Giant cellulitis‐like Sweet's syndrome induced by gilteritinib

Dear Editors, Neutrophilic dermatoses (ND) are a heterogeneous group of inflammatory skin disorders characterized by dense neutrophilic infiltration in the absence of infection. Among them, Sweet's syndrome (SS) is the prototypical presentation, typically manifesting as painful, erythematous plaques accompanied by fever and systemic inflammation.1 We present the case of a 67-year-old woman with relapsed NPM1/FLT3-ITD–mutated acute myeloid leukemia (AML), who was undergoing cytoreduction with hydroxyurea and induction therapy with azacitidine, venetoclax and gilteritinib. After one month of consolidation therapy with gilteritinib, she developed high fever and a tender, indurated erythematous-violaceous plaque affecting the right periorbital and malar regions (Figure 1a). The lesion was warm, painful and infiltrated, but ocular motility remained intact. Preseptal cellulitis, invasive fungal infection and leukaemia cutis were suspected. Given the patient's relapsed AML, profound cytopenia and periorbital involvement, broad-spectrum antibacterial and antifungal therapy (meropenem, vancomycin and amphotericin B) was initiated according to institutional sepsis protocols, but without improvement. In the following days, new tender plaques appeared at sites of subcutaneous low-molecular-weight heparin injections (Figure 1b,c), suggestive of pathergy. Laboratory findings included leucopenia (2,560/µL), thrombocytopenia (33,000/µL), elevated C-reactive protein (314 mg/L) and low procalcitonin (0.29 ng/mL). Imaging ruled out orbital involvement. Skin biopsy revealed dense neutrophilic infiltration of the dermis and hypodermis without microorganisms (Figure 1e,f). Special stains and microbiological workup were negative. A diagnosis of giant cellulitis-like Sweet's syndrome (GCSS) was established. Gilteritinib was discontinued, and intravenous methylprednisolone (125 mg/day) was administered for five days, followed by a tapering course of oral prednisone and adjunctive topical fluticasone. Lesions resolved rapidly (Figure 1d). Colchicine 0.5 mg/day was initiated after completion of corticosteroids as maintenance therapy, and was maintained for six months until transplantation, with good tolerance. The patient underwent hematopoietic stem cell transplantation, with no recurrence at six months. GCSS is a rare variant of ND characterized by extensive, erythematous, painful plaques that mimic bacterial infection.2 Systemic symptoms such as fever and elevated inflammatory markers are frequent. GCSS often leads to antibiotic overuse and delay in appropriate management.2 In our case, early biopsy was critical to avoid unnecessary prolonged antimicrobial therapy. FLT3 inhibitors like gilteritinib are increasingly used in relapsed AML.3 Rash is a common adverse event,4 but SS and other neutrophilic dermatoses are rare and under-recognised.4-10 Thus far, ten cases of FLT3 inhibitor–associated neutrophilic dermatoses have been described in the literature, six of which were related to gilteritinib (Table 1).4-9 The most accepted pathogenic theory proposes that FLT3 inhibitors induce rapid differentiation of myeloid precursors retained in the bone marrow, leading to extramedullary migration and onset of clinical features. Most reported cases occurred in women, with latency periods ranging from 2 to eight weeks.4-9 Seervai et al. recently described recurrent SS with gilteritinib and quizartinib, including mucosal lesions, and proposed a class-effect mechanism.4 Gilteritinib has also been associated with exacerbation of pre-existing ND with multiorgan involvement.10 However, to our knowledge, this is the first report of GCSS induced by FLT3 inhibition, with prominent periorbital involvement and pathergy. Notably, most reported cases of FLT3 inhibitor – associated Sweet's syndrome had poor outcomes, often related to underlying disease progression, underscoring the importance of early recognition and multidisciplinary management.4-10 This raises the hypothesis that FLT3 inhibition may stimulate leukemic myeloid precursors in certain patients, contributing to the development of neutrophilic dermatoses in the context of disease progression. Martín et al. (2024)4 W 38 y.o. Neutropenia Rash Granuloma annulare Seervai et al. (2024)5 W 73 y.o. Fever Neutropenia Mucosal lesions Yang et al. (2024)6 W 57 y.o. Fever Neutrophilia Systemic CS Death (pneumonia and respiratory failure) Paudel et al. (2020)7 W 55 y.o. Fever Pancytopenia Neutropenia W 40 y.o. Systemic CS Death (disease progression) M 70 y.o. Topical CS FLT3i discontinuation (disease progression) W 60 y.o. Fathi et al. (2013)9 W 29 y.o. Systemic CS FLT3i discontinuation (disease progression) Fathi et al. (2013)9 W 60 y.o. Pulmonary nodules (subclinic) Systemic CS Death (sepsis) Fathi et al. (2013)9 M 56 y.o. Pulmonary nodules (subclinic) Death (disease progression) The Naranjo scale yielded a score of 7, consistent with a probable adverse drug reaction. The patient fulfilled all five Walker–Cohen criteria. The temporal association, exclusion of infection, and rapid response to corticosteroids strongly support causality. Colchicine maintenance was effective and well tolerated. Although dapsone is a therapeutic alternative for neutrophilic dermatoses, it was avoided in this case due to the patient's hematological condition and risk of hemolysis/methemoglobinemia. This case illustrates the need to recognize GCSS as a rare but distinct entity.2 In leukemia patients, cellulitis-like eruptions may signal neutrophilic dermatoses rather than infection. FLT3 inhibitors like gilteritinib can trigger these reactions, which may, in certain cases, suggest underlying disease progression. We sincerely thank Dr. Juan Ruano, from whom we continue to learn in the field of research. We also extend our gratitude to the Maimonides Biomedical Research Institute of Cordoba (IMIBIC) and to the Dermatology and Hematology departments of our hospital for their continued support and collaboration. Funding for open access charge: Universidad de Córdoba / CBUA. None.