POMALIDOMIDE DESENSITIZATION, Seki et al. CASE REPORT Pomalidomide desensitization in a patient hypersensitive to immunomodulating agents † ‡ J.T. Seki PharmD,* N. Sakurai BSc MSc,* W. Lam BSc(Phm),* and D.E. Reece MD ABSTRACT Despite progressive treatments with tandem stem-cell transplantation, patients with incurable myeloma eventually succumb to relapsed or refractory disease if left untreated. Promising agents such as proteasome inhibitors and im- munomodulating imide drugs (imids), including the newer-generation agent pomalidomide, in combination with lower-dose dexamethasone, have been shown to be effective and to significantly improve and prolong survival in pretreated patients. Although the incidence of pomalidomide hypersensitivity reaction (hsr) in this class of drugs is not as well known, we have documented cutaneous toxicity (grade 3 by the Common Terminology Criteria for Adverse Events, version 4) in 2 separate cases (not yet published). Because the imids are chemically, structurally, and pharmacologi- cally similar, it is not unreasonable to consider possible cross-reactivity in pomalidomide recipients who developed hsr when receiving previous lines of imids. As a patient’s advocate, it is only prudent to provide a responsible, and yet practical, means to better address cross-sensitivity for patients. Intervention with the use of a rapid desensitization program (rdp) as a preventive measure should be introduced before initiating pomalidomide. Such a proactive measure for the patient’s safety will ensure a smooth transition into pomalidomide treatment. A hsr can be either related or non-related to immunoglobulin E. As imids become an essential treatment backbone for myeloma and other plasma-cell diseases, an increasing number of patients could experience skin and other life-threatening toxicities, resulting in unnecessary discontinuation of these life-prolonging agents. An extemporaneously prepared pomalidomide suspension developed at our centre enables patients to undergo rdp safely. Patients enjoy a good quality of life and clinical response after the rdp procedure. Key Words Desensitization, hypersensitivity reactions, immunomodulating agents Curr Oncol. 2017 Aug;24(4):e328-e332 www.current-oncology.com INTRODUCTION Pomalidomide is a particularly potent imid, with studies in relapsed patients having demonstrated efficacy Plasma-cell diseases, including multiple myeloma and for those in whom both bortezomib- and lenalidomide- amyloidosis, are considered incurable, and patients typi- containing regimens have failed or were intolerable, and for cally relapse at some point despite the evolution of more those with documented disease progression on the preced- effective frontline treatment strategies1. Lenalidomide ing regimen4,5,10,11. Although belonging to the same family and pomalidomide are newer-generation immunomodu- of drugs, pomalidomide has incomplete cross-resistance lating imide drugs (imids) approved as additional thera- with lenalidomide in terms of anti-myeloma effect11–14. Not peutic options when prior treatments have failed. These surprisingly, pomalidomide and dexamethasone are also orally administered derivatives of thalidomide are chemi- being used in combination with carfilzomib, ixazomib, cally structured to improve efficacy and safety. Lenalido- and monoclonal antibodies such as elotuzumab and dara- mide is used in combination with other chemotherapy tumumab in people for whom prior lenalidomide has agents and as maintenance until relapse after autologous failed15–18. The key role played by the imids in the manage- stem-cell transplantation2–7. Importantly, lenalidomide ment of myeloma cannot, therefore, be underestimated. and dexamethasone have become the backbone of the A hypersensitivity reaction (hsr) manifested by der- next generation of highly effective combination regimens matologic eruptions secondary to an imid is often prob- when administered with carfilzomib, ixazomib, or mono- lematic, resulting in the withholding of critically needed clonal antibodies8,9. treatment in advanced disease. The observed rates of hsr Correspondence to: Jack T. Seki, Department of Pharmacy, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, Ontario M5G 2M9. E-mail: [email protected] n DOI: https://doi.org/10.3747/co.24.3572 e328 Current Oncology, Vol. 24, No. 4, August 2017 © 2017 Multimed Inc. POMALIDOMIDE DESENSITIZATION, Seki et al. in clinical trials are limited, having been reported to range medications without the occurrence of adverse events: between 1% or greater and less than 5%19. Of 35 patients, oral penicillin 300 mg daily (continuous prevention for 1 (2.9%) withdrew from a study of pomalidomide plus a previous encapsulated bacterial infection), ranitidine, low-dose dexamethasone because of skin rash, and of famciclovir (recent herpes infection), oral dexamethasone 38 patients, 1 (2.6%) was suspected of a grade 2 skin rash 12 mg weekly (part of her chemotherapy regimen), and oral in a separate phase i maximal tolerated dose study of aspirin 81 mg daily (for thrombosis prevention while on an pomalidomide10,20. But those reports might not reflect immunomodulating agent). rates observed in clinical practice, given that the eligibil- Lenalidomide was discontinued, and on 31 August ity criteria clearly excluded patients with a prior history of 2011, the patient commenced weekly oral cyclophospha- drug hypersensitivity to lenalidomide or thalidomide19. mide and dexamethasone instead. That combination Benefits of drug desensitization protocols have been treatment was discontinued in November 2013 because of demonstrated in immunologic reactions related to immu- myeloma progression. During the next 17 months, the pa- noglobulin E, as well as in some non–immunoglobulin E tient received multiple chemotherapies: bortezomib-based immune-mediated reactions21,22. Such protocols have therapy, and trametinib plus an Akt inhibitor, followed proved to offer a potential solution for many patients by selinexor (KPT-330)25,26 plus dexamethasone, both on when treatment alternatives are limited and the benefits clinical trial, without a durable response. In desperation, of desensitization outweigh the risks21,22. Principles d-pace (dexamethasone plus cisplatin–doxorubicin– and protocols for rapid drug desensitization have been cyclophosphamide–etoposide) was administered for described and used with success for patients with hsrs 1 cycle, but her course was complicated by significant to many classes of drugs, including chemotherapy23,24. infections and chemotherapy-related toxicity; further An oral suspension of pomalidomide—which is essen- cycles were felt to be excessively risky. tial for rdp—is not available in the market. However, we Given that this patient had not experienced an ad- managed to develop an extemporaneously prepared in- equate trial of the imid family of drugs because of her house pomalidomide suspension for that purpose. Here, well-documented hsrs to thalidomide and lenalidomide we report our first experience with rdp in a patient for (as already described), there was concern about a potential whom all other available treatment options had failed, intolerance to pomalidomide. The team decision was then including two clinical trials. This first successful case to attempt a rdp for pomalidomide to offset the anticipated of pomalidomide-related rdp involved a patient whose cross-sensitivity to the imids that had already been tried. initial moderately severe hypersensitivity was related to During the protocol, the patient denied any adverse thalidomide and lenalidomide. events and experienced only minor fluctuations of her sys- tolic blood pressure, and those only at the first few steps of CASE DESCRIPTION the procedure. An intravenous line infusing normal saline was maintained to keep a vein open. The patient’s overnight Medical History and Treatments hospitalization was uneventful, and the next morning, In 2004, a 54-year-old woman was diagnosed, by fluo- she was rechallenged with the target dose and discharged rescence in situ hybridization, with immunoglobulin G about 4 hours later without any adverse reaction. lambda multiple myeloma with del 13q. Despite a strong family history of rheumatoid arthritis, the patient was not RDP Method diagnosed with that disease. She did not have asthma, and After informed consent had been obtained from the patient she had no food or medication allergies to report. and all questions about potential risks and benefits were Thalidomide was initiated as maintenance after up- answered, her clinical history was assessed. On the day front tandem autologous stem-cell transplantation, but scheduled for the rdp, 3 mg capsules of pomalidomide its use was complicated by the development of signifi- (Pomalyst: Celgene, Mississauga, ON) were suspended in cant hives and generalized rash (grade 3 by the Common 0.5% carboxymethylcellulose sodium usp (Sigma-Aldrich, Terminology Criteria for Adverse Events, version 4), which Oakville ON); 0.5 mL food-grade 0.25% Tween 80 (Sigma- required its cessation about a week and a half after the start Aldrich) was admixed to facilitate serial dilutions for use in of the 1st cycle of treatment. At the time of the thalidomide the preparation of dosing syringes for the desensitization. hsr, the patient was taking multivitamins and minerals, Literature search results supported the idea that carboxy- and vitamin D and calcium supplements, with the oc- methylcellulose could be used to suspend pomalidomide