Malignancy-associated hemophagocytic lymphohistiocytosis in adults: Relation to hemophagocytosis, characteristics, and outcomes

Abstract

Background: Malignancy-associated hemophagocytic lymphohistiocytosis (HLH) in adults is a highly lethal disorder. Knowledge gaps have resulted in under diagnosis or delayed diagnosis.

Methods: The University of Texas MD Anderson Cancer Center pathology database (1991-2014) was retrospectively interrogated for the keywords "hemophagocytosis" and/or "lymphohistiocytosis." Seventy-seven adult patients were identified. All had an underlying malignancy. Sixteen patients who had insufficient documentation were excluded.

Results: The majority of patients who had pathologic evidence of hemophagocytosis/lymphohistiocytosis had an incomplete workup to confirm or refute HLH using the 2004 HLH criteria (HLH-2004; n = 8 variables), which is a common problem in adult HLH. Only 13 of 61 patients (21%) met the HLH-2004 diagnostic criteria based on available retrospective data. To identify potentially missed cases of HLH, the published literature was reviewed, and selected additional variables known to be associated with adult HLH were selected, resulting in extended diagnostic criteria of 18 variables. Thirty-five patients met the extended criteria, and 33 had follow-up data available. The median overall survival of the 13 patients who met both the extended criteria and the HLH-2004 criteria was similar to that of the 20 patients who met the extended criteria but NOT the HLH-2004 criteria (1.43 vs 1.76 months, respectively; P = .34) indicating a similar underlying, aggressive, systemic process. Twenty-six patients did not meet either criteria, and 17 had follow-up data available. The median overall survival of the 17 patients who had pathologic hemophagocytosis or lymphohistiocytosis but met neither criteria was significantly superior to the survival of those who met both the extended criteria and the HLH-2004 criteria and those who met the extended criteria but not the HLH-2004 criteria (17.27 vs 1.43 vs 1.76, respectively; P = .002).

Conclusions: The addition of diagnostic laboratory variables that are more easily and rapidly available in smaller institutions and primary care settings than the HLH-2004 variables may be a good surrogate to raise early suspicion of malignancy-associated HLH. Prospective validation is warranted. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2857-2866. © 2016 American Cancer Society.

Keywords: adults; ferritin; hemophagocytosis; lymphohistiocytosis.

Figure 1

Sensitivity Plot

Figure 2A

Overall survival of patients classified by the extended HLH criteria

Figure 2B

Overall survival of patients classified by both the extended HLH and HLH 2004 criteria

Figure 3. Hemophagocytic histiocytosis characteristics

Each closed circle (○) 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 4

Alemtuzumab in combination with Etoposide and Dexamethasone for the treatment of adult patients with Hemophagocytic Lymphohistiocytosis