Epstein–Barr virus reactivation and hemophagocytic lymphohistiocytosis in a patient with chronic lymphocytic leukemia

Abstract

A 76-year-old man with asymptomatic stage I chronic lymphocytic leukemia (CLL) diagnosed 20 years previously, on surveillance without any prior therapy, presented to his primary care physician for right foot cellulitis. His medical history included hypertension and diet-controlled diabetes. He was started on levofl oxacin, with clinical improvement. However, 8 days after initiation of therapy, he developed spiking fevers up to 38.9 ° C, non-bilious vomiting and diarrhea, requiring hospitalization. Physical examination revealed jaundice, palpable hepatosplenomegaly and right axillary lymphadenopathy. A complete blood count demonstrated leukocytosis (17.6 ϫ 10 9 /L [normal range: 4.5 -11.0 ϫ 10 9 /L]) with stable persistent lymphocytosis (15.5 ϫ 10 9 /L [normal range: 1.5 -5.0 ϫ 10 9 /L]), anemia (hemoglobin [Hgb] 8.8 g/dL [normal range: 12.0 -16.0 g/dL]) and thrombocytopenia (platelets 75 ϫ 10 9 /L [normal range: 150 -440 ϫ 10 9 /L]). A year previously, his Hgb had been 15.5 g/dL, white blood count 51.9 ϫ 10 9 /L and platelet count 110 ϫ 10 9 /L. A comprehensive metabolic profi le was signifi cant only for hyperbilirubinemia, with a total bilirubin of 2.0 mg/dL (normal range: 0.0 -1.2 mg/dL). Serum creatinine (1.1 mg/dL [normal range: 0.7 -1.3 mg/dL]), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were within normal limits. An ultrasound scan of the right upper quadrant was unremarkable. Th e patient was also found to be hypogammaglobulinemic (serum immunoglobulin A [IgA] 25 mg/dL [normal range: 70 -400 mg/dL], IgG 401 mg/dL [normal range: 700 -1600 mg/dL], IgM Ͻ 21 mg/dL [normal range: 40 -230 mg/dL]). Immunoglobulin levels checked 2 years previously were IgA 32 mg/dL, IgG 798 mg/dL and IgM Ͻ 21 mg/dL. Over the next week, his hospital course was complicated by worsening jaundice (total bilirubin 16.8 mg/dL), elevated liver enzyme levels (AST 629 U/L [normal range: 19 -55 U/L], ALT 234 U/L [normal range: 19 -72 U/L], alkaline phosphatase [ALP] 154 U/L [normal range: 38-126 U/L]), renal dysfunction (creatinine 2.6 mg/dL), bronchopneumonia with positive induced sputum cultures for Klebsiella and Aspergillus and atrial fi brillation requiring direct cardioversion. Additional work-up included signifi cant hyperferritinemia, 13 406 ng/ mL (normal range: 27 -377 ng/mL). At this time, clinical and laboratory fi ndings raised suspicion for hemophagocytic lymphohistiocytosis (HLH). A bone marrow biopsy was performed; however, it was suboptimal for morphologic and immunohistochemical assessment. Th e bone marrow examination revealed a hypercellular marrow (70%), with involvement by CLL, representing 20 -30% of the marrow cellularity. Only rare hemophagocytic forms were identifi ed on the markedly hemodiluted bone marrow aspirate. With regard to the patient ' s CLL, expression of the 70 kDa zeta-associated protein (ZAP-70) and CD38 were negative via fl ow cytometry. Conventional chromosomal analysis of his bone marrow did not reveal any abnormal clone. Fluorescence in situ hybridization (FISH) to...

A Case of Chronic Lymphocytic Leukemia Complicated by Hemophagocytic Lymphohistiocytosis: Identifying the Aberrant Immune Response

“…Pasvolsky et al recently described a case series highlighting the diagnostic challenge of M-HLH as the presenting manifestation of lymphoma, with two of the four patients dying before a diagnosis of lymphoma was made despite HLH-directed therapy. 18 HLH associated with CLL has been described with disease transformation, 19,20 (seeTable 2) infections [21][22][23][24][25][26] , or ibrutinib treatment 27 (Table 2). Ours is the fourth case reported in which no trigger was identified 28,29,32 (see Table 2).…”

“Hemophagocytic Lymphohistiocytosis after EBV reactivation and ibrutinib treatment in relapsed/refractory Chronic Lymphocytic Leukemia”

“…Hematologic malignancies, especially T-cell malignancies, with or without coexisting suspected infections represent possible triggers of HLH [2] and a few cases with CLL progression possibly responsible for HLH were described 8 , 9 . Thus, we speculate that Ibrutinib may have contributed to HLH because of the strict temporal association between ibrutinib start and the onset HLH, which was possibly also favoured by the immunosuppression related with the recent treatment with CP.…”