Download New Biologic Drugs: Evaluation and Treatment of Hypersensitivity

Drug Hypersensitivity to Chemotherapy
in the XXI Century
The role of Rapid Desensitization
Mariana Castells, M.D., Ph.D.
Associate Professor in Medicine
Allergy and Clinical Immunology Training Program Director
Director, Adverse Drug Reactions and Desensitization Program
email message dated September 29. 2011 after video
conference on Desensitizations attended by allergists,
oncologists and other specialists
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69 yo f Oxaliplatin hypersensitivity: after 5 exposures:
severe flushing, back pain and hypotension
unresponsive to increased pre-medications
Desensitization Protocol Oncologist
Patient with hypotension, flushing for several minutes
before infusion is stopped and patient treated
What should I do?
Can I desensitize the patient?
Does the patient need a skin test?
What are the risks factors and potential outcomes for
the patient?
Desensitization Algorithm
• Is this the first exposure?
• What is the nature and severity of the
reaction?
• Is skin testing helpful?
• What are the risks factors for the patient?
• Is rapid desensitization indicated?
• What protocol should be used?
• What outcomes should be expected ?
Complex Allergies
• Cancer patients survive longer and are exposed to
multiple chemotherapy treatments
• Patients with chronic inflammatory diseases (RA, IBD,
Psoriasis) are repeatedly exposed to new monoclonal
Abs and other biological agents
• Patients with cystic fibrosis survive longer, receive lung
transplants and are exposed to multiple courses of
antibiotics
• Increase in Atopic diseases
Allergy Therapy Mechanisms
I. Classical Immunotherapy
Thr, IgG4
months to years
pollen, dust mites, other allergens
II. Rush Immunotherapy
Syk
weeks to months
hymenoptera venom, specific pollen
III. Rapid desensitizations
hours to days
chemotherapy, antibiotics, monoclonals,
aspirin, foods (peanut, milk, others)
Hypersensitivity Reaction to Carboplatin
Anaphylactic IgE
• 49 year old female with ovarian cancer
• Treated with Taxol and carboplatin x 6 cycles
with no side effects
• Recurrence of cancer, restarted on Taxol and
Carboplatin for 6 more cycles
• 2nd infusion with Carboplatin (8 cycle):cramping,
abdominal pain, flushing/pruritus, diffuse
urticarial rash, SOB, hypotension, code
• Skin test to carboplatin : positive
Incidence of Carboplatin HSR
• patients receiving > 7 cycles of carboplatin
have 27% of HSR, and 50% of those patients
develop moderate to severe symptoms
(anaphylaxis).
Increased pre-medication (steroids) and reinfusion does not prevent HSR reactions.
• Cross-reactivity among platins is high.
Can carboplatin be used if it is first line
therapy?
How to overcome IgE and non-IgE
mediated anaphylactic reactions?
• Avoidance
• Substituting
• Control/Inhibition mast cell/IgE reactions
Rapid Desensitization:
- no substitute or first line therapy
- life-threatening condition
- less efficacy
Definition Corollaries
AAAAI Drug Allergy Practice Parameters 2010
Drug Desensitization: temporary induction of
clinical tolerance.
The long term effect related to drug1/2 life.
Needs to be repeated at each exposure or when
2 1/2 lifes have lapsed (platins, antibiotics,
monoclonals)
Risk for anaphylaxis.
Evolving concepts
• High risk procedure: requires the introduction of a
potentially lethal medication to a highly sensitized patient
• Performed in critically ill patients: survival depends on
administration of a medication to which a patient has a
previous history of a severe adverse reaction
• No alternative medications are available or the
alternatives (second and third line choices)have less
demonstrated therapeutic value than first line treatment
(diminished life expectancy or quality of life)
Current understanding
• It is a temporary phenomenon
• Antigen specific
• Achieved by increasing doubling non-activating
doses
• Can be maintained by continuous administration
• Re-desensitization is needed if 2 half lives of the
medication have spanned
• Can only be done by trained allergists
Effect of desensitization on skin test reactivity
Lee ChW, Matulonis UA, Castells MC; Gyn Onc Nov 2004
Mechanisms of rapid desensitizations
antiLILRB4
LILRB4
Tyrosine Phosphorylation/
Activation of Lyn, Syk, PLC-
SHP-1
Mast Cell activation
Castells et al. Nature Immunology 2001
Desensitization to
DNP-HSA
Desensitization to
OVA
Rapid desensitization blocks the release of pre-formed mediators
Sancho et al EJI 2011
Desensitization impairs calcium influx and is specific
Sancho et al EJI 2011 in press
Cells desensitized to one antigen (DNP)
respond to a challenge with a second antigen (OVA)
Antigen/IgE/FceRI complex is not internalized during
rapid desensitization
Sancho et al. EJI 2011
OVA antigen
Cholera toxin
Who is a candidate for
Rapid Desensitization?
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No age limitations
Informed consent
Type I hypersensitivity reaction ( anaphylaxis)
Positive skin test : platins, taxenes, MoAbs, antibiotics
Negative skin test: MoAbs, taxenes
No skin test available: adriamycin and other vessicants
Exclusion criteria:
• Type III or Type IV reactions (slow desensitization)
• Stevens Johnson Syndrome/TEN
• DRESS/ eosinophilia reactions
• ACE-induced angioedema
Evaluation of patients for desensitization to chemotherapy including MoAbs
Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment.
Brennan et al. J. Allergy Clin. Immunol. 2009; 124:1259-66
Risk Stratification
Low/Moderate Risk
- FEV1 > 1.5 L
- No cardiac history
- Moderate/Mild reaction: skin, GI, respiratory, neuromuscular
1 or 2 organs
No changes in Vital Signs
High Risk
- FEV1 < 1.5 L
- Cardiac Disease w/wo beta blockade
- Severe reaction : anaphylaxis/intubation
Changes in vitals signs: BP, O2
Location of desensitizations
MICU :
first time, high risk
In-patient:
first time, moderate risk
Out-patient:
after first desensitization
first time low risk
Brigham and Women’s Hospital Location
of Desensitizations
Clinical Symptoms amendable to Rapid
Desensitization
100
Cutaneous
Cardiovascular
Respiratory
Throat Tightness
Gastrointestinal
Neurological/Muscular
90
Percentage of Patients (%)
80
70
60
50
40
30
20
10
0
Carboplatin
Paclitaxel
Doxorubicin/Adriamycin
Rituximab
Chemotherapeutic Agents
Castells et al JACI 2008
What protocol should be used?
BWH Standard Protocol for Rapid Desensitization
Full Dose
Solution 1
Solution 2
Solution 3
Feldweg et al 2004; Lee et al 2005; Castells et al 2008;Brennan et al
2009
500.0 mg
250 cc of
250 cc of
250 cc of
0.020 mg/ml
0.200 mg/ml
1.984 mg/ml
total mg to be injected
in each bottle
5.000
50.000
496.065
*note to pharmacy* the total mg injected is more than the final dose
because solutions 1 and 2 are not completely infused
Ste p
1
2
3
4
5
6
7
8
9
10
11
12
Solution
1
1
1
1
2
2
2
2
3
3
3
3
Ra te (cc/h) Tim e (m in) Adm iniste re d dose (m
Cum
g) ula tive dose (m g)
2
15
0.0100
0.0100
5
15
0.0250
0.0350
10
15
0.0500
0.0850
20
15
0.1000
0.1850
5
15
0.2500
0.4350
10
15
0.5000
0.9350
20
15
1.0000
1.9350
40
15
2.0000
3.9350
10
15
4.9607
8.8957
20
15
9.9213
18.8170
40
15
19.8426
38.6596
75
186
461.3405
500.0000
----------------------------------------Total time =
351
minutes
Safety and Effectiveness
99% of patients completed desensitization protocol at BWH in 2007-2010
over 2500 cases chemotherapy
over 300 cases monoclonals
over 100 cases antibiotics
No Deaths
Brennan et al 2009, Legere et al 2009, Castells et al. JACI , 2008
1 case of failed oxaliplatin desensitization:
previous mantel radiation for Hogkin lymphoma with FVC 1.5 L
8th oxaliplatin exposures : O2 desaturation 80%, intubation, no rash,
Skin Test Pos at 0.3mg/ml
Tryptase : 11ng/ml
12 step desensitization : step 8 SOB, desaturation , intubation
Desensitization Step at which reactions occurred
Castells et al JACI 2008
100
90
80
No. of Reactions
70
60
50
40
30
20
10
0
1
2
3
4
5
6
7
Step of Desensitization Protocol
8
9
10
11
12
Acetylsalicylic acid and montelukast block mast
cell mediator–related symptoms during
rapid desensitization
Rebecca G. Breslow, MD*; Joana Caiado, MD*†; and Mariana C. Castells, MD, PhD*
2009
Safety of Rapid Desensitizations 413 cases
Castells et al. JACI 2008
Mild Reaction: 27%
(111/413)
No Reaction: 67%
(278/413)
Severe Reaction: 6%
(24/413)
94 % of cases with mild o no reactions
Desensitization Algorythm
• Is this the first exposure? YES/NO
• What is the nature and severity of the
reaction? Type I Grade 1 to 3/Anaphylaxis
• Is skin testing helpful? YES/NO
• What are the risks factors for the patient? H/L
• Is rapid desensitization indicated? YES
• What protocol to used? 12-16 STEPS BWH
• What outcomes should be expected ?
Improved QOL, Increased life expectancy
Selected Publications
Castells M. Drug Desensitization in Oncology: Chemotherapy Agents and
Monoclonal Antibodies. In: Pichler WJ, editor. Drug Hypersensitivity. New York: Karger, 2007
Feldweg AM, Lee CW, Matulonis UA, Castells M. Rapid desensitization for hypersensitivity
reactions to paclitaxel and docetaxel: a new standard protocol used in 77 successful
treatments. Gyn Onc 2005; 96(3):824.
Lee CW, Matulonis UA, Castells MC. Rapid inpatient/outpatient desensitization for
chemotherapy hypersensitivity: Standard protocol effective in 57 patients for
255 courses. Gyn Onc 2005;99:393.
Morales AR, Shah N, Castells M. Antigen-IgE desensitization in signal transducer
and activator of transcription 6-deficient mast cells by suboptimal doses of
antigen. Ann Allergy Asthma Immunol 2005; 94(5):575.
Castells MC et al. Hypersensitivity Reactions to chemotherapy:Outcomes and
safety of rapid desensitizations in 413 cases J All Clin Immunol 122:574, 2008
Breslow R et al Acetylsalicylic acid and montelukast block mast cell mediatorrelated symptoms during rapid desensitization Ann All Clin Immunol 2009
Legere HJ III et al A safe protocol for rapid desensitization in
patients with cystic fibrosis and antibiotic hypersensitivity Journal of
Cystic Fibrosis 8 (2009) 418-424
Brennan et al Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients,
from evaluation to treatment J. Allergy Clin. Immunol. 2009; 124:1259-66
Castells Editor Springer Humana Press Anaphylaxis and Hypersensitivity Reactions 2011
Sancho et al. Rapid IgE desensitization is antigen specific and impairs early and late mast cell responses
targeting FcRI internalization EJI 2011
BWH DFCI Quality Improvement Award
Partners in Excellence Award
2004-2008-2010
Thank you to the Ovations for the Cure Desensitization Program!!!!