A Case of Bullous Sweet Syndrome: In the Setting of AML/MDS Treated with Azacitadine and GilteritinibChang Su, MD1, Emma Weiss, MD2, Goran Micevic, MD, PhD2, Alexander Fogel, MD, MBA2, Mary Laird, MD2, Michael Gowen, MD, MBA2,

Anjela Galan, MD3, Sarika Ramachandran, MD2, Caroline Nelson, MD2

Department of 1 Internal Medicine, 2 Dermatology, 3 Dermatology and Pathology, Yale School of Medicine, New Haven, CT

-8 monthsMDS-RCMD with

fibrosis

-3 monthsMDS/AML, FLT3-

ITD

-2 monthsTendonitis;

prednisone taper 4 days

-1 monthsNecrotizing cellulitis +

bacteremia

CurrentBacteremia + rash

Sweet SyndromeDiagnostic criteria ( 2 major & ≥ 2 minor) Mr. C

Major criteria

1. Abrupt onset of typical cutaneous lesions2. Histopathology consistent with Sweet syndrome

XX

Minor criteria

1. Preceded by one of the associated infections or vaccinations; accompanied by one of the associated malignancies or inflammatory disorders; associated with drug exposure or pregnancy2. Presence of fever and constitutional signs and symptoms3. Leukocytosis4. Excellent response to systemic corticosteroids

X

X

X

Classifications

Case Summary• Mr. C: 37 year old man with past medical history of myelodysplastic syndrome

(MDS)/acute myeloid leukemia (AML) • Vitals: fever, otherwise normal; labs: baseline; cultures: Clostridium septicum

bacteremia, otherwise negative• Day 7: dozens of 3-8mm tender, edematous red-purple papules surrounded by

pink thin edematous patches and plaques on his legs, buttocks, arms, chest, face, scalp, arms, and oral mucosa. Day 10: papules -> bullae

• Fever persisted despite broad-spectrum antiviral, antifungal, and antibacterial treatments; full infectious workup negative

• Skin biopsy: neutrophilic dermatosis, sterile tissue cultures negative• Diagnosis: bullous Sweet syndrome (acute febrile neutrophilic dermatosis)• Treatment: high dose corticosteroids; lesions improved & fever resolved after

2 weeks; discharged on 4-week corticosteroid taper.

Classic Infection, inflammatory, vaccination, pregnancy

30%

Drug –other2%

AML 43%

MDS18%

Other hematologic malignancies

21%

Solid tumor18%

Malignancy44%

Drug –malignancy

22%

ReferencesFathi AT, Le L, Hasserjian RP, Sadrzadeh H, Levis M, Chen YB. FLT3 inhibitor-induced neutrophilic dermatosis. Blood 2013; 122(2): 239-42.Kaur A, Jacobs MS, Raza S. Characteristics of Sweet's syndrome associated with novel acute myeloid leukemia targeted drugs—Midostaurin and Enasidenib. Advances in Cell and Gene Therapy 2019; 2(4): e61.Kazmi SM, Pemmaraju N, Patel KP, et al. Characteristics of Sweet Syndrome in patients with acute myeloid leukemia. Clin Lymphoma Myeloma Leuk 2015; 15(6): 358-63.Nelson CA, Noe MH, McMahon CM, et al. Sweet syndrome in patients with and without malignancy: A retrospective analysis of 83 patients from a tertiary academic referral center. J Am AcadDermatol 2018; 78(2): 303-9 e4.Paudel A, Dhital R, Areoye G, Basnet S, Tachamo N. Sweet’s syndrome in a granulocytopenic patient with acute myeloid leukemia on FLT3 inhibitor. Journal of Community Hospital Internal Medicine Perspectives 2020; 10(3): 275-8.Su WP, Liu HN. Diagnostic criteria for Sweet's syndrome. Cutis 1986; 37(3): 167-74.Varadarajan N, Boni A, Elder DE, et al. FLT3 Inhibitor-Associated Neutrophilic Dermatoses. JAMA Dermatol 2016; 152(4): 480-2.Walker DC, Cohen PR. Trimethoprim-sulfamethoxazole-associated acute febrile neutrophilic dermatosis: case report and review of drug-induced Sweet's syndrome. J Am Acad Dermatol1996; 34(5 Pt 2): 918-23.Bolognia JL, Schaffer JV, Cerroni L. Dermatology Fourth ed: Elsevier Health Sciences; 2018.

DiscussionFLT3 inhibitor & Neutrophilic Dermatosis

Age/Sex Location(s) FLT3 inhibitor Onset (weeks) Treatment

29/F Lower extremities Quizartinib 8 PO dexamethasone

60/F Right thigh & pulmonary

Quizartinib 6 PO dexamethasone

56/F Left thigh & pulmonary

Sorafenib 2 n/a

61/F forearm, shins, anterior chest

Midostaurin 1.3 PO prednisone

55/F All 4 extremities Gilteritinib 4 PO prednisone

70s/M cheeks, ears, scalp

Gilteritinib 8 Topical steroids

60s/F Neck, arms Quizartinib 8 PO prednisone

• 1% AML patients develop Sweet syndrome, among which FLT-3 is the most common mutation (~40%)

• Differentiated neutrophils in the skin lesions have the same ancestry as the original FLT3-mutant myeloblasts

• FLT3 inhibitor associated neutrophilic dermatosis ≈ differentiation syndrome for patients with acute promelocytic leukemia treated with all-trans retinoic acid (terminal differentiation of leukemic clones)

ConclusionMr. C had Sweet syndrome most likely associated with his AML/MDS, with azacitadine and gilteritinib as other possible triggers. High dose corticosteroid taper is the treatment of choice for Sweet syndrome.

Gilteritinib (FLT3 inhibitor)

Azacitadine (demyelinating agent)

Day 0 Day 3 (started corticosteroids) Day 7 Day 18

A month before the current presentation, Mr. C was admitted for coagulase negative Staphylococcus (CoNS) bacteremia and necrotizing cellulitis of the face due to CoNS and Cutibacterium acne.Left: initial presentation. Middle: immediately after debridement x2. Right: one week post debridement & antibiotics.

Case Summary

Initial vitals/labs: Temp: 102.7 °FPulse: 86BP: 128/65SpO2: 99% on room air

ALT 28, AST 17Alk Phos 59, Eos 0, ANC 1.7

137 101 13

3.1 27 0.66107

8

22.52.3 33