1. 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

2. 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?

3. 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 ?

4. 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

5. 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)

6. 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 2 nd infusion with Carboplatin (8 cycle):cramping, abdominal pain, flushing/pruritus, diffuse urticarial rash, SOB, hypotension, code Skin test to carboplatin : positive

7. 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?

8. 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

9. 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.

10. 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)

11. 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

12. Lee ChW, Matulonis UA, Castells MC; Gyn Onc Nov 2004 Effect of desensitization on skin test reactivity

13. Castells et al. Nature Immunology 2001 Tyrosine Phosphorylation/ Activation of Lyn, Syk, PLC-  Mast Cell activation SHP-1 LILRB4 anti- LILRB4 Mechanisms of rapid desensitizations

14. Rapid desensitization blocks the release of pre-formed mediators Sancho et al EJI 2011 Desensitization to DNP-HSA Desensitization to OVA

15. Desensitization impairs calcium influx and is specific Sancho et al EJI 2011 in press Sancho et al EJI 2011 in press Cells desensitized to one antigen (DNP) respond to a challenge with a second antigen (OVA)

16. Antigen/IgE/FceRI complex is not internalized during rapid desensitization Sancho et al. EJI 2011 OVA antigen Cholera toxin

17. 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

18. 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

19. 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

20. Location of desensitizations MICU : first time, high risk In-patient: first time, moderate risk Out-patient: after first desensitization first time low risk

21. Brigham and Women’s Hospital Location of Desensitizations

22. Clinical Symptoms amendable to Rapid Desensitization Castells et al JACI 2008

23. 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

24. 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

25. Desensitization Step at which reactions occurred Castells et al JACI 2008

26. 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

27. 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

28. 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

29. Selected Publications Castells M. Drug Desensitization in Oncology: Chemotherapy Agents and Monoclonal Antibodies. In: Pichler WJ, editor. Drug Hypersensitivity. New York: Karger, 2007 Monoclonal Antibodies. In: Pichler WJ, editor. Drug Hypersensitivity. New York: Karger, 2007 Feldweg AM, Lee CW, Matulonis UA, Castells M. Rapid desensitization for hypersensitivity 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 reactions to paclitaxel and docetaxel: a new standard protocol used in 77 successful treatments. Gyn Onc 2005; 96(3):824. 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 chemotherapy hypersensitivity: Standard protocol effective in 57 patients for 255 courses. Gyn Onc 2005;99:393. 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 and activator of transcription 6-deficient mast cells by suboptimal doses of antigen. Ann Allergy Asthma Immunol 2005; 94(5):575. antigen. Ann Allergy Asthma Immunol 2005; 94(5):575. Castells MC et al. Hypersensitivity Reactions to chemotherapy:Outcomes and Castells MC et al. Hypersensitivity Reactions to chemotherapy:Outcomes and safety of rapid desensitizations in 413 cases J All Clin Immunol 122:574, 2008 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 mediator- Breslow R et al Acetylsalicylic acid and montelukast block mast cell mediator- related symptoms during rapid desensitization Ann All Clin Immunol 2009 related 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

30. BWH DFCI Quality Improvement Award Partners in Excellence Award 2004-2008-2010 Thank you to the Ovations for the Cure Desensitization Program!!!!