MULTI-ORGAN DYSFUNCTION, PANCYTOPENIA, AND ELEVATED INFLAMMATORY MARKERS DURING NEUROBLASTOMA THERAPY

Abstract

Introduction Thrombotic microangiopathy (TMA) and hemophagocytic lymphohistiocytosis (HLH) have overlapping features, including multi-organ dysfunction and cytopenias. Herein we present the challenging case of a 13-year old boy with manifestations of both TMA and HLH, whose diagnosis was not clarified until weeks into the course with renal-biopsy electron microscopy (EM). Case Description The patient is a 13 year-old male with stage 4 neuroblastoma, status-post 6 cycles of chemotherapy (cisplatin/etoposide/vincristine/cyclophosphamide /doxorubicin/carboplatin/topotecan), two tandem stem cell transplants (with thiotepa/cyclophosphamide/carboplatin/etoposide/melphalan) followed by dinutuximab and isotretinoin. During his first cycle of consolidation therapy with Hu-3f8, he developed transverse myelitis, followed by heart failure. In his subsequent 6-week admission, his course was complicated by hypertension and renal failure; pan-cytopenia (hemolytic anemia, thrombocytopenia, lymphopenia) with intermittently positive Coombs; diffuse alveolar hemorrhage; and transaminitis with direct hyperbilirubinemia. He was diagnosed with and treated for Legionella pneumonia 12 days into this course; additional comprehensive infectious workup was unrevealing. He had persistently elevated ferritin (10,000 to 30,000 ng/mL), procalcitonin, CRP and triglycerides. Renal biopsy immunohistochemistry showed diffuse acute tubular injury, without immune complex-mediated glomerular lesions. C5b9 and ADAMTS13 were normal. Soluble IL-25 was elevated (2388 ng/mL). Bone marrow biopsy showed occasional hemophagocytes. Renal-biopsy EM eventually showed microangiopathic changes consistent with chronic TMA. Discussion Chronic drug-induced, toxicity-mediated TMA may present with features of HLH and TMA. As symptoms may manifest weeks to months after drug administration, the inciting agent may be difficult to identify. Without a specific biomarker, the diagnosis may not be apparent without renal-biopsy EM.