A consensus review on malignancy-associated hemophagocytic lymphohistiocytosis in adults

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune activation and dysregulation resulting in extreme and often life-threatening inflammation. HLH has been well recognized in pediatric populations, and most current diagnostic and therapeutic guidelines are based on pediatric HLH. Recently there has been recognition of HLH in adults, especially secondary to immune deregulation by an underlying rheumatologic, infectious, or malignant condition. This review is focused on malignancy-associated HLH (M-HLH), in which possible mechanisms of pathogenesis include severe inflammation, persistent antigen stimulation by the tumor cells, and loss of immune homeostasis because of chemotherapy, hematopoietic stem cell transplantation, or infection. Previously considered rare, M-HLH may occur in up to 1% of patients with hematologic malignancies. M-HLH is often missed or diagnosed late in most published studies, and it has been associated with a poor median survival of less than 2 months. Identification of the clinical and laboratory features specific to M-HLH in adults may allow early detection, consultation with HLH experts, and intervention. Improved management of adult M-HLH with optimal combinations of T-lympholytic and immunosuppressive agents and the incorporation of novel agents based on the pediatric experience hopefully will improve outcomes in adults with M-HLH. Cancer 2017;123:3229-40. © 2017 American Cancer Society.

Keywords: adults; hemophagocytosis; lymphohistiocytosis; malignancy.

Figure 1

Morphologic features of hemophagocytosis on bone marrow aspirate smear (Wright-Giemsa, original magnification × 500); blue arrow, WBC; black arrow, nucleated RBC; red arrow, platelet.

Figure 2

Adult Hemophagocytic Histiocytosis characteristics and Diagnostic Variables. Each closed circle ((x025CB)) represents a negative result. Blanks represent missing information. Each row is one patient and each column is a variable. Numbers show percent positive patients (for each characteristic) or percent positive characteristics (for each patient) excluding missing information. Variables evaluated (listed in order of columns) included BM/lymph node/spleen hemophagocytosis per pathology evaluation, fever, splenomegaly (clinically palpable spleen), hepatomegaly (clinically palpable liver), anemia (hemoglobin < 9.0 g/L), thrombocytopenia (platelets < 100 × 10⁹/L), neutropenia (absolute neutrophil count (ANC) < 1.0 × 10⁹/L), monocytosis (absolute monocyte count (AMC) > 1.0 × 10⁹/L), renal failure (≥ 50% increase in creatinine over baseline), elevation of hepatic enzymes (≥ 2.5× upper limit of normal), hypofibrinogenemia (fibrinogen ≤ 150mg/dL), hyperferritinemia (ferritin ≥ 500micrograms/L), coagulopathy (PT ≥ 1.5× upper limit of normal and/or PTT ≥ 1.5× upper limit of normal and/or D-dimer ≥ 10.0mcg/mL), hypoalbuminemia (< 3.5g/dL), elevated LDH (≥ 2.5× upper limit of normal), hypertriglyceridemia (≥ 265 mg/dL), elevated b2-microglobulin (≥ 2mg/L), and elevated soluble IL-2 receptor (CD25) ≥ 2400U/mL. Abbreviations: Hb, hemoglobin; ULN, upper limit of normal; LDH, lactate dehydrogenase; HLH 2004, Hemophagocytic lymphohistiocytosis 2004 diagnostic criteria; MDS, myelodysplastic syndromes; PTLD, post-transplant lymphoproliferative disorder; CML, chronic myeloid leukemia; DLBCL, diffuse large B-cell lymphoma; CLL, chronic lymphocytic leukemia; XLP, X-linked lymphoproliferative disease; AML, acute myeloid leukemia; HL, Hodgkin's lymphoma.

Figure 3. Alemtuzumab in combination with Etoposide and Dexamethasone for the treatment of Adult Patients with Secondary Hemophagocytic Lymphohistiocytosis