Pharmacy considerations: Use of anti-CD38 monoclonal antibodies in relapsed and/or refractory multiple myeloma.

OBJECTIVE: This article reviews current evidence for the approved anti-CD38 monoclonal antibodies, isatuximab and daratumumab, for the treatment of patients with relapsed and/or refractory multiple myeloma (RRMM) and the implications for pharmacists. DATA SOURCES: We conducted a literature search on PubMed/Medline and other sources using the drug names and the terms CD38, multiple myeloma, and pharmacists. DATA SUMMARY: Monoclonal antibodies targeting the CD38 transmembrane glycoprotein offer a promising treatment approach for patients with RRMM. Isatuximab and daratumumab bind to different epitopes on CD38. In this review, we describe the similarities and differences in their mechanism of action, regulatory labeling, and the current guidelines for isatuximab and daratumumab use in RRMM. We review the current evidence for the efficacy and safety of these agents in combination with pomalidomide or carfilzomib and dexamethasone from the landmark phase 3 clinical trials that led to their approval. We discuss key differences in the eligibility criteria between the clinical trials, and differences in dosing, administration, available formulations, and pre- and post-infusion medications for the two agents. We outline recent data from pharmacoeconomic analyses comparing the cost-effectiveness of isatuximab-based regimens with that of daratumumab-based regimens. A brief overview of other anti-CD38 agents in the pipeline for the treatment of patients with RRMM is presented. CONCLUSIONS: Given that pharmacists play an integral role in driving cost-effective use of drugs without compromising efficacy and safety for the end user, educating pharmacists on the key differences between isatuximab and daratumumab can guide the selection of the appropriate anti-CD38 antibody.

Front-line use of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia: Practice considerations.

The development of BCR-ABL-targeting tyrosine kinase inhibitors has transformed chronic phase chronic myeloid leukemia (CP CML) from a disease with a terminal prognosis to a treatable chronic illness. Long-term treatment with tyrosine kinase inhibitors means that patients have to be clinically managed and monitored over extended periods of time, thus a patient-centered, medically integrated, and multidisciplinary oncology healthcare team is required to support patients through their journey. Pharmacists work with patients, physicians, and the wider support team to select the optimum therapy plan for a given patient. These decisions are based on risk factors, comorbidities, concomitant medications, and personal circumstances and pharmacists advise on the efficacy and safety of different treatment options. Additionally, pharmacists are a key point-of-contact and resource for monitoring patient response to treatment, identifying and managing adverse events and drug-drug interactions, any subsequent therapy plan modifications, and, potentially, treatment-free remission. Pharmacists also assist with patient education, medication adherence, and financial discussions with patients throughout the long course of the disease. This review provides an overview of BCR-ABL tyrosine kinase inhibitors, discusses the role of the medically integrated pharmacy team, and suggests strategies that pharmacists can use in patient management and clinical decision-making to optimize the treatment of CP CML.

Intensive Pharmacy Care Improves Outcomes of Hepatitis C Treatment in a Vulnerable Patient Population at a Safety-Net Hospital.

BACKGROUND: Treatment of hepatitis C virus (HCV) with direct-acting antiviral (DAA) regimens has resulted in high rates of sustained virologic response (SVR). Treatment of vulnerable populations may be improved by incorporating an on-site intensive specialty pharmacy (ON-ISP). AIMS: To describe outcomes of HCV treatment at a safety-net hospital and proportion of subjects achieving SVR for those using the ON-ISP compared to an off-site pharmacy (OFF-SP). METHODS: A retrospective cohort study of 219 subjects treated for HCV with DAA at Boston Medical Center was conducted. Subject characteristics, virologic response, and pharmacy services used were recorded. We used multivariable logistic regression to test the association between ON-ISP and SVR after adjusting for covariates. RESULTS: SVR occurred in 71% of subjects by intention-to-treat (73% among ON-ISP users vs 57% among OFF-SP users) and 95% completing treatment per-protocol (96% among ON-ISP users vs 87% among OFF-SP users). Adjustment for age, sex, ethnicity, insurance, fibrosis, prior treatment, and MELD revealed an increased likelihood of SVR among users of ON-ISP: OR 6.0 (95% CI 1.18-31.0). No significant difference in treatment delay or adverse events was seen among users of either pharmacy type. CONCLUSIONS: HCV treatment with DAA was well tolerated, but the rate of SVR was low (71%) compared to trials. This was due to loss to follow-up, as the per-protocol rate of SVR was much higher (95%). Use of ON-ISP was associated with an increase in SVR and may be valuable for improving care for vulnerable populations.

The Tolerability and Efficacy of Rapid Infliximab Infusions in Patients with Inflammatory Bowel Disease.

OBJECTIVE: Few studies have assessed the loss of efficacy or patient and caregiver satisfaction with rapid infliximab infusions. The aim of this study is to assess the tolerability, loss of efficacy and to describe the impact on resource utilization and patient satisfaction in rapid infliximab infusions. METHODS: Subjects with inflammatory bowel disease receiving rapid infliximab infusions were included in the study. Subjects received maintenance infusions from June 2011 to June 2013. Incidence of adverse reactions and the total number of rapid infliximab infusions were recorded. Efficacy was compared to published studies evaluating the long-term efficacy of infliximab infusions. Patient satisfaction was addressed through a survey following the implementation of the rapid infusion protocol. RESULTS: Seventy-five subjects with IBD were included in the study. Five hundred and twenty-two rapid infliximab infusions were provided to patients. There were no acute or delayed infusion reactions. Ten subjects (13 %) required either a dose escalation or interval adjustment between infliximab infusions. A majority of patients reported increased satisfaction with 1-h infliximab infusions, and 97 % of surveyed patients opted to continue rapid infusions. The rapid infliximab infusion protocol increased infusion unit efficiency by increasing capacity by 15 %. Cost savings in the elimination of nursing time translated to approximately $108,150 savings at our institution. CONCLUSIONS: Rapid infliximab infusions do not appear to increase the risk of loss of response compared to historical studies of long-term infliximab efficiency. A rapid infliximab infusion protocol improved efficiency in our infusion unit and increased patient and nursing satisfaction.

Inflammation-initiating illnesses, inflammation-related proteins, and cognitive impairment in extremely preterm infants.

Neonatal inflammation is associated with perinatal brain damage. We evaluated to what extent elevated blood levels of inflammation-related proteins supplement information about the risk of impaired early cognitive function provided by inflammation-related illnesses. From 800 infants born before the 28th week of gestation, we collected blood spots on days 1, 7 and 14, for analysis of 25 inflammation-related proteins, and data about culture-positive bacteremia, necrotizing enterocolitis (Bell stage IIIb), and isolated perforation of the intestine, during the first two weeks, and whether they were ventilated on postnatal day 14. We considered a protein to be persistently or recurrently elevated if its concentration was in the top quartile (for gestational age and day blood was collected) on two separate days one week apart. We assessed the children at 2 years of age with the Bayley Mental Development Index (MDI). The combinations of NEC and ventilation on day 14, and of bacteremia and ventilation on day 14 consistently provided information about elevated risk of MDI <55, regardless of whether or not a variable for an elevated protein concentration was included in the model. A variable for a persistently or recurrently elevated concentration of each of the following proteins provided additional information about an increased risk of MDI <55: CRP, SAA, IL-6, TNF-alpha, IL-8, MIP-1beta, ICAM-1, E-SEL, and IGFBP-1. We conclude that elevated blood concentrations of inflammation-related proteins provide information about the risk of impaired cognitive function at age 2 years that supplements information provided by inflammation-associated illnesses.

A prospective, single-center, randomized phase 2 trial of etoposide in severe COVID-19.

The systemic inflammatory response seen in patients with severe COVID-19 shares many similarities with the changes observed in hemophagocytic lymphohistiocytosis (HLH); a disease characterized by excessive immune activation. Many patients with severe COVID qualify for a diagnosis of HLH. Etoposide, an inhibitor of topoisomerase II is used to control inflammation in HLH. This randomized, open-label, single center phase II trial attempted to determine whether etoposide can be used to blunt the inflammatory response in severe COVID. This trial was closed early after eight patients were randomized. This underpowered trial did not meet its primary endpoint of improvement in pulmonary status by two categories on an 8 point ordinal scale of respiratory function. There were not significant differences in secondary outcomes including overall survival at 30 days, cumulative incidence of grade 2 through 4 adverse events during hospitalization, duration of hospitalization, duration of ventilation and improvement in oxygenation or paO2/FIO2 ratio or improvement in inflammatory markers associated with cytokine storm. A high rate of grade 3 myelosuppression was noted in this critically ill population despite dose reduction, a toxicity which will limit future attempts to explore the utility of etoposide for virally-driven cytokine storm or HLH.

Device malfunctions with use of EUS-guided fine-needle biopsy devices: Analysis of the MAUDE database.

Background: The safety of endoscopic ultrasound-guided tissue acquisition through fine-needle biopsy devices is well-established in clinical trials. The real-world experience of using these devices is not known. The authors analyzed the postmarketing surveillance data from the Food and Drug Administration Manufacturer and User Facility Device Experience (MAUDE) database to answer this question. Methods: The Food and Drug Administration MAUDE database from January 2012 to June 2022 was accessed to evaluate for device malfunctions and patient-related adverse consequences of these malfunctions. Results: There were 344 device-related issues. Most issues were due to detachment or breakage of the device (n = 185 [53.7%]). Seventy-six of the breakages (40.8%) occurred during the procedure, whereas 89 cases (47.8%) occurred while removing the needle from the endoscope. The most common site of tissue biopsy at the time of needle breakage was the pancreas (44 [23.8%]).The common patient-related adverse events were retained foreign body (n = 50 [14.5%]) followed by bleeding (16, 4.6%). Six patients (3.4%) required a second intervention for removal of the retained foreign bodies including surgery in 2 cases. The device breakage damaged the endoscope in 3 cases (1.7%), and there was 1 case of needlestick injury to the nurse. Conclusion: The fine-needle biopsy devices can be associated with needle breakage and bending; these adverse events were not previously reported. Needle breakages can result in a retained foreign body that may require additional procedures including surgery. These real-world findings from the MAUDE database may inform clinical decisions and help improve clinical outcomes.

Accessory Spleen: A Rare and Incidental Finding in the Stomach Wall.

An accessory spleen is splenic tissue located separately from the anatomical location of the spleen and is a rare phenomenon. It can be found within the gastrointestinal tract. Clinically, accessory spleens are benign but can be misidentified as reactive lymph nodes or malignant gastrointestinal tumors. They are often diagnosed via endoscopy or imaging. We report the case of a woman presenting with iron deficiency anemia who was incidentally noted to have a gastric submucosal lesion with pathology significant for accessory spleen. As this case illustrates, when submucosal lesions are present in the stomach, especially in patients with a history of splenectomy, the endoscopic ultrasound (EUS) operator should consider the possible presence of an accessory spleen to minimize invasive removal procedures.

Transitioning From Thrombopoietin Agonists to the Novel SYK Inhibitor Fostamatinib: A Multicenter, Real-World Case Series.

Fostamatinib is an oral spleen tyrosine kinase (SYK) inhibitor used for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment. Clinical and operational barriers may exist that warrant bridging or switching from thrombopoietin receptor agonists (TPO-RAs), such as volatility or unpredictability of platelets, adverse events, and quality of life or patient preference. While fostamatinib demonstrated durable platelet responses, the safety and efficacy in combination, bridging, and/or switching with TPO-RAs is not well documented. The objective of this article is to provide guidance from real-world case studies for a safe and effective strategy for the transitioning of patients from TPO-RAs to fostamatinib, with some degree of overlap between the two agents. Currently, the evidence does not exist to guide the safe and effective use of combination therapy or transition between therapies in ITP. This case series highlights the importance to further understand the complexities of managing this disease, as well as successfully combining, bridging, and/or switching patients over to fostamatinib without the need for rescue therapy or increase in adverse events. The need for real-world evidence that guides providers on the safety and efficacy of short- and long-term combination therapy of fostamatinib and TPO-RAs is crucial. The rationale for combination therapy is to target different pathways, platelet destruction, and production without added toxicities. Additionally, gradual tapering off of TPO-RAs may provide a more favorable clinical outcome when switching to fostamatinib. The need for additional data is necessary to provide clinicians with guidance when managing patients with ITP.

Process and Clinical Outcomes of a Biosimilar Adoption Program with Infliximab-Dyyb.

BACKGROUND: In 2016, the FDA approved infliximab-dyyb (IFX-dyyb) as a biosimilar to infliximab (IFX). Deemed to have comparable efficacy and safety to IFX, IFX-dyyb is 20%-30% less expensive, allowing significant cost savings for institutions and some payers. In 2018, IFX was reported to be the drug with the highest spend since 2013, costing $3.8 billion; however, transition to IFX-dyyb would save $1.1 billion. Regardless, many institutions have not transitioned to IFX-dyyb or other IFX biosimilars (e.g., IFX-abda) because of concerns about clinical outcomes, uncertainty regarding financial impact, and barriers to operationalizing biosimilar adoption. At Boston Medical Center, a decision was made in March 2018 to adopt IFX-dyyb and transition patients who have been on IFX for ≥ 6 months for all indications to IFX-dyyb. OBJECTIVES: To (a) describe a biosimilar adoption process of IFX-dyyb in patients on IFX for ≥ 6 months; (b) characterize cost savings of transitioning patients to IFX-dyyb; and (c) evaluate real-world clinical outcomes of adult patients with inflammatory bowel disease (IBD) who transitioned to IFX-dyyb. METHODS: This is a retrospective cohort study of patients eligible for the IFX-dyyb switch from March 2018 to June 2019 at a large academic medical center. For process outcomes, we collected the proportion of patients who transitioned to IFX-dyyb and calculated the cost savings generated. To assess clinical outcomes of adult IBD patients who transitioned, we collected IFX and IFX-dyyb dosage, Harvey Bradshaw Index (HBI) or Simple Clinical Colitis Activity Index (SCCAI) scores, c-reactive protein (CRP) levels, and colonoscopy results. Descriptive statistics, Wilcoxon signed-rank test, and McNemar's test were used for statistical analyses. RESULTS: Of 151 eligible patients, 146 (97%) successfully transitioned to IFX-dyyb. Based on our conversion rate to IFX-dyyb, our health system is forecasted to save approximately $500,000 annually. From March to June 2018, 63 of 75 (84%) eligible IBD patients transitioned from IFX to IFX-dyyb. In this cohort, of the 40 patients with HBI or SCCAI scores before and after transition, 36 (90%) maintained remission. For 32 patients, the mean CRP (SD) before transition was 11.2 (22) and 4.1 (4.8) after transition (P = 0.09). Since the IFX-dyyb transition, 9 patients had a colonoscopy, of which 5 (56%) were in endoscopic remission. As of October 2018, 56 (89%) patients continued with IFX-dyyb after transition. Of the 46 patients who had 12-15 months posttransition data, 38 (83%) remained on IFX-dyyb. CONCLUSIONS: Implementation of a biosimilar adoption program can be successful and result in significant cost savings without compromising clinical outcomes. A model that uses actionable strategies and embraces collaboration among stakeholders is described here, with outcomes demonstrating successful IFX-dyyb uptake and no changes in clinical outcomes of transitioned adult patients with IBD. DISCLOSURES: No outside funding supported this study. Farraye reports advisory board fees from Janssen, Merck, and Pfizer. Shah reports speaker fees from Pfizer. The other authors have nothing to disclose.

Antecedents of epilepsy and seizures among children born at extremely low gestational age.

OBJECTIVE: To identify specific risk factors for epilepsy for individuals born extremely preterm. STUDY DESIGN: In a prospective cohort study, at 10-year follow-up, children were classified as having epilepsy or seizures not associated with epilepsy. We evaluated for association of perinatal factors using time-oriented, multinomial logistic regression models. RESULTS: Of the 888 children included in the study, 66 had epilepsy and 39 had seizures not associated with epilepsy. Epilepsy was associated with an indicator of low socioeconomic status, maternal gestational fever, early physiologic instability, postnatal exposure to hydrocortisone, cerebral white matter disease and severe bronchopulmonary dysplasia. Seizure without epilepsy was associated with indicators of placental infection and inflammation, and hypoxemia during the first 24 postnatal hours. CONCLUSIONS: In children born extremely preterm, epilepsy and seizures not associated with epilepsy have different risk profiles. Though both profiles included indicators of infection and inflammation, the profile of risk factors for epilepsy included multiple indicators of endogenous vulnerability.

The economics of hepatitis C virus.

Hepatitis C virus is a disease of major public health significance throughout the world in terms of overall morbidity and mortality and in its economic consequences and demands on medical resources. The global economic burden of this disease has yet to be fully realized. In this article the authors discuss the economic burden of hepatitis C, the economics of therapy, and the economics of its prevention and screening.

The relationship between TSH and systemic inflammation in extremely preterm newborns.

Elevated thyrotropin (TSH) levels in critically ill extremely premature infants have been attributed to transient hypothyroidism of prematurity or non-thyroidal illness syndrome. We evaluated the hypothesis that relatively high TSH levels in the first 2 postnatal weeks follow recovery from systemic inflammation, similar to non-thyroidal illness syndrome. The study was conducted in 14 Neonatal Intensive Care Units and approved by each individual Institutional Review Board. We measured the concentrations of TSH and 25 inflammation-related proteins in blood spots obtained on postnatal days 1, 7, and 14. We then evaluated the temporal relationships between hyperthyrotropinemia (HTT), defined as a TSH concentration in the highest quartile for gestational age and postnatal day, and elevated levels of inflammation-related proteins. 880 newborns less than 28 weeks of gestation were included. Elevated concentrations of inflammation-related proteins during the first or second week did not precede day-14 HTT. Systemic inflammation on day 7 was associated with day-14 HTT only if inflammation persisted through the end of the 2 week period. HTT frequently accompanied elevated concentrations of inflammation-related proteins on the same day. The hypothesis that HTT follows recovery from severe illness, defined as preceding systemic inflammation, is weakly supported by our study. Our findings more prominently support the hypothesis that TSH conveys information about concomitant inflammation in the extremely premature newborn.

Non-drainage scleral buckling with solid silicone elements.

BACKGROUND: With the increasing number of cataract surgeries, incidence of posterior segment complications including rhegmatogenous retinal detachment (RRD) is likely to rise. Scleral buckling (SB) surgery is an effective and less expensive option. The primary advantage of non-drainage procedure is avoidance of possible complications associated with trans-choroidal drainage. The aim of present study is to describe the clinical profile of subjects undergoing non-drainage SB surgery with solid silicone elements for RRD and analyze their treatment outcomes. MATERIALS AND METHODS: This was a retrospective, non-randomized, interventional study at a tertiary care center. Three hundred and six eyes of 298 patients undergoing non-drainage SB surgery with solid silicone elements from year 2000 to 2006 were included. Inclusion criteria were primary RRD, peripheral depressible retinal break, media clarity affording peripheral retinal view and proliferative vitreo-retinopathy (PVR) up to grade C2. Uni- and multivariate analyses was done to analyze factors affecting anatomical and visual outcomes. Statistical analysis was performed using SPSS Version 10. RESULTS: Mean follow-up was 303 ± 393.33 days. Primary anatomical success was obtained in 279 (91.2%) eyes; primary functional success in 286 (93.5%) eyes. PVR (grade B or C), intraocular pressure <10 mm Hg and the inability to find a retinal break were significantly associated with final anatomical failure. Baseline vision ≤3/60 was significantly associated with poor visual recovery. CONCLUSIONS: SB surgery is reasonably safe and highly efficacious. Solid silicone elements are effective in non-drainage SB surgery. However, case selection is important.

Preference for infant-directed speech in preterm infants.

The current study explores the effects of exposure to maternal voice on infant sucking in preterm infants. Twenty-four preterm infants averaging 35 weeks gestational age were divided randomly into two groups. A contingency between high-amplitude sucking and presentation of maternal voice was instituted for one group while the other group served as a yoked control. No significant differences were observed in sucking of the two groups, but the degree of pitch modulation of the maternal voice predicted an increase in the rate of infant sucking.

Early blood gas predictors of bronchopulmonary dysplasia in extremely low gestational age newborns.

Aim. To determine among infants born before the 28th week of gestation to what extent blood gas abnormalities during the first three postnatal days provide information about the risk of bronchopulmonary dysplasia (BPD). Methods. We studied the association of extreme quartiles of blood gas measurements (hypoxemia, hyperoxemia, hypocapnea, and hypercapnea) in the first three postnatal days, with bronchopulmonary dysplasia, among 906 newborns, using multivariable models adjusting for potential confounders. We approximated NIH criteria by classifying severity of BPD on the basis of the receipt of any O2 on postnatal day 28 and at 36 weeks PMA and assisted ventilation. Results. In models that did not adjust for ventilation, hypoxemia was associated with increased risk of severe BPD and very severe BPD, while infants who had hypercapnea were at increased risk of very severe BPD only. In contrast, infants who had hypocapnea were at reduced risk of severe BPD. Including ventilation for 14 or more days eliminated the associations with hypoxemia and with hypercapnea and made the decreased risk of very severe BPD statistically significant. Conclusions. Among ELGANs, recurrent/persistent blood gas abnormalities in the first three postnatal days convey information about the risk of severe and very severe BPD.

Neurobehavioral assessment of infants born at term and in utero exposure to serotonin reuptake inhibitors.

BACKGROUND: Some studies report neurobehavioral symptoms in neonates exposed to serotonin reuptake inhibitors (SRIs) in utero. However, maternal psychiatric illness during the last trimester of pregnancy, as a confounding factor, has not always been assessed. AIMS: In this prospective study we compared neurobehavioral complications among neonates who were born to euthymic women who either took or did not take an SRI during the last trimester of pregnancy. STUDY DESIGN: Exposed and unexposed infants were assessed for: 1) temperament as measured by the Neonatal Behavioral Assessment Scale (NBAS); 2) activity via Actiwatch electronic monitoring; 3) sleep state using trained observer ratings; and 4) perinatal complications through medical record review. T-tests, Fisher's exact tests, and analyses of covariance were used to assess the relationship between clinical and neurobehavioral factors and exposure status. SUBJECTS: 67 infants (61 controls and 6 exposed to SRIs). OUTCOME MEASURES: Neonatal Assessment Behavioral Scale, APGAR scores, infant sleep state (% sleep, % wakeful), startles and tremulousness, gestational age, birth weight, and head circumference. RESULTS: Infants exposed to SRIs in the third trimester had poorer motor development, lower 5-minute APGAR scores, and shorter mean gestational age as compared to unexposed infants. CONCLUSION: Results of this study show differences in autonomic and gross motor activity between neonates who were or were not exposed to SRIs in utero after controlling for active maternal psychiatric illness. Future longitudinal work should compare longer term outcomes of exposed and unexposed infants of depressed mothers.

Second stage of labor and intraventricular hemorrhage in early preterm infants in the vertex presentation.

OBJECTIVE: To investigate the association between exposure to second stage of labor and duration of second stage, and risk of intraventricular hemorrhage (IVH) among infants delivered <30 weeks of gestation. METHODS: We conducted a retrospective cohort study among 158 singleton vertex deliveries (97 vaginal and 61 cesarean). Multivariable logistic regression was used to evaluate the risk of IVH related to second stage. RESULTS: Infants exposed to second stage as compared to those not exposed to second stage irrespective of their mode of delivery had increased risk of mild IVH (odds ratio [OR] 2.69; 95% confidence interval [CI] 1.15, 6.29) but not of severe IVH (OR 1.14; 95% CI 0.33, 3.84). No relation with risk of mild (OR 0.98; 95% CI 0.95, 1.01) and severe (OR 1.00; 95% CI 0.95, 1.05) IVH was observed for each 1 min increase in duration of second stage. We also observed no significant association between quartiles of duration of second stage and risk of mild (p = 0.20) and severe (p = 0.29) IVH. We did not observe any significant interaction by gestational age, chorioamnionitis, birth weight or presenting complaint on admission. CONCLUSION: The risk of mild IVH was increased in those exposed to a second stage of labor. However, no clear association was observed between duration of second stage and mild or severe IVH.