Daratumumab infusion reaction rates pre- and post-addition of montelukast to pre-medications

Daratumumab, a CD38-directed monoclonal antibody indicated for multiple myeloma treatment in adult patients, is associated with a high incidence of infusion-related reactions (IRRs). Due to CD38 receptor presence in the lungs, many reactions present similarly to asthma or allergic rhinitis. Montelukast, a leukotriene receptor antagonist, has been hypothesized to reduce daratumumab IRRs due to its efficacy in treating allergic rhinitis and asthma and the presence of leukotriene receptors in the lungs. Recently published data reported daratumumab can be safely administered via rapid rate protocol that reduces infusion time from 195 min to 90 min after completion of two doses. This retrospective, observational cohort study examined 73 patients who received daratumumab in the outpatient setting between December 2015 and April 2020. Patients were included if they were 18 years or older, had an International Classification of Disease (ICD)-10 diagnosis code for multiple myeloma, and received daratumumab intravenously. The primary outcome was a comparison of IRRs between those who did and did not receive montelukast. Secondary outcomes included IRR symptoms, rescue medications utilized for IRRs, and rapid rate administration outcomes. Montelukast use was associated with a lower rate of IRRs (44.4% vs. 65.2%, p = 0.044). Pulmonary IRR symptoms were more common in those who did not receive montelukast. Rapid rate administration of daratumumab did not lead to any IRRs. Adding montelukast as a pre-medication for daratumumab infusions led to a reduction in IRRs, and rapid rate administration was found to be safe after completion of two full doses of daratumumab.

Evaluation of the Safety of Rapid Administration of Undiluted High-Dose Intravenous Levetiracetam

Background Intravenous (IV) levetiracetam (LEV) is an antiseizure medication traditionally given as an intermittent infusion to mitigate potential adverse effects given its acidic formulation. The process of compounding may lead to delays in treating status epilepticus, which is why administration of undiluted doses is of interest. Prior studies have shown safety of IV doses from 1000 mg to 4500 mg; however, assessments of adverse side effects outside IV site reactions have not been studied. Methods A retrospective analysis was completed with patients who received 1500 mg doses of undiluted IV LEV. We included patients ≥ 18 years old that received at least 1 dose of IV LEV 1500 mg from January 2018 to February 2021. Study end points included assessment of hemodynamic disturbance (bradycardia [HR less than 50 beats per minute] or hypotension [SBP less than 90 mmHg] within 1 hour or documented infusion reaction within 12 hours of LEV. Descriptive statistics were utilized. Results A total 213 doses of 1500 mg of IV LEV were administered to 107 patients. Peripheral lines were used for 85.9% of doses. Approximately half of doses (57) were administered to patients on the general wards, with the remainder in the intensive care unit or emergency department. Two patients (1.9%) experienced bradycardia; however, 1 patient had pre-existing bradycardia. Three patients (3.8%) experienced hypotension; however, those patients were receiving vasopressors prior to the dose. There were no cases of infusion reaction. Conclusion Undiluted, rapid administration of IV LEV 1500 mg was well tolerated and safe.

Vasculitis induced by biological agents used in rheumatology practice: A systematic review

Objectives: Biological medications have been used with an increasing frequency to treat rheumatological diseases. Autoimmune events can be induced by these drugs, such as psoriasiform lesions, alopecia, lupus and, vasculitis, which more often affects the skin (small-sized vessels) and eventually other organs. In this review, we describe the clinical profile of patients with vasculitis induced by the main biological agents used in rheumatology. Patients and methods: We performed a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. The PubMed database was used for searching eligible articles. We included case reports, case series, and letter to the editor of patients on anti-tumor necrosis factor-alpha (anti-TNF-a) molecules, as well as tocilizumab, ustekinumab, secukinumab, rituximab, and abatacept, who had vasculitis induced by these agents. Results: Eighty-one articles were included for final analysis (n=89). Twenty-seven patients were using infliximab, 20 adalimumab, 18 etanercept, seven secukinumab, four certolizumab, four rituximab, three golimumab, three ustekinumab, two abatacept, and one tocilizumab. Unspecific leukocytoclastic vasculitis (LCV) was the most common type of vasculitis (n=37), followed by anti-neutrophil cytoplasmic antibody (ANCA)- associated vasculitis (n=16). The medication was replaced with another biological molecule in 23 cases, with only four relapses. In six cases, the biological was maintained, but vasculitis worsened/persisted in one case, being necessary drug removal. Conclusion: Infections, infusion reaction, cancer, and autoimmune events are well-known side effects of biological therapy. This review demonstrates that vasculitis is another adverse effect of this type of therapy, particularly the anti-TNF-a molecules, and LCV the most reported type of vasculitis.

The Preferred Premedication Order to Prevent Infusion Reactions in Patients with Breast Cancer Receiving Pertuzumab Plus Trastuzumab and Docetaxel

Aims:Pertuzumab plus trastuzumab and docetaxel is a standard regimen for human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the metastatic, adjuvant, and neoadjuvant settings. Infusion reaction represents one of the common side effects of anti-HER2 agents. There is no standard premedication to prevent infusion reactions, although antihistamines, acetaminophen, and/or corticosteroids are often used for this purpose. This study evaluated the ability of premedication to prevent induction reactions in patients receiving pertuzumab, trastuzumab, and docetaxel. Methods: This retrospective, single-institute study assessed infusion reactions in 72 women with HER2-positive early breast cancer who received pertuzumab, trastuzumab, and docetaxel between November 2018 and April 2021. Thirty-six patients received premedication consisting of oral acetaminophen prior to pertuzumab and trastuzumab administration and dexamethasone and D-chlorpheniramine maleate intravenously prior to docetaxel administration (previous regimen). Thirty-six patients received premedication consisting of acetaminophen, dexamethasone, and D-chlorpheniramine maleate sequentially prior to pertuzumab, trastuzumab, and docetaxel administration (current regimen). Results: The rates of infusion reaction after the initial injection were 55.6 and 16.7% in the previous and current regiment groups, respectively (p = 0.001). Trastuzumab more frequently caused infusion reactions than pertuzumab and docetaxel. Chills, vomiting, and nausea were the major symptoms of infusion reactions. Conclusion: Premedication featuring the upfront use of dexamethasone and D-chlorpheniramine maleate prior to the administration of anti-HER2 targeted agents significantly prevented infusion reactions.

352 Target modulation within the tumor microenvironment (TME) by daratumumab (anti-CD38) but not edicotinib (CSF-1R inhibitor) in men with high-risk localized prostate cancer

BackgroundProstate cancer is ”immunologically cold,” with enrichment of myeloid populations, immunosuppressive cytokines, and few T cells within the tumor microenvironment (TME). CD38 is expressed on myeloid cells, T cells, plasma B cells, and NK cells. Macrophage colony-stimulating factor-1 receptor (CSF-1R) controls macrophage differentiation and function. We hypothesized that either anti-CD38 (daratumumab) or CSF-1R inhibitor (edicotinib) would be safe and well-tolerated for primary prostate cancer, with successful target modulation on immune populations within the TME.MethodsIn this single-center, open-label, presurgical study, patients were enrolled into Arm A (daratumumab, four weekly doses pre-surgery) or Arm B (edicotinib, orally daily for four weeks pre-surgery). Patients had high-risk localized or locally advanced prostate cancer (at least 1 core Gleason ≥8) appropriate for radical prostatectomy (RP), ≥3 biopsies involved with cancer, and no radiographic evidence of metastatic disease. Treated and untreated (Gleason-matched) fresh and formalin-fixed paraffin-embedded prostatectomy specimens and paired blood (PBMCs), bone marrow biopsies (BMBx) and aspirates (BMA) were evaluated for target modulation using IHC (prostate, BMBx) and flow cytometry (prostate, BMA, PBMCs). The primary endpoint was incidence of adverse events (AEs). The secondary endpoint was pathologic complete remission (pCR) rate.ResultsTwenty-five patients were treated (Arm A, n=15; Arm B, n=10) and completed four doses of daratumumab or four weeks of edicotinib prior to RP. The most common AEs were Arm A: daratumumab infusion reaction (33%, 5/15); Arm B: increased aspartate aminotransferase (40%, 4/10). Grade 3 related AEs in Arm A occurred in 3 patients (12%; infusion reaction, n=2; urticaria, n=1), with no Grade 4/5 related events. No ≥Grade 3 related AEs occurred in Arm B. All patients completed surgery, however no patients achieved pCR. IHC revealed lower density of CD38+ cells in daratumumab-treated vs. untreated prostate tumors and in patient-matched post-treatment vs. pre-treatment BMBx. Similarly, flow cytometry showed decreased frequency of CD38+ T cells and macrophages in daratumumab-treated vs. untreated prostate tumors and patient-matched post-treatment vs. pre-treatment PBMCs and BMAs. Edicotinib did not demonstrate an impact on CSF-1R+ immune cells in prostate, bone marrow, or PBMCs.ConclusionsDaratumumab and edicotinib were safe and well-tolerated as presurgical therapy for high-risk localized prostate cancer, with no pCRs. Evidence of target modulation was consistently observed in prostate tumors, bone marrow, and PBMCs for daratumumab, but not edicotinib. Myeloid-targeted agents such as daratumumab alone are insufficient to generate anti-tumor responses in prostate cancer.Trial RegistrationNCT03177460Ethics ApprovalThis study was approved by MD Anderson Cancer Center Institutional Review Board; protocol numbers 2017–0103 and PA13-0291.

MACROPHAGE ACTIVATION SYNDROME IN RHEUMATIC DISEASES IN CHILDREN: A RETROSPECTIVE STUDY

Macrophage activation syndrome (MAS) is a rare life-threatening complication of rheumatic diseases (RD) that requires early recognition and adequate immediate treatment. Objective of the study: to identify the features of onset of RD in patients who developed MAS, the clinical and laboratory characteristics of the MAS, possible trigger factors and the timing of development. Materials and methods of research: 57 patients (20 boys and 37 girls) with RD who developed MAS were included in a retrospective continuous non-randomized study: 36 (63%) with systemic juvenile idiopathic arthritis (sJIA), 19 (33%) with Systemic lupus erythematosus (SLE), 1 (2%) – with juvenile dermatomyositis (JDM), one (2%) – with overlapping syndrome. Results: in the structure of patients with sJIA, patients with a history of MAS accounted for 28%, among patients with SLE – 7,6%. The median age at the time of sJIA debut in the study group was 2,6 years [1,5; 5,75], patients with SLE – 11,8 years [8,6; 13,95]. The ratio of boys and girls in the study group was 1:1,85. 70 MAS episodes were recorded: 48 – with sJIA, 20 – with SLE, one episode each for JDM and crossover syndrome. A single episode of MAS at the onset had 22% of patients with sJIA, 47% – with SLE, MAS during the course of the disease – 55% and 47%, repeated episodes of MAS – 25% and 5% of patients, respectively. Clinical manifestations of MAS included fever in 91% of children, hepatomegaly in 54%, pericarditis in 51%, skin lesions in 68%, CNS damage in 44%, lung damage in 33%, hyperferritinemia in 96%, thrombocytopenia – in 79%, increased aminotransferases – in 89%, hypertriglyceridemia – in 53%. Patients with sJIA and MAS had statistically significantly earlier onset (p=0,047), a greater number of systemic manifestations (p=0,012), a typical exanthema (p<0,0001), and a smaller number of active joints (p=0,041). 83% of them had episodes of MAS before the initiation of therapy with biological disease-modifying antirheumatic drugs (bDMARDs). There was no statistically significant relationship between the development of MAS with the use of bDMARDs with a clear positive relationship with the violation of the therapy regimen. 19% of patients with sJIA and MAS had a history of infusion reaction to tocilizumab, 8% later had interstitial lung damage. Patients with SLE and MAS at the onset were statistically significantly more likely to have serositis (p=0,0028), ulcers of the oral mucosa (p<0,0001), neuropsychiatric disorders (p=0,0024), positive Coombs' test (p=0,026). All patients received glucocorticoid therapy; experience with the use of GIBP in the study group was limited. Conclusion: MAS in children develops more often with sJIA; the dominant provoking factor is the activity of the underlying disease. The overwhelming majority of patients developed MAS during the course of the disease, less often at the onset. Patients with a history of MAS with sJIA are characterized by an earlier age of onset, a predominance of systemic manifestations, the need for early administration of bDMARDs therapy, and a tendency to infusion reaction to tocilizumab. Against the background of bDMARDs, a subclinical course of MAS with the absence of fever is possible. The risk of developing MAS along with SLE is higher in patients with onset of serositis, ulcers of the oral mucosa, neuropsychiatric disorders, and a positive Coombs' test. MAS cases were detected with high SLE activity at the onset, violation of the treatment protocol.

Barriers to patient-centered oncology care: Pilot study of home infusion of anticancer immunotherapy.

36 Background: ASCO published a position statement regarding home infusion of anticancer therapy in June 2020. This statement recommends independent research to evaluate the safety and effectiveness of home infusions. Intermountain Healthcare (IM) incorporated this statement into its oncology care with an IRB-approved, prospective single-arm pilot study to determine the safety and feasibility of home administration of checkpoint inhibitor (CPI) immunotherapy with synchronous telemedicine visits. Methods: Patients with cancer receiving treatment at Intermountain Medical Center and Intermountain Cancer Center St. George were screened for enrollment into an IRB-approved, non-randomized pilot study of 20 patients. Eligibility criteria required patients to receive a CPI for an FDA-approved indication, live in Washington County or Salt Lake County, Utah, and have commercial payer coverage of CPI home infusion. Eligible patients were required to receive 2 doses of CPI at an infusion center, and patients who experienced an infusion reaction were excluded from receiving home infusion. Home infusion nurses are trained in oncology, CPIs, and home infusion reaction protocol. During synchronous video visits, infusion nurses are trained to perform the hands-on portions of the physical exam. A financial analysis estimated cost to IM and commercial payers for routine and home CPI infusions. Results: 622 patients were screened, of which 104 were receiving a CPI. 64 patients lived in an eligible county and 19 patients had commercial payer coverage. Of patients on CPIs, 8.7% (9/104) met all eligibility criteria accounting for 1.4% (9/622) of all patients with cancer screened (Table). Financial analysis estimated $829 cost (excluding drug cost) to IM for standard infusion reimbursement compared to $599 for in-home CPI infusions, accounting for savings of $230 per infusion. Majority of cost savings are from elimination of infusion center facilities fee ($495). Analysis includes $269 for home infusion nurse wages. Subsequent analysis for commercial payer SelectHealth estimates $270 reimbursement savings for the payer. Conclusions: Home immunotherapy infusions are estimated to be cost effective for both IM and commercial payers. However, lack of drug coverage and the rural demographics of Utahns with cancer are barriers to home CPI infusions. The pilot study was discontinued per infeasibility stopping criteria.[Table: see text]

Takotsubo cardiomyopathy caused by infusion reaction to paclitaxel

Takotsubo cardiomyopathy (TCM) secondary to an infusion reaction is extremely rare in the literature. Here, we present an unusual case of TCM in a patient with cervical squamous cell carcinoma who presented with acute hypoxic respiratory failure following the initiation of the first-cycle paclitaxel infusion therapy.