Sweet syndrome induced by FLT3 inhibitors: case report and literature review

ABSTRACT

Background:

Acute febrile neutrophilic dermatosis, also commonly referred to as Sweet syndrome, is often associated with tumors, infections, immune disorders and medications. FLT3 inhibitor-induced Sweet syndrome is a rare complication.

Methods and results:

We report a patient with relapsed and refractory acute monocytic leukemia harboring high-frequency FLT3-ITD and DNMT3a mutations. The FLT3 inhibitor gilteritinib was administered for reinduction therapy after failure of chemotherapy with a combination of venetoclax, decitabine, aclarubicin, cytarabine and granulocyte colony-stimulating factor. The leukemia patient achieved remission after 1 month of treatment. However, Sweet syndrome induced by gilteritinib, which was confirmed by skin biopsy, developed during induction therapy. Similar cases of Sweet syndrome following FLT3 inhibitor therapy for acute myeloid leukemia were reviewed.

Conclusion:

Attention should be given to this rare complication when FLT3 inhibitors are used for acute myeloid leukemia therapy, and appropriate treatments need to be administered in a timely manner.

KEYWORDS:

• Sweet syndrome
• gilteritinib
• acute myeloid leukemia

Introduction

Acute febrile neutrophilic dermatosis, also commonly referred to as Sweet syndrome, is characterized by fever, leukocytosis, tender plaques and nodules and histologically manifests as superficial dermal neutrophil infiltration. Sweet syndrome is often associated with tumors, infections, immune disorders, medications, etc[1]. Among those with tumor-related Sweet syndrome, hematologic malignancies are more common than solid tumors.[2,3] Drug-induced Sweet syndrome can be triggered by a variety of medications, including colony-stimulating factors, immunosuppressants, antineoplastics and antibiotics [4]. The potential correlation between drugs and Sweet syndrome needs to be carefully evaluated and distinguished, especially when multiple factors co-exist in clinical circumstances.

The receptor tyrosine kinase FMS-like tyrosine kinase-3 (FLT3) gene is the most commonly mutated gene in acute myeloblastic leukemia (AML), accounting for approximately 30% of patients with mutated genes.[5] FLT3 inhibitors have been widely used for the treatment of AML with FLT3-internal tandem duplication (ITD) or tyrosine kinase domain (TKD) mutations. Here, we report a patient with relapsed and refractory AML who suffered from Sweet syndrome, a rare complication during the administration of gilteritinib. Additionally, similar cases were also reviewed under the circumstances of FLT3 inhibitors for AML therapy, which reminded clinicians to consider the development of this rare complication when FLT3 inhibitors are administered.

Case presentation

A 57-year-old woman was diagnosed with acute monocytic leukemia harboring high-frequency FLT3-ITD and DNMT3a mutations in March 2022. A cycle of daunorubicin and cytarabine led to complete remission (CR). However, the AML relapsed 1 month after CR. Reinduction chemotherapy with a combination of venetoclax, decitabine, aclarubicin, cytarabine and granulocyte colony-stimulating factor resulted in no response. An increasing number of blast cells were detected in the peripheral blood. Reexamination of gene mutations via next-generation sequencing (NGS) revealed the same mutations at the time of diagnosis. Gilteritinib (120 mg daily) was administered, and the dose was reduced to 80 mg daily due to prolonged Q-T intervals on the 8th day. On the 13th day, the patient complained of swelling and pain in the right forearm, accompanied by fever the next day. Cellulitis was suspected, and linezolid was administered. However, the symptoms did not resolve. On the 16th day, well-demarcated red plaques appeared at the puncture sites on both forearms (Figure 1(A and B)), and the erythema turned dark red, with nodules that could be seen on it. Moreover, continuous monitoring of peripheral blood revealed that white blood cells and absolute neutrophil counts gradually recovered without the presence of blast cells (Figure 2(A)). A diagnosis of Sweet syndrome was suspected. Therefore, skin biopsy was performed, and 40 mg of methylprednisolone was used daily for 11 days. Notably, on the second day of medication, the rash started to progressively fade with alleviated pain. The patient's red plaques on both forearms gradually disappeared as her temperature recovered. Skin biopsy revealed severe inflammatory cell infiltration in the dermis layer in a low-power view (Figure 2(B), hematoxylin–eosin, original magnificationx40), and the infiltrated inflammatory cells were mainly composed of neutrophils in a high-power view (Supplementary figure, hematoxylin–eosin, original magnificationx400). Immunohistochemistry revealed no myeloblasts, which confirmed the diagnosis of Sweet syndrome. Gene mutation analysis with NGS from the skin revealed the same FLT3-ITD and DNMT3a mutations as in the blast cells of peripheral blood (Figure 3(A and B)), indicating that the neutrophils differentiated from the blast cells. Bone marrow smears were checked for 3.5% blast cells on the 30th day, and flow cytometry indicated no measurable residual disease in the bone marrow. A complete blood test revealed a white blood cell count of 4.31 × 10⁹/L (3.5–9.5, x10⁹/L), an absolute neutrophil count of 3.85 × 10⁹/L (1.8–6.3, x10⁹/L), a hemoglobin level of 57 g/L (130–175, g/L) and a platelet count of 43 × 10⁹/L (100–300, x10⁹/L). Complete remission with incomplete recovery was achieved. Unfortunately, the patient suffered from severe pneumonia and respiratory failure. Anti-infection therapy led to little response. The patient and her family decided to stop treatment, and the patient died the day after discharge.

Figure 1. (A) Red plaques and nodules on the forearm. (B) Circular red plaques with nodules at the edge of the forearm.

Figure 2. (A) Changes in blood cell counts and rash during gilteritinib administration. WBC, white blood cell; ANC, absolute neutrophil count; Hb, hemoglobin; PLT, platelet count. (B) Skin biopsy indicated severe inflammatory cell infiltration in the dermis layer (40×).

Figure 3. (A) and (B) Gene mutation analysis of FLT3 and DNMT3A in the skin via next-generation sequencing; the results were the same as those for AML cells with mutations in the bone marrow. (Complementary image) The infiltrated inflammatory cells were mainly composed of neutrophils in the dermis layer (hematoxylin-eosin, original magnification x400).

Discussion

Usually, patients with drug-induced Sweet syndrome need to meet the following criteria [6,7]: (1) have appropriate signs and symptoms, such as fever and painful red plaques; (2) have a temporal relationship between the above symptoms and drug ingestion; (3) have histopathological manifestations consistent with Sweet syndrome; and (4) have temporal relationships between lesion regression and drug withdrawal or treatment with corticosteroids. In our case, the patient developed painful red plaques at puncture sites on both upper limbs during the administration of gilteritinib, and skin biopsy revealed neutrophil infiltration in the dermis layer, which was consistent with Sweet syndrome. Additionally, her red rash and temperature gradually returned to normal after treatment with methylprednisolone rather than antibiotics. More importantly, genetic analysis revealed that the FLT3-ITD-positive neutrophils that infiltrated the skin differentiated from the FLT3-ITD-positive AML cells. Therefore, gilteritinib-induced Sweet syndrome was considered because the differentiation process was caused by it. Due to the alleviation of Sweet syndrome with corticosteroids as well as incomplete remission of AML, gilteritinib was not discontinued after the onset of Sweet syndrome.

Gilteritinib is a highly selective FLT3 inhibitor and is used to treat relapsed, refractory AML patients with FLT3 mutations. In addition to gilteritinib, other FLT3 inhibitors have been widely integrated into the treatment of AML patients with FLT3-ITD or TKD mutations. FLT3 mutations are known to inhibit CCAAT/enhancer binding protein alpha (CEBPA), which is a basic leucine zipper transcription factor that directs granulocyte differentiation and plays an important role in the transcriptional process driving self-differentiation and myeloid differentiation of hematopoietic stem cells. Therefore, FLT3 mutations promote rapid cell division without differentiation [8]. FLT3 inhibitors block the activation of FLT3, which causes the dephosphorylation of CEBPA, thereby allowing further differentiation and maturation of AML cells. During this process, chemokines and systemic inflammatory responses are increased, which can cause the appearance of fever and painful red plaques, known as Sweet syndrome [9]. However, to date, the exact mechanism by which differentiated and mature AML cells accumulate in large numbers in the dermis layer of the skin is unknown. Recently, Fathi AT et al. suggest that differentiation syndrome results from a severe systemic inflammatory response mediated by increased expression of cytokines (cytokine storm), chemokines, and adhesion molecules (e.g. integrins) on differentiating blast cells that exhibit some morphological and functional characteristics of mature monocytes or neutrophils [10]. Moreover, incidents of differentiation syndrome have also been documented in association with IDH inhibitors for AML therapy [11]. Hence, FLT3 inhibitor-induced Sweet syndrome has some similarities to differentiation syndrome during low-intensity therapy with FLT3 or IDH inhibitors for AML, and it may be a special manifestation of differentiation syndrome [12,13].

Similar manifestations can also be triggered by other FLT3 inhibitors, such as sorafenib and quizartinib. In our summary concerning FLT3 inhibitor-associated Sweet syndrome (Table 1), Sweet syndrome developed within weeks to months after the initiation of FLT3 inhibitors. Tender and erythematous nodules in the extremities were the most common signs, and neutrophil infiltration was mainly in the dermis or subcutaneous fat. In addition, genetic testing of skin lesions has also been conducted in some patients, and all of these studies confirmed that the neutrophils in the skin differentiated from FLT3-mutated leukemia cells [12, 13]. However, further studies are needed to prove whether mature neutrophils differentiated from AML cells have the same physiological functions as normal mature neutrophils.

Table 1. The clinical characteristics of Sweet Syndrome induced by FLT3 inhibitors.

Research	Case number	Diagnosis	FLT3 inhibitor	Presentation	Time to onset of skin lesion, wk	Skin biopsy	Treatment	The outcome of the skin lesion
Fathi AT, et al.	Case 1	Cytogenetically normal AML, with FLT3-ITD and nucleophosmin (NPM1) mutations.	Quizartinib	Tender, erythematous nodules on lower extremities	8	Subcutaneous, lobular mixed inflammatory infiltration, including numerous neutrophils	Oral dexamethasone, discontinue quizartinib	Resolution
	Case 2	FLT3-ITD and NPM1-mutant AML, characterized by translocation t(10;17) (q24;p13) and partial deletion of chromosome 15 (q15q24)	Quizartinib	A tender, erythematous skin nodule on right thigh	6	Deep dermal and subcutaneous inflammatory infiltration consisting of abundant neutrophils	Oral dexamethasone, no mention of discontinuing quizartinib	Resolution
	Case 3	Therapy-related AML, with deletion of 7q and no FLT3 or NPM1 mutations	Lenalidomide and sorafenib	Tender subcutaneous nodules on left thigh	2	Dermal and subcutaneous lobular neutrophilic infiltration	N/A, no mention of discontinuing lenalidomide and sorafenib	N/A
Varadarajan N, et al.	Case 1	Cytogenetically normal AML complicated by relapsed disease with FLT3-ITD	Gilteritinib	Multiple tender, red subcutaneous nodules on back and lower extremities	8	Neutrophil-predominant lobular panniculitis	Prednisone, no mention of discontinuing gilteritinib	Resolution
	Case 2	Acute erythroleukemia with normal karyotype complicated by relapsed disease with FLT3 ITD after induction	Gilteritinib	Pustulonodules on the cheeks, ears, and scalp	8	interstitial neutrophil-rich inflammatory infiltration and clusters of atypical mononuclear cells	Topical corticosteroids, discontinue gilteritinib	Resolution
	Case 3	FLT3 ITD – positive AML	Quizartinib	A tender, red eruption on the neck and arms	8	Neutrophilic inflammatory infiltration and subepidermal edema	Prednisone, discontinue quizartinib	Resolution
Paudel A, et al.	Case 1	Adriamycin-related myelodysblastic syndrome/myeloproliferative neoplasm with blasts and FLT3 ITD mutation	Gilteritinib	Reddish macular, papular and nodular rashes on left arm and forearm, right forearm and on bilateral legs	4	Superficial dermal edema with a perivascular and interstitial cellular infiltration	Prednisone, continue gilteritinib	Resolution
Linhui Y, et al.	Case 1	AML harboring high-frequency FLT3-ITD and DNMT3a mutations	Gilteritinib	Well demarcated red plaques appeared at puncture sites on both forearms	2	Neutrophil infiltration in dermis layer	Methylprednisolone, continue gilteritinib	Resolution

Withdrawing medicine plays a critical role in drug-induced Sweet syndrome. However, suspending therapy for the underlying disease may also lead to more unfavorable outcomes, especially during the early stage of induction therapy for AML. Therefore, the pros and cons of discontinuing the drug need to be weighed. Fortunately, as seen from the summary of patients with FLT3 inhibitor-induced Sweet syndrome (Table 1), it can be relieved well by intravenous or oral glucocorticoids even without the withdrawal of FLT3 inhibitors, which may result from the anti-inflammatory effects of glucocorticoids. However, glucocorticoids inevitably increase the risk of infections. Therefore, infection should be carefully ruled out, and glucocorticoids should be used with caution when patients present with symptoms such as a tender rash and fever, as described above.

In conclusion, attention should be given to the rare occurrence of Sweet syndrome when FLT3 inhibitors are used for AML, and appropriate treatment should be administered in a timely manner.

Author contributions

All the authors contributed substantially to the work presented in this article. LHY managed the patient in the case and wrote the draft. RZ contributed to the skin biopsy and revision of this article. HBM is mainly responsible for treatment of the patient, completing genetic sequencing of the patient, article revision and overall work coordination.

Ethical approval

This study is a case report and literature review, consent has been obtained from the patient’s family.

Disclosure statement

No potential conflict of interest was reported by the author(s).