understanding and managing pcn/cephalosporin

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


▪ 2. Solid diagnostic tools: biomarkers

▪ 3. Delabeling strategies


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




▪ 2. Solid diagnostic tools



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




▪ 2. Solid diagnostic tools



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

understanding and managing pcn/cephalosporin

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