A Review of Current and Emerging Therapeutic Options for Hemophagocytic Lymphohistiocytosis.

OBJECTIVE: To provide an overview of clinical sequelae and emerging treatment options for hemophagocytic lymphohistiocytosis (HLH). DATA SOURCES: A literature search was conducted using the search terms "hemophagocytic lymphohistiocytosis," "hemophagocytic syndrome," "macrophage activation syndrome," and "treatment" on Ovid and PubMed from January 1, 2017, through September 28, 2022. STUDY SELECTION AND DATA EXTRACTION: Relevant clinical trials, meta-analyses, case reports, review articles, package inserts, and guidelines to identify current and emerging therapeutic options for the management of HLH. DATA SYNTHESIS: Genetic disorders and secondary causes may trigger HLH in both children and adults. Notable improvements in the diagnosis of HLH were seen with implementation of the HLH-2004 standard diagnostic criteria; however, timely and accurate identification of HLH remain significant barriers to optimal management. Multiagent immunochemotherapy are the backbone of aggressive therapy for acutely ill patients with HLH. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The global coronavirus 2019 (COVID-19) pandemic and emerging immune effector cell therapies have served to highlight the concerns with immune dysregulation and subsequent HLH precipitation. Without prompt identification and treatment, HLH can be fatal. Historically, the clinician's armamentarium for managing HLH was sparse, with etoposide-based protocols serving as the standard of care. Relapsed or refractory disease portends a poor prognosis and requires additional treatment options. Second- or subsequent-line options now include hematopoietic stem cell transplantation, emapalumab, alemtuzumab, anakinra, ruxolitinib, and tocilizumab. CONCLUSIONS: Improvements in diagnostic methods and novel immunosuppressive treatment strategies, including noncytotoxic immunochemotherapy, have transformed the therapeutic landscape. Unfortunately, many unanswered questions remain. Additional studies are required to optimize dosing, schedules, treatment sequences, and indications for novel treatment options.

A Review of Selumetinib in the Treatment of Neurofibromatosis Type 1-Related Plexiform Neurofibromas.

OBJECTIVE: To evaluate the safety and efficacy of selumetinib, a novel MEK inhibitor, for the treatment of plexiform neurofibromas (PN) in patients with neurofibromatosis type 1 (NF1). DATA SOURCES: An English-based literature search of PubMed, EMBASE, and ClinicalTrials.gov was conducted using the terms selumetinib AND neurofibromatosis from inception to August 1, 2021. STUDY SELECTION AND DATA EXTRACTION: Relevant prescribing information, abstracts, and articles identified through the search were considered for inclusion in this review. DATA SYNTHESIS: The open-label, multicenter, single-arm, phase II SPRINT trial demonstrated clinically significant improvements in PN-related complications. Of 50 symptomatic patients, 68% experienced a partial response, with a median change in tumor volume of -27.9% from baseline. Estimated progression-free survival at 3 years was 84%. Additionally, clinically meaningful improvements were seen on patient- and parent-reported assessments evaluating pain, range of motion, disfigurement, and quality of life. Overall, the adverse effect profile for selumetinib appears mild and manageable. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Selumetinib is the first FDA-approved treatment for inoperable PN in patients with NF1, demonstrating that MEK inhibition is a promising therapeutic strategy. Studies are ongoing to assess the effect of selumetinib on other NF1-associated tumor types and to determine the optimal dosing schedule and treatment duration. Cost and treatment burden must be considered when selecting selumetinib therapy. CONCLUSION: Selumetinib exhibits impressive antitumor activity and sustained clinical benefit in patients lacking other viable treatment options. Further studies are warranted to determine the optimal age of initiation, treatment duration, and overall cost-effectiveness of selumetinib.

Brexucabtagene Autoleucel: A Novel Chimeric Antigen Receptor T-cell Therapy for the Treatment of Mantle Cell Lymphoma.

OBJECTIVE: To identify and assess the current literature surrounding the safety, efficacy, and practical considerations of brexucabtagene autoleucel (brexu-cel) for the treatment of relapsed or refractory (r/r) mantle cell lymphoma (MCL). DATA SOURCES: An English-based literature search was conducted using the terms "brexucabtagene autoleucel" AND "mantle cell lymphoma" OR "KTE-X19"in PubMed (inception through May 1, 2021), EMBASE (inception through May 1, 2021), and ClinicalTrials.gov. STUDY SELECTION AND DATA EXTRACTION: All studies evaluating the use of brexu-cel in MCL were considered for inclusion. DATA SYNTHESIS: In the pivotal ZUMA-2 trial, brexu-cel demonstrated objective response and complete response rates of 85% and 59%, respectively. These results were consistent among high-risk subgroups. Noteworthy treatment-related adverse effects included grade ≥3 cytopenias (94%), immune effector cell-associated neurotoxicity syndrome (31%), and cytokine release syndrome (15%). Brexu-cel elicited a toxicity profile similar to that of other novel chimeric antigen receptor (CAR) T-cell products, with no new safety signals. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: There are currently no head-to-head clinical trials evaluating brexu-cel against other approved subsequent-line options in r/r MCL. In a relatively small phase II trial, brexu-cel demonstrated impressive response rates in heavily pretreated patients, with few viable alternatives. Long-term safety and efficacy outcomes with brexu-cel are unknown. The prevention, identification, and management of unique CAR T-cell toxicities requires expert care from a well-trained interdisciplinary team. CONCLUSION: Brexu-cel has emerged as a viable treatment option in MCL. Additional studies are required to determine the optimal sequencing and place in therapy for brexu-cel in this highly heterogeneous, pathobiologically distinct, and incurable malignancy.

Tisagenlecleucel in Acute Lymphoblastic Leukemia: A Review of the Literature and Practical Considerations.

OBJECTIVE: To evaluate the current literature for tisagenlecleucel in the treatment of relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). DATA SOURCES: A literature search of PubMed (inception to June 18, 2020) and ClinicalTrials.gov was conducted using the following search terms: CTL019, chimeric antigen receptor, CAR-T, and tisagenlecleucel. STUDY SELECTION AND DATA EXTRACTION: All trials evaluating the use of tisagenlecleucel in B-cell ALL were reviewed and considered for inclusion. DATA SYNTHESIS: Tisagenlecleucel displayed overall remission rates ranging from 69% to 93% in patients who historically respond extremely poorly to salvage therapy. Remissions were durable, with 12-month relapse-free survival (RFS) rates of 55% to 59%. These promising results are tempered by the unique adverse effect profile of chimeric antigen receptor (CAR) T-cell therapy. Potentially life-threatening cytokine release syndrome (CRS) occurred in 77% to 100% of patients, and immune effector cell-associated neurotoxicity syndrome (ICANS) developed in 31% to 45% of patients receiving tisagenlecleucel. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: The successful utilization of tisagenlecleucel therapy requires meticulous planning, prudent patient selection, multidisciplinary collaboration, and expert training to ensure optimal patient care. The complex interplay of patient- and treatment-related factors creates problematic barriers that must be expertly navigated by the health care team and authorized treatment center. CONCLUSIONS: As the first US Food and Drug Administration-approved gene therapy, tisagenlecleucel heralds an immunotherapeutic breakthrough for treating pediatric and young adult patients with r/r B-cell ALL. Many questions surrounding patient-specific gene and cellular therapies remain, but their transformative potential in cancer care remains promising.

Axicabtagene Ciloleucel: Clinical Data for the Use of CAR T-cell Therapy in Relapsed and Refractory Large B-cell Lymphoma.

OBJECTIVE: To evaluate the literature for axicabtagene ciloleucel (axi-cel), a first-in-class chimeric antigen receptor (CAR) T-cell therapy, in the treatment of relapsed/refractory (r/r) large B-cell lymphoma (LBCL). DATA SOURCES: We conducted a PubMed (inception to June 22, 2020) and ClinicalTrials.gov search using the following terms: CD19, chimeric antigen receptor, and lymphoma. STUDY SELECTION AND DATA EXTRACTION: All retrospective and prospective studies evaluating the use of axi-cel in LBCL were reviewed. DATA SYNTHESIS: In the pivotal ZUMA-1 trial, axi-cel exhibited unprecedented overall and complete response rates of 83% and 58%, respectively. With a median follow-up of 27.1 months, 39% of patients had ongoing responses. Furthermore, postmarketing retrospective analyses found similar response rates in a more clinically diverse LBCL patient population. Novel CAR T-cell therapy elicits unique and potentially life-threatening toxicities that include cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Studies reported grade ≥3 CRS in 7% to 14% of patients and grade ≥3 ICANS in 31% to 55% of patients. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Axi-cel was the first US Food and Drug Administration-approved genetically engineered autologous CAR T-cell agent in r/r LBCL, representing an important milestone and paradigm shift in cancer treatment. Adoptive T-cell immunotherapy is a breakthrough treatment modality requiring careful patient selection, multidisciplinary collaboration, comprehensive patient counseling, and expert training to ensure optimal treatment. CONCLUSIONS: The initial and ongoing results with axi-cel are encouraging, but long-term safety and efficacy data are lacking. Additional studies are required to identify axi-cel's ideal place in LBCL therapy.

Enfortumab Vedotin-ejfv: A First-in-Class Anti-Nectin-4 Antibody-Drug Conjugate for the Management of Urothelial Carcinoma.

OBJECTIVE: To evaluate the pharmacology, pharmacokinetics, clinical efficacy, safety, dosing, cost, and clinical implications of enfortumab vedotin-ejfv (EV) in the treatment of locally advanced or metastatic urothelial carcinoma (UC). DATA SOURCES: A literature search of PubMed (inception to August 2020) was conducted using the terms enfortumab, vedotin, Padcev, and Nectin. Data were also obtained from package inserts, meeting abstracts, and ongoing studies from ClinicalTrials.gov. STUDY SELECTION AND DATA EXTRACTION: All relevant published articles, package inserts, and meeting abstracts evaluating EV for the treatment of UC were analyzed. DATA SYNTHESIS: Antibody-drug conjugates (ADCs) deliver potent cytotoxic agents using highly selective monoclonal antibodies. Targeting the near-universal expression of Nectin-4 on UC cells is a viable therapeutic strategy. In a pivotal phase II trial, EV demonstrated an overall response rate of 44%, and a median duration of response of 7.6 months. Estimated overall survival was 11.7 months with a median estimated progression-free survival of 5.6 months. Results were similar among difficult-to-treat patients, including those with liver metastases. Unique toxicity concerns with EV require careful consideration and monitoring. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: EV, a first-in-class anti-Nectin-4 ADC, provides impressive response rates with manageable toxicities, making it a promising treatment option for patients with multiply relapsed or refractory UC. CONCLUSION: The US Food and Drug Administration-approved EV demonstrates antitumor activity in heavily pretreated patients with UC but harbors important adverse effects and financial concerns. Additional studies are required to identify the optimal sequencing, patient population, and place in therapy for EV.