Unveiling Discrepant and Rare Dihydropyrimidine Dehydrogenase (DPYD) Results Using an In-House Genotyping Test: A Case Series.

Fluoropyrimidine chemotherapy is a primary component of many solid tumor treatment regimens, particularly those for gastrointestinal malignancies. Approximately one-third of patients receiving fluoropyrimidine-based chemotherapies experience serious adverse effects. This risk is substantially higher in patients carrying DPYD genetic variants, which cause reduced fluoropyrimidine metabolism and inactivation (ie, dihydropyridine dehydrogenase [DPD] deficiency). Despite the known relationship between DPD deficiency and severe toxicity risk, including drug-related fatalities, pretreatment DPYD testing is not standard of care in the United States. We developed an in-house DPYD genotyping test that detects 5 clinically actionable variants associated with DPD deficiency, and genotyped 827 patients receiving fluoropyrimidines, of which 49 (6%) were identified as heterozygous carriers. We highlight 3 unique cases: (1) a patient with a false-negative result from a commercial laboratory that only tested for the c.1905 + 1G>A (*2A) variant, (2) a White patient in whom the c.557A>G variant (typically observed in people of African ancestry) was detected, and (3) a patient with the rare c.1679T>G (*13) variant. Lastly, we evaluated which DPYD variants are detected by commercial laboratories offering DPYD genotyping in the United States and found 6 of 13 (46%) did not test for all 5 variants included on our panel. We estimated that 20.4% to 81.6% of DPYD heterozygous carriers identified on our panel would have had a false-negative result if tested by 1 of these 6 laboratories. The sensitivity and negative predictive value of the diagnostic tests from these laboratories ranged from 18.4% to 79.6% and 95.1% to 98.7%, respectively. These cases underscore the importance of comprehensive DPYD genotyping to accurately identify patients with DPD deficiency who may require lower fluoropyrimidine doses to mitigate severe toxicities and hospitalizations. Clinicians should be aware of test limitations and variability in variant detection by commercial laboratories, and seek assistance by pharmacogenetic experts or available resources for test selection and result interpretation.

PD-1/PD-L1 inhibitor-induced immune thrombocytopenia: A pharmacovigilance study and systematic review.

INTRODUCTION: Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) are used for a variety of cancers and are associated with a risk of developing immune-related adverse events, most commonly dermatitis, colitis, hepatitis, and pneumonitis. Immune-mediated hematologic toxicities have been reported, but are less well-described in the literature. Immune thrombocytopenia (ITP) is a rare autoimmune, hematologic adverse event that has been reported with PD-1/PD-L1 inhibitors. METHODS: We performed a retrospective observational analysis of the United States Food and Drug Administration Adverse Event Reporting System (FAERS) data. We searched for cases of ITP reported with exposure to PD-1/PD-L1 inhibitors from initial FDA approval for each agent to September 30, 2022. Disproportionality signal analysis was done by calculating the reporting odds ratio (ROR). Oxaliplatin was used as a positive control for sensitivity analysis as it is an anticancer therapy that has been associated with drug-induced ITP. A systematic review of the PubMed database was also conducted to identify published cases of PD-1/PD-L1 inhibitor-induced ITP. RESULTS: There were 329 reports of ITP with ICIs in the FAERS database that were reviewed for a disproportionality signal, including atezolizumab (n = 27), durvalumab (n = 17), nivolumab (n = 160), and pembrolizumab (n = 125). The ROR was significant for atezolizumab (ROR 5.39, 95 % CI 3.69-7.87), avelumab (ROR 10.32, 95 % CI 4.91-21.69), durvalumab (ROR 7.91, 95 % CI 4.91-12.75), nivolumab (ROR 9.76, 95 % CI 8.34-11.43), and pembrolizumab (ROR 12.6, 95 % CI 10.55-15.06). In our systematic review, we summated 57 cases of ICI-induced ITP. Nivolumab and pembrolizumab had the most reported cases of ITP in the literature. Most cases reported (53 %) included ITP-directed therapies beyond corticosteroids for the management of ICI-induced ITP. CONCLUSION: There is a significant reporting signal of ITP with several ICI agents. Clinicians should be aware of and monitor for signs of this potentially serious adverse event.

Pharmacist perspectives on emerging T cell-engaging bispecific therapies in cancer therapeutics.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: To summarize the pharmacology, efficacy, safety, dosing, administration, and pharmacist perspectives related to operationalization of new and emerging bispecific therapies indicated for the treatment of various cancers. SUMMARY: In recent years, there have been significant advancements in the expansion of immunotherapeutics in the treatment of various malignancies. Bispecific T cell-engaging therapies represent an emerging therapeutic drug class for the treatment of cancer. These therapies are unique antibody constructs that bind simultaneously to 2 targets, a tumor-specific antigen and CD3 on T cells, to elicit an immune response. Recently, several bispecific therapies have been approved, including epcoritamab, glofitamab, mosunetuzumab, tebentafusp, and teclistamab. Epcoritamab and glofitamab have been approved for diffuse large B cell lymphoma, while mosunetuzumab, tebentafusp, and teclistamab have been approved for follicular lymphoma, uveal melanoma, and multiple myeloma, respectively. As a result of their mechanism of action, the approved bispecific therapies have the potential to cause cytokine release syndrome, and, along with this, they all have unique and specific monitoring parameters and operational considerations that require clinician awareness when administering these therapies. Such operational challenges include within-patient dose escalations at therapy initiation, hospitalization for monitoring, and various pharmacological strategies for prophylaxis of cytokine release syndrome. CONCLUSION: Bispecific therapies have continued to evolve the therapeutic landscape of cancer, primarily in hematological malignancies. Health-system pharmacists have the opportunity to play a key role in the operationalization and management of this new and emerging drug class.

Alpelisib-Induced Diabetic Ketoacidosis: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System and Review of the Literature.

BACKGROUND: Alpelisib is a PI3K inhibitor indicated with fulvestrant for treatment of advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated breast cancer. In the phase III SOLAR-1 trial, grade 3/4 hyperglycemic events were reported in 36.6% of patients receiving alpelisib-fulvestrant compared to 0.7% receiving placebo-fulvestrant. As case reports of diabetic ketoacidosis (DKA) have been associated with alpelisib use, the goal of this study was to characterize the FAERS reported cases of this severe adverse effect. METHODS: A retrospective disproportionality analysis was performed using the FAERS database by calculating the reporting odds ratio (ROR) of DKA events with alpelisib from 2019 to 2022. A PubMed literature review of case reports characterizing alpelisib-induced DKA was performed. RESULTS: Pharmacovigilance database analysis revealed significance in reporting among 87 DKA cases with alpelisib (ROR 9.84, 95% confidence interval 7.3-13.2), including hospitalization and death as reported outcomes. Review of 11 published case reports reveals median onset of DKA at 14 days with successful rechallenge possible. CONCLUSION: Significant association with reporting exists between DKA and alpelisib exposure. We observed similar median time to onset of hyperglycemia between our analysis compared to that reported in SOLAR-1. Considering early onset of this toxicity, it is imperative that patients be closely monitored when initiating alpelisib. Addition of a preemptive antihyperglycemic or escalation in those previously on antihyperglycemic medications is beneficial in decreasing the severity of hyperglycemia with alpelisib. Further study investigating risk factors is warranted to better elucidate which patients require preemptive therapy.

Post-Transplant Cyclophosphamide for the Prevention of Graft-vs.-Host Disease in Allogeneic Hematopoietic Cell Transplantation: A Guide to Management for the Advanced Practitioner.

Cyclophosphamide remains a critical component to haploidentical transplant conditioning regimens. Post-transplant cyclophosphamide (PTCy) emerged as an effective component of graft-vs.-host disease (GVHD) prophylaxis in the nonmyeloablative haploidentical bone marrow transplant setting. The relative ease of administration compared with ex vivo manipulations and efficacy in reducing GVHD has led to increasing PTCy use in transplant centers around the world. The role of PTCy has expanded to haploidentical transplantation with myeloablative conditioning regimens and peripheral blood progenitor cells as the donor source. Moreover, encouraging results in GVHD management have been shown with the use of PTCy alone or in combination with other immunosuppressives in the human leukocyte antigen-matched donor setting. The toxicity profile of cyclophosphamide varies extensively depending on dose, duration, overall drug exposure, and, potentially, pharmacogenetics. This review highlights the pharmacology, pharmacokinetics, and toxic effects of cyclophosphamide and offers practical guidance for clinical application in the post-transplant setting. We summarize data on the management of high-dose cyclophosphamide toxicities and provide insights into the pharmacogenetic implications on drug efficacy and safety data.

Use of patient-reported outcome measures for oncology drugs receiving accelerated approval.

Patient-reported outcomes (PROs) represent an important evaluation of health-related quality of life that has become more commonly incorporated into oncology drug clinical trials. The frequency of PRO inclusion as an endpoint in oncology drug clinical trials leading to the initial accelerated approval of a new therapy is not yet known. We conducted a cross-sectional study evaluating all new drug applications submitted to the FDA over the past 10 years (2013-2022) that led to the initial approval of an oncology drug through the accelerated approval process. The objective was to assess whether the trials leading to such an approval included PROs. Between 2013 and 2022, the FDA approved 59 unique drugs for an oncology indication via the accelerated approval pathway, and 35 (59%) included a PRO assessment in the clinical trial. A median of 1 PRO measurement was used in each trial, with 23 different types of PRO assessment tools were used across the 59 new drug applications. In summary, we found that PRO measurements are inconsistently utilized in trials leading to initial accelerated approval of oncology drugs, and there seems to be a lack of harmonization of different PRO measurement tools used across trials.

Ocular toxicities associated with antibody drug conjugates and immunotherapy in oncology: clinical presentation, pathogenesis, and management strategies.

INTRODUCTION: The development of molecularly targeted anticancer therapies and immunotherapy continues to revolutionize the treatment of cancer. FDA accelerated approvals of novel targeted therapies allowed for introduction of these agents into the clinic at a rapid rate. On-and off-target ocular toxicities are prevalent treatment-related adverse events of newer therapies including antibody drug conjugates (ADCs) and immunotherapy. Ocular toxicities associated with ADCs and immunotherapy have heterogeneous presentations and pathogenesis requiring unique and often complex monitoring, and management. AREAS COVERED: In this article, we provide an updated review of treatment-emergent ocular toxicity associated with new and novel oncologic therapies and summarize guidelines and best practice strategies for prevention, monitoring and management. A literature search was performed through PubMed, ClinicalTrials.gov, and FDA website (1 January 2017 to 10 May 2023) to identify relevant information. EXPERT OPINION: The implementation of a strategy for monitoring, prevention, and management of treatment-related ocular toxicities involves a multi-disciplinary, often cross-center approach. Communication with infusion nursing leadership, clinic staff, and eye care providers is crucial to the successful implementation of eye care plans to prevent and manage ocular toxicity.

Hepatitis B reactivation in patients with multiple myeloma treated with anti-CD38 monoclonal antibody-based therapies: a pharmacovigilance analysis.

BACKGROUND: Daratumumab and isatuximab are anti-CD38 monoclonal antibodies indicated for the treatment of multiple myeloma. These agents can increase the risk of infectious complications, including viral infections. Cases of hepatitis B virus (HBV) reactivation have been reported in the literature in patients receiving anti-CD38 monoclonal antibody-based therapies. AIM: The objective of this analysis was to determine if the association between anti-CD38 monoclonal antibody exposure and the development of hepatitis B reactivation had a detectable reporting signal in the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). METHOD: We conducted a post marketing pharmacovigilance analysis by querying the FAERS for reports of HBV reactivation with daratumumab or isatuximab exposure reported between 2015 and 2022. Disproportionality signal analysis was conducted by calculating reporting odds ratios (RORs). RESULTS: Sixteen cases of hepatitis B virus reactivation were reported in the FAERS database among patients receiving daratumumab or isatuximab reported between 2015 and 2022. The ROR for HBV reactivation was statistically significant for both daratumumab (ROR 4.76, 95% CI 2.76-8.22) and isatuximab (ROR 9.31, 95% CI 3.00-28.92). CONCLUSION: Overall, our analysis demonstrates a significant reporting signal for HBV reactivation with daratumumab and isatuximab.

Addressing barriers to increased adoption of DPYD genotyping at a large multisite cancer center.

PURPOSE: To describe the implementation of an in-house genotyping program to detect genetic variants linked to impaired dihydropyrimidine dehydrogenase (DPD) metabolism at a large multisite cancer center, including barriers to implementation and mechanisms to overcome barriers to facilitate test adoption. SUMMARY: Fluoropyrimidines, including fluorouracil and capecitabine, are commonly used chemotherapy agents in the treatment of solid tumors, such as gastrointestinal cancers. DPD is encoded by the DPYD gene, and individuals classified as DPYD intermediate and poor metabolizers due to certain genetic variations in DPYD can experience reduced fluoropyrimidine clearance and an increased risk of fluoropyrimidine-related adverse events. Although pharmacogenomic guidelines provide evidence-based recommendations for DPYD genotype-guided dosing, testing has not been widely adopted in the United States for numerous reasons, including limited education/awareness of clinical utility, lack of testing recommendations by oncology professional organizations, testing cost, lack of accessibility to a comprehensive in-house test and service, and prolonged test turnaround time. Based on stakeholder feedback regarding barriers to testing, we developed an in-house DPYD test and workflow to facilitate testing in multiple clinic locations at Levine Cancer Institute. Across 2 gastrointestinal oncology clinics from March 2020 through June 2022, 137 patients were genotyped, and 13 (9.5%) of those patients were heterozygous for a variant and identified as DPYD intermediate metabolizers. CONCLUSION: Implementation of DPYD genotyping at a multisite cancer center was feasible due to operationalization of workflows to overcome traditional barriers to testing and engagement from all stakeholders, including physicians, pharmacists, nurses, and laboratory personnel. Future directions to scale and sustain testing in all patients receiving a fluoropyrimidine across all Levine Cancer Institute locations include electronic medical record integration (eg, interruptive alerts), establishment of a billing infrastructure, and further refinement of workflows to improve the rate of pretreatment testing.

The Advanced Practitioner's Role in the Rapidly Evolving Landscape of Precision Medicine.

The advent of precision medicine targeting oncogenic mutations and other alterations has led to a paradigm shift in the treatment of many solid tumors and hematologic malignancies. For many of these agents, predictive biomarker testing is necessary to determine the presence of such alterations in order to select patients who are most likely to respond, and to avoid the use of ineffective and potentially harmful alternative therapy. Recent technological advances such as next-generation sequencing have facilitated the identification of targetable biomarkers in patients with cancer and thus help inform treatment decisions. Moreover, new molecular-guided therapies and associated predictive biomarkers continue to be discovered. For some cancer therapeutics, regulatory approval requires the use of a companion diagnostic to ensure proper patient selection. Advanced practitioners therefore need to be aware of current biomarker testing guidelines regarding who should be tested, how and when to test, and how these results can guide treatment decisions using molecular-based therapies. They should also recognize and address potential barriers and disparities in biomarker testing to ensure equitable care for all patients, and assist in educating patients and colleagues alike on the importance of testing and integration into clinical practice to enhance outcomes.

Biomarker-Driven Oncology Clinical Trials: Novel Designs in the Era of Precision Medicine.

Oncology drug development historically has followed a path of sequential phase I, II, and III clinical trials using traditional trial designs, with the goal of achieving regulatory approval. These studies are often conducted with inclusion criteria that limit enrollment to a single tumor type or tumor site of origin, excluding other patients who might also respond. Increased use of precision medicine targeting biomarkers or specific oncogenic mutations has led to novel clinical trial designs that can evaluate these therapies in a less limited fashion. Master protocols such as basket trials, umbrella trials, and platform trials can, for example, evaluate histology-specific therapies targeting a common oncogenic mutation across multiple tumor types or screen for the presence of multiple different biomarkers rather than a single one. In other cases, they can lead to more rapid evaluation of a drug and evaluate targeted therapies in tumor types for which they are not yet currently indicated. As the use of complex biomarker-based master protocols increases, advanced practitioners must understand these novel trial designs, their advantages and disadvantages, and how their use may advance drug development and maximize the clinical benefits of molecular precision therapy.

The Role of Biomarkers in Guiding Clinical Decision-Making in Oncology.

Recent advances in molecular diagnostics have led to the characterization of an increasing number of actionable genomic alterations and immune-based signatures, which have facilitated the development of many highly effective cancer therapies. In addition to their prognostic value, some of these biomarkers have been shown to have predictive value and have had a significant impact on clinical decision-making. The presence of these therapeutic targets can thus aid health-care professionals to select the optimal therapies and avoid use of ineffective, potentially toxic ones. Earlier agents were generally approved for only one or a limited number of malignancies and/or stages, but more recent approvals encompass multiple tumor types that bear a common molecular alteration regardless of tumor type (i.e., tumor-agnostic indications). The expanding use of tumor-agnostic biomarkers has the potential to greatly broaden the use of these therapies to a wider patient population. Yet the rapidly increasing number of tumor-specific and tumor-agnostic biomarkers, and the continually changing treatment guidelines regarding the use of targeted agents and associated testing requirements, present challenges for advanced practitioners to remain current on these topics and their ability to apply these advances to clinical care. Here, we review predictive oncology biomarkers currently in use and their role in clinical decision-making, including those specified in product prescribing information and clinical practice guidelines. Current clinical guidelines regarding recommended targeted therapies for selected malignancies, and when molecular testing should be performed, are discussed.

Revolutionizing Cancer Treatment: Harnessing the Power of Biomarkers to Improve Patient Outcomes.

There has been an increasing number of approvals for targeted therapies and immunotherapies in oncology in the past decade. This has changed the treatment paradigm for many solid tumors and hematologic malignancies, and therefore the outcomes of patients with cancer. Advanced practitioners should be up to date with advances in cancer biomarker testing and its implications for the use of targeted therapy and immunotherapy to integrate this information into clinical decision-making.

2021-2022 Drug Updates: Investigational Therapeutics in the Pipeline.

During JADPRO Live 2022, Donald C. Moore, PharmD, BCPS, BCOP, DPLA, FCCP, discussed investigational therapeutic agents in the drug development pipeline. Dr. Moore highlighted agents that represent either a new drug class, a novel mechanism of action, a rethinking of how to approach treating a disease, or those that have recently received FDA Breakthrough Designation status that advanced practitioners should be aware of.

Measuring the Impact of a Pharmacist-Driven Blood Factor Education Program: A Prospective, Single-Center Observational Study.

Introduction: Patients with bleeding disorders are best served by multidisciplinary teams. Pharmacists can play a critical role in the optimal management of patients with bleeding disorders through blood factor stewardship strategies and programs. An educational program was developed and implemented wherein a hematology pharmacist provided brief recorded lectures to an entire department of pharmacists in a multi-site health-system with the goal to improve the knowledge base and confidence among this population of general practitioners. Methods: The primary objective of this study was to evaluate the educational outcomes of a blood factor education program for pharmacists. The impact of the educational program was determined by measuring the difference in mean test scores between the pre- and post-program surveys. Results: The final analysis included 214 participants. The primary endpoint of mean competency test score was significantly improved in the post-test compared to pre-test (78.33% vs 52.83%; P < .0001). Any degree of test score improvement was observed in 99% (n = 212) of participants. Pharmacist confidence was significantly improved in all 20 domains of bleeding disorders and blood factor product verification and management. Conclusion: This program identified that most pharmacists in a large multi-site health-system were not familiar with bleeding disorders to a satisfactory degree, commonly because of the relative rare encounters with bleeding disorder-related orders, and that despite systems-based support there was an opportunity to improve practice through education. Such educational programming could be beneficial for the development of pharmacist-provided care and is a measure that could be implemented as part of blood factor stewardship initiatives.

Tafasitamab and lenalidomide for relapsed/refractory diffuse large B-cell lymphoma in a patient on chronic intermittent hemodialysis.

INTRODUCTION: Tafasitamab is an anti-CD19 monoclonal antibody indicated for the treatment of relapsed/refractory diffuse large B-cell lymphoma to be given in combination with lenalidomide. Experiences with tafasitamab in the setting of hemodialysis are limited and the efficacy and safety of this agent in this setting are unknown. CASE REPORT: We describe a patient with relapsed/refractory diffuse large B-cell lymphoma with hemodialysis-dependent end-stage renal disease who successfully received tafasitamab/lenalidomide. MANAGEMENT AND OUTCOME: Tafasitamab and reduced dose lenalidomide were initiated for relapsed diffuse large B-cell lymphoma. Tafasitamab was administered on non-dialysis days. Follow-up imaging for disease response assessment demonstrated a complete response. Therapy was well tolerated; the only major toxicity experienced was grade 4 neutropenia that resolved with dose adjustment to lenalidomide. Over a year from initiating therapy, the patient remains in a complete response. DISCUSSION/CONCLUSION: The combination of tafasitamab and dose-reduced lenalidomide produced a complete response in the treatment of relapsed/refractory diffuse large B-cell lymphoma in the setting of chronic intermittent hemodialysis.

Sutimlimab: A Complement C1s Inhibitor for the Management of Cold Agglutinin Disease-Associated Hemolysis.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, safety, dosing and administration, and place in therapy of sutimlimab for the management of cold agglutinin disease (CAD)-associated hemolysis. DATA SOURCES: A literature search of PubMed (1966-October 2022) was conducted using the keywords sutimlimab, BIVV009, and cold agglutinin. Data were also obtained from prescribing information, meeting abstracts, and clinicaltrials.gov. STUDY SELECTION AND DATA EXTRACTION: All published prospective clinical trials, prescribing information, and meeting abstracts on sutimlimab for the treatment of CAD were reviewed. DATA SYNTHESIS: Sutimlimab is a first-in-class complement C1s inhibitor indicated for the treatment of CAD-associated hemolysis. This approval was based on the phase III CARDINAL trial, which evaluated sutimlimab in patients with CAD-associated hemolysis. The primary endpoint of achieving a hemoglobin of ≥12 g/dL or increase of ≥2 above baseline was achieved by 54% of patients with sutimlimab in the 26-week trial. The phase III CADENZA trial was a placebo-controlled trial in which sutimlimab has demonstrated a significant improvement in the composite endpoint of hemoglobin increase of ≥1.5 g/dL, avoidance of transfusion, and avoidance of additional CAD therapies (73% sutimlimab vs 15% placebo). RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON WITH EXISTING DRUGS: Sutimlimab rapidly halts hemolysis, improves hemoglobin, and improves quality-of-life in patients with CAD. Safety issues with sutimlimab include infusion-related reactions and risk of serious infections with encapsulated bacteria. CONCLUSIONS: Sutimlimab provides an additional therapeutic option in the treatment of CAD-associated hemolysis that can lead to rapid improvement in hemoglobin and anemia-related symptoms.