Intravenous Formulation Research Articles

Subcutaneous Mosunetuzumab Is Active with a Manageable Safety Profile in Patients (pts) with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphomas (B-NHLs): Updated Results from a Phase I/II Study

Background: Mosunetuzumab (Mosun), a CD20xCD3 T-cell engaging bispecific monoclonal antibody (Bi-mAb) that redirects T cells to eliminate malignant B cells, is the first Bi-mAb approved for R/R follicular lymphoma (FL; EMA 2022; Budde et al. Lancet Oncol 2022) and can be administered intravenously in the outpatient setting with a fixed treatment duration. A subcutaneous (SC) formulation that aims to improve safety and convenience is under evaluation. We present results for SC Mosun in a larger population with longer follow-up than previously reported (Bartlett et al. ASH 2021). Methods: GO29781 is a Phase I/II, open-label, multicenter dose-escalation and expansion study of Mosun in pts with R/R B-NHL (NCT02500407). Pts with ≥1 prior line of systemic therapy (dose-escalation) or ≥2 prior lines (dose-expansion) were included. SC Mosun was administered with step-up dosing in Cycle (C) 1, then given on Day (D) 1 of subsequent 21-day cycles. The first 2 dose-escalation groups received Mosun 5mg on C1D1, 15mg or 45mg on C1D8, and 45mg on C1D15 and D1 from C2 onwards (5/15/45mg [Group 1] and 5/45/45mg [Group 2], respectively). A third group received Mosun 5mg on C1D1, 45mg on C1D8, 90mg on C1D15 and C2D1, and 45mg on D1 from C3 onwards (5/45/90/90/45mg [Group 3]). Pts with a complete response (CR) after 8 cycles completed therapy; pts with a partial response or stable disease continued treatment up to 17 cycles. Primary objectives included safety, tolerability and identification of the recommended Phase II dose. Results: At data cut-off (May 20, 2022) 89 pts with R/R B-NHL received SC Mosun (Group 1: n=39, Group 2: n=47, Group 3: n=3). Most common histologies were diffuse large B-cell lymphoma (56%), transformed FL (19%) and FL (12%). Median (range) age was 68 years (24-88). Median number of prior systemic therapies was 3; 85.1% and 83.9% of pts were refractory to their last prior therapy or prior anti-CD20 therapy, respectively; 32.6% had received prior CAR T-cell therapy. Median (range) time on study was 9.9 months (m; 0.4-19.7) and cycles completed was 5 (1-17). No dose-limiting toxicities were observed in dose escalation. Most common all-Grade (Gr) adverse events (AEs) were injection-site reaction (62%; all Gr 1/2) and cytokine release syndrome (CRS; 27%; all Gr 1/2). Gr 3/4 and serious AEs were reported in 49% and 45% of pts, respectively. One AE led to Mosun discontinuation (COVID-19; Group 1). Gr 5 AEs were reported in 5 pts; none were considered Mosun-related by investigators (Group 1: n=3 [COVID-19 n=2; large intestine perforation n=1]; Group 2: n=2 [COVID-19 pneumonia and septic shock]). CRS was reported in 15/39 pts (38%), 8/47 pts (17%) and 1/3 pts in Groups 1, 2 and 3, respectively. Most CRS events occurred during C1. Median onset time since prior Mosun and median duration was 2 days (ranges 0-4 and 1-6, respectively). CRS events were low Gr (Gr 1: 18%; Gr 2: 9%; Figures 1 and 2) and all resolved; 2 pts (2%) received corticosteroids and 4 (5%) received tocilizumab for CRS. Neutropenia was reported in 19 pts (21%; Gr 3/4 in 17 [19%]) and febrile neutropenia in 1 pt (1%; Gr 3); median (range) neutropenia duration was 8 days (2-64). Serious infections were reported in 12 (14%) pts (Gr 3/4: n=8; Gr 5: n=4). Treatment-related neurological AEs possibly consistent with immune effector cell-associated neurotoxicity syndrome (ICANS) were reported in 3 pts (3%; all Gr 1: lethargy, memory impairment, and ICANS [confusion] with Gr 1 CRS); all resolved. Tumor flare was reported in 4 pts (4%; Gr 2: n=2; Gr 3: n=2); all resolved. All pts with indolent NHL (iNHL; all FL; 11/11) and 75/76 pts with aggressive NHL (aNHL) were enrolled ≥3 m prior to cut-off and included in the efficacy analysis. Overall response rate was 82% in iNHL and 36% in aNHL; CR rate was 64% in iNHL and 20% in aNHL, with 18/22 CRs (82%) ongoing at data cut-off. Median duration of response was 6.7 m (95% CI: 4.8-not estimable) in aNHL and not reached in iNHL (9-m event-free rate: 78% [95% CI: 51-100]). Conclusions: SC Mosun demonstrated single-agent activity similar to the intravenous formulation in pts with R/R B-NHL. SC Mosun with C1 step-up dosing had a manageable safety profile, including low CRS rates across dose schedules. Based on exposure-response considerations regarding tolerability and clinical activity, 5/45/45mg was chosen as the recommended dose. SC Mosun could improve outcomes in R/R B-NHL while increasing convenience and reducing healthcare resource utilization. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract 12960: Effect of Iron Therapy on Exercise Capacity and Quality of Life in Patients With Systolic Heart Failure: A Systematic Review and Meta-Analysis

Background: Iron deficiency in patients with systolic heart failure (HF) was found to be associated with poorer exercise capacity and quality of life. We conducted this systematic review and meta-analysis to assess whether iron supplementation in patients with systolic HF can improve exercise capacity and quality of life. Methods: We searched MEDLINE, and Embase databases from inception to May 2022 to identify the studies that reported the impact of iron therapy including oral and intravenous (IV) iron forms in systolic HF patients with iron deficiency. Outcomes of interest included 1) six minute walk test (6MWT) and 2) Quality of life (QoL) assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ). Data from each study were combined using the random-effects model to calculate weight mean difference (WMD) and 95% confidence interval (CI) Results: Five studies (4 randomized controlled trials and 1 nonrandomized open-label study) with a total of 1,075 patients (610 in the intervention group and 465 in the control group) were included. In the intervention group, 474 patients received IV iron and 136 patients received oral iron therapy. Iron therapy was associated with significant improvement of 6MWT (WMD =22.81, 95% CI 0.47-45.14, p < 0.001) and KCCQ (WMD =4.68, 95%CI 0.43-8.93, p< 0.001). Interestingly, subgroup analysis showed that the main results were driven by IV iron therapy in both 6MWT (WMD =34.68, 95%CI 25.13-44.24, p< 0.001) and KCCQ (WMD =6.78, 95%CI 3.81-9.75, p< 0.001) as there was no significant improvement after oral iron therapy in 6MWT (WMD =0.15, 95% CI -23.86-24.16, p =0.99) and KCCQ (WMD =2.71, 95% CI-1.35-6.78, p =0.19). As shown in Figure 1. Conclusions: Intravenous iron therapy, but not oral iron therapy is associated with improved exercise capacity and QoL in patients with systolic HF.

Novel Therapeutic Approaches for Mitigating Complications in Short Bowel Syndrome.

Short bowel syndrome (SBS) is a particularly serious condition in which the small intestine does not absorb sufficient nutrients for biological needs, resulting in severe illness and potentially death if not treated. Given the important role of the gut in many signaling cascades throughout the body, SBS results in disruption of many pathways and imbalances in various hormones. Due to the inability to meet sufficient nutritional needs, an intravenous form of nutrition, total parental nutrition (TPN), is administered. However, TPN presents difficulties such as severe liver injury and altered signaling secondary to the continued lack of luminal contents. This manuscript aims to summarize relevant studies into the systemic effects of TPN on systems such as the gut-brain, gut-lung, and gut-liver axis, as well as present novel therapeutics currently under use or investigation as mitigation strategies for TPN induced injury.

Interventions for the long-term prevention of hereditary angioedema attacks.

Hereditary angioedema (HAE) is a serious and potentially life-threatening condition that causes acute attacks of swelling, pain and reduced quality of life. People with Type I HAE (approximately 80% of all HAE cases) have insufficient amounts of C1 esterase inhibitor (C1-INH) protein; people with Type II HAE (approximately 20% of all cases) may have normal C1-INH concentrations, but, due to genetic mutations, these do not function properly. A few people, predominantly females, experience HAE despite having normal C1-INH levels and C1-INH function (rare Type III HAE). Several new drugs have been developed to treat acute attacks and prevent recurrence of attacks. There is currently no systematic review and meta-analysis that included all preventive medications for HAE. To assess the benefits and harms of interventions for the long-term prevention of HAE attacks in people with Type I, Type II or Type III HAE. We used standard, extensive Cochrane search methods. The latest search date was 3 August 2021. We included randomised controlled trials in children or adults with HAE that used medications to prevent HAE attacks. The comparators could be placebo or active comparator, or both; approved and experimental drug trials were eligible for inclusion. There were no restrictions on dose, frequency or intensity of treatment. The minimum length of four weeks of treatment was required for inclusion; this criterion excluded the acute treatment of HAE attacks. We used standard Cochrane methods. Our primary outcomes were 1. HAE attacks (number of attacks per person, per population) and change in number of HAE attacks; 2. mortality and 3. serious adverse events (e.g. hepatic dysfunction, hepatic toxicity and deleterious changes in blood tests). Our secondary outcomes were 4. quality of life; 5. severity of breakthrough attacks; 6. disability and 7. adverse events (e.g. weight gain, mild psychological changes and body hair). We used GRADE to assess certainty of evidence for each outcome. We identified 15 studies (912 participants) that met the inclusion criteria. The studies included people with Type I and II HAE. The studies investigated avoralstat, berotralstat, subcutaneous C1-INH, plasma-derived C1-INH, nanofiltered C1-INH, recombinant human C1-INH, danazol, and lanadelumab for the prevention of HAE attacks. We did not find any studies on the use of tranexamic acid for prevention of HAE attacks. All drugs except avoralstat reduced the number of HAE attacks compared with placebo. For breakthrough attacks that occurred despite prophylactic treatment, intravenous and subcutaneous forms of C1-INH and lanadelumab reduced attack severity. It is not known whether other drugs have a similar effect, as the severity of breakthrough attacks in people taking drugs other than C1-INH and lanadelumab was not reported. For quality of life, avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increased quality of life compared with placebo; there were no data for danazol. Four studies reported on changes in disability during treatment with C1-INH, berotralstat and lanadelumab; all three drugs decreased disability compared with placebo. Adverse events, including serious adverse events, did not occur at a rate higher than placebo. However, serious adverse event data and other adverse event data were not available for danazol, which prevented us from drawing conclusions about the absolute or relative safety of this drug. No deaths were reported in the included studies. The analysis was limited by the small number of studies, the small number of participants in each study and the lack of data on older drugs, therefore the certainty of the evidence is low. Given the rarity of HAE, it is not surprising that drugs were rarely directly compared, which does not allow conclusions on the comparative efficacy of the various drugs for people with HAE. Finally, we did not identify any studies that included people with Type III HAE. Therefore, we cannot draw any conclusions about the efficacy or safety of any drug in people with this form of HAE. The available data suggest that berotralstat, C1-INH (subcutaneous, plasma-derived, nanofiltered and recombinant), danazol and lanadelumab are effective in lowering the risk or incidence (or both) of HAE attacks. In addition, C1-INH and lanadelumab decrease the severity of breakthrough attacks (data for other drugs were not available). Avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increase quality of life and do not increase the risk of adverse events, including serious adverse events. It is possible that danazol, subcutaneous C1-INH and recombinant human C1-INH are more effective than berotralstat and lanadelumab in reducing the risk of breakthrough attacks, but the small number of studies and the small size of the studies means that the certainty of the evidence is low. This and the lack of head-to-head trials prevented us from drawing firm conclusions on the relative efficacy of the drugs.

Molecular Dynamics Simulation of Drug Solubilization Behavior in Surfactant and Cosolvent Injections.

Surfactants and cosolvents are often combined to solubilize insoluble drugs in commercially available intravenous formulations to achieve better solubilization. In this study, six marketed parenteral formulations with surfactants and cosolvents were investigated on the aggregation processes of micelles, the structural characterization of micelles, and the properties of solvent using molecular dynamics simulations. The addition of cosolvents resulted in better hydration of the core and palisade regions of micelles and an increase in both radius of gyration (Rg) and the solvent accessible surface area (SASA), causing a rise in critical micelle concentration (CMC), which hindered the phase separation of micelles. At the same time, the presence of cosolvents disrupted the hydrogen bonding structure of water in solution, increasing the solubility of insoluble medicines. Therefore, the solubilization mechanism of the cosolvent and surfactant mixtures was successfully analyzed by molecular dynamics simulation, which will benefit future formulation development for drug delivery.

218 (PB-042) Poster - Impact of subcutaneous versus intravenous administration of pertuzumab and trastuzumab (PH) for the treatment of HER2-positive breast cancer in Montenegro

Background: Both PH are approved for use in patients with HER2-positive breast cancer and are available as intravenous formulations (PH IV) and subcutaneous fixed-dose combination of both drugs (PH FDC SC). SC formulations showed similar efficacy as IV counterparts, providing additional economic value to patients, physicians and health systems due to shorter administration and observation time.

Reduction of Infusion Time Using a 10% Intravenous Immunoglobulin Formulation With a 15-Minute Rate Escalation Protocol During Staffing Shortages Due to COVID-19.

The COVID-19 pandemic changed home infusion nursing dramatically by increasing demand for home infusion nurses while decreasing their availability. Home infusion of intravenous immunoglobulin (IVIg) is an option for treatment of numerous conditions and requires considerable infusion time. Use of a higher-concentration IVIg product and shorter escalation increments may decrease required infusion time. The authors conducted a retrospective database analysis that identified 23 patients receiving IVIg before transitioning to a 10% IVIg product with a 15-minute rate escalation protocol (Gammaplex 10% IVIg) and evaluated the total infusion time before and after the transition. Among the 23 who received IVIg, the mean ± SD IVIg dose per dosing cycle before transitioning was 1.2 ± 0.7 g/kg given in 1 to 5 infusions per cycle. The mean ± SD time per infusion was 2.8 ± 0.8 hours before the transition and 2.6 ± 0.7 hours per infusion after the transition. The infusion time decreased after transition in 13 patients (56.5%), did not change in 5 patients (21.7%), and increased in 5 patients (21.7%). Nurse education on IVIg rate escalation may facilitate faster achievement of the maximum safe infusion rate and reduce infusion times. A trial transition to this 10% IVIg product with a 15-minute rate escalation protocol may also reduce infusion times.

Risks for Anaphylaxis With Intravenous Iron Formulations.

Risks for Anaphylaxis With Intravenous Iron Formulations.

Risks for Anaphylaxis With Intravenous Iron Formulations.

Risks for Anaphylaxis With Intravenous Iron Formulations.

Darinaparsin: First Approval.

Darinaparsin (Darvias®), an organoarsenic drug, is a novel mitochondrial-targeted anticancer agent currently being developed by Solasia Pharma K.K for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL). An intravenous formulation of darinaparsin has been approved for the treatment of relapsed or refractory PTCL in Japan, and preparation for the next stage of the clinical development program for this indication is currently underway in China, the USA and the EU. This article summarizes the milestones in the development of darinaparsin leading to this first approval for relapsed or refractory PTCL.

The Impact of Pharmacogenomic CYP3A5 Variants on Calcineurin Inhibitor Metabolism and SLCO1B1 Variants on Methotrexate in Adult Allogeneic BMT Patients

Allogeneic blood and marrow transplant (BMT) is used to transplant a new immune system in patients with hematologic malignancies or immune-mediated disease. BMT patients require initial immune suppression to prevent graft rejection and graft versus host disease (GVHD). Tacrolimus and cyclosporine are calcineurin inhibitors (CNI) and methotrexate is an antimetabolite used to mitigate this immune response. Tacrolimus has data supporting oral dose variation based on pharmacogenomic (PGx) studies for Intermediate Metabolizers (IM) and Poor Metabolizers (PM) on studies done in kidney transplant patients. There are fewer studies on BMT patients in this field, and even less on the variability of IV to oral conversion dosing and first pass metabolism effect based on PGx profiles. Methotrexate has been shown to have PGx mutations affecting its metabolism at higher dosing used for chemotherapy, but its impact on BMT patient dosing is not well-defined. Based on our study, we found statistically significant variability in Tacrolimus concentration based on drug assay levels compared with dosing for Intravenous (IV) and oral formulation based on PGx predicted phenotypes. We further noted a profound effect on first pass metabolism when transitioning between IV and oral dosing of Tacrolimus based on PGx predicted phenotypes. The average oral dose in predicted IM phenotypes divided by the IV dose was 2.68. For the predicted PM phenotype, the average oral dose divided by the IV dose was 1.18. The p-value in a two-tailed nonparametric T-test with equal variance assessing the conversion factor from IV to oral dosing in predicted IM versus PM phenotypes was significant with a p-value of 0.002. Methotrexate metabolism did not seem to be affected by PGx mutations at the doses used for BMT GVHD prevention.

Fatal Systemic Toxicity with Topical Lidocaine Spray

Introduction: Lidocaine is a class of Ib antiarrhythmic agent which is available in various intravenous (IV) and topical forms. Systemic toxicity of lidocaine has been reported following its IV injection or local infiltration for anesthesia, mostly. However, toxicity following the application of its topical gel and oral spray is also possible. Manifestations of lidocaine induced systemic toxicity include neurologic and cardiac symptoms. Reported cases of systemic toxicity after ingestion of topical lidocaine are rare. In this case study, we present a patient who developed symptoms of severe systemic toxicity following oral ingestion of topical lidocaine spray.Case Presentation: A young woman was referred to the emergency department with agitation following ingestion of lidocaine spray solution to commit suicide. At the time of arrival, vital signs were stable. Blood tests and electrocardiogram were also normal. She underwent supportive care. Gradually, the symptoms of neuro and cardiac toxicity appeared. Standrad management include intralipid and bicarbonate administration was unsuccesfull and the patient experienced cardiac arrest.Conclusion: Lidocaine systemic toxicity with topical form could be severe and fetal, since the prompt diagnosis of systemic toxicity is the key factor to preventing death, physicians should be familiar with the symptoms of lidocaine systemic toxicity.

Ibuprofen for intravenous administration: new possibilities for the use of NSAIDs in postoperative pain management

Non-steroidal anti-inflammatory drugs are an essential component of postoperative multimodal analgesia. Their analgesic efficacy has been confirmed by data from evidence-based medicine. The appearance of an intravenous form of ibuprofen on the Russian pharmaceutical market expands the possibilities of using NSAIDs in postoperative pain managment schemes. Ibuprofen characterized a high analgesic potential and an optimal safety profile in relation to the risk of gastrointestinal and cardiovascular complications.

Profile of Intravenous Preparation Mixing in Patients at the Regional General Hospital's Intensive Care Unit Abdoel Wahab Sjahranie Samarinda

Compatibility is one of the quality characteristics of intravenous (IV) preparations that influences the effectiveness of patient therapy in the intensive care Unit (ICU). This study aimed to determine the compatibility profile of IV medication formulations given to ICU patients. This prospective observational research was undertaken on patients in the ICU of a private hospital in Samarinda. The data on the intravenous combination of drugs were compared in this study utilizing the ASHP Injectable Drug Information literature 21st edition, Injectable drug guide, and Manual Book. Injectable Drug Mixing was published in 2009 as a resource for determining the compatibility of intravenous formulations. Using certain criteria, combinations of intravenous medicines and their solvents are classed as compatible (C), incompatible (I), and unknown (U). The ICU had 25 patients, 15 of whom were male, and 10 of them were female. There is no mixing of drug compounds containing incompatible solvents. All drugs were carried out with 100% compatible solvents. The limited information related to the compatibility and stability of these intravenous preparations encourages continuous monitoring of the patient's condition and drug levels.

Subcutaneous injection of trastuzumab into the thigh versus abdominal wall in patients with HER2-positive early breast cancer: Pharmacokinetic, safety and patients' preference - Substudy of the randomised phase III GAIN-2 study

BackgroundTrastuzumab given intravenously in combination with chemotherapy is standard of care for patients with early HER2-positive breast cancer (BC). Different randomised studies have shown equivalent efficacy of a subcutaneous injection into the thigh compared to the intravenous formulation. Other body regions for injection have not been investigated but might be more convenient for patients. MethodsAfter surgery, patients were randomised to receive either subcutaneous trastuzumab into the thigh or into the abdominal wall (AW). Patient preferences were evaluated using validated questionnaires (PINT). Primary objectives of this multicentre, non-blinded, randomised substudy of the GAIN-2 study were to investigate pharmacokinetics of the injection into the thigh versus AW and to determine patients' preferences of either administration site versus the previously received intravenous application. Results226 patients were randomised and 219 patients (thigh: N = 110; AW: N = 109) formed the modified intent-to-treat (mITT). Overall, 83.5% (out of N = 182 with information about patients’ preference) preferred subcutaneous over previous intravenous application or had no preference. Preference was similar between both administration sites (thigh: 80.6%; AW: 86.5; p = 0.322). Pharmacokinetic analysis included 30 patients. Geometric means of Cmax and AUC0-21d were higher in thigh than in AW group (geometric mean ratio with body weight adjustment: Cmax: 1.291, 90%-CI 1.052–1.584; AUC0-21d: 1.291, 90%-CI 1.026–1.626). Safety profile was in line with previous reports of subcutaneous trastuzumab. ConclusionSubcutaneous trastuzumab into the thigh showed an approximately 30% higher bioavailability. Injections were well tolerated and preferred over intravenous administration. The subcutaneous injection into the thigh should remain the standard of care.

The incidence, complications, and treatment of iron deficiency in pregnancy.

Iron deficiency and/or iron deficiency anemia (IDA) complicate nearly 50% of pregnancies globally, negatively impacting both maternal and fetal outcomes. Iron deficiency can cause a range of symptoms that range from aggravating to debilitating including fatigue, poor quality of life, pagophagia, and restless leg syndrome. Iron deficiency and IDA are also associated with maternal complications including preterm labor, increased rates of cesarean delivery, postpartum hemorrhage, and maternal death. Fetal complications include increased rates of low birth weight and small for gestational age newborns. Prenatal maternal anemia has also been associated with autism spectrum disorders in the neonate, although causation is not established. Deficiency in the newborn is associated with compromised memory, processing, and bonding, with some of these deficits persisting into adulthood. Despite the prevalence and consequences associated with iron deficiency in pregnancy, data show that it is routinely undertreated. Due to the physiologic changes of pregnancy, all pregnant individuals should receive oral iron supplementation. However, the bioavailability of oral iron is poor and it is often ineffective at preventing and treating iron deficiency. Likewise, it frequently causes gastrointestinal symptoms that can worsen the quality of life in pregnancy. Intravenous iron formulations administered in a single or multiple dose series are now available. There is increasing data suggesting that newer intravenous formulations are safe and effective in the second and third trimesters and should be strongly considered in pregnant individuals without optimal response to oral iron repletion.

ARDS AND NECROTIZING PNEUMONIA FROM BLASTOMYCES INFECTION

ARDS AND NECROTIZING PNEUMONIA FROM BLASTOMYCES INFECTION

A Review of Population Pharmacokinetic Models of Posaconazole.

Posaconazole is often used for the prophylaxis and treatment of invasive fungal infections (IFI). However, intra- and inter-individual differences and drug interactions affect the efficacy and safety of posaconazole. Precision dosing of posaconazole based on the population pharmacokinetic (PopPK) model may assist in making significant clinical decisions. This review aimed to comprehensively summarize the published PopPK models of posaconazole and analyze covariates that significantly influence posaconazole exposure. Articles published until May 2022 for PopPK analysis of posaconazole were searched in PubMed and EMBASE databases. Demographic characteristics, model characteristics, and results of PopPK analysis were extracted from the selected articles. In addition, the steady-state pharmacokinetic profiles of posaconazole were simulated at different covariate levels and dosing regimens. Out of the 13 studies included in our review, nine studies included adults, three included children, and one included both adults and children. All oral administration models were one-compartment models, and all intravenous administration models were two-compartment models. Body weight, proton pump inhibitors, and incidence of diarrhea were found to be important covariates. Clinically, the potential impact of factors such as patient physiopathologic characteristics and comorbid medications on posaconazole pharmacokinetics should be considered. Dose adjustment in combination with TDM or replacement with a tablet or intravenous formulation with higher exposure may be an effective way to ensure drug efficacy as well as to reduce fungal resistance. Meanwhile, published models require further external evaluation to examine extrapolation.

Prevention and management of cetuximab-related hypomagnesemia.

321 Background: Cetuximab is an epidermal growth factor receptor monoclonal antibody indicated for the treatment of squamous cell carcinoma of the head and neck and RAS wild-type metastatic colorectal cancer. Hypomagnesemia is a reversible adverse event associated with cetuximab treatment. Here, we provide the key considerations in prevention and management of cetuximab-related hypomagnesemia events in clinical practice. Methods: A PubMed literature search was conducted for articles published between 18 March 2012 and 18 March 2022 using “cetuximab” and “hypomagnesemia” as keywords. Of the 75 articles retrieved, 20 were considered relevant and are included here.Articles were excluded if they focused on hypomagnesemia-associated clinical benefits. Data were summarized and grouped into the following categories: risk and risk factors; monitoring; prevention; and management. Results: The relative risk of grade 3/4 hypomagnesemia following cetuximab therapy appears to be approximately 1.5 times higher for colorectal cancer compared with head and neck cancer. Several risk factors have been identified including age, comorbidities, treatment duration, baseline electrolyte levels, concomitant platinum-based chemotherapy, and polypharmacy. Although the frequencies of hypomagnesemia events vary between the studies identified, data from the included meta-analyses suggest that the incidence of grade 3/4 hypomagnesemia is around 4% among patients receiving cetuximab therapy. Early and regular monitoring of magnesium levels is recommended ideally every 4 to 8 weeks, especially in patients at high risk of serious complications, and up to 8 weeks following treatment cessation. Proposed proactive prophylactic interventions include magnesium supplementation for patients with baseline magnesium levels < 1.8 mg/dL, to prevent severe hypomagnesemia. The management approach depends on the degree of hypomagnesemia, the symptoms and risk factors, and may include supplementation with oral magnesium salts and/or parenteral forms; intravenous forms may be preferred due to low bioavailability and gastrointestinal adverse events related to oral supplements. While recommendations for initiating magnesium replacement in grade 1 (> 1.2 mg/dL) and grade 2 (0.9–1.2 mg/dL) hypomagnesemia events vary, magnesium supplementation should be given to patients with grade 3 (0.7–0.9 mg/dL) or grade 4 (< 0.7 mg/dL) hypomagnesemia, due to high risk of serious adverse cardiac events. If magnesium levels do not improve or continue to decrease despite supplementation, a pause in cetuximab administration may be considered. Conclusions: Hypomagnesemia is a reversible and manageable cetuximab-related adverse event and should not interfere with treatment outcomes. A periodic check of magnesium levels during treatment with cetuximab is recommended.

Oral Chemotherapy Application in Elderly Patients With Diffuse Large B-Cell Lymphoma: An Alternative Regimen in Retrospective Analysis.

A combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard treatment for diffuse large B-cell lymphoma (DLBCL). However, no standard treatment has been established for older patients (age ≥ 75 years). This study retrospectively analyzed different treatment strategies in older patients with DLBCL with different chemotherapy regimens and compared the survival rate of patients using oral or intravenous form cyclophosphamide and etoposide in a single center. We reviewed the records of older patients with DLBCL, aged ≥ 75 years, from January 2010 to August 2019. The different treatment combinations, clinical characteristics, response rates, and toxicity profiles were analyzed. The median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier (KM) method. Cox regression model was used to identify the risk factors. Eighty-four patients were included. One-quarter of the patients received cytoreduction treatment because of their poor medical condition at the time of diagnosis. Twenty-six percent of the patients were aged ≥ 85 at the time of diagnosis and 46.7% completed the treatment course. Patients receiving non-anthracycline-containing (non-ACR) treatment had worse Charlson comorbidity index, worse PFS, lower body mass index, or were older. The mean anthracycline accumulative dose in the anthracycline-containing (ACR) group was 134 mg/m2. The median OS was 17.2 months and median PFS was 7.7 months. The PFS of R-CHOP is better than R-mini-CHOP and R-CVOP without statistical significance, but OS of R-CHOP is not better than the other regimens. The toxicity, efficacy, and KM curve for OS and PFS in the non-ACR group were lower compared to ACR group, without statistical significance. R-CVOP had similar OS with R-mini-CHOP in our study. The result does not mean etoposide could totally substitute for anthracycline, but etoposide did have lower early progression rate (12.5%), and it may be an option for frail patients with comorbidity. Oral form cyclophosphamide and etoposide could be considered as a substitute for intravenous administration because of the similar effect and toxic profile.