Faculty Bibliography

BACKGROUND:Despite significant progress, prostate cancer remains a leading cause of death. Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are already approved for the treatment of hormone receptor-positive breast cancer, are undergoing extensive testing as monotherapy and in various combinations as a potentially valuable treatment modality in prostate cancer patients. Thus far, a limited number of these studies have published results, which have been largely disappointing. AREAS COVERED/METHODS:In this review, we describe the biologic rationale for the use of CDK4/6 inhibitors in prostate cancer, the existing clinical data describing their use in prostate cancer, and ongoing clinical trials of CDK4/6 inhibitors as monotherapy and in combination for the treatment of prostate cancer. In particular, we focus on possible resistance mechanisms that may be particularly relevant in prostate cancer patients, leading to de novo and acquired resistance, and we highlight novel strategies that can overcome this resistance. CONCLUSIONS:Current clinical trials are actively working to (1) refine the role of CDK4/6 inhibitors in prostate cancer patients; (2) develop new inhibitors of other cell-cycle targets, such as CDK2 and CDK7; and (3) explore novel combination therapies with inhibitors of other relevant pathways, such as PI3K or MAPK. Further genomic subtyping of advanced prostate cancer will likely shed light on the subsets of patients most likely to benefit from cell-cycle-targeted agents.

PURPOSE:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematologic malignancy associated with overexpression of CD123. Allogeneic chimeric antigen receptor T cells (CAR-T) directed against CD123 in BPDCN have been studied in clinical trials. We performed post-mortem analysis of a patient treated with anti-CD123 CAR-T to elucidate cause of death, development of cytokine release syndrome (CRS), and tissue distribution of UCART123 cells. METHODS:A post-mortem multidisciplinary clinicopathologic analysis was performed with digital droplet polymerase chain reaction of isolated blood and tissue ribonucleic acid (RNA) to evaluate tissue distribution of infused CAR-T. Multiparameter flow cytometry for detection of CAR-T was used for whole blood samples. Cytokine levels in plasma were measured using multiplex bead assay. Gene expression profiling on isolated RNA was performed using semi-custom Nanostring immune gene panel and RNA-sequence method. RNA in situ hybridization was performed using CAR-specific probe. RESULTS:The patient developed severe clinical CRS refractory to corticosteroids, tocilizumab, and lymphodepletion. Despite significant reduction in BPDCN lesions, the patient passed away on day 9 of CAR-T. Autopsy results show that following lymphodepletion and UCART123 administration, the patient remained severely lymphopenic with few UCART123 cells detected, predominantly localized to spleen. CONCLUSIONS:No definitive cause of death was determined, but we hypothesized that the patient may have succumbed to CAR-T-mediated cardiopulmonary toxicity. UCART123 cells displayed low overall distribution, with predominance in immune organs and tissues. Mechanism of CRS development is still poorly understood in patients receiving CAR-T therapy. Future directions in the field developing CD123-targeted agents in BPDCN are discussed.

Testing for antibody against hepatitis C virus (anti-HCV) is a low-cost diagnostic method worldwide; however, an optimal screening test for HCV in patients with cancer has not been established. We sought to identify an appropriate screening test for HCV infection in patients with hematologic malignancies and/or hematopoietic cell transplants (HCT). Patients in our center were simultaneously screened using serological (anti-HCV) and molecular (HCV RNA) assays (February 2019-November 2019). In total, 214 patients were enrolled in this study. Three patients (1.4%) were positive for anti-HCV, and 2 (0.9%) were positive for HCV RNA. The overall percentage agreement was 99.5% (95% CI: 97.4-99.9). There were no cases of seronegative HCV virus infection. The positive percentage agreement was 66.7% (95% CI: 20.8-93.9), and the negative percentage agreement was 100.0% (95% CI: 98.2-100.0). Cohen kappa coefficient was 0.80 (95% CI: 0.41-1.00, P < .0001). The diagnostic yield of screening for chronic HCV infection in patients with cancer is similar for serologic and molecular testing.

BACKGROUND:Emerging data suggests improved outcomes in patients receiving neoadjuvant chemotherapy (NAC) prior to radical nephroureterectomy (RNU) for high-risk upper tract urothelial carcinoma. In one of the largest single-center experiences to date, we provide an updated analysis of outcomes of patients receiving NAC followed by RNU. PATIENTS AND METHODS:A retrospective review of patients with high-risk UTUC who received NAC followed by surgery between 2004 to 2017 was conducted. 126 patients were evaluated as part of the analysis. Kaplan-Meier method was used to estimate survival probabilities. Multivariable Cox modeling was used to evaluate for association with outcomes, and the cumulative incidence factor was used for competing risk analysis. RESULTS:Median OS time was 106 months. 14.3% of patients had a pathologic complete response and 60% were down-staged to ypT0-1 ypN0. The estimated 5 and 10-year DSS rates were 89.8% and 80.6%, respectively. The estimated 5 and 10-year metastasis-free survival rates were 81% and 75.4%, respectively. The estimated 5 and 10-year OS rates were 73.7% and 35.9 %, respectively. Recurrences mainly occurred in lymph nodes and lung at a median time of 15.5 months (IQR 8.9-27). The estimated 5 and 10-year cumulative incidence factor for death from UTUC was 9.5% and 16.1%, respectively. Limitations include retrospective nature and challenge of accurate pre-surgical staging. CONCLUSIONS:NAC prior to RNU in high-risk UTUC shows durable 5 and 10-year OS and DSS rates in a large single-institution series, confirming prior findings in prospective trials and retrospective studies.

INTRODUCTION:Two separate antiangiogenic tyrosine kinase inhibitors (TKIs) and immunotherapy (IO) combinations are FDA-approved as front-line treatment for metastatic renal cell carcinoma (mRCC). Little is known about off-protocol and post-front-line experience with combination TKI-IO approaches. METHODS:We conducted a retrospective analysis of mRCC patients who received combination TKI-IO post-first-line therapy between November 2015 and January 2019 at MD Anderson Cancer Center and Duke Cancer Institute. Chart review detailed patient characteristics, treatments, toxicity, and survival. Independent radiologists, blinded to clinical data, assessed best radiographic response using RECIST v1.1. RESULTS:We identified 48 mRCC patients for inclusion: median age 65 years, 75.0% clear cell histology, 68.8% IMDC intermediate risk, and median two prior systemic therapies. TKI-IO combinations included nivolumab-cabozantinib (N +C; 24 patients), nivolumab-pazopanib (N+P; 13), nivolumab-axitinib (6), nivolumab-lenvatinib (2), and nivolumab-ipilimumab-cabozantinib (3). The median progression-free survival was 11.6 months and the median overall survival was not reached. Response data were available in 45 patients: complete response (CR; n = 3, 6.7%), partial response (PR; 20, 44.4%), stable disease (SD; 19, 42.2%), and progressive disease (3, 6.7%). Overall response rate was 51% and disease control rate (CR+PR+SD) was 93%. Only one patient had a grade ≥3 adverse event. CONCLUSION:To our knowledge, this is the first case series reporting off-label use of combination TKI-IO for mRCC. TKI-IO combinations, particularly N+P and N+C, are well tolerated and efficacious. Although further prospective research is essential, slow disease progression on IO or TKI monotherapy may be safely controlled with addition of either TKI or IO.

INTRODUCTION:Pheochromocytomas and sympathetic paragangliomas (PPGL) are neuroendocrine catecholamine-secreting tumors that are usually localized. Metastatic disease is rare and systemic treatment consists of conventional chemotherapy and high-specific-activity iodine-131-MIBG which was approved by the FDA in 2018. Although chemotherapy combinations still have value in specific settings, the debilitating side effects of treatment with only modest benefit have limited their use. With the introduction of a new generation of targeted therapy and immunotherapy patients with metastatic PPGL may have improved therapeutic options. AREAS COVERED:The current paper presents a case of a patient with metastatic PPGL who received multiple lines of systemic treatment. Despite progression on previous single agent cabozantinib and single agent pembrolizumab on separate clinical trials, the patient has exhibited a major response to the combination of cabozantinib and nivolumab for the past 22 months. In addition, we will review the available therapies for metastatic PPGL and discuss novel agents under clinical development. CONCLUSION:Newer targeted therapies and immunotherapy options are under clinical development with promising results for patients with PPGL.

PURPOSE OF REVIEW:Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare, clinically aggressive hematologic malignancy that has heterogeneous presentation and can involve the skin, lymph nodes, and bone marrow. Recent advancements in our patho-biologic understanding of the disease have led to the development of new targeted therapies for BPDCN. In this review, we aimed to describe some of the novel treatments that are being put forward for the management of BPDCN. RECENT FINDINGS:Tagraxofusp is the first CD123-targeted therapy approved as the first ever targeted treatment of BPDCN in patients aged 2 years and older. This agent was approved based on a pivotal clinical trial that showed that it was associated with high rates of clinical responses in both treatment-naïve and treatment-experienced patients. The most serious adverse event was occurrence of the capillary leak syndrome. Other targeted therapies are actively being investigated in clinical trials. These include other CD123-targeted approaches, as well as active investigation in targets beyond CD123, such as the BCL-2 inhibitor, venetoclax. BPDCN is a rare hematologic clonal disorder with historically poor outcomes. Newer targeted therapies have been recently introduced, with promising results and novel toxicities that are important to recognize and understand. Stem cell transplantation after achievement of complete remission remains the mainstay of therapy among younger/fit, eligible patients, regardless of treatment modality used.

PURPOSE OF REVIEW:With increased understanding of the pathobiology of myeloproliferative neoplasms (MPNs), multiple new agents are now being investigated. We aim to cover some of the current treatment options for MPNs and discuss new agents in development. RECENT FINDINGS:The introduction of ruxolitinib improved the treatment of many patients with intermediate and higher risk myelofibrosis. However, ruxolitinib monotherapy does not benefit all patients, and not all patients can receive this therapy due to limiting cytopenias. The unraveling of new molecular abnormalities and cellular pathways led to the development of several novel targeted agents that are currently under investigation in clinical trials. These agents have different mechanisms of action and are being used either alone or in combination with ruxolitinib. Novel targets include inhibition of apoptosis, the tumor microenvironment, telomerase enzyme action, immunotherapy, and fibrosis with associated cytokines. We comprehensively review and summarize the available preclinical and clinical trials with novel agents for MPNs.