= CHEMOTHERAPY REACTIONS = Joana Caiado MAIN TOPICS DIAGNOSIS. Clinical evaluation. In vivo evaluation. In vitro evaluation

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1 1203 Course: Drug Hypersensitivity and Allergy: From Diagnosis To Treatment = CHEMOTHERAPY REACTIONS = Joana Caiado Immunoallergology Department Hospital Santa Maria Lisbon Portugal February 22 nd MAIN TOPICS Virtually all chemotherapeutic agents have the potential to initiate infusion reactions Oncologic patients have higher survival rates more re-exposure to the same chemotherapy agents due to recurrence of the disease Severe Hypersensitivity reactions (HSR) can lead to the suspension of first line treatments Allergic reactions Hypersensitivity reactions Standard infusion reactions DIAGNOSIS Clinical evaluation Description of the reaction Physical examination In vivo evaluation Skin testing In vitro evaluation Immediate analysis (serum tryptase, liver function, circulating immune complexe ) Further investigation (specific IgE) 1

2 CLINICAL EVALUATION Identification of the drug responsible for the reaction Other drugs infusing at the same time or immediately before To quantify previous infusions with the same drug with no HSR Allergic symptoms in previous infusions Drugs taken at home / over the counter Food ingestion before the infusion Evaluation of infectious symptoms CLINICAL EVALUATION Cutaneous symptoms: flushing, itching, urticaria, and/or angioedema (usually of face, eyelids, or lips) Respiratory symptoms: repetitive cough, sudden nasal congestion, shortness of breath, chest tightness, wheeze, sensation of throat closure or choking, and/or change in voice quality (due to laryngeal edema), hypoxia Cardiovascular symptoms: faintness, tachycardia (or less often bradycardia), hypotension, hypertension and/or loss of consciousness Gastrointestinal symptoms: nausea, vomiting, abdominal cramping, and/or diarrhea Neuromuscular symptoms: sense of impending doom, tunnel vision, dizziness, and/or seizure, severe back, chest, pelvic pain Castells MC, Matulonis UA. Infusion reactions to systemic chemotherapy. In UpToDate. Drews RE (Ed). Adkinson NF. Boston MA, 2012 PHYSICAL EXAM General appearance - State of consciousness - Temperature - Signs of respiratory distress / Oxygen saturation - Dysphonia - Chest tightness Arterial Pressure Lookout for hypotension Anaphylactic shock!!! Observation of the skin and mucosae - Oropharynx (Tongue/uvula edema) - Angioedema - Observation and characterization of skin lesions Pulmonary auscultation exclude wheezing 2

3 PHYSICAL EXAM CUTANEOUS LESIONS URTICARIA ANGIOEDEMA PHYSICAL EXAM MACULOPAPULAR RASH DRUG-INDUCED VIRAL PHYSICAL EXAM BLISTERING LESIONS ERYTHEMA MULTIFORME STEVENS-JOHNSON SYNDROME TOXIC EPIDERMAL NECROLYSIS 3

4 SERUM MEDIATORS Serum tryptase - In immediate reactions - Evaluates mast cell degranulation - Blood should be withdrawn from 20 minutes to 2 hours after the reaction Complement / Circulating immune complexes - For the diagnosis of type III reactions Exclusion of other potential causes - Reactive C protein - Viral serologies - Eosinophilia / liver function tests Total IgE and specificige to platins HYPERSENSITIVITY REACTIONS- CLASSIFICATION According to timing Immediate (< 1 hora) Acelerated (> 1 h; < 24h) Delayed (> 24h) According to Severity Adapted from: National Cancer Institute: Cancer Therapy Evaluation Program.Common terminology criteria for adverse events v3.0. Available from: PATIENT ASSESSMENT Castells M. Drug desensitization in Oncology: chemotherapy agents and monoclonal antibodies. In Pichler WJ (Ed). Drug hypersensitivity. 1st ed: Basel: Karger; 2007:

5 COLLABORATION WITH ONCOLOGY When a HSR occurs in Oncology Day Care Unit Call the Allergist Delayed reaction Immediate reaction Suspend and substitute the chemotherapy agent Pre-medication with antihistamine and/or corticosteroids Taxanes / others - Clinical evaluation - Risk assessment Platins/ Monoclonals - Clinical evaluation - Skin testing - Risk assessment No desensitization? Consider Desensitization MOST FREQUENT AGENTS INDUCING HSR PLATINUM SALTS (12-19%) - Cisplatin (5 to 20%) - Carboplatin (9% to 27%) - Oxaliplatin (12% to 25 %) TAXANES (5-45%) - Paclitaxel - Docetaxel 42 % incidence of infusion reactions in children receiving carboplatin for brain tumors PEGYLATED LIPOSOMAL DOXORUBYCIN PODOPHYLLOTOXINS - Etoposide and teniposide MONOCLONAL ANTIBODIES - Trastuzumab - Rituximab - Cetuximab Management and Preparedness for Infusion and Hypersensitivity Reactions. Oncologist 2007;12(5):601-9 IMMEDIATE REACTIONS ALLERGIC HYPERSENSITIVITY Immunologic mechanism identified NON-ALLERGIC HYPERSENSITIVITY Immunologic mechanism unknown Most frequently type I (IgE mediated) Hypothesis - Direct mast cell activation and degranulation? - Complement activation? Requires prior sensitization (usually more than 2 exposures) Reactions on the 1 st or 2 nd exposures Positive skin testing Skin testing persistently negative Diverse clinical presentation Clinical presentation similar to IgE- mediated reactions PLATINS TAXANES 5

6 PLATINUM SALTS Prevent cell division by inhibiting DNA replication good anti-tumor activity in several solid tumors RHS described in platinum refinery workers - identification of specific IgE to platinum salts Cleare MK, et al. Immediate (type I) allergic responses to platinum compounds. Clin Allergy.1976; 6: CISPLATIN: first to be used in the 70s Nephrotoxicity CARBOPLATIN: second-generation platinum salt - Better toxicity profile - Gynecologic malignancies OXALIPLATIN: third-generation platinum derivative - Metastatic colorectal cancer PLATINUM SALTS Classic type I IgE-mediated allergic reactions Require repeated exposures before the onset of the hypersensitivity Frequent presentation: Pruritus, urticaria, bronchospasm, facial swelling, and hypotension Severe anaphylaxis Less frequent presentation: type II reactions (immune-mediated hemolytic anemia or thrombocytopenia) type III reactions (delayed vasculitic urticaria) SKIN TESTING Crucial for the diagnosis of HSR to platins (good predictive value), and to some monoclonal antibodies Dilutions are prepared at the Pharmacy on the day of skin testing Performed by Allergists, two to four weeks after a HSR occurs, and to evaluate cutaneous sensitization even in the absence of a HSR Skin prick test Intradermal 6

7 SKIN TESTING 33x35mm 17x20mm SKIN TESTING Non irritant concentrations Prick Intradermal Carboplatin 10 mg/ml (1:1) 10* or 3 to 5 mg/ml Oxaliplatin 5 mg/ml (1:1) 3 to 5 mg/ml Cisplatin 1 mg/ml (1:1) 1 mg/ml Sensitization is far higher after 6 carboplatin infusions < 1% when less than 5 infusions % more than 6 infusions Leguy -Seguin V at al. Diagnostic and predictive value of skin testing in platinum salt hypersensitivity. J Allergy Clin Immunol 2007;119: Sliesoraitis S, Chikhale PJ. Carboplatin hypersensitivity. Int J Gynecol Cancer 2005, 15, Zanotti KM et al. Prevention and management of antineoplastic -induced hypersensitivity reactions. Drug Safety 2001;24(10): Castells M. Rapid desensitization for hypersensitivity reactions to chemotherapy agents. Curr Opin Allergy Clin Immunol 2006;6:271-7 SKIN TESTING High sensitivity of skin testing Castells et al 2008: 88% Hesterberg et al 2009: 36-83% (according to timing > or < 9 months after HSR) Very few false negative results (+/-1.5%) Patients needing more than 6 carboplatin infusions Maintain regular chemo infusions Suspend chemo/ Desensitization Negative Positive Skin testing after the 7 th infusion Skin testing reliably predicts the majority of anaphylactic reactions to platinum-type drugs Hesterberg AP et al. J Allergy Clin Immunol 2009;123: Leguy -Seguin V at al. Diagnostic and predictive value of skin testing in platinum salt hypersensitivity. J Allergy Clin Immunol 2007;119: Castells MC, et al. Hypersensitivity reactions to chemotherapy: outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin Immunol 2008;122(3):

8 SPECIFIC IgE TO PLATINS EAACI patients from Lisbon and Boston (Crb=12; Ox=12) Female-9; Male-5 (Mean age -61) with immediate hypersensitivity reactions to carboplatin and oxaliplatin Skin testing with culprit drug in 22 patients: Crb=12 10 mg/ml Ox=10 5 mg/ml sige (UniCAP; Phadia - Sweden) was performed for both platins (cut-off of 0.10 ku A/l) 24 Patients 17 Controls (Crb=5; Ox=12) RESULTS: carboplatin sensitized patients Pts Gender/ Age Drug Reaction Skin tests (mg/ml) sige Crb (ku A/l) sige Ox (ku A/l) 1 F/ 65 Crb Anaphylactic shock Crb: 0.1 ID < 0,10 < 0,10 2 F/ 52 Crb Crb: 10 SPT < 0,10 < 0,10 3 F/ 56 Crb Nasal obstruction; generalized urticaria Crb: 1 ID 1,20 < 0,10 4 F/ 71 Crb Generalized rash;, dyspnea Crb: 0.1 ID < 0,10 < 0,10 5 F/ 45 Crb Anaphylactic shock Crb: 0.1 ID 0,14 < 0,10 6 F/ 62 Crb Anaphylaxis, flushing, vomiting, fainting Crb: 1 ID 8.9 < 0,10 7 F/ 71 Crb Swelling tongue, ithcy hands,vomiting, rash, dyspnea Crb: 1 ID 1.2 < 0,10 8 F/ 69 Crb Dyspnea,flushing, wheezing, desaturation Crb: 10 SPT < 0,10 < 0,10 9 F/ 65 Crb Syncope, hypotension, vomiting, red rash Crb: 10 SPT 0.18 < 0,10 10 F/54 Crb Itchy palms, redness Crb: 1 ID < 0,10 < 0,10 11 F/ 51 Crb Hypotension, red rash, chest tightness, vomiting, Crb: 10 SPT 0.85 < 0,10 12 F/ 65 Crb Nausea, abdominal pain, collapse, cardiorespiratory arest Crb: 1 ID 0.49 < 0,10 F- female; M- male; Crb. Carboplatin; SPT- skin prick test; ID: intradermal RESULTS: oxaliplatin sensitized patients Pts Gender/ Age Drug Reaction Skin tests (mg/ml) sige Crb (ku A/l) sige Ox (ku A/l) 1 M/ 54 Ox Generalized rash; facial fushing, dyspnea, Ox: 5 TCP 1,60 0,16 2 F/ 62 Ox Itchy palmar Erytema, dyspnea Ox: 0.5 ID 1,70 2,80 3 M/ 69 Ox Facial flushing and lip angioedema Ox: 0.5 ID 0,31 0,22 4 M/ 62 Ox 5 F/ 57 Ox Facial flushing, dyspnea, bronchospasm and chills Facial flushing, dyspnea, bronchospasm and generalized rash Ox: 0.5 ID 8,8 4,9 Ox: 0.5 ID <0,10 1,5 6 F/ 51 Ox Facial flushing e generalized urticaria Ox: 0.5 ID <0,10 <0,10 7 F/ 46 Ox Itchy palms, redness, nausea, shortness of breath Ox: 5 TCP M/ 68 Ox Dyspnea, abdominal pain, hypertension, tremors Not done F/ 63 Ox Palmar erythema, facial flushing and generalized rash Ox: 0.5 ID <0,10 <0,10 10 F/ 63 Ox Dyspnea, thoracic pain, generalized rash Not done F/ 70 Ox Generalized rash and hypotension Ox: 0.5 ID M/ 61 Ox Itchy palmar erythema, facial flushnig and urticaria on the trunk Ox: 0.5 ID <0,10 <0,10 F- female; M- male; Crb. Carboplatin; SPT- skin prick test; ID: intradermal 8

9 RISK ASSESSMENT The timing of carboplatin ST in relation to initial HSR is vital for risk stratification and subsequent desensitization. Initial ST negative patients with a remote history of HSR are at high risk for conversion to ST positive and can develop more severe HSR Risk stratification for desensitization of patients with carboplatin hypersensitivity: Clinical presentation and management J Allergy Clin Immunol 2009;123: TAXANES Anti-mytotic activity Treatment of several solid malignancies (ovary, breast, testicle, bladder) incidence of HSR before the 90 s ( > 40%) Inclusion of pre-medication with H1 and H2 anti-histamines and systemic corticosteroid in oncology protocols Incidence dropped to <10% Cross-reactivity? Paclitaxel: Cremophor Different solvents Docetaxel: Polysorbate 80 Substitutions may lead to similar reactions Dizon DSet al. Cross-sensitivity between paclitaxel and docetaxelin a women s cancers program. Gynecol Oncol 2006;100(1): TAXANES HSR usually occur on the 1 st or 2 nd infusions (95%) Mechanism still not identified Direct Mast Cell Activation and degranulation? Complement activation? But Clinical presentation similar to IgE immediate reactions Facial flushing Chest discomfort/pain Back pain Tachycardia Erythematous rash Hypotension Pruritus/urticaria Facial swelling - Pneumonitis - Maculopapular rash - Erythrodysesthesia plaque Skin testing persistently negative NOT RECOMMENDED! Clinical assessment and treatment similar to IgE immediate reactions 9

10 MONOCLONALS Their use in Oncology is rising Rituximab (lymphoma) Trastuzumab (Breast cancer) Cetuximab (metastatic colorectal cancer) Skin testing Prick full-strenght Intradermal up to 1:10 dilution Clinical presentation Similar to other chemotherapy agents Hypersensitivity reactions to mabs: 105 desensitizations in 23 patients, from evaluation to treatment J Allergy Clin Immunol 2009;123: Castells M. Drug desensitization in Oncology: chemotherapy agents and monoclonal antibodies. In Pichler WJ (Ed). Drug hypersensitivity.1st ed: Basel: Karger;2007: PATIENT SELECTION Hypersensitivity reactions to mabs: 105 desensitizations in 23 patients, from evaluation to treatment J Allergy Clin Immunol 2009;123: DESENSITIZATION Daily Practice: results Total of chemotherapy desensitizations 440 Total of chemotherapy agents 106 Total of patients 103 Platins Taxanes Anthracyclines Monoclonal Antibodies 10

11 Example of a 12-step standard desensitization protocol Name of medication: CARBOPLATIN Target Dose (mg) 500,0 Standard volume per bag (ml) 250 Final rate of infusion (ml/hr) 80 Calculated final concentration (mg/ml) 2 Standard time of infusion (minutes) 187,5 Total mg per bag 1/100 Solution ml of 0,020 mg/ml 5,000 1/10 Solution ml of 0,200 mg/ml 50,000 1/1 Solution ml of 1,984 mg/ml 496,065 *** PLEASE NOTE *** The total volume and dose dispensed are more than the final dose given to patient because many of the solutions are not completely infused Volume infused per Dose administered Cumulative dose (mg) Step Solution Rate (ml/hr) Time (min) step (ml) with this step (mg) 1 1 2,0 15 0,50 0,0100 0, ,0 15 1,25 0,0250 0, ,0 15 2,50 0,0500 0, ,0 15 5,00 0,1000 0, ,0 15 1,25 0,2500 0, ,0 15 2,50 0,5000 0, ,0 15 5,00 1,0000 1, , ,00 2,0000 3, ,0 15 2,50 4,9607 8, ,0 15 5,00 9, , , ,00 19, , ,0 174, ,50 461, , ,375 = 5,66 Total time (minutes) = hrs DESENSITIZATION Daily Practice: results CHEMOTHERAPY AGENT PATIENT/ DESENSITIZATION NUMBER SKIN TESTING Carboplatin (ovarian/neuroendocrine cancers) 24 / 98 PLATINS (n= 56 / 230) Oxaliplatin (colorectall/testicle cancer) Cisplatin (uterine cervix cancer) 29 / / 14 Positive= 53 Negative= 3 TAXANES (n= 45 / 174) Docetaxel (Breast cancer) 27 / 82 Paclitaxel (Ovarian/breast/Lung cancer) 18 / 92 ND ANTHRACYCLINES (n= 1 / 2) Liposomal Doxorrubycin 1 / 2 ND (retroperitoneal leiomyosarcoma) MONOCLONAL ANTIBODIES (n= 2 / 34) * ND: not done Trastuzumab (Breast cancer) 3 / 31 Cetuximab (colorectal cancer) 1 / 1 Trast - ND Cet neg DESENSITIZATION Treatment of the reactions - Cardiac monitor - Equipment for arterial pressure and oxygen saturation evaluation - Equipment for oxygen supply Complete emergency kit: Epinephrine 1:1000 for intramuscular administration I.V. Methylprednisolone I.V. Clemastine 2 mg I.V. Ranitidine 50 mg Inhaled Salbutamol 11

12 CHARACTERISTICS OF THE REACTIONS 46 REACTIONS (11.5%) - in 35 patients Mild 32 (7.2%) Moderate 10 (2.2%) Severe 4 (0.9%) 394 (89.5%) Oxali - 20 Carbo - 19 Cisplatin - 1 Paclitaxel %! Severe 4 (0.7%) Oxaliplatin - 2 Carboplatin - 2 Docetaxel - 3 Oxaliplatin - 4 Moderate 10 (2.4%) Carboplatin - 2 Paclitaxel - 2 Docetaxel 2 Carboplatin 15 Oxaliplatin - 14 Mild 32 (7.2%) Cisplatin - 1 Paclitaxel - 1 Docetaxel -1 MODIFICATIONS AFTER A HSR IMMEDIATELY AFTER THE HSR Hold infusion Treat according to the protocol Resume desensitization EXACTLY at the point it was held ADAPTATIONS IN FURTHER INFUSIONS When there is only mild reaction, do not alter the protocol Premedicate with clemastine and methylprednisolone before the step at which the patient has reacted Add 1 or 2 additional steps In step 12, reduce the maximum rate to 75 or 60 ml/h Initiate with a 1/1000 dilution instead of 1/100 (16-step protocol) When recurrent HSR have occurred or when the initial reaction was moderate to severe, especially with platins Pre-medicate with aspirin and montelukast 2 days prior to the desensitization Breslow R et al. Acetylsalicylic acid and montelukast block mast cell mediator -related symptoms during rapid desensitization. Ann Allergy Asthma Immunol 2009 Feb;102(2): MODIFICATIONS AFTER A HSR Breslow R, Caiado J, Castells MCl. Acetylsalicylic acid and montelukast block mast cell mediator -related symptoms during rapid desensitization. Ann Allergy Asthma Immunol 2009 Feb;102(2):

13 FINAL COMMENTS Clinical assessment and risk stratification of HRS is crucial Skin testing may predict anaphylactic reactions to platinum-type drugs Similar clinical approach os immediate reactions (IgE and non-ige mediated) Importance in selection of patients amenable for desensitized Learn how to design and adapt a desensitization protocol Some patients may need special premedication protocols Desensitization procedures allow the reintroduction of chemotherapy agents in patients with previous HSR. From our experience, the majority of patients (426 97%) tolerated the procedure with only mild or no HSR. 13