Complex Interplay Between Sweet Syndrome and Therapy-Related Myelodysplastic Syndrome After B-Cell Lymphoma Treatment: A Case Report

Introduction

Sweet syndrome (SS), also termed acute febrile neutrophilic dermatosis, is a rare inflammatory condition associated with various disorders [1]. SS is classified into 3 types: classical, malignancy-associated, and drug-induced. Hematologic malignancies, such as acute myeloid leukemia and myelodysplastic syndromes (MDS), are more commonly associated with malignancy-associated SS [2].

Therapy-related MDS (tMDS) is a well-recognized subtype of myelodysplastic syndrome that arises due to exposure to chemotherapy or radiation therapy [3]. Typically, tMDS exhibits a more aggressive clinical course and worse outcomes compared with those of de novo MDS. Reports on SS associated with tMDS are limited, with unclear clinical features [4–7]. Herein, we present a case of SS that developed before tMDS diagnosis and ultimately progressed to a fatal infection.

Case Report

An 86-year-old woman was diagnosed with primary rectal lymphoma, classified as low-grade B-cell lymphoma, unclassifiable, and at Lugano stage I. Following 6 cycles of chemotherapy with bendamustine and rituximab (BR therapy), complete metabolic remission was confirmed via positron emission tomography-computed tomography (CT). This date is designated as day 0 in Figure 1A, which depicts the clinical course. On day 12, the patient presented to the Emergency Department with a fever. Laboratory tests revealed pancytopenia, with a white blood cell count of 2290/μL, hemoglobin level of 8.7 g/dL, and platelet count of 107 000/μL, which was initially attributed to bone marrow suppression caused by BR therapy. On day 14, PCR detected cytomegalovirus (CMV) viremia, and oral valganciclovir was initiated. On day 28, her fever persisted, and she developed a nodular erythematous rash. Dermatological examination revealed painful erythema with elevated nodules on the lateral aspect of her left thigh (Figure 1B) and lower leg (Figure 1C). Hematoxylin and eosin staining of a skin biopsy showed diffuse infiltration of mature neutrophils within the dermal layer (Figure 1D, 1E). An extensive workup, including blood cultures, antigen-antibody tests, and CT imaging, revealed no evidence of active infection. The diagnosis of SS was made in accordance with the Su and Liu criteria [1]. On day 34, treatment with oral prednisolone (1 mg/kg/day) and colchicine (1 mg/day) was initiated, and prophylactic fluconazole (100 mg/day) was administered to prevent fungal infections. This treatment promptly improved both the skin lesions and the fever.

Pancytopenia persisted following BR therapy, and on day 33, the patient’s white blood cell count was 2030/μL, hemoglobin level was 6.2 g/dL, and platelet count was 89 000/μL, leading to transfusion-dependence from day 34. On day 41, bone marrow aspiration revealed granulocytic hypogranulation and a pseudo-Pelger-Huët anomaly, with 1.5% ring sideroblasts and 3.2% myeloblasts. Cytogenetic analysis showed a complex karyotype, including hyperdiploidy, leading to a diagnosis of MDS with low blast counts [8]. The IPSS-R score was calculated to be 7, corresponding to the very high-risk category [9]. On day 81, the patient received the first cycle of azacitidine (75 mg/m2 on days 1–7); however, her pancytopenia did not improve, and she opted for palliative care. On day 111, she was admitted to our hospital with impaired consciousness, and CT revealed a brain mass. However, her family opted for continued supportive care. She died on day 118. Following her wishes, a postmortem autopsy was performed, revealing an Aspergillus brain abscess, with no evidence of lymphoma recurrence. Throughout the clinical course, blood tests for β-D-glucan and Aspergillus galactomannan antigen remained negative.

Discussion

The terminal event in this case provides significant educational insights. A retrospective survey demonstrated that BR therapy was associated not only with an increased risk of secondary malignancies, including MDS, but also with a significantly shorter time to onset compared with regimens such as R-CHOP, R-CVP, and R-THPCOP [10]. In the present case, BR therapy might be considered as a trigger for the development of MDS. However, as genetic mutation analysis was not performed, the possibility that both lymphoma and MDS originated from a common ancestral clone, including age-related clonal hematopoiesis of indeterminate potential, should also be considered [11–16]. These mechanisms merit further exploration in future research.

To thoroughly assess this unique case, we conducted a comprehensive search on PubMed. We identified 4 cases of concurrent SS and tMDS (Table 1) [4–7]. The median age of these patients was 61 years, and 3 of the cases involved men. The preceding cancers included malignant lymphoma (Hodgkin’s lymphoma, marginal zone lymphoma), anaplastic astrocytoma, and uterine cancer. After SS diagnosis, all patients received corticosteroid treatment, and 1 patient also received colchicine. In 2 cases, SS was resolved, while in 3 cases, death due to progression to acute myeloid leukemia (AML), respiratory failure, and pneumonia was reported.

Our case is noteworthy as Sweet syndrome preceded the diagnosis of tMDS, in contrast to previous reports where SS typically followed tMDS. In a retrospective study of AML and SS, 8 of 21 patients (38.1%) were diagnosed with SS either before or at the time of AML diagnosis [17]. Similar to the present case, the possibility of concurrent myeloid malignancies should be considered when diagnosing SS. Differential diagnosis for pancytopenia included BR therapy-induced bone marrow suppression and drug-induced cytopenia from valganciclovir, complicating the simultaneous diagnosis of tMDS and SS. In addition, CMV-associated SS has been reported in the literature, suggesting that both MDS and CMV might be considered as potential triggers for SS [18]. This case highlights the complexity of differential diagnosis in patients with post-chemotherapy cutaneous complications and cytopenia.

While corticosteroids and colchicine improved the patient’s skin lesions, optimal treatment regimens for hematologic malignancy-associated SS remain undefined [2]. For the treatment of SS, corticosteroids, colchicine, and potassium iodide are generally used [1]. In cases of SS associated with MDS, some reports suggest azacitidine can improve SS in MDS patients [19]. However, contradictory reports of azacitidine-induced SS necessitate careful monitoring during combined therapy [20].

The patient’s death from aspergillosis highlights the infection risks in immunocompromised patients with neutropenia, hematologic malignancies, and corticosteroid use [21]. Although fluconazole, which we used for prophylaxis, does not cover filamentous fungi, the benefit of including mold-active agents in antifungal prophylaxis remains unestablished [22]. Additionally, β-D-glucan and Aspergillus galactomannan antigen remained negative in our patient, making preemptive antifungal strategy less justifiable [23]. This case underscores the need for cautious corticosteroid use in immunocompromised SS patients, considering dosage and duration to balance therapeutic benefits against infection risks.

Conclusions

In conclusion, this case deviates from the typical clinical course, as SS was evident prior to the diagnosis of MDS, prompting reconsideration of the potential links among lymphoma, SS, and MDS. It also underscores the inherent difficulty in optimizing the dosing and duration of corticosteroid therapy for SS in immunocompromised patients. We hope that the continued accumulation of evidence will lead to improved therapeutic strategies for patients with similar conditions.