Chemotherapy Desensitizations Mariana Castells, M.D, Ph.D Professor of Medicine, Harvard Medical School Director of Drug Hypersensitivity and Desensitization Center Brigham and Women’s Hospital NESA 2019 March 29, 2019
Chemotherapy Desensitizations
Mariana Castells, M.D, Ph.DProfessor of Medicine, Harvard Medical School
Director of Drug Hypersensitivity and Desensitization Center
Brigham and Women’s Hospital
NESA 2019
March 29, 2019
Objectives
▪ To understand the endotype and phentoypes
of drug hypersensitivity
▪ To review indications and outcomes of drug
desensitization
▪ To learn the role of tryptase, IL-6, and
biologicals in drug desensitization
Financial Relationships
Commercial Interest(s) Nature of Relationship
Sanofi Consultant
Genentech PI, Xolair Study
Merck ADR Board
Lytix Biopharma Consultant
Contrafect Consultant
Arete Discoveries Consultant
Bentham Science Consultant
Insys Consultant
Annexon Biosciences Consultant
Therma Consultant
UCB Biopharma SPRL Consultant
Q&A45 year old female with recurrent ovarian cancer, acute
hypertension and desaturation during her 6th carboplatin
exposure. Her tryptase is 52 ng/µl.
What is the best approach ____________________
A. Avoid carboplatin
B. Substitute with cisplatin
C. Increase premedication
D. Evaluate with stratification and if indicated desensitize
Drug Allergy in Precision Medicine
47 FDA approved Monoclonal Antibodies
(50% of pharmaceutical sales)
70 FDA approved by 2020 and revenue 125 billion
(almost 100% pharmaceutical sales)
Catumaxomab
Trifunctional Antibody
Hybrid rat-mouse
Malignant ascitis
Fever, nausea, vomiting
(cytokine storm)
NSAIDS, antiemetics
Precision Medicine in Allergic Diseases PRACTALL Drug Allergy European Academy of Allergy and Clinical Immunology
American Academy of Allergy, Asthma & Immunology Antonella Muraro1, Robert F. Lemanske, Jr.2, Mariana Castells3, Maria J. Torres4, David Khan5, Hans- UweSimon6, Carsten Bindslev-Jensen7, Wesley Burks8,
Lars K. Poulsen9, HughA.Sampson10,MargittaWorm11, Kari C. Nadeau12,13 2017
▪ Drug Allergy Phenotypes
▪ Immediate onset (1-6 hours): hives, angioedema, wheezing, hypotension
▪ Delayed Onset: maculopapular rashes
▪ Drug Allergy Endotype :
▪ Immediate onset (1-6 hours):
▪ IgE, direct Mast Cell/Basophil, COX-1, MRGPRX2 (THIQ motifs,atracuronium),
▪ cytokine storm
▪ Delayed Onset: T cells, Virus, HLA (Host susceptibility/Target exposure)
▪ Biomarkers : ST, sIgE, BAT, Mediators (tryptase, cytokines), Patch Testing, ID delayed
readings, AERD, HLA restricted
Castells JACI 2017Precision Medicine
Drug Hypersensitivity/Anaphylaxis
Personalized/Precision Medicine in Drug Allergy
▪ 1. Clinical and Basic understanding of the mechanisms of reactions
▪ 2. Diagnostic tools
▪ 3. Delabeling strategies : YES/NO
▪ 4. Desensitizations: Sound and evidence based interventions with informed and calculated risks to enhance patient safety when patients needs first line therapy
Hypersensitivity Reaction to Carboplatin
Anaphylactic IgE
▪ 49 yo female ovarian cancer: paclitaxel and carboplatin x 6 cycles (flushed , itchy last cycle) : PHENOTYPE
▪ Recurrence 2 years late , restarted on paclitaxel and carboplatin
▪ 2nd infusion (8 exposure: 3-4g): flushed , itchy
▪ 3th infusion (9 exposure >4g) : cramping, abdominal pain, flushing/pruritus, diffuse urticarial rash
▪ SOB, hypotension, code Epinephrine
▪ Trytpase : 42ng/m BIOMARKER
Skin test to carboplatin : positive 1 mg/ml mast cell/IgE ENDOTYPE
• patients receiving > 7 cycles of carboplatin have 27% of HSR, and 50% of those patients develop moderate to severe symptoms (anaphylaxis).
• BRCA mutation carriers have 10 fold increase in hypersensitivity (Moon 2013)
• Increased pre-medication (steroids) and re-infusion does not prevent HSR reactions.
• Cross-reactivity among platins is high.
Outcome: discontinue
mogamulizumab
Phenotype
Endotype
Biomarker
Personalized/Precision Medicine
In Drug Allergy Requirements
▪ 1. Clinical and Basic understanding of the mechanisms of reactions
▪ 2. Solid diagnostic tools: biomarkers
▪ 3. Delabeling strategies
▪ 4. Desensitizations: Sound and evidence based interventions with informed and calculated risks to enhance patient safety when patients needs first line therapy
Biomarkers for Chemotherapy and
Monoclonals Skin testing
Sloane JACI In Practice 2016
Expensive
Unavailable
Unmet need:
-vials with 0.5ml
In Vitro Platins Specific IgE
Caiado et al 2013
Patients sensitized to oxaliplatin develop IgE against carboplatin and cisplatin
Basophil Activation Test
Negative Control
Carboplatin
CD 63 CD 203c
Giavina-Bianchi P et al 2014
Biomarkers for Monoclonals
Basophil Activation Test in Pertuzumab AnaphylaxisGonzalez de Olano et al 2016 JACI In Practice
Skin test Prick and ID at 1.6
mg/ml was negative
Positive Basophil Activation Test
Successful Desensitization
Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to
treatment. Brennan et al. J. Allergy Clin. Immunol. 2009; 124:1259-66
Monoclonals Hypersensitivity Evaluation
TryptaseType IV
Specific IgE
BAT
Tryptase: a marker of mast cell activation
39.2
13.9 14.6
6.3
56.2
5.5 50
10
20
30
40
50
60
Initial Reaction Before Desensitization After Desensitization
Reaction during
desensitization
No reaction during
desensitization
Tryptase
Level
Unmet needs:
Test quick turnaround
Systematic Use
Biomarkers
Tryptase and IL-6
Isawbe et al JACI 2018
Personalized/Precision Medicine
In Drug Allergy Requirements
▪ 1. Clinical and Basic understanding of the mechanisms of reactions
▪ 2. Solid diagnostic tools
▪ 3. Delabeling strategies
▪ 4. Desensitizations: Sound and evidence based interventions with informed and calculated risks to enhance patient safety when patients needs first line therapy
Drug Allergy Impacts Quality
▪ Penicillin “allergic” patients/label receive antibiotics:
– For a longer duration
– Longer hospital stays (0.59 day/person)
– More broad-spectrum
• ↑ healthcare-associated infections
– More toxic
• ↑ adverse drug reactions
– Less effective in some clinical circumstances
• ↑ treatment failure
– Significant comorbidities
• Vancomycin-resistant enterococcus
• Clostridium difficile-associated diarrhea Picard M, et al. JACI Practice. 2013;252-257
Solensky R. et al. Ann Allergy Asthma Immunol 2010; 105:259-73
Sade K, et al. Clin Exp Allergy. 2003; 33:501-506
Reddy V., et al. JACI. 2013;131:AB170
23
Antimicrobial Stewardship
Personalized/Precision Medicine
In Drug Allergy Requirements
▪ 1. Clinical and Basic understanding of the mechanisms of reactions
▪ 2. Solid diagnostic tools
▪ 3. Delabeling strategies
▪ 4. Desensitizations: Sound and evidence based interventions with informed and calculated risks to enhance patient safety when patients needs first line therapy
Hypersensitivity Reaction to Carboplatin
Anaphylactic IgE
▪ 49 year old female with ovarian cancer: paclitaxel and carboplatin x 6 cycles (flushed , itchy last cycle)
▪ Recurrence 2 years late , restarted on paclitaxel and carboplatin
▪ 2nd infusion (8 exposure: 3-4g): flushed , itchy
▪ 3th infusion (9 exposure >4g) : cramping, abdominal pain, flushing/pruritus, diffuse urticarial rash, SOB, hypotension, code Epinephrine is administered
▪ Trytpase : 42ng/m
Skin test to carboplatin : positive 1 mg/ml
Candidate for Desensitization
Desensitization Current Understanding
▪ 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
▪ It is a temporary phenomenon
▪ Antigen specific, not IgE depleting, not hapten inhibition nor depletion of mast cell mediators
▪ It is done by repetitive increasing sub-optimal doses (suboptimal concentrations) of the medication involved in the adverse reaction
▪ Once desensitization is complete, the tolerization can be maintained by continuous administration of the medication
Rapidly (hours to days ) inducing a state of temporary tolerance / tolerization to a drug to which a patient had presented a hypersensitivity reaction
AAAAI Drug Hypersensitivity Practice Parameters 2010
ENDA Desensitization Position Paper 2012
Desensitization Type I
(IgE/Mast Cell/Basophil)Desensitization Type IV
(T cells, dendritic cells)
TRYPTASEMRGPRX2
Rapid desensitization
for delayed reactions
Mechanisms for Antigen/IgE desensitizations
Inhibitory
receptorsSub
clinical
mediators
release
Internalization of
antigen/IgE/FceRIa
Syk
degradation
Monomeric/Low
antigen dose
decrease cross-
linking
Rapid desensitization blocks the release of pre-formed mediators
and calcium influx in a specific fashion
Desensitization to DNP-HSA
Sancho Serra et al 2011
Individual doses
Cumulative
doses
In Vitro Mast Cell Model Antigen/IgE desensitization
Influence of fold-increase per stepPicard el all submitted 2018
Influence of starting
concentration/dose
1/100-
1/200
Picard el all submitted 2018
Influence of time interval between steps
2X protocol
Starting at 0.02 AU/ml
Picard el all submitted 2018
Mast cell desensitization aberrantly remodels actinW.X. Ang JCI 2016
Lack of
degranulation
of desensitized
mast cells
Sensitized Activate
dDesensitized Desensitized /Activated
Aberrant Actin
remodeling
Lack of IgE internalization
Principles of IgE Desensitization
1. Occurs at the membrane level
2. Starting dose, the time between the doses, the increments
(X2) are critical to support the inhibitory state
3. It is specific
4. Can be maintained
Lee et al 2004
Sancho Serra et al 2011
Target dose
Dose
Cu
mu
lati
veD
rug
Co
nce
ntr
atio
n
BWH Universal Desensitization Protocols
Intravenous Desensitization
1 bag (4 step)
2 bag (8 step)
3 bag (12 step)
4 bag (16 step)
0 500 1000 1500 2000
H1 anti-histamine
H2 anti-histamine
5LO and Leukotriene R2 blockers
NSAIDS
Steroids
Bronchodilators
Anti-emetics
Musle Relaxants
Opiods
Chemotherapy Premedications
0 50 100 150 200 250 300
H1 anti-histamine
H2 anti-histamine
5LO and Leukotriene R2 blockers
NSAIDS
Steroids
Bronchodilators
Anti-emetics
Musle Relaxants
Opiods
Monoclonals Premedications
Premedications for desensitization
Sloane et al JACI IP 2016
Clinical Symptoms amendable to Rapid Desensitization
Type I hypersensitivity IgE/non IgE
0
10
20
30
40
50
60
70
80
90
100
Carboplatin Paclitaxel Doxorubicin/Adriamycin Rituximab
Chemotherapeutic Agents
Per
cen
tage
of
Pat
ien
ts (
%)
Cutaneous
Cardiovascular
Respiratory
Throat Tightness
Gastrointestinal
Neurological/Muscular
Castells et al JACI 2008
Pain
Candidates for desensitization
• IgE: require repeated exposures
platins, antibiotics, iron, some monoclonals,
taxenes
• Non-IgE: cytokine, mixed, direct mast cell, complement
can occur upon first exposure
Taxenes. Doxorubicin,
Monoclonals : Rituximab
Aspirin
Type IV : antibiotics, chemotherapy (taxenes), monoclonals
Risk Stratification
Low Risk (Out patient) 3 bags 12 steps
- Mild reaction
- Grade 1-2 (skin +/- other organ)
High Risk (MICU) 4 bags 16 steps
- Pulmonary Disease (FEV1<1L)
- Cardiac Disease w/wo beta blockade
- Severe reactio : Grade 3 intubation
/hypotension/O2desaturation
/laryngeal edema/seizures/collapse
Grade Severity Description
1 Mild Symptoms are limited to the skin (eg. flushing) or
involve a single organ system and are mild (eg.
mild back pain)
2 Moderate Symptoms involve at least 2 organ systems (eg.
flushing and dyspnea), but there is no significant
drop in blood pressure or in oxygen saturation
3 Severe Symptoms typically involve at least 2 organ
systems and there is a significant drop in blood
pressure (systolic ≤ 90 mmHg and or syncope)
and/or oxygen saturation (≤ 92%)
A Taxanes Hypersensitivity
Piccard M 2014
Pain
JACI 2016
1st Taxol Desensitization Protocol: 3 bag 12 step + cetrizine, famotidine, ativan , montelukast
End of bag 1, patient had 3/10 throbbing lower back pain treated with ketorolac, benadryl and pepcid. Restarted and completed
2st Taxol Desensitization Protocol: 3 bag 12 step + IVF and ibuprofen
@ 80cc/hr
@
80cc/hr
3st Taxol Desensitization Protocol: 2 bag 8 step
@ 80cc/hr
4st Taxol Desensitization Protocol: 1 bag 4step
@ 80cc/hr
1 and 2 Taxol Challenge Protocol: 1 bag 3step ,
final step run over 1 hr
Returned to Regular Taxol
Infusion
with Premedication
30 min in to step 12, pt with facial flushing, palm of hands red and itchy. Treated with
diphenhydramine , famotidine. 15 min later hives/flush noted on back, neck, abdomen,
arms and legs , cough , chest tight . Benadryl, methylprednisolone, atarax with
improvement of symptoms. Tryptase 15 (Nl 11.4 ng/ml). Infusion completed.
1st Carboplatin Desensitization Protocol: 3 bag 12 step
+ cetrizine, famotidine, ativan, montelukast
@ 80cc/hr
2st Carboplatin Desensitization Protocol: 4 bag 16 step
One into step 16, itchy palms treated with atarax ceterizine. Pt. developed
redness to ear lobes, around nostrils and eyebrows and flat rash area to right
wrist. Treated with famotidine,diphenhydramine Redness to ears, nostrils and
eye brows and rash to right wrist resolved but left palm remained itchy, treated
with ceterizine and Atarax. Tryptase 12 Infusion completed.
@
80cc/hr
3st Carboplatin Desensitization Protocol: 3 bag 12 step+ omalizumab
Step 12 patient developed palmar erythema and mild
pruritus treated with famotadine, hydroxyzine, IV normal
saline at 250 mL/h. Infusion completed. Tryptase 5 ng/ml
@ 80cc/hr
4st Carboplatin Desensitization Protocol: 3 bag 12 step+ omalizumab
@ 80cc/hrStep 12 developed palmar itching and mild palmar
erythema. Treated with ice packs, diphenhydramine,
famotidine. Itching resolved. Infusion completed.
More bags, mores steps, more time
Drugs with Successful Desensitization Protocols
intravenous, oral, subcutaneous, intraperitoneal
▪ Platins: carboplatin, cisplatin , oxaliplatin
▪ Taxenes: paclitaxel, docetaxel, cabazitaxel, Abraxene
▪ Monoclonals :
▪ Rituximab, Trastuzumab, Cituximab, Tocilizumab, Bevacizumab,
Ofatumumab, Alemtuzumab, Pertuzumab
TNFa : ertanercept, adalimumab, infliximab
▪ Antibiotics: beta lactams, cephalosporins, sulfonamides, vancomycin
▪ Enzymes : laronidase
▪ Iron : sodium ferric gluconate
▪ Aspirin
▪ Progesterone : infertility (Foer et al 2016 )
74%
19%
3% 4%
no reaction
Grade I reaction
Grade II reaction
Grade III reaction
72%
19%
5% 4%
Rituximab
85%
11%2% 2%Paclitaxel
68%
24%
4%4%
Carboplatin
A)
B) C) D)
Outcomes of desensitizations
in 370 patients and 2177cases Sloane et al 2016
2016 JACI In Practice
Life
expectancy
Costs
Characteristics of Initial versus Desensitization Reactions
in 104 patients, 526 desensitizations for 16 MonoclonalsIsabwe JACI 2018
Severity Location
Severity in subsequent desensitizations
Proposed new classification and new management recommendations for HSR to mAbs.
Immunogencitiy of mAbs, the proposed underlying mechanisms, endoytpes and biomarkers of mAb HSRs and indications for desensitization.
Isawbe et al JACI 2018
Personalizing drug hypersensitivity and
desensitization
▪ Phenotype, endotype and biomarkers
▪ Drug Specificity : Platins bound to continued desensitization, taxenes
can go back to regular infusions
▪ Risk stratify: Investigate biomarkers, skin testing, tryptase, BAT, sIgE
▪ Choose the right protocol and advance as tolerated (Taxenes,
Doxorubicin, Monoclonals)
▪ Pre-medications based on initial reaction symptoms (montelukast,
aspirin)
▪ Future: anti-IgE
anti-IL-6
Outcomes Desensitizations
▪ Safety is outstanding : thousands of cases with no deaths
▪ Drug efficacy is maintained:
▪ Cancer patients have similar or better life expectancy
▪ Chronic inflammatory diseases patients have
▪ increased quality of life
▪ Cystic Fibrosis patients undergo effective clean ups
▪ Aspirin intolerant patients can smell and decrease
▪ polyp surgeries and steroid usage
▪ Progesterone/estrogen allergic patients can conceive
▪ Costs are not superior to standard treatments
Q&A45 year old female with recurrent ovarian cancer, acute
hypertension and desaturation during her 6th carboplatin
exposure. Her tryptase is 52 ng/µl.
What is the best approach ____________________
A. Avoid carboplatin
B. Substitute with cisplatin
C. Increase premedication
D. Evaluate with stratification and if indicated desensitize
BWH DFCI Quality Improvement Award
Partners in Excellence Award
2004-2008-2012
Nursing, Pharmacy , Medical Specialties,
Allergy/Immunology
BWH Drug Hypersensitivity and Desensitization Center
2018: USA, Portugal, Spain, Greece, Canada, Hawaii, Brazil,
Argentina, Colombia, Chile, Israel, Mexico, Austria, Switzerland,
Germany, France, Italy, Thailand, Singapore, India, Mexico, Peru