Annals of Oncology 3: 605-610, 1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands.

Review Allergic reactions to cytotoxic drugs — an update M. E. R. O'Brien1 & B. E. Souberbielle2 'Dept of Medicine, Royal Marsden Hospital, London; 2Di\ision of Oncology, Cellular and Molecular Sciences Department, St George's Hospital Medical School, London, United Kingdom

Key words: anaphylaxis, anaphylactoid, cytotoxics

evokes immediate hypersensitivity with cisplatin rating second [1]. Immediate hypersensitivity is triggered by Anticancer drugs, like all other drugs, have the ability cross-linking of antigen-specific immunoglobulins E to incite allergic (hypersensitivity) reactions [1] which, (IgE) bound to mast cells and basophils which bear the when they occur, can be serious enough to necessitate high affinity Fc receptor for IgE. Crosslinking of the discontinuation of the responsible agent. These events receptors induces mast cell degranulation with release are rare and are separate from the known and predict- of different mediators (e.g. histamine, leukotriens and able side effects of antitumour agents. Because many prostaglandins) which in turn induce secretion of a casancillary drugs given to a cancer patient may also cade of other mediators (e.g. proteolytic enzymes and evoke a hypersensitivity reaction, it may be extremely eosinophil peroxidase) by other cells which have been difficult to specifically implicate a chemotherapeutic recruited (neutrophils, eosinophils, basophils and drug as the aetiological agent for an allergic reaction. mononuclear cells). Some of these mediators are Moreover additives, impurities or interaction with an- potent bronchoconstrictors, vasodilators or induce vasother drug may be the trigger for allergy. In one study cular permeability or mucous secretion [4]. The clinical looking at adverse drug reactions to a wide range of end result of type I allergic reactions range from clascytotoxics and non-cytotoxics, reactions accounted for sical anaphylactic shock including flushing, hypoten4.1% of hospital admissions in a patient population of sion, angioedema, asthma or vomiting to milder reac2499 patients. Forty-four percent of these reactions tions such as pruritus, urticaria or diaphoresis, hi were hypersensitivity reactions - the rest were due to general the route of inoculation of the drug is imporeither predictable side effects or a secondary pharma- tant with a much higher risk of hypersensitivity reaction cological action of the drug [2]. Very few antitumour when the drug is given intravenously in comparison to agents have not had at least one reported instance of intramuscular administration [5] and prolonged infucausing a hypersensitivity reaction, however some sion appears to cause less hypersensitivity than bolus agents, e.g. L-asparaginase, cause this more frequently injection [6]. than others. In most cases reactions cannot be predictAnaphylactic reactions do not occur on first contact ed, therefore clinicians must be aware of the potential with a drug as immunological memory has to be induced. for a reaction and institute measures as appropriate. However, there have been many reports of similar reactions which have occured on first contact and these reactions should be called 'anaphylactoid' meaning that they have a non-immunological mechanism. It has been Mechanism suggested that anaphylactoid reactions are mediated by Allergic reactions can be described following Coombs drugs which directly trigger the release of histamine by and Gell's classification which uses 4 groups (I to IV) mast cells (non immune direct histamine releasing depending on mechanism, either antibody-mediated agents) but it may be that molecular cross reactivity be(type I to III) or T cell mediated (type IV), but in clini- tween the responsible drug and a drug (or another subcal practice drug allergy may not be always so clear cut stance) previously used triggers IgE mediated hyper[3). sensitivity. Cross reactivities between drugs often arise Most reported allergic reactions caused by antineo- through similarity between side chains of the complastic agents are of the type I category (immediate, pounds [7, 8]. One important question is to determine usually less than 30 minutes after contact with the which part of the drug is responsible for the triggering drug). L-asparaginase is the drug that most commonly of the allergic reaction. Some drugs appear to act mereIntroduction

606 Table I. Types of hypersensitivity. Types

Mechanisms

Major clinical signs

Type I IgE mediated

Crosslinking of Fc receptors for IgE on mast cells and basophils by antigen-specific IgE resulting in degranulation and release of different mediators.

- Usually immediate < 30 minutes. - Anaphylactic shock: hypotension, angioedema, asthma, vomiting.

Type II Cytotoxic

Antibodies react to antigens bound to cells or to tissue specific components resulting in cytotoxiclty by activation of complement and killer cells.

- destruction of a blood cell type e.g. haemolytic anemia or immune thrombocytopenia. - bullous skin eruption.

Type III Immune complex mediated

Deposition of antigen-antibody immune complexes in certain tissues with activation of complement and neutrophils.

- Fever, chronic urticaria, arthralgia, proteinuria, vasculitis, pneumonitis or erythema multiforme depending on the site of immune complexes deposition.

Type IV Cell mediated

Antigen specific T lymphocytes react with antigens and induce the secretion of lymphokines followed by the formation of a granuloma (inflammatory reaction).

- contact dermatitis. - chronic granuloma in certain organs.

ly as haptens which bind to endogeneous carrier macromolecules and induce an immune response only as a drug-carrier conjugate (e.g. cyclophosphamide, melphalan). In addition some drugs induce allergic reactions when they are biotransformed [9, 10]. In the clinical context of chemotherapeutic drug-induced type I allergic reactions, clinical symptoms and rechallenge with the implicated drug in a controlled manner have been the accepted diagnostic criterias. Other tests, e.g. skin test (patch or prick) or radio allergosorbent test (RAST), have had little predictive value as they have never been done in carefully controlled studies with enough controls due to the small number of subjects involved. Histamine release from patients' blood leucocytes (histamine release from basophil leucocytes (HRL) test) is thought to correlate with the potential for a non immune hypersensitivity reaction, e.g. in the case of neuromuscular blockers hypersensitivity [7], but has had little value in the chemotherapy context. In most of the cases of the other allergy types (II, III and IV) reported in the literature, no specific immunological tests have been presented and most of the hypersensitivity reactions were proposed on clinical and histopathological grounds, in other words, allergy was implicated as the most probably explanation after the elimination of alternative diagnoses. In type II allergic reactions, antibodies (IgG or IgM), through their Fab portion, react to drugs absorbed onto cells e.g. haematopoietic cells (platelets, red blood cells or white cells). The Fc portion of the antibodies can engage the Fc receptor on the surface of K cells which will lead to cytotoxicity of the cells or can trigger complement deposition on the cells which will lead to complementmediated lysis. Drug induced reactions have involved mainly blood cells including red blood cells and platelets (e.g. chlorambucil) [11]. In some cases, e.g. secondary immune thrombocytopenia, the drug reacts first with the antibody and then the immune complex is absorbed onto the platelet. Type II reactions have very rarely been reported with cytotoxic agents even though

- urticaria.

they may be misdiagnosed as a direct effect of the drug on blood cell precursors. Antibodies directed to tissue specific components have also been incriminated as type II allergic reaction mediators, e.g. in the case of bullous skin eruptions induced by high dose chemotherapeutic agents [12]. Laboratory tests in favour of the type II reaction demonstrate the presence of antibodies (IgG or IgM) against the organ or cell injured, e.g. by direct immunofluorescence. However the target antigens (drug or tissue component) are rarely characterised. In type HI allergic reactions immune complexes between drugs and antibodies are deposited in the tissues. They are clinically characterised by a generalised syndrome with fever, chronic urticaria, arthralgia and proteinuria, vasculitis and erythema multiforme or pneumonitis depending on the site of immune complexes deposition and on where the antigen is released in the circulation [13]. Immune complex deposition is usually detected in biopsy sections of the organ involved using an anti-immunoglobulin antibody and an anti-complement C3 antibody. Type IV allergic reactions are mediated by drug specific T lymphocytes and not by antibodies. T cells secrete lymphokines which promote an inflammatory reaction with a cellular infiltrate where lymphocytes and macrophages predominate [14]. Clinically cellmediated immune reactions are characterised by allergic contact dermatitis or chronic granulomas in some organs. The lymphocyte proliferation assay is an indicator of T cell sensitisation to a particular antigen and correlates positively with this type of allergy but is also positive in other types of allergy.

Drugs Most of the commonly used cytotoxic drugs have been reported to cause anaphylactic reactions and some of the important reactions are described below; the

607 Table 2. Drugs and types of hypersensitivity described. Drug group

Chemotherapeutic agent

Type of hypersensitivity

Antimetabolites

Methotrexate 5-fluorouracil

I, 11, III I

Alkylating agents

Cyclophosphamide Chlorambucil Melphalan

I I, II. IV I, anaphylactoid

Cisplatin Carboplatin

I, anaphvlactoid I

Vinca alkaloids

Vinblastine

I

Anthracycline

Doxorubicin Epirubicin

I I

Mitozantrone

I, HI

Antibiotic derived

Bleomycin Mitomycin

III I

Epipodophyllotoxin

Etoposide Teniposide

I I, II

Others

L-a.sparaginase Procarbazine Dacarbazine Deoxycoformycin Taxol

I, anaphylactoid I, II III I I

majority of these reactions are type I, but there are also instances of types II, III and IV reactions. The mechanisms of such reactions have been poorly evaluated in many reports. Using L-asparaginase, one or more symptoms of hypersensitivity have occurred in 6% to 43% of patients studied [1] with 1% mortality rate from anaphylaxis among all treated patients. With this particular drug the route of administration is important in determining the rate of reactions; 28.5% of 80 patients receiving intravenous asparaginase had anaphylaxis while 12% of 73 patients receiving intramuscular asparaginase reacted. In addition all reactions to intramuscular injection were mild in comparison with 6% mild reactions in the intravenous group [5]. L-asparaginase hypersensitivity appears to be type I; IgE specific for L-asparaginase has been shown to correlate with the reaction in some patients but IgG antibodies have also been identified. There are also reports of anaphylactoid reactions suggesting that L-asparaginase can release vasoactive substances nonimmunologically. When L-asparaginase is administered in combination with 6-mercaptopurine and/or prednisolone, the risk of a hypersensitivity reaction is reduced by half, either through suppression of mediator release, inhibition of antibody production or by some other as yet unknown mechanism [16). Reactions to cisplatin occur shortly after infusion and are classical type I allergic reactions. The frequency of these life threatening reactions varies from 5% when cisplatin is given as a single agent to 20% when cisplatin is given in combination with other chemotherapeutic drugs. As described by Saunders et al. |49] carboplatin can also induce a reaction. In general these

are being prevented by the increasing use of dexamethasone as an antiemetic. Methotrexate has produced type I, II and type III reactions: a teenage girl in bone marrow remission with acute lymphocytic leukaemia died suddenly from pulmonary oedema 10 hours after her first dose of oral methotrexate. She had received 4 doses of intrathecal methotrexate. The authors suggested that she had been sensitised by the intrathecal methotrexate and had an anaphylactic reaction to the oral treatment - lung toxicity due to methotrexate takes at least 12 days to develop after administration of the drug [16]. Oral methotrexate has caused agranulocytosis in a patient with rheumatoid arthritis. A toxic effect cannot be excluded but the authors supported their diagnosis of type II allergy by a lymphocyte transformation test [17]. Cutaneous vasculitis after intermediate dose of methotrexate has been reported in a patient with acute lymphoblastic leukaemia and did not occur with low dose oral maintenance [18]. As the appearance clinically and pathologically was of classical vasculitis, a type III reaction was assumed although specific tests were not done to verify this. Cyclophosphamide has been reported to cause type I reactions [19] and in one patient rechallenge with chlorambucil caused the same symptoms [20] but another patient has been described in whom chlorambucil was substituted for cyclophosphamide with no cross-sensitivity noted [21]. Cyclophosphamide is a low molecular weight substance which binds to serum proteins and would probably act as a hapten. Reactions to chlorambucil therapy are rare. However there are 2 reports in patients with chronic lymphocytic leukemia and one report in a patient with a low grade lymphoma. The skin lesions were all characterised by oedematous erythematous plaques with periorbital oedema occurring early in the course of therapy. In the 2 cases the lesions appeared eight days and 3 weeks, respectively, after initiation of chlorambucil therapy, resolved on stopping treatment but recurred with a more severe eruption on rechallenge. In the first case a skin biopsy revealed perivascular chronic inflammatory infiltrate and a negative direct immunofluorescence for complement and immunoglobulin deposition. In the second case, there were positive delayed reactions to purified chlorambucil on patch and scratch testing [22]. Not only has chlorambucil been implicated in a type IV reaction but it may also have caused a type II reaction: a 73-year-old man with chronic lymphocytic leukemia developed shivering, high fever and haemolytic anaemia following chlorambucil administration. Re-exposure in a controlled clinical situation suggested an allergic drug reaction. In an in vitro assay, chlorambucil was shown as the causative agent of immune haemolysis (11). Certain cytotoxic drugs may induce pulmonary injury through alteration of the normal balance between oxidants and antioxidants which is the most frequent type of lung damage and is non-allergic. Bleomycin

608 induced pulmonary toxicity is generally thought to be dose-related and to occur infrequently at a total dose of under 300 units. However there have been cases of fatal interstitial pneumonitis at less than this dose which are in keeping with a type III allergic reaction and therefore steroid cover should probably be given at all times and with all doses of bleomycin [23]. Melphalan causes allergic reactions in an estimated 3.9% of 255 patients receiving this drug as a single agent given intravenously [24]. Of five patients rechallenged with oral melphalan, four developed a similar reaction. The reactions were classical type I and ranged from oedema and generalised rash to a full blown anaphylactic reaction consisting of respiratory insufficiency and hypotension. The mechanism of these reactions is unknown but it has been shown that an alkylation reaction between melphalan and serum proteins may occur in vivo and that such altered proteins may act as hapten-carrier complexes [25]. Melphalan has also caused a type EH reaction in the form of an acute reversible interstitial pneumopathy in a patient with myeloma after cessation of corticosteroids [26]. This differed clinically and histopathologically from the subacute fibrosing pneumonitis due to melphalan. Mitomycin and vinblastine have been reported to have caused acute respiratory distress and death in a non-smoker with metastatic breast cancer suggesting an acute hypersensitivity reaction as the cause of the respiratory distress [27]. A further unusual manifestation of type I hypersensitivity has been described with vinblastine; vaginitis occurred in the wife of a man receiving vinblastine for Hodgkin's disease and recurred each time the man was exposed to the drug. This was prevented by using a condom and was thought to be due either to a local irritant effect of the drug secreted in seminal fluid or an allergy to vinblastine [28]. Dermatologic reactions to 5-fluorouracil (5-FU) occur in 15%-20% of patients and are usually dose dependent [29]. However, these are not true allergic reactions. 5-FU given as an infusion has caused angioneurotic oedema which was not prevented by using antihistamines and steroids during a rechallenge and therefore necessitated the discontinuation of therapy [30]. A number of cases of a type I hypersensitivity skin reaction have been described with infusional treatment after patients had previously received topical 5-FU for actinic keratosis suggesting sensitisation to 5-FU via the topical route. As the application of topical 5-FU is a fairly common procedure, doctors should be aware of this potential reaction if administrating chemotherapy at a later date [31]. The cause of an allergic reaction can be difficult to determine as many patients receive combination therapy and the actual contribution of each drug can only be guessed at: 2 patients with Hodgkin's disease developed diffuse pulmonary disease after treatment with nitrogen mustard, vincristine, procarbazine and prednisolone. Lung biopsy showed diffuse alveoliris characterised by an interstitial infiltrate of eosinophils. lym-

phocytes, plasma cells and histiocytes, and one patient had a granuloma. The patients responded to further corticosteroid treatment and the authors suggested that procarbazine was the causative agent of this type III or type IV hypersensitivity reaction but no immunological tests were performed [14]. Etoposide can cause an acute vasomotor response which is more commonly seen than reported and is usually overcome by decreasing the rate of infusion [32]. In a series of 8 patients with documented hypersensitivity to etoposide, 5 reacted on first exposure to the drug. Patients presented with either bronchospasm or flushing and one patient deteriorated rapidly and died - post mortem showed adult respiratory distress syndrome. Only 2 out of 8 patients were successfully retreated with the use of premedication [33]. Immunological testing of these patients was not performed. Teniposide has also caused allergic reactions: during a 7-year period, 16 episodes of hypersensitivity to teniposide occurred in 22 children. Eight of the episodes (50%) were observed in neuroblastoma patients. The predominant signs were of classical type I reactions with facial oedema, flushing, urticaria, bronchospasm, tachycardia and hypotension. All of the children recovered but 4 of them were critically ill. No risk factors were found [34]. In another series the incidence of hypersensitivity to teniposide was l % - 5 % among lymphoma/leukaemia patients but was 13% in children with neuroblastoma, suggesting that the latter group are at particular risk of allergic reactions to this drug [35]. No immunological tests were done in the above patients but one patient has been described with an IgG, antibody to teniposide but a further series of 4 patients with hypersensitivity to teniposide did not demonstrate this type of antibody [36]. Teniposide has also been associated with a type II reaction: a patient with teniposide antibodies was found to have an associated red blood cell autoantibody [37]. A further suggested mechanism for reaction to teniposide is the action of Cremophor EL which is used as a solvent. However, etoposide - which differs from teniposide only by the substitution of the thenylidine group on the glucopyranoside with a methyl group - does not require this solvent for preparation and hypersensitivity reactions still occur with etoposide. Doxorubicin can produce both a generalised reaction and a urticarial reaction localised to the vein [38]. The first reported case is of a type I reaction with angioedema and urticaria. No specific allergy tests were done using doxorubicin but the patient was rechallenged and developed classical symptoms. In recent years some new drugs have come into clinical use: these are usually analogues of known drugs with similar activity to the parent compound but decreased or different toxicity. Epirubicin is an example of this and hypersensitivity has been described: a patient with metastatic breast cancer treated with epirubicin developed a severe urticarial reaction which progressed to ulceration following possible sensitisation to the drug

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by preceding extravasation [39]. No immunological tests were done but this was clinically a type I reaction. This report highlights the point that not only is extravasation locally harmful and painful but it can also sensitise patients. Mitozantrone has also been described as the cause of allergic-type reactions in 3 patients with advanced breast cancer [40]. In the first case symptoms occurred 7 days after administration of the drug and skin biopsy showed a vasculitic lesion in keeping with a type III reaction. The second case was more typical of a type I reaction but the third patient developed symptoms immediately after the seventh course of mitozantrone and again 16 days after the eighth course suggesting both a type I and type III reaction in this patient. No tests were done. Dacarbazine has been associated with allergy-induced hepatic toxicity [13] which has been fatal. Autopsy findings in reported cases revealed massive hepatic necrosis, thrombus in small hepatic veins, and frequently revealed a vasculitis with associated lymphocytic and eosinophilic infiltration. This allergic-induced Budd-Chiari syndrome usually occurred during the second cycle of dacarbazine and was associated with peripheral eosinophilia. This serious toxicity, although rare, suggests that this drug should only be used where it has been shown to have activity e.g. in palliating metastatic melanoma and therefore has no place at present as adjuvant therapy. Taxol inhibits cell division by promoting the assembly and stabilisation of microtubules. In the phase I study, 2 of the first 5 patients who received taxol as a 60-minute infusion developed anaphylactoid reactions during the first course - one of which was life threatening. The other 3 patients developed less severe allergic symptoms during their second courses. When the drug was given as a 6-hour infusion with antihistamine and prednisolone premedication reactions were less frequent and less severe [6, 41] but still developed in 41% of patients in one reported series |42|. Again the Cremophor vehicle has been implicated as the cause of this reaction but this has not been proven as yet. In view of the frequency of these reactions patients should receive prophylactic measures with first and all subsequent courses of taxol. Deoxycoformycin is a new antineoplastic agent in the treatment of lymphoid malignancies, particularly hairy cell leukaemia. Skin toxicity and systemic manifestations indicating an allergic aetiology have now been reported [43]. Trimetrexate is a nonclassical antifolate currently being tested for efficacy in cancer patients and as an antiparasitic agent against pneumocystis carinii pneumonia in AIDS patients. Classical hypersensitivity reactions have now been reported in the current phase II trials and occurred in