Management Of Infusion Reactions Research Articles

Expert consensus guidelines: Intravenous iron uses, formulations, administration, and management of reactions.

Intravenous iron has become an essential component for the treatment of iron deficiency and iron deficiency anemia. Individuals administering Intravenous iron should have knowledge in intravenous iron administration, including a pre-infusion assessment to evaluate infusion reaction risks, pre- and post-infusion monitoring, identification of and management of infusion reactions, accurate documentation of these reactions, laboratory monitoring and recognition and management of treatment-emergent hypophosphatemia. This comprehensive consensus provides step-by-step guidance and tools for practitioners to promote safe delivery of intravenous iron, recognition, and management of infusion reactions and treatment-emergent hypophosphatemia.

IV iron formulations and use in adults.

Intravenous iron has become a major component of the therapeutic armamentarium for iron deficiency and iron deficiency anemia. The earliest formulations were associated with unacceptable toxicity. Newer formulations, with complex carbohydrate cores that bind elemental iron more tightly, allow the administration of full therapeutic doses in 15 to 60 minutes. Nonetheless, a folklore of danger, fueled by earlier formulations no longer available, continues to foment caution. Complement-mediated minor infusion reactions, referred to as complement activation-related pseudo-allergy, resolve without therapy. Inappropriate intervention with vasopressors and H1 blockers converts these minor reactions into hemodynamically significant adverse events. Four new formulations, low-molecular-weight iron dextran, ferumoxytol, ferric carboxymaltose, and ferric derisomaltose, all approved for the treatment of iron deficiency in a host of conditions, are now widely used with an excellent safety profile. Herein, the administration, safety, indications, and management of infusion reactions are discussed. Treatment-emergent hypophosphatemia, a newly recognized side effect for some formulations, is also reviewed. Based on the preponderance of published evidence, intravenous iron should be moved up-front for the treatment of iron deficiency and iron deficiency anemia in those conditions in which oral iron is suboptimal.

Evaluation of a Pharmacist-Developed, Nurse-Driven Protocol for Management of Parenteral Anticancer Therapy Infusion Reactions in an Ambulatory Infusion Center.

Intravenous anticancer therapy can be associated with hypersensitivity- and/or infusion-related reactions (IRRs) which may result in life-threatening symptoms. As part of a quality improvement project, oncology pharmacists developed and implemented a nurse-driven, symptom-based IRR protocol. The objective of the evaluation was to evaluate IRR treatment failure after implementation of a symptom-based protocol in an ambulatory infusion center. Secondary objectives included determining the most common anticancer agents requiring IRR treatment, documentation of ED visits or hospital admissions within 72 h of treatment, documentation of mortality due to an IRR, and evaluating whether there were multiple documented IRRs to the same medication. A total of 456 patients, who received an infusion of anticancer therapy at Grady Health System (GHS) between February 2014 and March 2018, were retrospectively evaluated. Patients were included if they received a protocol-specific medication for infusion reaction management of a parenterally administered anticancer agent. The primary outcome was the rate of treatment failure within 72 h of treatment for an IRR. Seventy-eight patients experiencing 108 IRRs were included in the analysis. Five percent of IRRs consisted of rigors only, 57% of IRRs were mild/moderate severity, 31% of IRRs were severe/anaphylactic severity and 7% of IRRs were rigors in addition to a mild/moderate/severe reaction. Of the 108 IRRs, treatment failure within 72 h was observed in eight reactions; six were evaluated in the emergency department and two required a hospital admission. Overall, 93% of reactions resolved in the infusion center and patients were discharged home; there were no patient deaths. The most common offending agents were paclitaxel and oxaliplatin. Following implementation of a novel pharmacist-developed, symptom-based nurse-driven protocol, infusion reaction treatment failure occurred in 7% of IRRs evaluated. Although the failure rate was low, additional nurse education and improved access to protocol-directed medications may optimize use of the protocol.

A Pilot Study of the Anti-SLAMF7 Monoclonal Antibody, Elotuzumab, in Myelofibrosis

A Pilot Study of the Anti-SLAMF7 Monoclonal Antibody, Elotuzumab, in Myelofibrosis

Supportive Management of Patients with Advanced Pheochromocytomas and Paragangliomas Receiving PRRT.

Peptide receptor radionuclide therapy (PRRT) is used to treat patients with advanced malignant pheochromocytomas (PCCs) and paragangliomas (PGLs). Patients are at risk of a PRRT-induced catecholamine crisis, and standard guidelines regarding the prevention and management of infusion reactions are lacking. In this case series, the institutional experience of five sequential patients with metastatic PCCs and PGLs receiving PRRT on an outpatient basis is described, of which four had symptomatic tumors and three had a high burden of disease. All patients with symptomatic tumors were treated with preventive management prior to the initiation of PRRT, and no infusion reactions or catecholamine crises were documented. PRRT may be delivered safely on an outpatient basis for patients with metastatic PCCs and PGLs with the involvement of an interdisciplinary team.

Rapid Infusion Daratumumab Is Safe and Well Tolerated in Clinical Practice

Introduction: Daratumumab is an anti-CD38 monoclonal antibody, currently FDA approved for treatment of newly diagnosed transplant ineligible multiple myeloma (MM) in combination with melphalan, prednisone and bortezomib, in combination with lenalidomide-dexamethasone and bortezomib-dexamethasone for early relapse MM, and in combination with pomalidomide-dexamethasone and monotherapy for relapsed/refractory MM (RRMM). Recent data demonstrated the feasibility of infusing daratumumab at an accelerated rate over 90 minutes from Cycle1 day 15 onwards [1], reducing the standard infusion time of 3-4 hours. Considering these data, all daratumumab protocols at our institution were updated to implement the rapid infusion protocol in routine clinical practice. Herein, we report the safety profile of rapid daratumumab infusion at our center.Methods: Retrospective chart review was performed from April 2016 through July 2018 to identify patients who completed at least one cycle of daratumumab or any daratumumab containing regimen for RRMM or amyloidosis at the Levine Cancer Institute (LCI). LCI includes a large infusion center at the main tertiary center and several other small infusion centers distributed throughout the states of North and South Carolina. Patients were divided into two cohorts; cohort 1 included patients who received daratumumab administered at the standard infusion rate recommended by manufacturer, whereas cohort 2 received rapid infusion daratumumab following the institution-wide implementation of the rapid infusion protocol in March 2018. Cohort 2 patients started on daratumumab received the first two doses of cycle 1 at the standard infusion rate followed by a 90-minute infusion with third and subsequent doses. Furthermore, 20% of dose was given over 30 minutes and the remaining 80% over 60 minutes (overall duration: 90 minutes). Patients in both cohorts were pre-medicated with: acetaminophen, diphenhydramine, dexamethasone and montelukast (for first two doses of first cycle), given 30 minutes prior to initiating daratumumab. The primary endpoint was to compare rates of infusion related reactions between the rapid and standard daratumumab infusion protocols using Fischer's exact test. Data collected included but not limited to: patient demographics, comorbidities, plasma cell disorder, pre-medications, type and management of infusion reactions, as well as post-infusion monitoring if documented.Results: A total of 73 RRMM (37 in cohort 1 and 36 in cohort 2) and 6 amyloidosis patients (3 in each cohort) were included in this study. Baseline characteristics are shown in table 1. Overall, there was no statistically significant difference in the rates of infusion related reactions between the rapid and standard infusion cohorts (2.6% vs. 5.0%, p=0.6). Of 39 patients in cohort 2, 8 patients received rapid infusion daratumumab on day 15 (3rd dose) of first cycle, whereas remaining received a median of 7 cycles (range: 2-30) before the switch was commenced. Among those 8 patients where daratumumab was started on day 15, only 1 developed an infusion related reaction. Notably, this patient had a history of prior exposure, and subsequently daratumumab was administered at the rapid infusion rate on day 1 instead of day 15, approximately 4 months later. All infusion reactions reported in both cohorts were grade 1 which were managed according to institutional guidelines followed by resumption of infusion at lower rates.Conclusion and future directions: Our findings indicate that rapid daratumumab infusion beyond day 8 of cycle 1 is a safe, tolerable and convenient option for RRMM and amyloidosis patients. Additional studies are underway to evaluate cost benefits of rapid infusion daratumumab as well as patient/provider satisfaction.

Incidence and Management of Infusion Reactions to Infliximab in an Alternate Care Setting

BackgroundInfliximab is a chimeric anti-tumor necrosis factor alpha (TNF-α) monoclonal antibody that ameliorates inflammation when it binds to and neutralizes TNF-α. It is often used in patients with Crohn’s disease and ulcerative colitis to reduce the severity of disease symptoms and induce disease remission. Infusions are generally administered in the hospital setting due to concerns over patient safety, and limited data exist regarding the incidence and management of infusion reactions (IRs) in an alternate care setting without direct physician oversight.AimsThe aim of this study was to evaluate the incidence of IRs following administration of infliximab and associated management approaches in an alternate care setting.MethodsA retrospective chart review of 796 patients with Crohn’s disease or ulcerative colitis that received a combined 5581 infusions with one home infusion provider between January 2014 and November 2016 was conducted. Timing, severity, management approach, and outcomes of IRs were abstracted and analyzed.ResultsA total of 109 infusion reactions (2.0% of all infusions) were recorded in 62 patients (7.8% of all patients). The majority of these reactions were acute and mild or moderate in severity and resolved with rate adjustments and/or medication. Emergency room visits were required in 0.1% of all infusions, and 0.3% of all infusions were not completed due to a reaction.ConclusionsIRs to infliximab were uncommon and mostly mild or moderate in severity. Resolution of the IR and continuation of therapy was achieved in most patients through a management approach that included prompt recognition and initial treatment via rate adjustments and medications according to physician’s orders.

How Well Do Rheumatology Fellows Manage Acute Infusion Reactions? A Pilot Curricular Intervention.

Infusible disease-modifying antirheumatic drugs (DMARDs) are commonly prescribed in rheumatology and other fields. There are no published formal educational curricula that rheumatology fellowship programs can use to teach infusion reaction management skills to fellows. We aimed to better understand this educational gap and implement and assess the effectiveness of an experiential curriculum on acute infusion reaction management. We included current rheumatology fellows and recent graduates from 5 fellowship programs. Using a novel behavioral checklist, we assessed fellows' performance managing an infusion reaction in a simulation, followed by a didactic session focused on infusion reactions. Pre- and postsurveys assessed experiences to determine relevance, as well as attitudes and knowledge. Despite ubiquitous prescribing of infusible biologic DMARDs, >50% of fellows were uncomfortable managing infusion reactions. Only 11% of fellows reported infusion reaction training during fellowship, but 56% reported managing actual patient infusion reactions. In the simulated infusion reaction, fellows managed grade-1 reactions appropriately, but grade-4 reactions poorly, meeting <50% of objectives. All fellows discontinued the infusion in the setting of anaphylaxis, but only 56% administered epinephrine. There was no difference in performance or written knowledge by training year. All fellows felt more prepared to manage infusion reactions postcurriculum and were satisfied with the experience. We confirmed an education gap in rheumatology fellowship training regarding infusion reactions, both in knowledge and performance. We developed and implemented a brief experiential curriculum including simulation of a high-risk patient-care scenario. This curriculum was well received and is easily exportable to other programs.

Brentuximab Vedotin Infusion Reaction Management: A Case Study

We report a case of a grade 3 (Common Terminology Criteria for Adverse Events [CTCAE]) infusion reaction to brentuximab vedotin (Adcetris), in a patient with refractory Hodgkin lymphoma, at a large National Cancer Institute-designated cancer center in the Midwest (National Cancer Institute, 2010). Acute infusion reaction management and subsequent premedication strategies are outlined. Ms. R is a 30-year-old woman who presented with stage IV Hodgkin lymphoma at the age of 29. Initial staging revealed lymphadenopathy above and below the diaphragm, as well as fluorodeoxyglucose (FDG)-avid lung lesions, splenic lesions, and multiple sites of bony involvement. Bone marrow biopsy was negative. She was treated with six cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), to which she obtained a complete response by positron emission tomography-computed tomography (PET-CT) criteria. Ten months after chemotherapy completion, she presented with new PET-avid adenopathy in the cervical and paratracheal regions, and a biopsy revealed recurrent Hodgkin lymphoma. Salvage chemotherapy was administered with ifosfamide carboplatin, and etoposide (ICE). After two cycles of salvage chemotherapy, a PET-CT confirmed a complete response, and she proceeded to an autologous stem cell transplant with a preparative regimen of carmustine, etoposide, cytosine arabinoside, and melphalan (BEAM). Brentuximab vedotin consolidation therapy was prescribed in the post-transplant consolidation setting, beginning 45 days after stem cell reinfusion, given the patient's high risk for recurrence. This strategy was based upon the results of the AETHERA phase III clinical trial (Moskowitz et al., 2015), showing improvement in progression-free survival with brentuximab vedotin consolidation therapy, post autologous transplant. The first dose of brentuximab vedotin was administered without difficulty, at full dose (1.8 mg/kg) at a standard infusion time of 30 minutes. The second dose of brentuximab vedotin was complicated by nausea, chest pain, and dysphagia within 10 minutes of medication initiation. Upon the emergence of these symptoms, the brentuximab vedotin infusion was held. Vital signs were stable, with a temperature of 36.9˚C, pulse 84, respirations of 20, and blood pressure of 107/67 mm Hg. Oxygen saturations were 99% on room air. Diphenhydramine (50 mg) was administered intravenously (IV), along with 20 mg of IV famotidine. An electrocardiogram (ECG) was obtained, which was unremarkable, showing normal sinus rhythm. Fifteen minutes later, the symptoms of chest pain and shortness of breath persisted, so hydrocortisone at 100 mg IV was administered, with an additional 25 mg of IV diphenhydramine and 20 mg of IV famotidine. Intraveous granisetron was given for nausea. Thirty minutes after onset, the chest pain was persistent, and oxygen saturations were normal. Hydrocortisone (50 mg) was administered intravenously, and Ms. R's condition improved, with resolution of her symptoms within 30 minutes of the second hydrocortisone dose. The brentuximab vedotin was restarted 30 minutes after symptom resolution at a decreased infusion rate to be administered over 60 minutes. Thirty minutes later, however, Ms. R developed tingling and numbness in her feet and tongue. The brentuximab vedotin infusion was again held, and 100 mg of IV methylprednisolone was administered. Ms. R's symptoms resolved within 40 minutes, and the brentuximab vedotin infusion was able to be continued over a prolonged period of more than 4 hours. Vital signs were checked every 15 minutes during the infusion reaction and remained stable throughout. The infusion was discontinued with 40 mg of drug remaining, due to the prolonged infusion time. Given the clear benefits of brentuximab consolidation in improving progression-free survival post transplant (Moskowitz et al., 2015) in high-risk Hodgkin lymphoma, it was thought the benefit of brentuximab vedotin consolidation outweighed the possible risks of subsequent infusions. Upon reviewing the available literature regarding brentuximab vedotin hypersensitivity reactions, which will be outlined in the discussion summary, we instituted the premedication strategy for subsequent infusions outlined in the Table on p 628. Standard epinephrine and methylprednisolone were available at the bedside in the event of any anaphylactic reaction. This regimen was chosen based on the clinical rationale for H1 and H2 blockade, as well as corticosteroid and antipyretic coverage, in the prevention of hypersensitivity reactions, not classified as anaphylaxis. With the institution of the outlined premedications, Ms. R tolerated subsequent infusions well, at full dose and at standard infusion rates, with no documented infusion reactions, and was able to complete a total of 16 cycles of consolidation therapy.

Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines.

Management of infusion reactions to systemic anticancer therapy: ESMO Clinical Practice Guidelines.

Management of infusion reactions associated with cetuximab treatment: A case report.

Cetuximab is a drug targeting the epidermal growth factor receptor, which is indicated for the treatment of unresectable advanced or recurrent head and neck or colorectal cancer. Cetuximab also enhances the cytotoxic effects of radiation in squamous cell carcinoma. The severity of infusion reactions (IR) is categorized from grade 1 to 5; grades 3 and 4 are associated with life-threatening reactions (anaphylaxis), whereas grade 5 indicates death. The incidence of grade 3–4 IR with premedication is reported to be 1.1%. We herein describe a case of a 77-year-old man who developed IR during intravenous administration of cetuximab. The patient developed grade 3–4 anaphylaxis with pruritus, rash and urticaria, followed by hypotension and bradycardia. The timely diagnosis and treatment with intravenous infusion of a vasopressor drug and Ringer's acetate solution proved to be effective. The case presented herein demonstrated an unfeatured aspect of cetuximab-related IR as dermatological reactions over the entire body followed by circulatory collapse.

Role of elosulfase alfa in mucopolysaccharidosis IVA.

Mucopolysaccharidosis type IVA (MPS IVA or Morquio A) is an autosomal recessive lysosomal storage disease which results in a striking skeletal phenotype, but does not negatively impact the intellect of the patient. MPS IVA has a phenotypic continuum that ranges from a severe and rapidly progressing form to a slowly progressive form. The clinical diagnosis is often made in the preschool years based on abnormal bone findings on physical examination and dysplasia on radiographic imaging. Supportive care has been the mainstay in caring for patients. Orthopedic physicians often form the core of the care team due to the early and severe skeletal abnormalities; however, systemic disease is common and requires aggressive monitoring and management. Interdisciplinary care teams often consist of medical geneticists, cardiologists, pulmonary specialists, gastroenterologists, otolaryngologists, audiologists, and ophthalmologists. With the US Food and Drug Administration’s approval of elosulfase alfa, patients >5 years of age now have access to this medication from the time of diagnosis. The clinical trial with once weekly intravenous dosing (2.0 mg/kg per week) showed improvement in the 6-minute walk test. The composite end point analysis to evaluate the combining changes from baseline in 6-minute walk test, 3-minute stair climb test, and respiratory function showed that at a dose of 2.0 mg/kg per week, subjects performed better when compared to placebo. This indication was clinically meaningful in the treatment group. The treatment was generally well tolerated, and the uncommon infusion reactions responded well to traditional enzyme replacement therapy infusion reaction management algorithms. Currently, clinical trials are underway to determine the efficacy and safety in MPS IVA patients <5 years of age.

Infliximab-Related Infusion Reactions: Systematic Review.

Objective:Administration of infliximab is associated with a well-recognised risk of infusion reactions. Lack of a mechanism-based rationale for their prevention, and absence of adequate and well-controlled studies, has led to the use of diverse empirical administration protocols. The aim of this study is to perform a systematic review of the evidence behind the strategies for preventing infusion reactions to infliximab, and for controlling the reactions once they occur.Methods:We conducted extensive search of electronic databases of MEDLINE [PubMed] for reports that communicate various aspects of infusion reactions to infliximab in IBD patients.Results:We examined full texts of 105 potentially eligible articles. No randomised controlled trials that pre-defined infusion reaction as a primary outcome were found. Three RCTs evaluated infusion reactions as a secondary outcome; another four RCTs included infusion reactions in the safety evaluation analysis; and 62 additional studies focused on various aspects of mechanism/s, risk, primary and secondary preventive measures, and management algorithms. Seven studies were added by a manual search of reference lists of the relevant articles. A total of 76 original studies were included in quantitative analysis of the existing strategies.Conclusions:There is still paucity of systematic and controlled data on the risk, prevention, and management of infusion reactions to infliximab. We present working algorithms based on systematic and extensive review of the available data. More randomised controlled trials are needed in order to investigate the efficacy of the proposed preventive and management algorithms.

Incidence and Management of Infusion Reactions to Infliximab in a Prospective Real-world Community Registry.

Infliximab (IFX) is a therapeutic monoclonal antibody targeting tumor necrosis factor-α indicated in the treatment of chronic inflammatory diseases. IFX is administered by intravenous infusion and may be associated with different types of infusion reactions. RemiTRAC Infusion (NCT00723905) is a Canadian observational registry in which patients receiving IFX are followed prospectively to document premedication use, adverse events, infusion reactions, and the management of infusion reactions. The primary endpoint was to assess factors associated with infusion reactions. There were 1632 patients enrolled and 24,852 infusions recorded. Most patients (63.1%) were treated for rheumatologic conditions such as rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis. Of the 1632 patients, 201 (12.3%) reported at least 1 infusion reaction. Three hundred twenty-two infusions were associated with an infusion reaction (1.3%), and most were mild to moderate in severity (95%). The most common infusion reactions were pruritus (19.9%), flushing (9.9%), or dyspnea (6.2%). Multivariate analysis showed that antihistamines premedication, number of previous infusion reactions, and female sex were significantly associated with an increased incidence of infusion reactions (p < 0.0011). The use of any concomitant immunosuppressant or corticosteroids did not influence the incidence of infusion reactions. Antihistamine premedication was associated with an increased incidence of infusion reactions (OR 1.58, p = 0.0007). This registry shows that in community-based infusion clinics, infusion reactions to IFX are uncommon and mild to moderate in nature. Antihistamines, intravenous steroids, and acetaminophen are widely used as preventative premedication, although this study showed an absence of benefit with their use.

THU0195 Incidence of Infliximab (IFX) Infusion Reactions with and Without Premedication

BackgroundSome patients may experience adverse drug reactions (ADR) during infusion with IFX and this could be due to immunogenicity.ObjectivesTo evaluate the incidence of infusion reactions in rheumatoid arthritis (RA) patients,...

Incidence and Management of Infusion Reactions to Infliximab in a Prospective Real-Life Community Registry

Infliximab (IFX) is a therapeutic monoclonal antibody targeting TNFα indicated in the treatment of a number of chronic inflammatory diseases. IFX is administered by intravenous infusion and may be associated with infusion reactions (IR). RemiTRAC Infusion is a prospective Canadian observational registry in which IFX infusions are followed to document the incidence and management of IR, pre-medication use and adverse events (AE). An IR was defined as any AE occurring during the infusion or within 1 hour post infusion. Since its inception in 2005, 1398 patients have been enrolled and 18,121 infusions were recorded. There were 253 Crohn's disease patients (16%) and 80 UC patients (6%). The majority of remaining patients (64%) were treated for rheumatologic conditions. A total of 181/1398 patients reported at least one IR (13%). Only 292/18,121 infusions resulted in an IR (1.6%) and most IRs were mild to moderate in severity (94%). The most common infusion AE was pruritus which occurred in 14.2% of IR. Flushing (9.9%), urticaria (9.2%), nausea (6.3%) dyspnoea (6.0%) and chest discomfort (5.0%) were the only other infusion AEs occurring in ≥5% of IR. Pre-medication, which included anti-histamines, intravenous steroids and/or acetaminophen, was used in 42% of infusions and 1.8% of them were associated with an IR. Interestingly, infusions without any pre-medication were associated with a 1.4% incidence of IR. Infusions pre-medicated with anti-histamines, either alone or in combination with steroids, were associated with a significantly higher incidence of IR, up to 3.3% in the presence of anti-histamines (P < 0.0001) and up to 5.3% in the presence of anti-histamines and steroids (P < 0.0001). In contrast, only acetaminophen pre-medication was associated with a reduced incidence of IR (0.8%, P < 0.0001). We noted that infusions immediately following an IR were associated with a 31% incidence of a subsequent IR (44/140) despite the prevalent use of prophylactic pre-medication. This likely explains the higher incidence of IR in the presence of anti-histamines and/or steroids. This registry shows that, in community-based infusion clinics, infusion reactions to IFX are rare in incidence and largely mild to moderate in nature. Only the use of acetaminophen pre-medication was associated with a lower incidence of IR.

485P - Challenge in the Pharmacokinetic Evaluation of DTS-108, a New Topoisomerase I Inhibitor, in Patients with Advanced Carcinomas

ABSTRACT Background DTS-108 is a soluble pro-drug of SN38, the active metabolite of irinotecan, where the SN38 moiety is covalently linked to a 20AA peptide through a specific cross-linker that releases SN38 by esterase bond cleavage. DTS-108 was designed to achieve therapeutic levels of SN38, while reducing diarrhea. Methods SN-38 and SN-38G levels were evaluate with fluorescence HPLC test and LC/MS/MS methods. The pharmacokinetics of DTS-108, the adverse event (AE) profile, the dose limiting toxicities (DLT) at cycle 1, the maximum tolerated dose (MTD), and the recommended phase II dose (RD) of intravenous DTS-108 (1-2 hours) every two weeks (q2w) in patients (pts) with advanced/metastatic carcinomas was conducted. Results Forty-Two pts received DTS-108 across 14 dosing cohorts (range: 3-416mg/m2). All grade AEs were asthenia (43%), nausea (43%), diarrhea (41%), vomiting (33%), anemia (31%), rash (21%), anorexia (21%), alopecia (19%), abdominal pain (19%), and neutropenia (19%). Neutropenia was the dose limiting toxicity of DTS-108. Neutropenia started to be observed at doses >56 mg/m2. At 416 mg/m2, 3/6 pts had grade 4 neutropenia. Fluorescence HPLC was initially used to quantify DTS-108 and its metabolites (SN-38 and SN-38G). Sample stability analysis of this method showed that SN38 values were inaccurate as DTS-108 degraded forming ex-vivo SN-38 during the blood collection, plasma storage, and/or sample extraction. New processes and analytical LC/MS/MS methods for testing SN-38 were implemented. At the dose of 313 mg/m2, mean DTS-108, SN38, and SN38G AUCINF (CV%) were 439293 (24%), 1992 (34%), and 4538 (46%) h*ng/mL. Tumor stabilization (RECIST) was observed in 9 pts and confirmed in 6 pts. Conclusions SN-38 concentration using Fluorescence HPLC failed to monitor drug escalation in topoisomerase I inhibitor because of ex vivo degradation. SN-38 exposures using LC/MS/MS methods are consistent with less variables values and allow drug monitoring. DTS-108 induced no dose-limiting diarrhea but neutropenia and infusion skin reactions. The dose level 313 mg/m2 was declared the MTD based on 5 of the 6 patients treated at this dose level having no dose-limiting neutropenia and the overall improvement in the management of infusion reactions. Disclosure All authors have declared no conflicts of interest.

Infusion Reactions Related to Infliximab Therapy Are Not Usually Associated with Drug Discontinuation

Infliximab has had a major influence on the treatment of a variety of chronic inflammatory diseases since its introduction in the late 1990s and is commonly used in the management of inflammatory arthritis, inflammatory bowel disease (IBD), and psoriasis. Infliximab is administered as an intravenous infusion and, following induction therapy of 3 weight-based doses over 6 weeks, patients receive scheduled therapy every 8 weeks. A major issue for tumor necrosis factor (TNF) inhibitors is their durability. In the major trials of anti-TNF therapy in IBD, only 25% of initial responders remained in remission after 1 year. This dropoff is mostly due to a combination of secondary loss of response to the medication and adverse effects. Infusion reactions to infliximab can be alarming for patients, physicians, and nurses, and, if misunderstood, may unnecessarily limit further use of the drug. Patients who fail anti-TNF therapy may have limited treatment options, so accurate diagnosis and management of infusion reactions is vital in our attempts to fully optimize these important medications. Infusion reactions to infliximab are not uncommon, although the true incidence is difficult to estimate due to variations in the reporting of reactions, differing definitions, and issues with retrospectively collected data. In IBD, it is estimated that infusion reactions affect 5%–20% of patients and are typically mild1,2. The TREAT registry, a large post-marketing registry of patients with Crohn’s disease (CD), reported a 3.1% reaction rate in 48,279 infliximab infusions. However, reactions severe enough to limit further use of the drug occurred in only 0.07%3. In this month’s issue of The Journal , Kelsall and colleagues report their 8-year experience of infusion reactions in patients with inflammatory arthritis treated at a tertiary referral center in Vancouver, Canada4. Data were available on 4399 infliximab infusions in 200 … Address correspondence to Dr. A. Cheifetz, Center for Inflammatory Bowel Disease, Division of Gastroenterology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215. E-mail: acheifet{at}bidmc.harvard.edu

The impact of infusion reactions associated with monoclonal antibodies in metastatic colorectal cancer: A European perspective

Published data on the clinical and economic impact of infusion reactions to monoclonal antibodies are limited. This study investigated oncologists' and oncology nurses' opinions about resource use associated with infusion reactions and the impact on patient management in Europe. Eighty oncologists and nurses from Denmark, France, Germany, Greece, Italy, Spain, Sweden and the UK currently treating patients with metastatic colorectal cancer were interviewed by telephone using a 27-item questionnaire developed for this study. The mean estimated number of staff (physicians and nurses) involved in managing an infusion reaction was 1.97 for a grade 1, 2.35 for a grade 2, 3.6 for a grade 3 and 5.3 for a grade 4 reaction. In respondents' experiences, most patients with grade 3 infusion reactions (73.4%) were admitted to hospital for treatment; 82.5% of those with grade 4 infusion reactions were treated in intensive care. The estimated duration of hospital treatment was 13.3 ± 29 h for a grade 3 infusion reaction, increasing to 48.1 ± 43.7 h for a grade 4 infusion reaction. According to respondents, management of infusion reactions led to substantial resource use, which increased with the severity of the reaction. More severe reactions also led to anxiety in patients and distress to staff.

Incidence and management of infusion reactions to infliximab in 186 italian patient’s with rheumatoid arthritis: the Padua experience

We report the incidence and treatment of infusion reactions to infliximab, a chimeric monoclonal IgG1 antibody against tumor necrosis factor alpha, in a large cohort of patients with rheumatoid arthritis. One hundred eighty six patients with rheumatoid arthritis treated with infliximab for a total of 216.6 patient years were retrospectively evaluated. Patients received 2160 infliximab infusions at the Division of Rheumatology at the University Hospital of Padua from May, 2000 to April, 2004. Specific treatment protocols for initial and subsequent acute infusion reactions were followed and the outcomes documented. The overall incidence of infusion reactions to infliximab was 0.8% (19 out of 2160 of infusions), affecting 10.2% of patients (19 out of 186). Mild, moderate, or severe acute reactions occurred in 0.1% (3 of 2160), 0.6% (13 of 2160), and 0.04% (1 of 2160) of infliximab infusions, respectively. Delayed infusion reactions occurred in 0.09% (2 of 2160) of infusions. Use of specific treatment protocols resulted in rapid resolution of all acute reactions to infliximab. With a prophylaxis protocol, all patients who experienced an initial mild acute reaction were able to receive additional infusions. Using appropriate treatment protocols, infliximab infusion reactions were effectively treated and prevented in patients with mild acute reactions upon retreatment. In the case of moderate to severe infusion reactions, the risks and the benefits of the continuation of infliximab therapy need to be carefully considered.