Bruton's Tyrosine Kinase Inhibitors: Recent Updates.

Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the landscape for the treatment of hematological malignancies, solid tumors, and, recently, autoimmune disorders. The BTK receptor is expressed in several hematopoietic cells such as macrophages, neutrophils, mast cells, and osteoclasts. Similarly, the BTK receptor is involved in signaling pathways such as chemokine receptor signaling, Toll-like receptor signaling, and Fc receptor signaling. Due to their unique mechanism, these agents provide a diverse utility in a variety of disease states not limited to the field of malignant hematology and are generally well-tolerated.

Importance of ROS1 gene fusions in non-small cell lung cancer.

Targeted therapy has become one of the standards of care for advanced lung cancer. More than 10 genetic aberrations have been discovered that are actionable and several tyrosine kinase inhibitors (TKIs) have been approved to target each of them. Among several genetic aberrations that are actionable in non-small cell lung cancer (NSCLC), ROS1 translocations also known as gene fusion proteins, are found in only 1%-2% of the patient population. ROS1 mutations can usually be detected using a combination of techniques such as immunohistochemistry (IHC), Fluorescence in-situ testing (FISH), polymerase chain reaction (PCR), and next-generation sequencing (NGS). However, RNA NGS and ctDNA NGS (liquid biopsies) also contribute to the diagnosis. There are currently numerous FDA-approved agents for these tumors, including crizotinib and entrectinib; however, there is in-vitro sensitivity data and clinical data documenting responses to ceritinib and lorlatinib. Clinical responses and survival rates with these agents are frequently among the best compared to other TKIs with genetic aberrations; however, intrinsic or extrinsic mechanisms of resistance may develop, necessitating research for alternative treatment modalities. To combat the mechanisms of resistance, novel agents such as repotrectenib, cabozantinib, talotrectinib, and others are being developed. In this article, we examine the literature pertaining to patients with ROS1 tumors, including epidemiology, clinical outcomes, resistance mechanisms, and treatment options.

Pancreatic adverse events in patients treated with immune checkpoint inhibitors.

Background and Aim: The inhibition of cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) has been a target for multiple drugs to enhance the T-cell antitumor activity. However, these immune checkpoint inhibitors (ICIs) come with a panel of immune-related adverse events (irAEs) that include mainly endocrine, skin, and gastrointestinal effects. We report seven cases of pancreatic irAEs in patients treated with ICIs at our institute. Methods: This is a case series; data was collected through chart review by 3 different data collectors and was analyzed separately by 2 physicians. Results: Of these seven cases, two had diabetic ketoacidosis (DKA), while five had pancreatitis diagnosed by a substantial rise in serum lipase. Pancreatitis was asymptomatic in two cases. A pancreatic biopsy in one case revealed type 2 autoimmune pancreatitis. The ICIs used included pembrolizumab, nivolumab, durvalumab, and avelumab. Treatment included steroids and holding the ICI therapy: three cases had complete resolution of pancreatitis while two cases required either a prolonged taper or a second course of prednisone for recurrence of pancreatitis. On the other hand, the DKA cases were treated with withdrawal of the ICI and starting insulin with no steroid therapy. Conclusions: Pancreatitis and DKA are rare adverse events of ICIs that can be controlled by holding the ICI with or without starting steroids. Rechallenging the patient with the same ICI is possible in selected cases.

Mortality and prognostic factors in hospitalized COVID-19 patients with cancer: an analysis from a large healthcare system in the United States.

Background: To evaluate clinical outcomes in patients with malignancy who are SARS-CoV-2 (COVID-19) positive and investigate if factors such as age, gender, and race contribute to COVID-19 mortality in patients with malignancy. Methods: Retrospective data was gathered from Memorial Healthcare System of COVID-19 patients hospitalized from March 1, 2020 to January 18, 2021. Active malignancy was defined as either receiving antineoplastic therapy or being under surveillance. The primary endpoint was in-hospital mortality. Descriptive statistics were used to summarize the characteristics and outcomes. Univariate and multivariate logistic analysis were performed to define baseline clinical characteristics potentially associated with mortality in cancer patients with COVID-19. Results: A total of 4,870 COVID-19 patients were enrolled in the study, and 265 of those patients had a diagnosis of active malignancy. The study population was diverse which included non-Hispanic whites (NHW) 816 (16.8%), Hispanics 2,271 (46.6%) and Blacks 1,534 (31.5%). Of the cancer patients, 24.1% were NHW, 43% were Hispanic and 28.7% were Black. Amongst the races, 37.5% of in-hospital mortalities were NHW, while 18.4% were Hispanics and 19.7% were Black. The in-hospital mortalities amongst the two malignancy types, solid and hematological, accounted for 24.6% and 23.5% of deaths and they were not found to be statistically significant (P=0.845). After adjustments for age, gender and race were made, cancer was independently associated with an increased in-hospital mortality, with an adjusted odds ratio of 1.48 [95% confidence interval (CI): 1.08-2.01]. Increased age and elevated serum levels of creatinine and C-reactive protein (CRP) were associated with an increased risk of death in cancer patients with COVID-19. Conclusions: COVID-19 in patients with cancer had poorer outcomes in comparison to those who were cancer-free. Both hematological and solid malignancies had similar in-hospital mortality rates. The highest in-hospital mortalities of cancer patients with COVID-19 were non-Hispanic whites in-comparison to Hispanics with the least. Age, elevated levels of creatinine and CRP were independently associated with increased risk of death in cancer patients hospitalized with COVID-19. The findings indicate the need for close surveillance and monitoring of these patients as they are more likely to have higher risk of death from COVID-19.