Drug Hypersensitivity to Chemotherapyin 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

• 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 CarboplatinAnaphylactic 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 re-infusion 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

Lee ChW, Matulonis UA, Castells MC; Gyn Onc Nov 2004

Effect of desensitization on skin test reactivity

Castells et al. Nature Immunology 2001

Tyrosine Phosphorylation/Activation of Lyn, Syk, PLC-

Mast Cell activationSHP-1

LILRB4

anti-LILRB4

Mechanisms of rapid desensitizationsMechanisms of rapid desensitizations

Rapid desensitization blocks the release of pre-formed mediators Sancho et al EJI 2011

Desensitization to DNP-HSA

Desensitization to OVA

Desensitization impairs calcium influx and is specificDesensitization impairs calcium influx and is specific Sancho et al EJI 2011 in pressSancho 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 antigenCholera toxin

Who is a candidate for Rapid Desensitization?

• 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

Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment. Brennan et al. J. Allergy Clin. Immunol. 2009; 124:1259-66

Evaluation of patients for desensitization to chemotherapy including MoAbs

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

Castells et al JACI 2008

What protocol should be used?

BWH Standard Protocol for Rapid Desensitization Feldweg et al 2004; Lee et al 2005; Castells et al 2008;Brennan et al

2009

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

Acetylsalicylic acid and montelukast block mastcell mediator–related symptoms during

rapid desensitizationRebecca G. Breslow, MD*; Joana Caiado, MD*†; and Mariana C. Castells, MD, PhD* 2009

Safety of Rapid Desensitizations 413 cases Castells et al. JACI 2008

No Reaction: 67%(278/413)

Severe Reaction: 6%(24/413)

Mild Reaction: 27%(111/413)

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. Castells M. Drug Desensitization in Oncology: Chemotherapy Agents and Drug Desensitization in Oncology: Chemotherapy Agents and Monoclonal AntibodiesMonoclonal Antibodies. In: Pichler WJ, editor. Drug Hypersensitivity. New York: Karger, 2007 . In: Pichler WJ, editor. Drug Hypersensitivity. New York: Karger, 2007 Feldweg AM, Lee CW, Matulonis UA, Castells M. Feldweg AM, Lee CW, Matulonis UA, Castells M. Rapid desensitization for hypersensitivityRapid desensitization for hypersensitivity reactions to paclitaxel and docetaxel: a new standard protocol used in 77 successful reactions to paclitaxel and docetaxel: a new standard protocol used in 77 successful treatmentstreatments. Gyn Onc 2005; 96(3):824.. Gyn Onc 2005; 96(3):824.

Lee CW, Matulonis UA, Castells MC. Lee CW, Matulonis UA, Castells MC. Rapid inpatient/outpatient desensitization for Rapid inpatient/outpatient desensitization for chemotherapy hypersensitivity: Standard protocol effective in 57 patients for chemotherapy hypersensitivity: Standard protocol effective in 57 patients for 255 courses.255 courses. Gyn Onc 2005;99:393. Gyn Onc 2005;99:393.

Morales AR, Shah N, Castells M. Morales AR, Shah N, Castells M. Antigen-IgE desensitization in signal transducer Antigen-IgE desensitization in signal transducer and activator of transcription 6-deficient mast cells by suboptimal doses of and activator of transcription 6-deficient mast cells by suboptimal doses of antigenantigen. Ann Allergy Asthma Immunol 2005; 94(5):575.. Ann Allergy Asthma Immunol 2005; 94(5):575.

Castells MC et al. Castells MC et al. Hypersensitivity Reactions to chemotherapy:Outcomes and Hypersensitivity Reactions to chemotherapy:Outcomes and safety of rapid desensitizations in 413 casessafety of rapid desensitizations in 413 cases J All Clin Immunol 122:574, 2008 J All Clin Immunol 122:574, 2008

Breslow R et al Breslow R et al Acetylsalicylic acid and montelukast block mast cell mediator-Acetylsalicylic acid and montelukast block mast cell mediator- related symptoms during rapid desensitizationrelated symptoms during rapid desensitization Ann All Clin Immunol 2009 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 FcRI 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!!!!