Background, physiology, immunology and recommended managements for patients in chemotherapy-induced hypersensitivity reactions. Details both cytotoxic and monoclonal antibody therapies. Delivered at HSE South East Regional Ongology Meeting March 2016.

1. Chemotherapy-induced
Hypersensitivity
reactions
A look at what’s causing them and what to do when they happen
EoinTabb MPSI 18/4/2016

2. Definitions
 Hypersensitivity Reaction: An over-expressed immune response
that results in tissue harm or changes throughout the body in
response to an antigen or foreign substance.
 Anaphylaxis reaction: An acute inflammatory reaction which
results from the release of histamine from mast cells, causing a
hypersensitivity immune response. Can cause SOB, light-
headedness, hypotension, loss of consciousness and can lead to
death.
 Cytokine-release syndrome: Caused by the release of cytokines.
Can cause nausea, headache, tachycardia, hypotension, rash and
SOB. IT ONLY OCCURSWITH MONOCLONALANTIBODIES

3. Allergy
vs.
side effect
 Most side effects in chemotherapy
are predictable such as hair loss,
mucositis, nephrotoxicity,
hepatotoxicity, ototoxicity,
immunosuppression etc. are
caused by the chemotherapy
affecting the non-cancerous
“normal” cells in the body.
 Hypersensitivity reactions are not
common, are unpredictable, and is
unrelated to the known
pharmacologic reactions of the
chemotherapeutic agent.

4. Immunology
Type Mechanism Signs and Symptoms
I Anaphylactic: Immediate
immunoglobulin E (IgE) mediated
reaction
Fever, nausea,
vomiting, flushing, back
pain, angioedema,
rash, dyspnea,
bronchospasm, feelings
of impending doom,
circulatory collapse
II Cytotoxic: Antigen-antibody complexes
activate inflammatory pathways
Hemolysis
III Serum Sickness: Immune complexes
form and deposit in various tissues
Vasculitis, nephritis,
arthritis
IV Delayed Cytotoxic: ActivatedT-Cells
destroy targeted cells
Graft rejection, contact
dermatitis, granuloma
formation, Graft-Vs-
Host Disease
Acute hypersensitivity reactions are mostly IgE mediated

5. IgE
Mechanism of
Action

6. KeyOffenders:
Monoclonal
Antibodies
 Monoclonal antibodies may lead to rare, non-allergic, cytokine
mediated hypersensitivity reactions within the first hours after
infusion.
 Unlike, type 1 mediated reactions, symptoms appear to subside
with each subsequent dose.
 Reactions of cytokine release may be managed through short-
term cessation of drug infusion, administration of H1 antagonists
and restarting the infusion at a slower rate.

7. Key
Offenders:
Monoclonal
Antibodies
Drug Target Type of AB Incidence of
Severe HSR
(%)
Specific Symptoms SPC Pre-meds Rechallenge
Rituximab CD20 Chimeric <10 URT, F, AE, DYSP and ARDS Paracet. + Diphen At 50%
Alemtuzumab CD52 Humanised n.a. BP↓, RIG, F, DYSP, Rash and
Pruritus
Steroid
+ Diphen
+ Parac.
Restart stepwise
dose titration
with adequate
premeds
Bevacizumab VEGF Humanised <1 BP↑, DYSP and RIG None n/a
Cetuximab EGFR Chimeric 3 DYSP, URT, and BP↓ Steroid + Diphen. D/C after severe
reactions;
rechallenge @
50% for mild-to-
mod
Panitunumab EGFR Humanised 0.1 DYSP, F, BP↓ and A None D/C after severe
reactions;
rechallenge @
50% for mild-to-
mod
Trastuzumab HER2 Humanised <1 URT, DYSP,AE and BP↓ Paracet. for 1st
infusions
D/C after A;
rechallenge with
pre-meds after
mild-to-mod
Pertuzumab HER2 Humanised 2 DYSP,ARDS, rash, itch None n/a
Ipilimumab CTLA4 Humanised <1 Prutius, Flushing, rash, DYSP Paracetamol D/C after A;
rechallenge with
pre-meds after
mild-to-mod

8. KeyOffenders:
Cytotoxics

9. KeyOffenders:
PlatinumSalts
 Oxaliplatin: Hypersensitivity reactions are normally mild-to-
moderate in nature with less than 1% of cases being life-
threatening.
 The hypersensitivity reactions are normally associated with
pruritus and erythema on the palms and soles of the feet.
 More severe reactions are associated with urticaria, facial swelling,
and bronchospasm.
 On average associated with the 7th or 8th administration of
oxaliplatin, 5-10 minutes after the start of the infusion.
 The first hypersensitivity reaction to oxaliplatin can be mild but
may become more severe with rechallenge i.e. higher risk with
cumulative dosing.

10. Chemotherapy
induced acral
erythema
(Hand and foot
syndrome)

11. KeyOffenders:
PlatinumSalts
 Carboplatin: Cumulative dose increase in risk of HSR (1% cycle <5,
6.5% cycle 6, 7% cycle 7 and 19.5% cycle 8)
 Most carboplatin associated HSR are mild with symptoms of
itching, localised erythema, facial flushing, abdominal cramps,
diarrhoea, dyspnoea, chest pain, tachycardia, hypo-/hypertension
 As with other IgE-mediated hypersensitivity reactions,
premedication with antihistamines and steroids is insufficient.
 Due to cross-reacting platinum IgE antibodies, there is little value
in substituting Carboplatin for Cisplatin.
 Cisplatin: Most reactions are mild and usually develop at ≥6 cycles

12. KeyOffenders:
Taxanes
 Hypersensitivity reactions to docetaxel and paclitaxel are primarily
due to type 1 reactions to cremophor (polysorbate 80), the
pharmaceutical vehicle for paclitaxel and docetaxel.
 HSRs occur in 30% of patients without premedication decreasing
to <4% with premedication using antihistamines and steroids.
 The reactions are dose- and rate-dependent and most frequently
occur within the first few minutes of the 1st or 2nd infusions.
 Symptoms include dyspnoea, hypotension, bronchospasm,
urticarial and erythematous rash.
 Note: Cremophor-free formulations of albumin-bound paclitaxel
do not cause HSR.
 There is a cross-reactivity rate of 90% between docetaxel and
paclitaxel, therefore, substitution of the two is not recommended.

13. Carbo/Taxol
combo… who’s
causing the
HSR??
 To distinguish the most likely agent causing a hypersensitivity
reaction in this regimen:
1. Carboplatin provokes HSR after several doses, Paclitaxel after
normally 1 or 2
2. Carboplatin-related HSR greatly vary in the timing of
appearance and in severity, paclitaxel-related HSR are more
uniform.
3. Paclitaxel-related HSR quickly resolve after discontinuation of
the drug, carboplatin-related HSR’s normally take hours to
resolve.
4. Premedication is effective with paclitaxel but not with
carboplatin.

14. KeyOffenders:
Others
 PEG-aspariginase: Risk factors: IV admin, interval >1 week
between admins, doses >6000IU/m2/day and previous exposure to
L-aspariginase
 Procarbazine:Type 1,3 and 4 associated reactions with an
incidence of 6% to 18%
 Epipodophyllotoxins:Teniposide/Etoposide. Etoposide HSRs are
again caused by the polysorbate 80 solvent and can be prevented
through adequate premedication and slow infusion rates.

15. CTCAE v4.03
HSR
Classification
Grade
1 2 3 4 5
Transient
flushing or
rash, drug
fever <38⁰C;
intervention
not indicated
Urticaria, drug
fever ≥38⁰C,
and/or
asymptomatic
bronchospasm
Symptomatic
bronchospasm
, with or
without
urticarial;
parenteral
intervention
indicated;
allergy related
oedema/angio
edema;
hypotension
Life-
threatening
anaphylaxis;
urgent
intervention
indicated
Death

16. Grade 2
Intervention
(Draft
Guidelines)
 Grade 2 (Moderate Intervention) – e.g. moderate rash, flushing,
pruritis, mild dyspnoea, chest discomfort, abdominal discomfort,
lower back pain, mild hypotension
 Stop infusion
 Give chlorphenamine 10mg IV push and/or hydrocortisone sodium
succinate 100mg IV push.
 After recovery of symptoms, resume infusion at a rate per
protocol. If no specific direction in chemotherapy protocol consider
resuming at 25% of previous rate for at least five minutes, 50% for
at least 5 minutes, 75% for at least 5 minutes and then full rate if
no reaction.
 Depending on the severity of the reaction, may increase to full rate
at physician’s discretion.
 For future cycles, consider prophylactic premedication as detailed
in Section 3. Initiate infusion at a slower rate (consider 50% of full
rate) as per physician’s orders.

17. Grade 3
Intervention
(Draft
Guidelines)
 Grade 3 or 4 (Severe Intervention) – e.g. one or more of respiratory distress requiring
treatment, angioedema, hypotension requiring therapy.
 Stop infusion and do not restart.
 Activate the Emergency Response System/ NEWS 555 alert (4)
 Give adrenaline 0.5mg* IM stat. Repeat adrenaline at 5 minute intervals twice more as
needed** (i.e. if breathing becomes more laboured or level of unconsciousness decreases).
 *Adrenaline 1:1000 = 1mg/ml, therefore 0.5ml to be injected.
 Adrenaline 1:10000 = 1mg/10ml, therefore 5ml to be injected.
 ** A maximum of 3 doses of adrenaline can be administered.
 Give chlorphenamine 10mg push IV and/or hydrocortisone sodium succinate 100mg IV push per
physician’s orders.
 Oxygen to be supplied if required for dyspnoea.
 Administer NaCl 0.9% to maintain blood pressure (e.g. 300ml/hr) if required to maintain blood
pressure in hypotensive patients.
 Give Salbutamol 5mg by nebuliser to patients with bronchospasm. Add Ipratropium bromide
0.5mg by nebuliser if severe bronchospasm is present.
 Either permanently discontinue the drug that caused the reaction or attempt to rechallenge on
another occasion after prophylactic premedication has been administered. Consideration
should be given to reducing the infusion rate for the rechallenge.

18. HSR Proposed
Audit
Date Patient
Name
MRN Drug
Details
Dose HSR Grading
(1/2/3/4/5)
Description
of Symptoms
Action
Taken
Outcome/
Did
symptoms
resolve?
Follow
up
actions
Details of
rechallenge
(where
applicable)
•AuditTool to determine the best course of action

19. Discussion
 Now for a reasonable discussion