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The chemotherapeutic agent cytarabine represents an effective treatment for acute myeloid leukemia and lymphomas. Cytarabine is a pyrimidine nucleoside that induces DNA damage in the S phase of the cell cycle. Moreover, cytarabine inhibits DNA and RNA polymerases as well as nucleotide reductase. Thereby, rapidly cycling cells are the most affected. Due to its strong biological effects on a variety of cells and tissues, important adverse reactions might occur during treatment with cytarabine, such as myelosuppression, gastrointestinal disorders, neurotoxicity, hepatitis and an immediate infusion reaction, known as “cytarabine syndrome”. This latter clinical entity is dose-dependent and includes fever, diaphoresis, myalgia and skin eruptions [1]. Although cases of hypersensitivity reactions to chemotherapeutic agents have been observed, allergy to cytarabine is uncommon and only sporadic reports exist [2]. Particularly, no delayed hypersensitivity reactions have been described in adults, so far. Here, we report 2 cases of adult patients with delayed hypersensitivity to cytarabine that resolved successfully after desensitization. Case 1: A 66-year-old woman was diagnosed with acute myeloid leukemia in March 2012 and started a cytarabine treatment (160 mg/day, for 3 days), with no adverse effects. Likewise, in April and May 2012, two further cytarabine courses were well tolerated. However, in June 2012, she developed a severe cutaneous rash with intensively itchy and partially eroded erythematous maculae, widespread to the trunk and the extremities, 3 days after the treatment (Figure 1 A). Of note, the patient presented a marked eosinophilia (4730 cells/μl) and developed a sterile dental abscess after the cytarabine administration course, in the absence of any dental diseases prior to the therapy. In order to exclude a possible cytarabine syndrome, a second cycle of treatment with reduced dosage was performed (80 mg/day, for 3 days). However, the patient developed the same symptoms, with similar time of onset as above (including the same sterile dental abscess), suggesting that the adverse reaction was immunologic in nature and delayed in presentation. After 15 days, we performed skin tests, with two distinct techniques: skin prick testing and intradermal testing. The patient was first subjected to skin prick testing, using a 20 mg/ml cytarabine solution and, successively, to intradermal tests with 4 different 10-fold concentrations (0.02, 0.2, 2 and 20 mg/ml). Both skin testing procedures proved negative. Neither patch tests (the patient declined) nor any in vitro tests were performed. Lymphocyte proliferation test (LPT) was not yet established. Thus, based on the clinical symptoms, the time of onset of the adverse reaction, the lack of dependency on the dose administered and the negative results of the skin tests, the patient was diagnosed with delayed hypersensitivity to cytarabine (clinically). Importantly, the eosinophilia at the time of diagnosis and the finding of the recurrent sterile dental abscess concomitant with cytarabine treatment rendered the adverse reaction compatible with a possible drug reaction with eosinophilia and systemic symptom (DRESS), according to RegiSCAR scoring system [3]. Case 2: A 69-year-old man, also diagnosed with acute myeloid leukemia, started a cytarabine treatment course in December 2015 with no adverse effects. Likewise, in January 2016, a second cytarabine course was well tol-

A desensitization protocol for delayed allergy to cytarabine: analysis of two cases