Omalizumab for successful chemotherapy desensitisation: What we know so far

Abstract Background Hypersensitivity reactions induced by chemotherapeutic drugs may influence the course of the oncologic disease by preventing doctors from prescribing first‐line therapy. In order to prevent another hypersensitivity reaction to the culprit chemotherapeutic agent, the physician can decide between two possibilities: premedication or desensitisation protocols. Rapid drug desensitisation showed successful results for most patients, but some of them may develop symptoms. Although omalizumab is not licensed as premedication or adjuvant therapy in chemotherapy desensitisation protocols, there have been published some case reports and small sample size studies that indicated promising results. Methods We reviewed all the published literature regarding the use of omalizumab during chemotherapy desensitisation protocols. Results and conclusions We found a great heterogeneity between the doses and the interval between omalizumab injections and chemotherapy ‐ rapid drug desensitisation, but most of the studies showed promising results. As a corollary, we propose a dose regimen of omalizumab administered before the first desensitisation protocol. Then, omalizumab should be administered one day before every chemotherapy regimen. Omalizumab might be used as an adjuvant therapy and might be a solution for a hopeless situation.


| INTRODUCTION
Chemotherapy (CHT) is one of the basic medical approaches for treating patients with different types of cancer. Chemotherapy agents are used either alone or in combination with targeted therapies constituted by monoclonal antibodies or other biologicals. 1 Hypersensitivity reactions (HSRs) induced by CHT can be defined as unpredicted signs and symptoms not consistent with a toxicity reaction. 2 The mechanisms responsible for HSRs are not fully understood and may vary between IgE-mediated, non-IgE-mediated or unclear pathogenic events. 3 Almost all CHT drugs can induce HSRs, but they are reported only in about 5% of patients; this percentage may be substantially underestimated because of unreported mild and moderate reactions. 4 According to recent data, CHT-induced HSRs are the third leading cause of fatal drug-induced anaphylaxis in the United States 5 ; in Europe they are amongst top 5 inducers. 6 Based on the risk of generating HSRs, it is possible to divide the chemotherapeutic agents into three groups: drugs with high, intermediate, or low potential to cause HSRs, as summarized in Table 1. The reactions can be caused by the parent compound, its metabolites, or by the solvent. Depending on this grouping, the problem of CHT-induced HSRs is notable for patients treated with platinum compounds, taxanes, L-asparaginase, epipodophyllotoxins and is lower for others. 7 Unlike other drugs that can be easily replaced when a HSR occurs, CHT drugs are often unique and essential in the treatment of neoplastic disease and thereby the management of HSRs to CHT is crucial. 8 The diagnosis of HSR is based on history, in vivo tests (skin prick, intradermal and provocation tests) and in vitro tests. The clinical manifestations are variable, unpredictable and involve the skin (e.g., rash, pruritus, urticaria, angioedema, palmar erythema, facial flushing), the respiratory tract (e.g., bronchospasm), the gastrointestinal tract (e.g., abdominal pain, nausea, diarrhea), and the cardiovascular system (alterations in blood pressure and heart rate). 9 Severe reactions usually develop during the infusion of the chemotherapy and most of them are IgE-mediated as it has been clearly demonstrated for platinum salts, 10,11 whereas mild to moderate reactions can occur either during treatment or in the 24 up to 72 h after CHT administration and are apparently related to other mechanisms like mast cell and basophil activation and degranulation or complement activation. 12,13 In respect of skin tests usefulness, their importance has been proved in platin salts-induced HSRs, demonstrating an IgE-mediated mechanism particularly for carboplatin and oxaliplatin. 14 Prick and intradermal skin tests to platinum drugs are valuable diagnostic tools; their high sensitivity has been shown by several studies on carboplatin (66%-100%) and oxaliplatin (26%-100%). 15,16 In addition, the severity of the reaction appears to be related to the sensitivity of skin tests. 11 In clinical practice, if the first-line treatment led to a HSR, the oncologist might switch to a second line therapy which can be less effective and can lead to significant morbidity. 17 However, if the culprit drug is associated with increased life expectancy and increased quality of life or if there is no therapeutic alternative, the physician must weigh the benefit of continuing the treatment against the risk of a potential fatal anaphylactic reaction during the following administration of chemotherapy. 7 In order to prevent another HSR to the culprit chemotherapeutic agent, the physician can decide between two possibilities: premedication or desensitisation protocols.

| PREMEDICATION
Premedication schedules are carried out to prevent HSRs; they include administration of corticosteroids and antihistamines prior to chemotherapy infusion. Premedication is effective as well as recommended to prevent HSRs to different CHT, such as taxanes, epipodophillotoxins and pegasparaginase. 7,18 This procedure has dramatically decreased the incidence of HSRs to taxanes down to 2%-4% of cases. 19 Instead, for platinum salts, premedication is ineffective in preventing IgE-mediated HSRs. 20,21 Occasionally, in case of premedication failure or if the procedure cannot be implemented, a drug desensitisation protocol could be recommended. Rapid drug desensitisation (RDD) is the best option for mast cell-mediated HSRs, whether the involved mechanism is IgEmediated or not. 17

| DESENSITISATION TO CHEMOTHERAPEUTIC AGENTS
RDD is a procedure that induces a temporary tolerance to a drug, by Etoposide RDD induces transient unresponsiveness, so patients need to be re-desensitised each time they are re-exposed to the culprit CHT.
Throughout RDD, patients with IgE and non-IgE HSRs can safely receive needed medication while minimizing or completely inhibiting adverse reactions. Due to the extensive clinical usefulness and success of RDD, the molecular mechanisms of inducing temporary tolerance have been extensively investigated but are still incompletely understood. 17 The standardized 12-step protocol is the most used in RDD and can help achieve a temporary tolerance of the drug; the protocol usually starts with 1/1000 from the final dose and subsequently, the doses are doubled at each step at fixed time intervals. 17,22 Patients who have had severe anaphylactic reactions to CHT or who have reacted at an early stage in the standard 12-step RDD, may experience fewer symptoms when using a 16-step protocol according to Mariana Castells' one. 17 RDD showed successful results for most patients, but some of them may develop symptoms despite intense pre-treatment and extra antiallergic medication received during the desensitisation procedure. For these special cases, omalizumab might be used as an adjuvant therapy to induce CHT tolerance.
Omalizumab has also been used in achieving tolerance to other drugs such as insulin, elosulfase ɑ, acetylsalicylic acid. [23][24][25] The largest evidence is regarding the use of omalizumab in acetylsalicylic acid desensitisation for aspirin exacerbated respiratory disease. 25

| OMALIZUMAB
Omalizumab is a recombinant humanized anti-IgE monoclonal antibody that specifically binds to the C-ε-3 domain of free IgE and the surface IgE of IgE expressing B cells but not to IgE bound to high or low affinity IgE receptors (FcεRI, respectively FcεRII) and therefore they do not trigger effector cell degranulation. 26 The complexes formed between omalizumab and IgE result in a significant decrease in free IgE in serum. They also prevent IgE from binding to effector cells, resulting in decreased mediator release in response to allergens 27  This approach was also combined with a manual search of references in all selected studies. Until now, there have been published two clinical trials and ten case reports. [34][35][36][37][38][39][40][41][42][43][44][45] All the results are synthesized chronologically in Table 2.
The first description of omalizumab use as premedication for A series of three patients who benefited from pre-treatment with omalizumab before chemotherapy desensitisation was reported by Saura et al. 36 All three cases had a history of carboplatin anaphylactic reaction (proven by tryptase elevation) during classical desensitisation protocols. By using omalizumab before RDD, all three patients tolerated the total number of 15 desensitisation procedures.
Another case report of successful use of omalizumab as premedication to carboplatin desensitisation was described by Garcia et al in a 52-year-old female. 37 Hong's study 38  had a mild reaction with slight increase of the tryptase level; subsequently, she tolerated four more RDD with omalizumab premedication with no noticeable reactions. The high sensitisation to oxaliplatin and the elevated total IgE (>5000 kU/L) might be the reason for deciding on the high initial dose of omalizumab.
The only unsuccessful reported omalizumab-RDD was described in a patient who received 300 mg 6 days prior to oxaliplatin desensitisation. 42 Clinical symptoms and increased tryptase levels were reported during the first step of the desensitisation protocol. No other attempt to achieve tolerance was noted.
Sanchez-Morillas et al. 43  We found a great heterogeneity between the doses and the interval between omalizumab injections and CHT-RDD; some studies used the anti-IgE therapy only before the first RDD, but most of the studies used it before all the subsequent RDD.
Most of the authors preferred to administer omalizumab fortnightly, except Hong et al. 38 The time interval between the last omalizumab injection and the desensitisation protocol varied largely, ranging from 24 h to 19 days. Some of the authors preferred using every other week regimen for omalizumab, while administering the chemotherapy as prescribed by the oncologist every 21 days. 35,44 As a corollary of these results, we propose a dose regimen of 300 mg omalizumab administered twice before the first CHT-RDD, 15 days and 1 day prior to the first CHT infusion. Then, omalizumab should be administered one day before the CHT regimen, while the F I G U R E 1 Timeframe between Omalizumab (Oma) and CHT-RDD: (A) Patients whose CHT regimen is every 14 days and (B) Patients whose CHT regimen is every 21 days. CHT, chemotherapy; RDD, rapid drug desensitisation BUMBACEA ET AL.
-5 of 7 interval between CHT might vary depending on the drug used in the respective oncologic disease (Figure 1).
The results of most of the studies were promising, the patients tolerated subsequent CHT-RDD without HSRs or accompanied by mild reactions only. Unfortunately, a homogeneous definition of mild reactions was not given in the above-mentioned studies.

| FINAL REMARKS
RDD has become a key component of the management of CHT-HSR.
It is the only effective approach for overcoming the HSR to first-line therapy, thus representing an important progression in patients' treatment and prognosis. Understanding the mechanism of action implied to RDD will allow improvement in patients' treatment.
Omalizumab, an anti-IgE drug, may be used as an adjuvant therapy in RDD for patients with IgE-mediated CHT-HSRs in troublesome desensitisations despite premedication. Although the abovementioned case reports and small size clinical trials showed promising results, further studies with larger number of patients are necessary for setting up standard recommendations for omalizumab adjuvant-RDD protocol.

ACKNOWLEDGEMENT
The authors would like to thank Rama Boustani and Ruxandra Udrea for their help and support with the language editing and figure design.

CONFLICT OF INTEREST
All authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.