How should the various types of acute infusion-related adverse events be managed? 7. How should patients experiencing an acute infusion-related adverse events be followed-up?The PubMed and EMBASE database were searched for relevant studies, guidelines and consensus documents published up to May 2019. The specific search strategy, search terms, and search results, are presented in Appendix A, and evidence tables are available upon request. Online resources from oncology-based health organizations and guideline developers were also systematically searched, and relevant guidelines from the following organizations were considered in the development of our recommendations: Cancer Care Ontario (CCO), The Comite de l'evoltion des pratiques en oncologie (CEPO), and the European Society for Medical Oncology (ESMO).# Background
Many chemotherapy drugs and monoclonal antibodies are reported to cause acute infusion-related allergic and allergic-like reactions in cancer patients. These reactions range from mild cutaneous appearances (e.g. pruritus and hives) to life-threatening anaphylaxis with hypotension, oxygen desaturation and cardiovascular collapse, and death. 1 Acute infusion-related adverse events vary based on the type of drug used, as well as the duration, frequency of infusion and prior exposure to the drug. 2 Understanding the pathophysiology of these acute infusion-related adverse events and the terminology used to describe them is confusing. The traditional classification relies on the clinical presentation of typical symptoms and their timing, and include: 3 - type I (IgE mediated reactions) - type II (antibody mediated cytotoxicity reactions) - type III (immune complex-mediated reactions)
- type IV (delayed reactions)
The traditional classification, however, does not encompass the current spectrum of reactions and symptoms occurring in cancer patients. 1,4,5 Some of the reactions have no known underlying mechanism, others have a known mechanism which is not part of the traditional classification, while some drugs induce mixed reactions with two or more proposed mechanisms. 1 Regardless of the underlying mechanism, acute infusion-related adverse events to chemotherapy drugs and monoclonal antibodies are unexpected, can be severe, and can prevent the use of first-line therapies which has the potential to negatively impact patient's survival and quality of life. 1 To facilitate prompt identification and management of these reactions, a shared understanding of the terminology, incidence, characteristics, and management approaches is required between healthcare professionals.

# Guideline Questions
As it pertains to chemotherapy drugs and monoclonal antibodies: 1. How are acute infusion-related adverse events defined? 2. What are the risk factors for acute infusion-related adverse events? 3. What is the incidence of acute infusion-related adverse events? 4. What are the characteristics (signs, symptoms, timing, and grading) of acute infusion-related adverse events? 5. What is unique about acute infusion-related adverse events with the following drugs classes: a. Platinum derivatives? b. Anthracyclines? c. Taxanes? d. Monoclonal antibodies?

# Target Population
The recommendations presented in this guideline apply to adult patients over the age of 18 who are receiving chemotherapy and/or monoclonal antibodies. Different principles may apply to pediatric patients.

# Guideline Development Notes
Acute infusion-related adverse events associated with chemotherapy drugs and monoclonal antibodies is difficult to evaluate through prospective randomized studies because of the unexpected nature of these reactions. 6 The available published data is largely drug-specific, and while reported as secondary outcomes or included in safety analysis from randomized controlled trials, the data is primarily derived from single-center cohort, retrospective, or case reports.
We chose to provide high-level recommendations about the identification and management of infusion-related adverse events in this guideline and refer clinicians to the drug table in Appendix B for specific details about individual chemotherapy drugs and monoclonal antibodies. The information presented in Appendix B was largely identified in Lexicomp (specific drug or drug class) using a combination of search terms, including infusion reaction, infusion-related reaction, anaphylaxis, cytokine release, and hypersensitivity. For some drugs, additional new information was added from Cancer Care Ontario's Cancer Medication Infusion Reactions Drug Table. 7 Acute infusion-related adverse associated with supportive drugs used during cancer treatment (e.g. sargramostim) are beyond the scope of this guideline.
For recommendations about the management of acute infusion-related adverse events following treatment with immune effectors cells, please refer to Alberta Health Services' Alberta Bone Marrow and Blood Cell Transplant Program: Standard Practice Manual. 8 Recommendations

# Acute Infusion-Related Adverse Events Terminology
Several terms are used to describe acute infusion-related adverse events to chemotherapy and monoclonal antibodies, including drug hypersensitivity reactions, infusion-related reactions, cytokine release syndrome and anaphylaxis. We recommend using the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 to help standardize the definitions of some of these terms. 9 The CTCAE is a commonly used system of nomenclature for classifying adverse events and their associated severity in cancer clinical trials. 10 - Drug hypersensitivity reactions (HSR) are the adverse effects of pharmaceutical formulations (including active drugs and excipients) that clinically resemble allergic reactions. 11 - Infusion-related reaction (IRR) is a disorder characterized by adverse reaction to the infusion of pharmacological or biological substances. 9 An IRR may occur during administration (intravenous/subcutaneous) or sometime after on the first day of drug administration. 12 - Cytokine release syndrome (CRS) is a disorder characterized by fever, tachypnea, headache, tachycardia, hypotension, rash, and/or hypoxia caused by the release of cytokines. 9 CRS is a specific type of nonantibody-mediated infusion reaction (often referred to as anaphylactoid reactions) that is associated with monoclonal antibodies and T-cell-directed therapies. 13 - Anaphylaxis is a disorder characterized by an acute inflammatory reaction resulting from the release of histamine and histamine-like substances from mast cells, causing a hypersensitivity immune response. Clinically, anaphylaxis presents with breathing difficulty, dizziness, hypotension, cyanosis and loss of consciousness and may lead to death. 9

# Risk Factors for Acute Infusion-Related Adverse Events
There are no well-established risk factors to identify who may experience an acute infusion-related adverse events. Low-level evidence has identified some drug-related, treatment regimen-related, and patient-related risk factors, which are summarized in Table 1.  

# Incidence of Acute Infusion-Related Adverse Events
Capturing the incidence of acute infusion-related adverse events, drugs involved, management, treatment, and outcomes has been possible only through volunteer registries. 31,32 Thus, it can be expected that the incidence of acute infusion-related adverse events with chemotherapy drugs and monoclonal antibodies is often different depending on the source of evidence. To assist healthcare professionals with risk recognition we chose Lexicomp as our source of evidence and allocated individual chemotherapy drugs and monoclonal antibodies into one of three categories based on arbitrarily selected ranges: 26-30, 33-60
- High potential (30%): blinatumomab, daratumumab, obinutuzumab (1 st infusion), paclitaxel (conventional), rituximab (decreases with subsequent infusions)
- Moderate potential (<30% to 10%): asparaginase (E. coli), carboplatin, cetuximab, cisplatin, daunorubicin (liposomal), docetaxel, nivolumab, obinutuzumab (2 nd infusion), pertuzumab, ramucirumab, trastuzumab
- Low potential (<10%): alemtuzumab, atezolizumab, bevacizumab, bleomycin, brentuimab vedotin, cabazitaxel, daunorubicin (conventional), doxorubicin (conventional), doxorubicin (liposomal), epirubicin, etoposide, idarubicin, inotuzumab ozogamicin, ipilimumab, obitutuzumab ( 3 rd infusion), oxaliplatin, paclitaxel (protein bound), panitumumab, pembrolizumab, While most chemotherapy drugs and monoclonal antibodies have an anaphylactic incidence rate of less than 1%, they are reported as the third leading cause of fatal drug-induced anaphylaxis. 61

# Characteristics of Acute Infusion-Related Adverse Events
Signs and symptoms. Common signs and symptoms of acute infusion-related adverse events include:
- Cutaneous e.g. rash, flushing, urticaria, pruritus  Acute infusion-related adverse events to taxanes and monoclonal antibodies usually occur during the first or second infusion  versus platinum compounds where they typically occur after multiple cycles. 24,  For example, in retrospective reviews, reactions to oxaliplatin occurred at a median of 7 to 9 cycles as reported in Lexicomp (see Appendix B).
Grading. The CTCAE differentiates Grades 1 through 5 for acute infusion-related adverse events with unique clinical descriptions of severity for each (see Table 3). 9 These grades should be used to guide diagnosis and management decisions associated with acute infusion-related adverse events caused by chemotherapy drugs and monoclonal antibodies. 

# Unique Characteristics of Acute Infusion-Related Adverse Events by Main Drug Class
Anthracyclines (Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Valrubicin) 73 - Reactions usually occur immediately.
- Reactions appear to be immunologically mediated. However, in the case of liposomal formulations, complement activation may be an important factor. - Systemic hypersensitivity and anaphylaxis are rarely reported. 74 - Reactions are thought to be mainly caused by type I IgE-mediated or type IV T-cell-mediated hypersensitivity although nonimmune mechanisms may also play a role. - Most reactions to platinum derivatives occur after multiple infusions.

# Platinum derivatives (Carboplatin, Cisplatin, Oxaliplatin)
- Reactions usually occur during or shortly after the infusion.
- The chance of hypersensitivity reactions is increased when platinum derivatives are given in combination with other chemotherapy. - Cross-sensitivity may occur between the platinum derivatives.
- There is insufficient evidence that routine premedication with antihistamines, H2 blockers, and corticosteroids are effective in preventing hypersensitivity reactions to platinum salts. 75 - Special considerations:
- Corticosteroids and H1-receptor antagonists  H2-receptor antagonists may reduce infusion-related reaction rates for some patients receiving carboplatin (e.g. gynecological patients with a platinum-free interval >12 months or a history of drug allergy who are receiving carboplatin starting from the 7 th cycle) but no optimal premedication regimen has been established. 7
Taxanes (Cabazitaxel, Docetaxel, Paclitaxel) 76 - Hypersensitivity reactions are similar in nature between the taxanes and may include shortness of breath, itching, hypotension, back pain and erythematous rashes. Rarely, bronchospasm and death have occurred. - Most hypersensitivity reactions are understood to be non-IgE-mediated. It is likely that allergic reactions can be attributed, at least in some instances to the vehicle (e.g. Cremophor EL, polysorbate 80) - Most hypersensitivity reactions occur with the first or second dose.
- Cross-reactivity may exist between the taxanes.
- Special considerations:
- Evidence indicates that premedications can be discontinued in patients who have completed two cycles of paclitaxel without a documented infusion-related reaction. 72 o If the patient has reacted, or subsequently reacts, premedications should be given on every cycle
Monoclonal Antibodies 77 - Most reactions are mild and non-life-threatening.
- Anaphylaxis is uncommon but has been reported with rituximab trastuzumab and cetuximab.
- Infusion-related reaction are typically immediate and occur during the initial few minutes of the first or second infusion. - Reactions may occur after the first exposure or after many exposures, but in general, the risk of an infusion-related reaction decreases following each treatment. - Most reactions appear to be due to antibody-antigen reactions prompting cytokine release.
- Information about cross-reactivity is lacking.

# Biosimilars
- Biosimilars are currently available for bevacizumab, trastuzumab, and rituximab.
- For a drug to be called a biosimilar, the manufacturer must provide Health Canada with information to show that the biosimilar is highly similar to the reference biologic drug, and that there are no clinically meaningful differences in terms of safety and efficacy. 78 Therefore, clinicians should expect to see the same rate of acute infusion-related adverse events in biosimilars that they would expect to see in the biologic drug. - Despite reported safety profiles and similar rates of adverse events, clinicians should be vigilant when switching patients who have already been treated with an originator drug.

# Management of Acute Infusion-Related Adverse Events

# Preparation
- All healthcare professionals should be trained to understand the risk and recognize the signs and symptoms of an acute infusion-related adverse events.
- Before chemotherapy drugs and monoclonal antibodies are administered, all patients should be asked about their medical history and history of acute infusion-related adverse events. 6
- An updated organizational protocol for the management of acute infusion-related adverse events should be accessible.
- Emergency equipment and medications should be available for immediate use in case of serious, life threatening infusion-related adverse events.

# Use of Premedication
- Premedication can be used to help prevent and/or reduce the severity of acute infusion-related adverse events, although it is less effective in preventing anaphylaxis. 79 - For certain drugs that are associated with a high incidence of acute infusion-related adverse events, prophylaxis with one or more of the following is reported in the literature:
- H1 antihistamine (diphenhydramine)
- Glucocorticoid (dexamethasone, hydrocortisone, methylprednisolone) o H2 antihistamine (ranitidine, cimetidine, famotidine)
- Antipyretic (acetaminophen)
- Leukotriene receptor antagonist (montelukast)
- Specific prophylactic regimens that are recommended for individual drugs can be found in Appendix B. Note that these regimens are derived using empirical evidence rather than through randomized trials. 79
Observation 6
- Premedication does not exclude the possibility of an acute infusion-related adverse events.
- Patients should be observed closely during and after their infusion for acute infusion-related adverse events.
- Patients should be educated on a drug's potential to cause an acute infusion-related adverse event and notify healthcare providers promptly about any signs and symptoms.
- Recommended observation periods for certain drugs that are associated with a high incidence of acute infusion-related adverse events can be found in Appendix B.

# General Treatment Recommendations (for more retailed recommendations see Appendix B)
Acute infusion-related adverse events require a rapid response from healthcare professionals. Management of the event is based on the severity of presenting symptoms, but also symptoms as the reaction is monitored and progresses (worsens/resolves). Because acute infusion reactions often unfold and change quickly, grading using CTCAE to document the severity of the reaction, should be reserved until after the reaction has resolved and all of the required treatment for the reaction has been administered. We recommend differentiating treatment as follows:
Mild to moderate reactions (no features suggestive of anaphylaxis). If the reaction is mild or moderate without features suggestive of anaphylaxis, interrupt or slow the rate of infusion (generally by 50%) and manage symptoms as appropriate. Upon symptom resolution, restart at reduced rate or slowly increase infusion from 50% as tolerated by the patient. Assess vitals, body systems for symptoms of further reaction, and level of consciousness often.
Severe reactions: If the reaction is severe, interrupt therapy and assess for features of anaphylaxis. If the patient fulfills any of the criteria for anaphylaxis (Table 2) refer to Alberta Health Services' policy for Anaphylaxis Management: Administration of Intramuscular Epinephrine. 63 If vital symptoms were affected, permanently discontinue therapy.
If anaphylaxis criteria are not met (i.e. vital signs were not affected), manage symptoms as appropriate. Upon symptom resolution, the infusion may be reinitiated at no more than 50% of the rate at which the reaction occurred. If no further infusion-related symptoms occur, infusion rate escalation may resume at the increments and intervals as appropriate for the treatment cycle dose. Assess vitals and level of consciousness often.
Note: Some drugs should be discontinued immediately if a severe infusion-related adverse event, including:
- Alemtuzumab - Atezolizumab - Cetuximab - Pembrolizumab - Ramucirumab
Diagnostic tools. Serum, plasma, and urine obtained during or shortly after an acute infusion-related adverse events can support the clinical diagnosis of anaphylaxis. While assays for mediators released during anaphylaxis such as tryptase (serum/plasma) and histamine (plasma, urine) are commercially available, they are not routinely recommended in practice because these tests are not universally available, not performed in real time (i.e. emergency situations), and normal levels do not exclude the possibility of anaphylaxis. 6,80,81 Re-start/Re-challenge: 6 No re-start/rechallenge should be undertaken for patients with suspected or confirmed anaphylaxis. The severity and nature of the acute infusion-related adverse event will determine the decision to restart the treatment once symptoms have been managed (usually at a reduced infusion rate), or to re-challenge (re-expose the patient to the treatment) at a later date (usually with a reduced infusion rate and additional premedications).
Desensitization: Desensitization protocols are potentially dangerous procedures and should only be performed by experienced individuals in an area with immediate access to emergency drugs and equipment 79,82 Successful desensitization has been reported using the following drugs:
- Carboplatin 66, 69, 71, 83-87
- Etoposide 88, 89
- Oxaliplatin  - Pegaspargase 94
- Trastuzumab 83,95 - Infliximab 96
- Rituximab 71 We discourage the use of desensitization protocols unless performed by allergists, or oncologists who have experience with desensitization protocols. 79 

# Acute Infusion-Related Adverse Event Follow-up 6
Following an acute infusion-related adverse event, healthcare professionals should attempt to establish, based on the suspect drug and the characteristics of the event, the steps that could be taken to prevent future episodes. This information, including confirmation that a reaction occurred, should be communicated to patients and family members once any medication affecting cognitive function has worn off.
For drugs that are restarted/rechallenged, patients should be observation for lengths of time that are based on the severity of the reaction and proximity to an emergency facility, with prolonged observation times or hospital admission for patients with severe or refractory symptoms.
If an acute infusion-related adverse event causes significant anxiety and distress for patients who require further treatment, an open discussion about the potential benefits of continuing with the drug and the risk of recurring acute infusion-related adverse events is recommended. Psychological intervention should be provided to alleviate symptoms of anxiety and distress related to a potential infusion-related adverse event with chemotherapy drugs or monoclonal antibodies.
- Gadducci A, Tana R, Teti G, Zanca G, Fanucchi A, Genazzani AR. Analysis of the pattern of hypersensitivity reactions in patients receiving carboplatin retreatment for recurrent ovarian cancer. - Overall incidence of reactions: 1-44%
- Anaphylaxis: <1% (post-marketing, and/or case reports)

# Onset
- Most reactions to platinum derivatives occur after multiple infusions, typically with 7 th -10 th exposure, although reactions may occur after initial infusion
- Reactions usually occur during or shortly after infusion; however, some reports of delayed reactions occurring hrs. later - Anaphylactic-like reactions may occur within mins. of administration

# Risk factors
- Previous exposure to platinum therapy, platinum-free interval >12 months, history of other systemic reactions, cumulative carboplatin dose, past drug allergies, disease severity, histological type, and malignant ascites, patients sensitized to oxaliplatin
- Chance of HSR increased when platinum derivatives given in combination with other chemotherapy and with multiple infusions

# Mechanism
- Exact mechanism of platinum reactions unknown; reactions thought to be mainly caused by type I IgE-mediated or type IV T-cell-mediated hypersensitivity although nonimmune mechanisms may also play a role

# Symptoms
- Mild to moderate reactions consisting of itching or erythema alone, on palms and soles, or facial flushing - Rash, abdominal cramps, facial edema, hypotension, bronchospasm, chest pain, tachycardia, systemic anaphylaxis

# Cross-reactivity
- Cross-sensitivity may occur between platinum derivatives. Substitution of one platinum derivative has been done successfully in some instances, but it has also been unsuccessful and fatal in others

# Pre-medication
- Insufficient evidence that routine pre-medications reduce IRR rates - Based on low level evidence, corticosteroids and H1 antagonists  H2 antagonists may reduce IRR rates for some patients (e.g. gynecological patients with PFI >12 months or history of drug allergy who are receiving carboplatin starting from 7 th cycle) but no optimal pre-medication regimen established

# Extended infusion
- Insufficient evidence that routine prophylaxis with extended infusion reduces IRR rates

# Management
- Mild to moderate HSRs: range of different treatment strategies have been used, including lowering infusion rate and use of pre-medication with corticosteroids and H2 antagonists
- Patients reacting to carboplatin may be able to tolerate oxaliplatin or cisplatin

# Re-challenge
- Successful re-challenges to platinum derivatives have occurred using pre-medication with steroids, antihistamines and various desensitization techniques
- May consider adding montelukast  acetylsalicylic acid. Up to 50% of patients can experience recurrent reactions during re-challenge despite using pre-medications (e.g. corticosteroid and H1/H2 antagonist)
- Following carboplatin reactions, a dose escalation desensitization technique has been used to successfully treat patients with either cisplatin or carboplatin
- Decision to continue therapy with platinum drug after reaction using desensitization or substitution of another platinum derivative should be done carefully and only if benefits outweigh risks - HSR: 6-21%
- Anaphylactic shock: <1% (post-marketing, and/or case reports)

# Onset
- Most HSRs occur with 1 st or 2 nd dose

# Mechanism
- Most HSRs thought to be non-IgE-mediated

# Symptoms
- Minor reactions including flushing or localized skin reactions may occur - Severe HSRs, characterized by generalized rash/erythema, hypotension, bronchospasms, or rare anaphylaxis may occur (may be fatal; has occurred in patients receiving 3-day corticosteroid pre-medication)
- Dyspnea, urticaria, chest or back pain, tachycardia

# Cross-reactivity
- Cross-reactivity may exist between taxanes - Nab-paclitaxel has been well-tolerated in patients with previous histories of taxane HSRs

# Pre-medication
- Pre-medication with oral corticosteroids recommended to decrease incidence and severity of HSRs o Dexamethasone 16 mg/day (8 mg twice daily) orally for 3 days, starting day before docetaxel administration. Dexamethasone 10-20 mg IV can be given if patient forgot to take oral doses o For prostate cancer, when prednisone part of antineoplastic regimen, dexamethasone 8 mg orally administered at 12 hrs., 3 hrs., and 1 hr. prior to docetaxel o Do not discontinue dexamethasone, even in absence of IRR, due to benefits on other adverse effects (e.g. pain and edema)

# Management
- Do not administer to patients with severe hypersensitivity to docetaxel or polysorbate 80 - Observe for hypersensitivity, especially with first 2 infusions - HSRs require immediate discontinuation and administration of appropriate therapy - Patients with history of HSR to paclitaxel may develop hypersensitivity to docetaxel; may be severe or fatal (including anaphylaxis); monitor patients with paclitaxel hypersensitivity closely during initiation of docetaxel Ranitidine 50 mg IV OR famotidine 20 mg IV 30-60 mins. pre-infusion *Oral and IV dexamethasone both effective at reducing overall IRR rates. Some evidence suggests that oral dexamethasone may be more effective for reducing severe reactions; however, adverse effects and compliance remain a concern

# Pre-medication for weekly paclitaxel
To be given 30-60 mins. prior to paclitaxel infusion:
- Patients may be able to undergo rapid drug desensitization to remain on first-line therapy - Do not re-challenge after severe HSRs 

# Other considerations
- Consider discontinuing pre-medications if there was no IRR in 1 st 2 doses - Extended infusion not recommended as primary prophylaxis to reduce IRRs - Insufficient evidence to recommend addition of hydrocortisone 100 mg IV to existing standard pre-medication regimen

# Management
- IRR hypotension, bradycardia, and/or hypertension may occur; frequent monitoring of vital signs recommended, especially during 1 st hr. of infusion - Minor HSRs (flushing, skin reactions, dyspnea, hypotension, or tachycardia) do not require interruption of treatment - If severe hypersensitivity occurs, stop infusion and do not re-challenge

# Re-challenge 
Patients may be able to undergo rapid drug desensitization to remain on first-line therapy 

# Pre-medication
- Administer 1-3 hrs. prior to each infusion. If dexamethasone is the background regimen-specific corticosteroid, the dexamethasone treatment dose will serve as the corticosteroid pre-medication on daratumumab infusion days. Additional background regimen-specific corticosteroids (e.g. prednisone) should NOT be administered on daratumumab infusion days when patients receive dexamethasone (or equivalent) as a premedication.
Corticosteroid:
- Monotherapy: Methylprednisolone 100 mg IV or equivalent intermediate-or long-acting corticosteroid; following the second infusion, the dose may be decreased (e.g. methylprednisolone 60 mg  or equivalent) o Combination therapy: Dexamethasone 20 mg (or equivalent) prior to each daratumumab infusion; administer IV prior to the first infusion; oral administration may be considered prior to subsequent infusions plus - Antipyretic: Oral: Acetaminophen 650 to 1,000 mg plus - Antihistamine: IV or Oral: Diphenhydramine 25 to 50 mg or equivalent 
The following pre-medication regimen has also been reported: o First infusion: Acetaminophen 325 mg orally, diphenhydramine 25 mg orally or IV, dexamethasone 20 mg IV, montelukast 10 mg orally, and famotidine 20 mg IV. o Subsequent infusions: Acetaminophen 325 mg orally, diphenhydramine 25 mg IV, and dexamethasone 20 mg IV 

# Post-medication