Hypersensitivity Reactions

Background

All biologic agents, particularly monoclonal antibodies, or chemotherapies derived from plant- or metal-based materials can cause hypersensitivity reactions (HSRs) or allergic-type reactions. HSRs occur when the immune system identifies an infused or oral agent as an antigen and initiates a complex reaction involving sensitization of T lymphocytes (T cells) and macrophages, production of antibodies, and release of histamine.

Figure 1

• Anaphylactic reactions are caused by the sudden release of mast cell and basophil mediators (granules). The fixation of immunoglobulin E (IgE) to human mast cells and basophils, a process termed sensitization, prepares these cells for antigen-specific activation with subsequent exposure to the antigen. When the reaction is mediated by IgE, anaphylaxis occurs¹
• If the reaction is not IgE mediated, it is termed anaphylactoid, occurs because of partial hypersensitivity, and is less life threatening¹

The clinical features of HSR can be categorized as

• HSR may be manifested by a macular, erythematous skin rash, hives, nausea, fever or chills, or dizziness, or it may present emergently with full anaphylaxis²
  HSR reactions with monoclonal antibodies, referred to as cytokine-release syndrome, typically occur with the first infusion, in comparison to platinum compounds, reactions to which often occur after the sixth infusion³
• HSR reactions can be biphasic, with symptoms returning several hours after the original presentation; therefore, an observation period of 4 to 6 hours is recommended for mild to moderate reactions; for serious reactions, a prolonged observation or hospitalization may be necessary⁴

Data based on information from package inserts.

Hypersensitivity With Cetuximab

Cetuximab is an important agent in the armamentarium of drugs used in the treatment of metastatic CRC, and in the clinical trials, the incidence of severe infusion reactions was approximately 3%. However, anecdotal reports of much higher infusion reaction rates in specific parts of the United States persisted, and in 2007, O’Neil and colleagues¹⁴ reviewed data reporting a 22% rate of severe infusion reactions in Tennessee and North Carolina. The authors noted that a history of prior allergy was a strong predictor of HSR in their patient population.

Chung et al further studied the connection between cetuximab infusion reactions and specific areas of the United States.¹⁵ They analyzed serum samples for IgE antibodies against cetuximab from 4 groups: 76 case subjects treated with cetuximab in centers predominantly in Tennessee, Arkansas, and North Carolina; 72 control subjects in Tennessee; 49 control subjects with cancer in northern California; and 341 female control subjects in Boston.¹⁵  The results showed that of the 76 cetuximab-treated patients, 25 had a drug-related HSR. IgE antibodies against cetuximab were found in pretreatment samples from 17 of these patients; only 1 of the remaining 51 subjects (who had no HSR) had such antibodies (P < .001). IgE antibodies against cetuximab were found in 20.8% of the control subjects from Tennessee, 6.1% of the patients from northern California, and 0.6% of the subjects from Boston. Interestingly, the IgE antibodies were specific for an oligosaccharide, galactose-a-1,3,-galactose, which is part of the Fab portion of the cetuximab monoclonal antibody structure. These data show that in most of the subjects with a cetuximab-associated HSR, the IgE antibodies were already present in the serum before therapy.¹⁵

An alternative to cetuximab could be the fully human monoclonal antibody, panitumumab.¹¹ This agent has had no reports of fatal infusion reaction, although recently a report of fatal angioedema occurred in an elderly patient.¹⁴ Oncology nurses caring for patients residing in areas where severe infusion reactions are more prevalent should be aware of the potential for a reaction and assess patients accordingly for their allergy history.¹⁶ In addition, the cetuximab manufacturer is currently working on a serum blood test to identify sensitive patients up front, before drug administration.

Effect of HSRs on Staff and Hospital Resources

There is little published research on the responses of oncology nurses when patients experience an HSR or infusion reaction. However, a paper published in the Journal of Infusion Nursing in 2007 describes the responses of oncology nurses surveyed at the 2005 annual meeting of the Oncology Nursing Society (ONS). Because infusion reactions may be fatal, it is not surprising that oncology nurses are frightened of having patients experience a significant reaction.¹⁷ Over half of the respondents stated that infusion reactions were draining and frightening; 88% of outpatient and 62% of inpatient nurses believed that reactions were frightening to other patients, given the communal outpatient setting, where the patient and staff responses are within view of others.
Scwartzberg¹⁸ et al conducted a retrospective chart review of monoclonal antibodies and severe infusion reactions, noting that most reactions occur during the first cycle of therapy and that many of the patients experiencing a significant reaction (22%) require hospitalization for care related to the event, adding considerable cost. Although most of the reactions were in patients receiving rituximab and cetuximab, 5 of the study patients did receive bevacizumab, a commonly used monoclonal antibody for the treatment of metastatic CRC.

Monitoring of patients experiencing even a mild infusion reaction can increase the time and resource expenditure.¹⁹

Management of Anaphylaxis

Mild to moderate infusion reactions to monoclonal antibodies are often managed by altering the infusion to a slower rate; oncology nurses are well versed in the management of these reactions (Vectibix [panitumumab] prescribing information¹¹; Erbitux [cetuximab] prescribing information).⁷ However, anaphylactic reactions require a swift response to prevent escalation to life-threatening conditions, such as airway obstruction or vascular collapse. Patients who express feelings of impending doom or begin to develop respiratory distress, urticaria, or erythema should receive emergent management of their symptoms. Per general guidelines, first-line treatment is epinephrine given intramuscularly (0.2 to maximum 0.5 mL aqueous epinephrine 1:1000).^1,2 Subsequent management of HSRs should follow your institution’s protocol; a suggested algorithm is provided in Figure 1. An anaphylaxis kit should be kept in the infusion room at all times and should have the following components^1,2:

• 2 automated delivery devices with epinephrine 1:1,000 (EpiPen, TwinJect)
• 1 L normal saline solution for infusion
• 1 intravenous (IV) tubing set
• 1 IV start kit
• 1 20-mg vial dexamethasone
• 1 50-mg vial diphenhydramine
• 1 50-mg vial ranitidine

Rechallenge may be appropriate in some case, but the guidelines for rechallenging patients are very case specific.³ For patients who experience a severe infusion reaction with cetuximab, a rechallenge is not recommended. In several case reports in the literature, patients have successfully received panitumumab in place of cetuximab once retreatment with cetuximab was not appropriate; however, more data are needed to definitively recommend this approach.²⁰
Premedications are commonly used to prevent reactions with taxanes and are frequently used with the monoclonal antibodies as discussed above, but this approach has not been very successful with platinum agents.²¹ Although skin testing has been done on patients receiving later treatment with oxaliplatin (as these reactions are typically delayed), this is not standard practice in the community. Oncology nurses treating patients with subsequent doses of oxaliplatin should anticipate possible HSR with this agent. Because oxaliplatin is such an important part of treatment for CRC, management of HSR is crucial for this patient population. One published paper described a preventive strategy against allergic reactions for FOLFOX4 patients, using a primary and secondary prevention regimen with premedications.²²

Table 2. Premedication for Prevention of HSRs

Prevention Strategy

All oxaliplatin-treated patients received the “primary prevention regimen”

• Patients who showed grade 1 or 2 allergic reactions despite primary prevention then received the “secondary prevention regimen.” Patients with grade 3 or 4 reactions discontinued therapy
• Patients who showed allergic reactions despite secondary prevention discontinued treatment

The study results show that the preventive strategy was safe and effective, assisting patients to continue their therapy; of 272 patients, 17.6% developed allergic reactions, which occurred after a median of 9 cycles. Thirty patients underwent retreatment with the secondary prevention regimen, and 63.3% showed no reactions during at least 2 cycles; most were treated for 4 months longer than those who did not respond to secondary prevention.22,23 The report of a 10-year experience with oxaliplatin-associated HSRs concluded that their incidence is underestimated and they are a serious problem in patients who have been extensively re-treated. The authors caution that in the majority of patients, drug discontinuation may be unnecessary, but with a severe reaction, oxaliplatin retreatment should be considered only in patients who can tolerate the reaction and derive clinical benefit from therapy.²³ Although desensitization has been used in select patients requiring further therapy with chemotherapeutic agents such as oxaliplatin, this approach is time consuming and not considered standard for the community.²⁴

HSRs can occur with any agent; some agents used in the treatment of patients with CRC have higher risks. Oncology nurses should be aware of the possibility of HSR and identify patients at increased risk. Oncology nurses should be comfortable with the protocol for management of severe HSR; mock HSR drills can help familiarize staff with the rapid response needed to manage these reactions.¹⁶ A patient experiencing an anaphylactic reaction should be transferred to an emergency department for continued reaction management.¹

Assessment Tools

Table 3. Common Terminology Criteria (version 4.02) of the National Cancer Institute

Data from National Cancer Institute Cancer Therapy Evaluation Program.²⁵

Patient Care Management Protocols or Algorithms

Figure 2. Management of hypersensitivity reaction (HSR). Note: Individual institutions may have HSR protocols in place. Pharmacologic interventions should be based on individual institutional protocols.


Data from Leibermann et al1 and Zanotti and Markman.²

References

1. Lieberman P, Kemp SF, Oppenheimer J, et al. The diagnosis and management of anaphylaxis: an updated practice parameter. J Allergy Clin Immunol. 2005;115:S483-S523.
2. Zanotti KM, Markman M. Prevention and management of antineoplastic-induced hypersensitivity reactions. Drug Saf. 2001;24:767-779.
3. Chung CH. Managing premedications and the risk for reactions to infusional monoclonal antibody therapy. Oncologist. 2008;13:725-732.
4. Gleich GJ, Leiferman KM. Anaphylaxis: implications of monoclonal antibody use in oncology. Oncology. 23(suppl):7-13.
5. Eloxatin (oxaliplatin) full prescribing information. http://products.sanofi-aventis.us/eloxatin/eloxatin.html. Accessed February 4, 2010.
6. Avastin (bevacizumab) full prescribing information. http://www.gene.com/gene/products/information/oncology/avastin/insert.jsp.  Accessed February 4 2010.
7. Erbitux (cetuximab) full prescribing information.  http://packageinserts.bms.com/pi/pi_erbitux.pdf. Accessed February 4, 2010.
8. Meyer L, Zuberbier T, Worm M, et al. Hypersensitivity reactions to oxaliplatin: cross-reactivity to carboplatin and the introduction of a desensitization schedule. J Clin Oncol. 2002;20:1146-1147.
9. Bonosky K, Miller R. Hypersensitivity reactions to oxaliplatin: what nurses need to know. Clin J Oncol Nurs. 2005;9:325-330.
10. Thomas M. Cetuximab: adverse event profile and recommendations for toxicity management. Clin J Oncol Nurs. 2005;9:332-338.
11. Vectibix (panitumumab) full prescribing information. http://www.vectibix.com/pdfs/misc/vectibix_pi.pdf. Accessed February 4, 2010.
12. Camptosar (irinotecan) full prescribing information. http://www.pfizer.com/files/products/uspi_camptosar.pdf. Accessed February 4, 2010.
13. Fluorouracil full prescribing information.http://www.parentarx.com/files/prodfiles/5-FU%20PI%20Feb2010.pdf.  Accessed February 4, 2010.
14. O’Neil BH, Allen R, Spigel DR, et al. High incidence of cetuximab-related infusion reactions in Tennessee and North Carolina and the association with atopic history. J Clin Oncol. 2007;25:3644-3648.
15. Chung CH, Mirakhur B, Chang E, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-a-1,3-galactose. N Engl J Med. 2008;358:1109-1117.
16. Viale PH. Management of hypersensitivity reactions: a nursing perspective. Oncology. 23:(suppl):26-30.
17. Colwell HH, Mathias SD, Ngo NH, et al. The impact of infusion reactions on oncology patients and clinicians in the inpatient and outpatient practice settings: oncology nurses’ perspectives. J Infus Nurs. 2007;30:153-160.
18. Schwartzberg LS, Stepanski EJ, Fortner BV, et al. Retrospective chart review of severe infusion reactions with rituximab, cetuximab, and bevacizumab in community oncology practices: assessment of clinical consequences. Support Care Cancer. 2008;16:393-398.
19. Fortner B, Viale PH. Health economic analysis of the burden of infusion reactions on patients, caregivers, and providers. Oncology. 23(suppl):31-36.
20. Langerak A, River G, Mitchell E, et al. Panitumumab monotherapy in patients with metastatic colorectal cancer and cetuximab infusion reactions: a series of four case reports. Clin Colorectal Cancer. 2009;8:49-54.
21. Markman M, Kennedy A, Webster KM, et al. Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol 1999;17:1141-1145.
22. Suenaga M, Mizumuma N, Shinozaki E, et al. Management of allergic reactions to oxaliplatin in colorectal cancer patients. J Supp Oncol. 2008;6:373-378.
23. Polyzos A, Tsavaris N, Gogas H, et al. Clinical features of hypersensitivity reactions to oxaliplatin: a 10 year experience. Oncology. 2009;76:36-41.
24. Nozawa H, Muto Y, Yamada Y. Desensitization to oxaliplatin with two stages of premedication in a patient with metastatic rectal cancer. Clin Ther. 2008; 30:1160-1165.
25. National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v4.02 (page 26). http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.02_2009-09-15_QuickReference_8.5x11.pdf  Accessed February 15, 2010.

Key Definitions

anaphylactic reactions—unpredictable, immediate systemic reaction within seconds to minutes following administration of a foreign protein (allergen), resulting in a medical emergency to prevent respiratory or cardiac failure. Sometimes referred to as a type 1 reaction
basophils—bone marrow–derived granulocytes that respond to allergic reactions and release mediators
biologic agents—agents made from a living organism or its products and used in the prevention, diagnosis, or treatment of cancer and other diseases. These agents include antibodies, interleukins, and vaccines 
histamine—a short-lived vasodilator producing smooth muscle spasm in the respiratory and gastrointestinal tract, increased vascular permeability, and stimulation of nerve endings leading to flushing, urticaria, pruritus, bronchospasm, abdominal cramping, capillary-leakage, and myocardial dysfunction
immunoglobulin E (IgE)—an immunoglobulin that includes antibodies produced by B lymphocytes that attack and engage the allergens (ie, chemotherapy agents,) causing the mast cells to sensitize to the allergen. Future exposure of the allergen to sensitized mast cells causes the mast cells to release granules of mediators
mast cells—cells that line body surfaces and alert the immune system when a reaction is occurring. They release mediator granules (degranulation), one of which is histamine 
mediator—a substance or structure that mediates or acts as an intermediary to a specific physiologic response
monoclonal antibodies—biologic proteins that can locate and bind to tumor cells;  each is made to find 1 substance. There are 4 types: murine (mouse), chimeric (mouse and human), humanized (small part mouse fused with human), and fully human.

Video credit

Pamela Hallquist Viale, RN, MS, CS, ANP, AOCNP®, is a member of the www.manageCRC.com Advisory Panel and an oncology nurse practitioner, consultant and assistant clinical professor in the Department of Physiological Nursing at the University of California San Francisco (UCSF).
Poster 3645 presented at the 2009 Oncology Nursing Society Congress in San Antonio, TX. Infusion Reactions Associated with Monoclonal Antibodies: Issues for Oncology Nurses. Oncol Nurs Forum. 2009;36:5. http://www.ons.org/publications/journals/ONF/documents/PDFs/34thCongressAbstracts.pdf   nterviewed by
Carolyn Grande, MSN, CRNP, AOCNP^®, an oncology nurse practitioner at the Abramson Cancer Center at the Hospital of the University of Pennsylvania and a member of the www.manageCRC.com Advisory Panel.