achieving sustained remission with antiretroviral therapy alone.

Despite advances in the treatment of most human immunodeficiency virus (HIV)-related lymphomas, the outcomes for patients with HIV-related plasmablastic lymphoma (PBL) remain poor. While studies have shown an increased survival for patients with most kinds of HIV-related lymphomas since the introduction of highly active antiretroviral therapy (HAART), the impact of HAART on survival in patients with HIV-related PBL is unclear, mainly because the condition is rare and the number of published studies is small. Few case reports have shown regression of PBL after initiation of HAART, however, usually followed by recurrence of PBL or achieved with a need for chemotherapy. We report the first case of PBL in a 38-year-old man with newly diagnosed HIV who achieved sustained remission after the initiation of HAART alone and who remains in remission seven years after diagnosis, without a need for chemotherapy or radiation. We illustrate the importance of initiating HAART therapy under the supervision of infectious disease specialists as soon as the PBL is diagnosed until future studies provide clear evidence in the management of HIV-related PBL.

Benign ethnic neutropenia.

Benign ethnic neutropenia (BEN) is one of the most common causes of chronic neutropenia seen in individuals of African, Middle Eastern and West Indian descent, affecting many individuals worldwide. Despite its prevalence, many physicians are not familiar with this benign condition, resulting in unnecessary evaluation and testing for neutropenia in otherwise healthy individuals. Clinically, patients with BEN are at no increased risk of infection despite their neutropenia. Implications of this condition are highlighted in those patients receiving therapies that have a known side effect of neutropenia, most commonly chemotherapy agents. Studies have suggested that disparities in survival among those patients receiving chemotherapy between patients of European decent and African decent may be attributed to measured neutropenia in these populations, questioning whether BEN could be an influential factor. This review encompasses all aspects of benign ethnic neutropenia, providing information about this condition and helping to guide clinical decision-making as to when an aggressive work up and referral are indicated and when it is appropriate to monitor. Additionally, we review the role of genetic studies in identifying the genes related to BEN, summarize the theories that offer the most accepted mechanisms behind the condition, and address the importance of pursuing larger studies to assess the implication of BEN in oncology patients as well as patients taking neutropenia-causing medications.

Immune checkpoint inhibitor therapy and myocarditis: a systematic review of reported cases.

INTRODUCTION: The advent of immune checkpoint inhibitors in the treatment of certain types of cancers has revolutionized cancer therapy. In general, these novel agents are more tolerable and have better safety profiles than conventional chemotherapy agents. Although a low incidence of myocarditis was noted as a side effect of immune checkpoint inhibitors in clinical trials, it is being increasingly cited in the literature as their use also increases. METHODS: Using a combination of search terms in the PubMed/Medline database and manual searches on Google Scholar and the bibliographies of articles identified, we reviewed all cases reported in the English language citing myocarditis associated with either pembrolizumab, nivolumab, ipilimumab, or any combination of these agents. RESULTS: A total of 42 cases were included in the study. Mean age was 65.5 years; 64% were male, 36% were female. One or two doses preceded the onset of myocarditis in 33% and 29% of cases, respectively. Steroids were used as the first-line therapy in 90% of cases. Complete heart block occurred in 36% of cases. Fourteen (33%) deaths were reported, with 64% and 29% of deaths occurring after one or two doses, respectively. CONCLUSION: Most cases and fatalities of myocarditis occurred shortly after initiation of immune checkpoint inhibitor therapy. Arrhythmias, particularly complete heart block, appear to be related to the occurrence of more severe and fatal cases. The use of serial electrocardiograms or biomarkers of myocardial injury may be crucial in detecting early stages of the disease process. Further research establishing more specific guidelines is necessary in dealing with this potentially fatal side effect.

Small Cell Lung Cancer with Pituitary Metastasis Presenting as Secondary Adrenal Insufficiency: A Case Report and Literature Review.

BACKGROUND Pituitary gland metastasis is rarely the initial presentation of metastatic cancer. Most cases of pituitary gland metastasis are asymptomatic with diabetes insipidus being the most common symptomatic presentation. It can rarely present with symptoms of hormone underproduction such as secondary adrenal insufficiency. Although pituitary gland metastasis is rare, it is underestimated, as it is commonly misdiagnosed with pituitary gland adenoma due to the lack of clear radiological criteria differentiating between both. CASE REPORT We present a case of a 62-year-old male who presented with weakness, blurry vision, and persistent hypoglycemia despite intravenous dextrose infusion and having discontinued taking his diabetes medications. Chest x-ray showed a left hilar mass, while computed tomography scan demonstrated a left superior hilar mass and hilar lymphadenopathy with bilateral adrenal nodules and a T6 vertebral lesion suspicious for metastasis. Further workup showed secondary adrenal insufficiency with a low adrenocorticotropic hormone (ACTH) level. Vertebral biopsy was performed and confirmed the diagnosis of small cell carcinoma of the lung. This was followed by a brain magnetic resonance imaging (MRI), which showed multiple metastatic lesions with an enhancing mass involving the right clivus, sella, and suprasellar cistern with mass effect on the optic chiasm and involvement of the cavernous sinus supporting the diagnosis of pituitary gland metastasis of small cell lung cancer. The patient received brain radiation, and repeated MRI showed regression of the previous MRI findings. CONCLUSIONS Secondary adrenal insufficiency is an unusual presentation of pituitary gland metastasis. Physicians should take into consideration both radiological findings and presentation to differentiate between pituitary gland metastasis and pituitary adenoma.

Pericardial effusion due to pembrolizumab-induced immunotoxicity: A case report and literature review.

The advent of immune checkpoint inhibitors has revolutionized cancer treatment. These novel agents have provided promising treatment options in patients with different types of cancers. One of these agents is pembrolizumab, which works by blocking the binding of T-lymphocytes to programmed cell death ligand 1 receptors on tumor cells, thus enabling immune activation of T-lymphocytes against tumor cells. Pembrolizumab is commonly used in metastatic nonsmall cell lung cancer and melanoma. However, despite the remarkable efficacy this agent has achieved, multiple immune-related adverse events have been reported including hepatitis, colitis, thyroid dysfunction, and pneumonitis. Only 2 other cases of pericardial effusion as a side effect of pembrolizumab have been cited in the literature; however, its incidence may be on the rise. Despite the rarity of this side effect, its complications are potentially life threatening and no clear platform currently exists to help guide healthcare professionals in the management of these adverse events. Herein we present the case of a 66-year-old female who developed pericardial effusion as a side effect of pembrolizumab and review the data currently available to assist in the management of this life-threatening condition.

Drug-Induced Thrombotic Microangiopathy due to Cumulative Toxicity of Ixazomib.

Drug-induced thrombotic microangiopathies (DTMAs) are increasingly being recognized as an important category of thrombotic microangiopathies (TMAs). Cancer therapeutic agents including proteasome inhibitors (PIs) are among the most common medications reported to cause DTMA. PIs could cause DTMA either by an immune mechanism or dose-dependent/cumulative toxicity. Eleven cases of DTMA have been reported with bortezomib and carfilzomib. To the best of our knowledge, only one case of DTMA has been reported with ixazomib due to an immune-mediated mechanism. Here, we report the first case of ixazomib-induced DTMA due to cumulative toxicity rather than immune-mediated mechanism. In this article, we discuss the precipitating factors for cumulative toxicity of ixazomib, resulting in DTMA, diagnostic workup, and management of DTMA. We also discuss clinical reasoning based analysis of DTMA versus cancer-associated TMA as well as DTMA versus cyclic thrombocytopenia seen in PI use.