Evaluation of the role of secretory sphingomyelinase and bioactive sphingolipids as biomarkers in hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare systemic inflammatory syndrome that results from unrestrained immune cell activation. Despite significant advances in the understanding of the pathophysiology of HLH, interventions remain limited for this often-fatal condition. Secretory sphingomyelinase (S-SMase) is a pro-inflammatory lipid hydrolase that is upregulated in several inflammatory conditions, including HLH. S-SMase promotes the formation of ceramide, a bioactive lipid implicated in several human disease states. However, the role of the S-SMase/ceramide pathway in HLH remains unexplored. To further evaluate the role of S-SMase upregulation in HLH, we tested the serum of patients with HLH (n = 16; primary = 3, secondary = 13) and healthy control patients (n = 25) for serum S-SMase activity with tandem sphingolipid metabolomic profiling. Patients with HLH exhibited elevated levels of serum S-SMase activity, with concomitant elevations in several ceramide species and sphingosine, while levels of sphingosine-1-phosphate were significantly decreased. Importantly, the ratio of C16 -ceramide:sphingosine was uniquely elevated in HLH patients that died despite appropriate treatment, but remained low in HLH patients that survived, suggesting that this ratio may be of prognostic significance. Together, these results demonstrate upregulation of the S-SMase/ceramide pathway in HLH, and suggest that the balance of ceramide and sphingosine determine clinical outcomes in HLH. .

Secondary hemophagocytic syndrome in adults: a case series of 18 patients in a single institution and a review of literature.

Hemophagocytic lymphohistiocytosis (HLH) is rare in adults and is usually fatal without treatment. We present a consecutive series of 18 adults with HLH diagnosed at our institution between 2004 and 2009. All diagnoses were confirmed by pathology. The median age at diagnosis was 56 years (range: 18-73 years), with a male: female ratio of 2:1. Patients uniformly presented with fever. Fifty-five per cent of the patients presented with evidence of hepatomegaly or splenomegaly. All of the patients had at least a bi- or trilineage cytopenia. Elevated liver enzymes, hyperferritinemia, hypertriglyceridemia and hyperfibrinogenemia were seen in 50, 100, 40 and 50% of patients, respectively. The presumed causes were as follows; haematological malignancies (n = 4), post-autologous stem cell transplant (n = 2), infection (n = 2), rheumatologic illness (n = 2), sickle cell disease (n = 1), post-orthotopic liver transplant (n = 1) and idiopathic (n = 3). The median time from suspicion to diagnosis was 5 days (1-27 days). Corticosteroids and/or cyclosporine were the most frequently used treatment regimen. Other agents used were etoposide, IVIG, cyclophosphamide and chemotherapy. The mortality rate was 72%, with multi-system organ failure being the most common cause of death. Median survival time from diagnosis was 35 days. Six patients are alive to date. In a univariate analysis, the presence of fever was the only factor that was statistically significant for predicting a poor prognosis (early mortality) (p = 0.05). In conclusion, a high index of suspicion is the critical factor for early diagnosis. Early treatment with immunosuppressant is warranted, and a thorough diagnostic evaluation to identify the underlying cause should be undertaken.

Lestaurtinib, a multitargeted tyrosine kinase inhibitor: from bench to bedside.

IMPORTANCE OF THE FIELD: Internal tandem duplication of the fms-like tyrosine kinase 3 (FLT3) gene (FLT3-ITD) is a common recurring mutation in acute myeloid leukemia (AML) with normal karyotype, and the presence of FLT3-ITD confers a poor prognosis on this large subgroup of AML patients. Since the discovery of lestaurtinib as a potent FLT3 inhibitor, in 1985, there has been considerable interest in the development of this agent (CEP-701, Cephalon, Frazer, PA, USA) for treatment of this population. AREAS COVERED IN THIS REVIEW: An extensive literature search was conducted that included published articles and abstracts on the preclinical and clinical development of this agent spanning the last decade. WHAT THE READER WILL GAIN: The review describes the historical development of this agent and reviews the available preclinical and clinical data on lestaurtinib and expands on potential future directions in development of this agent. TAKE HOME MESSAGE: Lestaurtinib is a multi targeted tyrosine kinase inhibitor which has been shown to potently inhibit FLT3 at nanomolar concentrations in preclinical studies, leading to its rapid development as a potential targeted agent for treatment of AML. Phase I studies have shown lestaturtinib to be an active agent particularly when used in combination with cytotoxic drugs. Currently, Phase II and Phase III studies are underway aiming to establish the future of this agent as a treatment option for patients with FLT3-ITD AML.