All-Transretinoic acid (ATRA)-Induced Sweet Syndrome in Relapsed Promyelocytic Leukemia

Dear Editor, Drug-related Sweet syndrome (SS) is an inflammatory skin disorder characterized by the abrupt onset of erythematous nodules or painful plaques. It is accompanied by a dermal neutrophilic infiltrate, without evidence of vasculitis. Three SS variants have been described: idiopathic, malignancy-associated (approximately 20% of all cases, 85% of which are of hematological origin), and drug-induced.[1] SS-causing drugs commonly used in the treatment of hematological disorders include filgrastim, bortezomib, azathioprine, lenalidomide, and azacitidine.[1-4] In the medical literature, there are 20 case reports of SS induced by all-transretinoic acid (ATRA), of which four patients simultaneously presented with ATRA syndrome, one presented with the histiocytoid variant, and one presented with scrotal ulceration [Table 1]. Theories on the etiopathogenesis of drug-related SS include inappropriate regulation and massive release of inflammatory cytokines, such as interleukins (IL)-1, IL-3, IL-6, IL-8, and granulocyte- colony stimulating factor (G-CSF).[3,4]Table 1: Cases of all-transretinoic acid (ATRA)-induced Sweet syndrome in acute promyelocytic leukemia reported in the literatureWe present the case of a 57-year-old man with a history of acute promyelocytic leukemia (APL), who visited our hospital in 2020. He was under medical surveillance after meeting the PETHEMA-2012 protocol response criteria; there was no history of toxicity to any drug (including ATRA). In February 2024, he went to the emergency room due to a 48-hour history of bleeding gums and lower-extremity ecchymosis. Bone marrow aspirate analyses revealed 82% promyelocytes with azurophilic hypergranulation and the presence of Auer rods in the cytoplasm of some cells. The patient was positive for PML/RARα t (15;17) (q22;q21), so relapse was finally diagnosed. Under the PETHEMA-2017 protocol guidelines, induction therapy with ATRA-idarubicin was initiated. On the 14th day after ATRA initiation (45 mg/m2/day), the patient presented with erythematous-edematous papules and plaques on the back, upper extremities, and dorsum of both hands, together with an ulcer on the left lateral border of the tongue [Figure 1a, 1b, 1c]. Dermatoscopy was not performed.Figure 1: Erythematous-edematous papules and plaques affecting (a) dorsum of both hands, and (b) posterior region of the forearm; (c) Ulcer on the left lateral border of the tongueThe dermatology unit performed a skin biopsy from the right arm and tongue ulcer scraping. Together with the hematology unit, it was agreed to administer prednisone (5–10 mg/day) for 10 days and to maintain ATRA, as signs of ATRA syndrome were lacking. The differential diagnosis proposed was leukemia cutis, the frequency of which varies from 10% to 15% of cases, depending on the subtype of primary leukemia (acute myelomonocytic leukemia and acute monocytic leukemia account for more than half of cases). The most common dermatological manifestations in APL are the presence of ecchymosis and hematomas due to its associated disseminated intravascular coagulopathy. Analysis of skin biopsy samples revealed a predominant neutrophilic infiltrate at the superficial and deep perivascular levels, accompanied by scattered eosinophils and histiocytes, extending to the sweat glands and ducts. A conspicuous neutrophilic infiltrate, mild spongiosis, and occasional necrolytic keratinocytes were observed in the epidermis, without major architectural alterations. Mitotic figures in stromal cells and reactive endothelial cells were also observed. Immunohistochemistry staining phenotypes were CD3+ (lymphocytes), CD5+ (lymphocytes), TdT-, CD79+, CD20+, Ki67+ (60% in lymphocytes), MPO+ (neutrophils), CD30-, and CD34-, and excluded neoplastic infiltrates or leukemia cutis [Figure 2a, 2b, 2c, 2d].Figure 2: (a, b, d) Neutrophilic infiltrate at the stromal, perivascular, interface line, and intraepidermal levels (Hematoxylin-eosin x100); (c) CD34 negative in inflammatory cells. (Hematoxylin-eosin x100)Scraping of the ulcer on the tongue excluded infiltration by leukemia or neutrophils. It was considered post-chemotherapy mucositis and was treated with nystatin mouthwash. Both ATRA syndrome and SS improve with steroids. However, they differ in that SS is limited to the skin and occasionally the muscular regions, with internal organs rarely being involved, as was the case with our patient, who did not present with systemic features (e.g., dyspnea, fever, or weight gain). SS can occur between 7 and 34 days after drug exposure.[3-5] The European Leukemia Net 2019 guidelines maintain the recommendation to immediately initiate corticosteroids at the first clinical suspicion of severe ATRA syndrome only.[4] Corticosteroids are the initial treatment; however, if there are any contraindications, potassium iodide or colchicine may be considered. Second-line systemic therapies include indomethacin, clofazimine, dapsone, and cyclosporine.[1] The patient’s dermatological lesions disappeared after corticosteroid treatment, allowing completion of the scheduled chemotherapy pending only consolidation of the response with allogenic stem cell transplantation. Taking into account the classic diagnostic criteria for SS (including those proposed by Von den Driesch), our patient met two major criteria and two minor criteria (high C-reactive protein and response to treatment with systemic corticosteroids), establishing the diagnosis.[6] Oncohematologic patients with relapsed disease are associated with a heightened inflammatory response, which could lead to increased susceptibility to dermatoses that produce excessive cytokine release upon drug exposure, despite prior tolerance. Our patient received a chemotherapy regimen similar to the first-line regimen (including idarubicin). We highlight the importance of interdisciplinary management approaches to these cases. Authors’ contributions We confirm that all authors have read and approved the manuscript for submission. All authors meet authorship criteria, and the manuscript represents honest work. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given her consent for her images and other clinical information to be reported in the journal. The patients understand that her name and initials will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Use of artificial intelligence (AI) The preparation of this manuscript was carried out entirely by the authors without the use of artificial intelligence technologies.