A Novel Protocol for Rituximab Administration with Reduced Incidence of Severe Infusion-Related Adverse Reactions in Patients with B-Cell Non-Hodgkin Lymphoma

Introduction: Rituximab is widely used as the standard treatment for most types of B-cell non-Hodgkin lymphomas (B-NHL). However, infusion-related reactions (IRRs), such as fever, chills, nausea, rashes, rigors, or hypotension, are a significant burden to patients and oncology practitioners. Thus, we developed a novel protocol on the rituximab administration to avoid severe IRRs during a short-time infusion in the outpatient chemotherapy center of Nihon University Itabashi Hospital. Methods: This observational study aimed to establish an effective dosing schedule for safely administering rituximab within a short time for patients with various B-NHL types. Rituximab was diluted to a concentration of 1 mg/mL and intravenously administered to patients at a dose of 375 mg/m 2. Before the rituximab administration, prophylactic premedications were given per guidelines. We stratified patients into low (n = 0), moderate (n = 1), or high risk (n = 2) groups according to the observed number of risk factors for IRRs identified in our previous study, i.e., indolent histology and presence of bulky disease (>10cm) (Hayama et al. 2017, PMID: 28144804). In the low- and moderate-risk groups, the infusion rate of rituximab was set at 25 mg/h (first 1h), 100 mg/h (next 1h), and a maximum of 200 mg/h thereafter (conventional infusion #1, approx. 4.3h). In the high-risk group, the infusion rate of rituximab was set at 25 mg/h (first 1h) and a maximum of 100 mg/h thereafter (long infusion, approx. 6.8h). The second infusion of rituximab was dependent on the occurrence of IRRs in the first cycle. If a patient in the low-risk group did not have IRRs in the first cycle, the infusion rate of rituximab in the second cycle was then started at 100 mg/h for the first 30min and increased by 100 mg/h every 30min to a maximum of 400 mg/h thereafter (short infusion, approx. 2.3h). Also, for a patient in the moderate-risk group without any grade of IRRs in the first cycle, the infusion rates of second rituximab was set at 100 mg/h (first 1h) and a maximum of 200 mg/h thereafter (conventional infusion #2, approx. 3.5h). Finally, a patient in the high-risk group without IRRs in the first cycle received the second rituximab as per the conventional infusion #1. If patients experienced any grades of IRR in the first cycle, the next rituximab was administered on the same schedule as the first cycle. The infusion procedure for the third cycle was at the discretion of attending physicians (Figure). The primary endpoint was the incidence of IRRs during the first and second doses of rituximab in each risk group. The secondary endpoints were; overall incidence of IRRs in the first and second doses of rituximab; infusion rates of rituximab at the IRRs; conversion rate of the short infusion at the third cycle in each group; overall conversion rate of the short infusion at the third cycle. Results: A total of 81 B-NHL patients treated with rituximab in 2018 and 2019 at Nihon University Itabashi Hospital was evaluated. The incidence of IRRs during the first and second cycles in each risk group was 31%, 20%, and 57% in the low- (n = 39), moderate- (n = 35), and high-risk (n = 7) groups, respectively, with no significant difference among the three risk groups (p = 0.1407). The overall incidence of IRRs was 28% without grade 3 or higher severity. The IRRs occurred most frequently at the infusion rate of 100 mg/h (n = 16). Conversion rates to the short infusion at the third cycle of rituximab were 82%, 29%, and 29%, in the low-, moderate-, and high-risk groups, respectively, with a significant imbalance between the groups (p <0.0001). The overall conversion rate of the short infusion in the third cycle was 54%, without any grades of IRRs (Table). Conclusions: Our step-by-step infusion protocol of rituximab provided a safe and comfortable drug administration for both patients and oncology practitioners. In addition, the protocol can reduce unexpected, severe adverse reactions to rituximab that typically require hospital admission and medical expenses (UMIN-CTR, UMIN000032309). Figure 1 Figure 1. Disclosures Miura: Chugai: Honoraria; Kyowa Kirin: Honoraria. Hatta: Pfizer Japan Inc.: Honoraria; Novartis KK: Honoraria; Bristol-Myers Squibb: Honoraria; Otsuka Pharmaceutical.: Honoraria.

602. Intravenous Push Versus Intravenous Piggyback Administration of Cephalosporin Antibiotics: Impact on Safety, Workflow, and Cost

Background IV piggyback (IVPB) infusion has been the standard method of administration of IV antibiotics since the 1970s. Literature has demonstrated that the IV push (IVP) method has similar pharmacokinetic exposures and risk for complications as short infusion IVPB, and may have potential benefits. The primary objective is to evaluate the incidence of infusion-related complications in patients receiving cefazolin, ceftriaxone, and cefepime administered via IVP versus short infusion IVPB at the Veteran Affairs Long Beach Healthcare System. The secondary objectives include evaluating the time-to-onset of complications, time-to-first-dose combination vancomycin in the emergency department (ED), cost, and nursing and pharmacy staff preference between IVP and IVPB. Methods This is a retrospective, single-center cohort study. Patients who received ceftriaxone, cefepime, or cefazolin between April 1st, 2019 – December 31st, 2019, and April 1st, 2020 – December 31st, 2020 were included. Patients who received the study antibiotics via IVPB during the IVP period were excluded. Statistical analyses were performed using the chi-square, fisher’s exact, Mann-Whitney U, and unpaired t-tests where appropriate. Complications associated with IVP or IVPB administration were assessed via chart review of electronic health records. Surveys to nursing and pharmacy staff were distributed using Microsoft Forms. Results 366 treatment episodes were evaluated for 355 unique patients. Complications occurred in 13 out of 183 (7.1%) treatment episodes in the IVP group compared to 18 out of 183 (9.8%) treatment episodes in the IVPB group (P = 0.35). The median time to complications was 2 days for both groups. IVP cefepime and ceftriaxone reduced the median time-to-first-dose vancomycin in the ED by 25 minutes. The use of cefazolin, ceftriaxone, and cefepime as IVP yielded a quarterly cost savings of &38,890.04. 55% of nursing staff and 85% of pharmacy staff prefer IVP administration for cefazolin, ceftriaxone, and cefepime. Conclusion Cefazolin, ceftriaxone, and cefepime given as IVP were observed to be as safe as IVPB while reducing time-to-first dose vancomycin in the ED and cost, and is the preferred method of administration among nursing and pharmacy staff. Disclosures All Authors: No reported disclosures

A novel rituximab administration protocol to minimize infusion-related adverse reactions in patients with B-cell non-Hodgkin lymphoma

Background Rituximab is widely used as a key component of immunochemotherapy to treat B-cell non-Hodgkin lymphoma (B-NHL). However, infusion-related reactions (IRRs) during drug administration are occasionally severe or even life-threatening and thus remain problematic for patients and healthcare providers. Aim To minimize IRRs to rituximab in patients with various types of B-NHL. Method: We stratified patients into low- (n = 39), moderate- (n = 35), and high-risk (n = 7) groups according to the number of risk factors, specifically, an indolent histology and the presence of bulky tumors (> 10 cm). For the first rituximab cycle, the low- and moderate-risk groups underwent conventional infusion #1 (~ 4.3 h), and the high-risk group underwent long infusion (6.8 h). Patients in the low-, moderate-, and high-risk groups without IRRs in the first cycle underwent short infusion (2.3 h), conventional infusion #2 (3.5 h), and conventional infusion #1, respectively. Patients with IRRs in the first cycle received a second rituximab cycle with the same schedule as that in the first cycle. The procedure for the third cycle was at the attending physician’s discretion. Results Among 81 B-NHL patients, the incidences of IRRs in the low-, moderate-, and high-risk groups were 31%, 20%, and 57%, respectively, without any grade ≥ 3 IRRs. The overall conversion rate to short infusion in the third cycle was 54%, without any IRRs. Conclusion Our step-by-step protocol provided safe and comfortable rituximab administration for both patients and practitioners (UMIN-CTR; UMIN000032309, registered on 19th April 2018).

Randomized Control Trial of Short Infusion of Low Dose Ketamine Vs Intravenous Morphine as Adjunct Analgesia for Acute Long Bone Fracture Pain in Emergency Department

BackgroundKetamine is known as an alternative for pain control, but reports of emergency reactions limits its widespread use. We assessed the efficacy of short infusion of low dose ketamine (LDK) compared with intravenous morphine (MOR) as adjunct analgesia for acute long bone fracture pain.MethodsPatients aged 18-60 years old, with acute long bone fracture and with numerical pain rating scale (NPRS) of 6 or more after 3mg intravenous morphine were eligible for enrolment. Subjects were consented and randomized to either short infusion LDK (0.3mg/kg) over 15 minutes or intravenous morphine (MOR) (0.1mg/kg) over 5 minutes. Evaluations of NPRS score and vital signs occurred at 15, 30, 60, 90 and 120 minutes. The primary outcome from this study was the mean reduction of numerical pain rating scale (NPRS) score from baseline and the mean time to achieve ³ 3 score reductions in NPRS. The secondary outcomes were the incidence of adverse events and mean consumption of rescue analgesia.ResultsFifty-eight subjects were enrolled (MOR 27, LDK 31). Demographic variables and baseline NPRS scores MOR (8.33) vs LDK (8.84) were similar. The mean reduction of NPRS were significantly different between LDK (Mean= 3.1, SD=2.03) and MOR (Mean =1.8, SD 1.59), p= 0.009 at 30 minutes. Incidence of dizziness was reported higher in Ketamine group 19.4% (p=0.026).ConclusionWhen used as an adjunct, short infusion low-dose ketamine at 0.3mg/kg over 15minutes provides greater analgesic effect in comparison to intravenous morphine alone for acute long bone fracture pain but has higher incidence of dizziness.Trial RegistrationNational Medical Research Register: https://www.nmrr.gov.my/ Registered 24 November 2017 ID:NMRR-17-3184-38970

Pharmacokinetics of Meropenem in People with Cystic Fibrosis—A Proof of Concept Clinical Trial

Anti-infective treatment of pulmonary exacerbations is a major issue in people with cystic fibrosis (CF). Individualized dosing strategies and adaptation of infusion times are important concepts to optimize anti-infective therapy. In this prospective non-randomized controlled open-label trial, we compared pharmacokinetics of meropenem in 12 people with CF experiencing a pulmonary exacerbation, of whom six received parenteral meropenem 2 g tid as short infusion over 30 min and six extended infusion over 120 min. We measured blood concentrations of meropenem at five predetermined time points over 240 min and calculated differences in the percentages of the time above the minimal inhibitory concentration (fT > MIC) for meropenem concentrations >16 and >32 mg/L, respectively. Mean percentages of fT > 16 and fT > 32 mg/L were higher in the extended compared to the short infusion group (83 and 56% vs. 59% and 34%), with a statistically significant prolongation of the fT > 32 mg/L (mean 134 vs. 82 min; p = 0.037). Our results demonstrate that, in people with CF, longer fT > MIC can be achieved with a simple modification of meropenem dosing. Further studies are needed to clarify if this may translate into improved microbiological and clinical outcomes, in particular in adults with difficult-to-treat chronic infection by carbapenem-resistant Pseudomonas aeruginosa.

Phase I study of mesothelin-targeted immunotoxin LMB-100 given as a long infusion with or without nab-paclitaxel.

3553 Background: LMB-100 recombinant immunotoxin consists of a mesothelin-binding Fab for targeting a modified Pseudomonas exotoxin A payload. Previous Phase 1 clinical testing of a 30-minute LMB-100 “short” infusion format identified a serum half-life of ~1 hour. Pre-clinical data suggested that extending infusion time could improve anti-tumor efficacy by increasing tumor cell duration of exposure to LMB-100. The primary objective of this study was to determine the safety and tolerability of administering LMB-100 in a long infusion format over 24-48 hours alone or with nab-paclitaxel chemotherapy in patients with mesothelin-expressing solid tumors. Methods: Patients (n = 15) with pancreatic adenocarcinoma and other mesothelin-expressing solid tumors (n = 3; mesothelioma, colon, and ampullary cancers) treated on 3 dose levels received long infusion of LMB-100 (65 or 100 mcg/kg/day) for 24 hour on Days 1 and 4 (n = 6) or 48 hour on Day 1 (n = 9) with or without a loading dose (40 mcg/kg over 30 minutes) for up to 2 cycles. In the second arm, patients (n = 5) with pancreatic adenocarcinoma were treated with LMB-100 over 24 hours on Day 1 concurrently with nab-paclitaxel (125 mg/m2) for up to 3 cycles. Results: DLT of proteinuria (grade 3) in one patient and acute kidney injury (grade 1) in one patient were observed amongst patients receiving 100 mcg/kg/day over 48 hours and 24 hours, respectively. No objective responses were seen but all patients receiving nab-paclitaxel had > 50% decrease in CA 19-9. Patients at all single agent dose levels (8 of 10 evaluable) developed high titer anti-drug antibodies (ADAs) against LMB-100. Those with ADAs (8 of 8) had undetectable cycle 2 peak plasma LMB-100 concentration. Development of high titer ADAs occurred more frequently with long infusion than seen previously with “short” infusion LMB-100. Most long infusion patients (19 of 20) developed increased serum IL-6 within 24 hours of LMB-100 infusion. However, the systemic inflammatory response to LMB-100 (as measured by increased serum CRP) which occurs in most “short” infusion patients was not observed. Conclusions: Long infusion format LMB-100 is generally well tolerated but immunogenicity limits treatment to 1 effective cycle. No anti-tumor efficacy of the single agent was observed. Clinical trial information: NCT02810418 .

Comparison of standard short infusion versus prolonged infusion of Doxorubicin in relation to its cardiotoxicity in South Indian population

Background: Anthracycline is one of the commonly used chemotherapeutic agents in the treatment of malignancies and their efficacy is undermined by potential life-threatening cardiotoxicity. The aim of this study is to compare the cardiotoxicity in patients receiving standard short infusion (15-30 minutes) versus prolonged infusion (6 hours) of doxorubicin in the study group.Methods: In this study 80 patients who were planned for treatment with Doxorubicin >200 mg/m2 were included in this study and they were randomly allotted to either of the treatment group. Each patient was assessed clinically (History, Pulse rate, Blood pressure) along with ECG ,ECHO prior to initiation of chemotherapy, after completion of 200 mg/m2 of Doxorubicin, 3 months and 6 months after chemotherapy.Results: There were 40 patients in each group, and they received a total of 384 cycles of Doxorubicin containing regimens according to respective protocols. The median number of cycles was four (range four to six cycles). The mean cumulative dose of doxorubicin was 271.5 mg/m2 in the group which received standard short infusion and 264 mg/m2 in the group which received the drug by prolonged infusion. However, none of the patients developed any cardiac symptoms during or after the planned chemotherapy nor was there a drop in ejection fraction on serial ECHO.Conclusions: There was no benefit of prolonged infusion of doxorubicin as compared to the standard rapid infusion in terms of doxorubicin induced cardiotoxicity. At present, standard rapid infusion is the best option.

Prolonged Versus Short Infusion Rates of IV Magnesium in Hospitalized General Medicine Patients with Hypomagnesemia

Introduction: Due to the renal handling mechanism of magnesium, prolonging the time for infusion of intravenous (IV) magnesium has been postulated to decrease magnesium requirements; however, a paucity of clinical evidence exists to support prolonging infusion rates. Objective: To assess if there is a difference in magnesium replacement required in the medicine population at an academic medical center when prolonged infusion rates (0.5 g/h) are compared to short infusion rates of > 0.5 g/h. Methods: A retrospective chart review was performed before and after implementation of the hypomagnesemia protocol (November 2015). Patients who received at least one dose of IV magnesium during hospitalization were selected from general medicine units. Primary aim was to determine if a difference exists in percent of days IV magnesium repletion required between patients receiving prolonged versus short infusion rates. Secondary objectives were to determine if a difference exists in total grams of magnesium received, percent of days magnesium levels were maintained in the optimal (1.4-2.7) and desired (2-2.7) therapeutic ranges, and incidence of hypomagnesemia (< 1.4 g/dL) and hypermagnesemia (> 2.7 g/dL). For safety, incidence of hypotension (systolic blood pressure < 90/60 mm Hg) during the magnesium infusion was recorded. Results: Totally, 45 patients were included in each cohort for a total of 90 patients to meet power. No differences existed between protocol groups for any demographic variables (all P > .05). Median infusion rate for the short infusion cohort was 1.8 g/h (range 1-2 g/h). Percent of days IV magnesium was replaced was 34.8% versus 37.8% ( P = .39) in the short and prolonged infusion groups, respectively. No difference existed between groups for secondary outcomes (all P > .05). Conclusion: Prolonged magnesium infusion rates did not decrease magnesium replacement requirements. These results have been used to propose revision of our current magnesium infusion protocol to reduce infusion length.