Ibrutinib and Pyoderma Gangrenosum in a Patient With B-Cell Chronic Lymphocytic Leukemia.

To the Editor: We read with interest the case reports of Stewart et al1 and El Halabi et al2 about ibrutinib-induced neutrophilic dermatoses. Ibrutinib is a newtargeted drug, which inhibits the Bruton tyrosine kinase, is highly effective in many lymphoproliferative disorders, and is usually well tolerated. We present the case of a 55-year-old man with chronic lymphocytic leukemia, which reached the criteria for treatment due to the occurrence of an autoimmune thrombocytopenia. He was successfully treated with short-course systemic steroids followed by fludarabine (30 mg/ mq), cyclophosphamide (300 mg/mq), and rituximab for 6 cycles and achieved a partial remission with normal platelet count. Relapse occurred 2 years later, and in May 2018, the patient developed an acute onset of autoimmune hemolytic anemia that responded to high-dose steroids associated with rituximab. The pretreatment diagnostic work-up revealed disease progression with diffuse enlarged lymph nodes and mild splenomegaly, bone marrow infiltration around 70% of chronic lymphocytic leukemia (CLL) cells, as well as mutation on the p53 and the p17 deletion on the other allele, known to confer very poor prognosis in CLL. Therefore, he started on the Bruton tyrosine kinase inhibitor ibrutinib at the recommended dose of 420 mg/die and showed response within 2 weeks with significant improvements on blood counts and lymph adenopathies. After 5 months of ibrutinib treatment, the patient experienced multiple, painful erythematous to violaceous nodules and pustules on abdomen and thighs that rapidly evolved in painful ulcer with undermined violaceous borders (Fig. 1). He was asymptomatic, and he was taking antiviral prophylaxis with valacyclovir that was discontinued. A biopsy from ulcer margin revealed massive neutrophil infiltration with leukocytoclasia and marked tissue necrosis with surrounding mononuclear cell infiltrates (Figs. 2 and 3). Totalbody computed tomography scan ruled out the presence of tissue abnormalities, and serologic testing for autoimmune antibodies was negative. Pyoderma gangrenosum (PG) was diagnosed, and ibrutinib was suspected as causative agent. Prednisone 75 mg/die was started and then slowly tapered every 3 weeks; ibrutinib was reduced to 210 mg/die because of risk of further disease progression. Improvement of skin lesion was observed, but maintenance of the remission needed daily low steroid dose and dapsone 50 mg/die as steroid-sparing. Soon after, ibrutinib was switched to venetoclax by the hematologist. Common skin side effects of ibrutinib are hematologic toxicities, diarrhea, nausea, fatigue, peripheral edema, upper respiratory tract infections, bruising, musculoskeletal pain, and dyspnea.3 In the literature review, only few reports of neutrophilic dermatitis related to ibrutinib have been reported (1 ibrutinib-induced neutrophilic panniculitis case,1 1 ibrutinib-induced sweet syndrome,2 and 1 ibrutinib-induced PG case4); moreover, other 5 ibrutinibinduced panniculitis in patients with B-cell CLL (B-CLL) have been described (Table 1).5,6 Other rare cutaneous side effects include bullous pemphigoid and recurrent paronychia.3 Although PG has been associated with hematologic malignancies in 8.9% of cases (most frequently monoclonal gammopathy),7 the temporal association of both the manifestations of neutrophilic dermatoses and the ibrutinib assumption suggests causality. Although the mechanism underlying ibrutinib-associated panniculitis has not been fully elucidated, its histopathological features are reminiscent of a localized adaptive cellular immune response against a novel hapten epitope.8 It has been postulated that ibrutinibconjugated peptides are presented to host immune cells through major histocompatibility complex, leading to a T-cell– driven immune response and bystander tissue destruction.5 The drug could contribute to the development of neutrophilic dermatosis inhibiting the inducible T-cell kinase.9 In conclusion, treatment of B-CLL with ibrutinib can lead in some cases to development of neutrophilic dermatoses, which may be caused by drug-induced immune process. Ibrutinib-dose tapering, low-dose