Long-term follow-up and future direction on the management of chronic lymphocytic leukemia/small lymphocytic leukemia.

OBJECTIVE: Chronic lymphocytic leukemia and small lymphocytic lymphoma remain the most prevalent adult leukemia in Western countries. Novel therapeutics have established long-term efficacy and have changed the landscape in patient management. In contrast, novel approaches pose opportunities for patients to be treated for finite durations. In this manuscript, we highlight long-term safety and efficacy data with Bruton's tyrosine kinase inhibitors and combination BCL2 + anti-CD20 therapies. We also offer key considerations for treatment selection and outline ongoing trials which may continue to expand therapeutic options and approaches. DATA SOURCES: An electronic search of the PubMed database was performed to obtain key literature in chronic lymphocytic leukemia and small lymphocytic lymphoma published using the following search terms: chronic lymphocytic leukemia/small lymphocytic lymphoma, Richter syndrome, and histologic transformation. The search results were narrowed by selecting studies in humans published in English. Results were confined to the following article types: Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Reviews; and Validation Studies. DATA SUMMARY: Chronic lymphocytic leukemia and small lymphocytic lymphoma are different manifestations of the same disease and are managed in much the same way. Bruton's tyrosine kinase inhibitors have demonstrated long and durable efficacy benefits in patients with newly diagnosed chronic lymphocytic leukemia/small lymphocytic lymphoma and in the relapsed/refractory setting. Despite these benefits, long terms adverse events have posed challenges for patients and have led to treatment discontinuations. Additionally, the use of monotherapy Bruton's tyrosine kinase inhibitor's requires chronic use of the medications leading to added financial implications. BCL2 inhibition with venetoclax in combination with anti-CD20 monoclonal antibodies has offered a novel and finite treatment approach in frontline and relapsed chronic lymphocytic leukemia/small lymphocytic lymphoma. Ongoing clinical trials are in investigating this modality further to enhance durable responses utilizing a combination Bruton's tyrosine kinase inhibitor's and BCL2 inhibitors. CONCLUSION: The treatment armamentarium of chronic lymphocytic leukemia/small lymphocytic lymphoma continues to evolve. Despite the long term, durable responses with Bruton's tyrosine kinase inhibitor's, it is likely that finite treatment durations could become the standard of care as a result of continued, long-term responses.

Clinical strategies for optimizing infusion center care through a pandemic.

The national pandemic resulting from the novel coronavirus, COVID-19, has made the delivery of care for patients with cancer a challenge. There are competing risks of mortality from cancer versus serious complications and higher risk of death from COVID-19 in immunocompromised hosts. Furthermore, compounding these concerns is the inadequate supply of personal protective equipment, decreased hospital capacity, and paucity of effective treatments or vaccines to date for COVID-19. Guidance measures and recommendations have been published by national organizations aiming to facilitate the delivery of care in a safe and effective manner, many of which, are permanently adoptable interventions. Given the critical importance to continue chemotherapy, there remains additional interventions to further enhance patient safety while conserving healthcare resources such as adjustments in medication administration, reduction in laboratory or drug monitoring, and home delivery of specialty infusions. In this manuscript, we outline how to implement these actionable interventions of chemotherapy and supportive care delivery to further enhance the current precautionary measures while maintaining safe and effective patient care. Coupled with current published standards, these strategies can help alleviate the numerous challenges associated with this pandemic.

Updates in the management and future landscape of urothelial carcinoma.

Urothelial carcinoma is the sixth most common cancer type in the United States. Although most patients present with early stage disease which is associated with improved outcomes, many will progress to locally advanced or metastatic disease. Immune checkpoint inhibitors have significantly impacted the treatment paradigm for patients and have resulted in improved survival rates. Despite their proven efficacy, many ongoing clinical trials continue to refine combinations with chemotherapy, sequencing of therapies and the role of ligand expression. Additionally, novel targets have been identified for advanced urothelial carcinoma and have led to the approval of the antibody-drug conjugate, enfortumab vedotin, and the fibroblast growth factor receptor-targeted, erdafitinib. Enrollment in a clinical trial is strongly encouraged for all stages of advanced or metastatic disease. Numerous ongoing clinical trials are likely to impact the treatment armamentarium for patients. In this manuscript, we highlight key updates in the clinical management for patients and outline ongoing trials.

Updates in the management of relapsed/refractory multiple myeloma.

Multiple myeloma, a malignant neoplasm of plasma cells that accumulate in bone marrow, accounts for approximately 18% of hematologic malignancies in the United States. Patients are often treated with triplet therapy and may undergo stem cell transplantation. Despite effective therapies, multiple myeloma remains incurable. Patients often require maintenance therapy, and many will progress or relapsed following upfront treatment. Selection of treatment in the relapse/refractory setting is complex due numerous active therapeutic agents and combinations. Treatment is often tailored to prior exposure and duration. In 2020, three novel pharmacological agents were approved in the relapsed setting. We highlight the clinical safety and efficacy of selinexor, isatuximab-irfc, and belantamab mafodotin for patients with multiple myeloma.

Updates in the management of chronic lymphocytic leukemia/small lymphocytic leukemia.

Chronic lymphocytic leukemia is one of the most common lymphoid malignancies. Often treatment modalities are tailored to individual patients based on age, presence of comorbidities and cytogenetics. The advent of ibrutinib has significantly changed the management of the disease in all patient groups and has had the largest impact on clinical practice to date. Over the last 15 years, a series of trials have established that chemoimmunotherapy improves both progression-free survival and overall survival compared to chemotherapy alone. Despite its proven role, efficacy of ibrutinib has not been well established in young, fit patients and in comparison with standard care and as combination therapy with other agents such as venetoclax. New data have strengthened the role of ibrutinib in the front-line setting and establish its place in therapy. In addition, combination therapies are geared to achieve negative minimal residual disease and allow patients to potentially be off of therapy. The management of this leukemia has extensively changed over the past years, and this review article will aim to highlight key trials that have changed practice and led to guideline updates. It is not unlikely that treatment modalities will continue to improve in light of new data.

A review of checkpoint inhibitors in the management of renal cell carcinoma.

Renal cell carcinoma is a common malignancy of the genitourinary system and is the eight most common cancer type in the United States. The overall incidence of renal cell carcinoma appears to be increasing but death rates have been declining. Patients with poor risk, advanced disease have a two-year survival rate of approximately 7%. Prior to the advent of tyrosine kinase inhibitors, anti-vascular endothelial growth factor antibodies, mammalian target of rapamycin inhibitors, and checkpoint inhibitors, IFN-α and high-dose IL-2, were standard of care treatment options but, conversely, their use is now limited to select patients. Immunotherapies have played a significant role in the treatment of various cancers and have continued to expand. It is of utmost importance that practitioners include checkpoint inhibitors as treatment options for renal cell carcinoma as they mark a new era in the treatment of advanced or relapsed setting. Nivolumab, pembrolizumab, avelumab, ipilimumab, and atezolizumab all play a role in management of disease as either monotherapy or in combination with other agents. Ongoing clinical trials are ongoing to further assess the benefits of inducing cellular immunity in the treatment of renal cell carcinoma. In this article, the available data on immune checkpoint inhibitors for the treatment of advanced or relapsed renal cell carcinoma and their place in therapy are reviewed.

The role of Bruton's tyrosine kinase inhibitors in the management of mantle cell lymphoma.

Mantle cell lymphoma is a rare subtype of B-cell non-Hodgkin's lymphomas that is generally classified as an aggressive lymphoma requiring front-line chemo-immunotherapy with stem cell rescue. Despite effective treatment, many patients relapse or are refractory to front-line therapy. In addition, these patients may also develop drug resistance requiring novel modalities for subsequent lines. Bruton's tyrosine kinase inhibitors have demonstrated a well-tolerated safety and efficacy profile across several B-cell malignancies. Ibrutinib, acalabrutinib, and zanubrutinib are FDA-approved as treatment options for patients with Mantle cell lymphoma following one prior line of therapy. Various factors should be considered which include the adverse event profile of these agents and ability to adhere to therapy. In this article, we review the role of Bruton's tyrosine kinase inhibitors for the management of Mantle cell lymphoma and review the clinical pharmacology, pharmacokinetics, safety and efficacy, and future directions.

Updates and novel treatments in urothelial carcinoma.

Urothelial Carcinoma (UC) is the second most common malignancy of the genitourinary system and is the sixth most common cancer in the USA. Over a decade prior to 2016, the standard of care for early disease consisted of transuretheral resection of the bladder tumor with or without intravesicular chemotherapy or immunotherapy. Systemic chemotherapies such as gemcitabine and cisplatin combinations or dose-dense methotrexate, vinblastine, doxorubicin, cisplatin were reserved for recurrent, muscle-invasive, advanced or metastatic disease. Novel treatment approaches for UC have significantly impacted the management of patients. In 2016-2017, five immune checkpoint inhibitors marked a new paradigm in the treatment of UC for patients with advanced or metastatic disease or who are unable to tolerate platinum-based chemotherapy. Most recently, the U.S. Food and Drug Administration set restrictions on two commonly utilized checkpoint inhibitors, atezolizumab and pembrolizumab, in the first-line setting in patients with UC due to decreased survival associated with low expression of the protein programmed death ligand 1. Furthermore, Breakthrough Therapy Designations have been granted for enfortumab vedotin and erdafitinib for patients following platinum-based chemotherapy and those with fibroblast growth factor receptor mutated UC, respectively. Additional updates include dose-dense gemcitabine and cisplatin for muscle-invasive bladder cancer and preoperative checkpoint blockade. This article will review the available data on updates in the treatment of UC and future direction of therapies.

Updates in the Management of Renal Cell Carcinoma.

At JADPRO Live Virtual 2021, advanced practitioner experts reviewed clinical updates in the treatment of renal cell carcinoma, key patient counseling and monitoring considerations, and best practices to manage adverse events associated with therapies for renal cell carcinoma.

The role of enfortumab vedotin and sacituzumab govitecan in treatment of advanced bladder cancer.

PURPOSE: The treatment landscape of advanced bladder cancer continues to evolve with novel therapeutics approved in recent years and many in the pipeline. Here we review the role of the novel agents enfortumab vedotin and sacituzumab govitecan in treatment of advanced disease. SUMMARY: Patients with advanced bladder cancer often first receive platinum-based therapy, while immune checkpoint inhibitors offer a maintenance option following cytotoxic chemotherapy or a second-line option. Despite various first- and second-line options, patients with significant comorbidities and treatment-related adverse events will experience disease progression requiring alternative treatment. Enfortumab vedotin and sacituzumab govitecan are novel antibody-drug conjugates approved in patients with advanced bladder cancer following platinum-based and immune checkpoint inhibitor therapy. Following platinum-based therapy and immunotherapy in patients with advanced bladder cancer, enfortumab vedotin, targeting Nectin-4, improves overall survival while sacituzumab govitecan, targeting Trop-2, is associated with a 27% response rate. With these new approaches to disease management, however, it remains critical to understand safety, efficacy, and operational considerations to optimize outcomes. CONCLUSION: When selecting an antibody-drug conjugate to treat patients with bladder cancer, it is important to note the adverse event profile of each agent to optimize outcomes and safety for patients.

2019-2020 Drug Updates in Solid Tumors.

During JADPRO Live Virtual 2020, Kirollos S. Hanna, PharmD, BCPS, BCOP, updated the audience on the pharmacology, new indications, and the clinical trial data of novel medications as well as expanded indications in solid tumors. Dr. Hanna also discussed signs and symptoms of potential serious and life-threatening adverse events, and how new therapeutic entities will impact the advanced practice setting.

Advancements in Therapy for Bladder Cancer: Enfortumab Vedotin.

The treatment paradigm for urothelial carcinoma (UC), a common genitourinary cancer, has significantly expanded in recent years. Enfortumab vedotin, a Nectin-4-targeted antibody-drug conjugate, was recently approved by the U.S. Food & Drug Administration for patients with advanced or metastatic UC following chemotherapy and immunotherapy. Approval of enfortumab vedotin was based on findings from the EV-201 trial, which demonstrated objective response rates of 44%. Patients treated with enfortumab vedotin should be monitored for specific toxicities, including peripheral neuropathy, rash, and hyperglycemia. In this article, the clinical implications of enfortumab vedotin for the treatment of advanced UC are reviewed.

Clinical Overview of Enfortumab Vedotin in the Management of Locally Advanced or Metastatic Urothelial Carcinoma.

The treatment landscape for locally advanced or metastatic urothelial carcinoma has broadened significantly over recent years. New therapeutic options include immunotherapy with checkpoint inhibitors and targeted therapy with erdafitinib. Despite these advances, gaps remain in the selection and sequencing of optimal therapies. Treatment decisions are often influenced by several patient-specific factors such as tolerability and biomarker expression. Following progression while receiving front- and second-line therapies, there is no widely accepted standard of care for patients. Enrollment into a clinical trial is recommended in all lines of therapy for advanced disease. Antibody-drug conjugates have recently emerged as novel therapeutics allowing for targeted delivery of chemotherapeutic agents. Enfortumab vedotin, a nectin-4-targeted antibody conjugated with monomethyl auristatin E, is the first-in-class therapeutic option and has demonstrated unprecedented response rates following progression on chemotherapy and immunotherapy for advanced disease with a tolerable safety profile. As a result, a biologics license application was submitted to the US FDA in July 2019. Ongoing clinical trials are aiming to further establish the role of enfortumab vedotin in urothelial carcinoma. In this article, we highlight the safety and efficacy of enfortumab vedotin for patients with advanced bladder cancer, ongoing clinical trials, clinical pharmacology, and pharmacokinetics.

A Review of Immune Checkpoint Inhibitors for the Management of Locally Advanced or Metastatic Urothelial Carcinoma.

Urothelial carcinoma (UC) is the second most common malignancy of the genitourinary system and the sixth most common cancer in the United States. The overall incidence of UC appears to be on the decline, but death rates have remained stable. Stage IV metastatic disease is associated with only a 5% survival rate at 5 years. Gemcitabine and cisplatin combinations or dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin are the preferred regimens for individuals with advance, metastatic disease and a good performance status and organ function. Second-line therapies in this setting are limited. During the course of 1 year, five immune checkpoint inhibitors were approved for treatment of cancers in the locally advanced or metastatic setting: atezolizumab, nivolumab, durvalumab, avelumab, and pembrolizumab. Immunotherapies have played a significant role in the treatment of various cancers and have continued to expand. It is of utmost importance that practitioners include checkpoint inhibitors as treatment options for UC. Based on the limited data, pembrolizumab and atezolizumab may be the drugs of choice, as they are supported by the most influential data to date; however, further research is warranted. Ongoing clinical trials will further assess the benefits of inducing cellular immunity in the treatment of UC. These therapies mark a new landscape in the treatment of UC. In this article, the available data on immune checkpoint inhibitors for the treatment of locally advanced or metastatic UC and their place in therapy are reviewed.

Optimizing proton pump inhibitor therapy for treatment of nonvariceal upper gastrointestinal bleeding.

PURPOSE: The pharmacology, rationale, and dosing optimization strategies of proton pump inhibitors (PPIs) for the treatment of upper gastrointestinal bleeding (UGIB) are discussed. SUMMARY: In combination with endoscopic therapy, PPIs are the treatment of choice for UGIB. While the advent of PPIs has improved patient outcomes, controversy still exists over optimal PPI therapy for UGIB. Pharmacologic treatment in combination with endoscopic therapy has demonstrated improved outcomes in patients with nonvariceal UGIB. PPIs are the treatment of choice for suppressing gastric acid and preventing rebleeding, though a mortality benefit from these agents has not been strongly established. Although the current guidelines recommend an i.v. bolus injection followed by continuous infusion of a high-dose PPI, intermittent PPI therapy has been found to be safe and effective while significantly reducing cost, even in patients with high-risk stigmata after endoscopy. Oral PPIs may be effective in patients who can tolerate oral therapy but require further evaluation in patients with higher-risk stigmata. Regardless of stigmata, after 72 hours of i.v. therapy, patients with UGIB may be safely transitioned to oral PPIs if hemodynamically stable and able to tolerate oral medication. As the risk of rebleeding significantly decreases after the first three days, continuation of high-dose therapy beyond 72 hours is not necessary in hemodynamically stable patients. CONCLUSION: Current guidelines recommend that PPIs be given as an i.v. bolus injection followed by a continuous infusion, but intermittent i.v. dosing and oral PPI therapy have been found to be effective in treating patients with UGIB and associated with reductions in cost.

A Rare Case of Pembrolizumab-Induced Uveitis in a Patient with Metastatic Melanoma.

Pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, is a humanized monoclonal antibody used in the treatment of metastatic or unresectable melanoma and advanced non-small cell lung cancer (NSCLC). We hereby report a case of pembrolizumab-induced uveitis to increase practitioner awareness. A 78-year-old woman presented with onset of panuveitis after initiation of pembrolizumab therapy for metastatic melanoma. The patient received three cycles of therapy every 21 days, during which her symptoms progressively worsened. She was treated with topical and systemic corticosteroids, and further pembrolizumab was discontinued despite a good response to therapy. Pembrolizumab has been associated with rapid onset of ocular inflammation and uveitis. PD-1 inhibitors mediate a T-cell response against cancer cells; however, autoimmune complications have been reported. Incidence of pembrolizumab-induced uveitis is reported to be < 1%. To date, three cases have been reported since its Food and Drug Administration approval in September 2014. Uveitis, if left untreated, may lead to permanent vision loss and ocular damage. Cases of immune-mediated uveitis have been reported with cancer immunotherapies. Oncologists and ophthalmologists should be aware of this complication. With the increasing targeted pharmaceuticals in oncology, effective management of adverse events is necessary to ensure patient safety and optimal outcomes.