In HLH-94, the first prospective international treatment study for hemophagocytic lymphohistiocytosis (HLH), diagnosis was based on five criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). In HLH-2004 three additional criteria are introduced; low/absent NK-cell-activity, hyperferritinemia, and high-soluble interleukin-2-receptor levels. Altogether five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH. HLH-2004 chemo-immunotherapy includes etoposide, dexamethasone, cyclosporine A upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids. Subsequent hematopoietic stem cell transplantation (HSCT) is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent, or reactivated, disease. In order to hopefully further improve diagnosis, therapy and biological understanding, participation in HLH studies is encouraged.

HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.

Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation.

Cancer and its treatments are well-recognized risk factors for venous thromboembolism (VTE). Evidence suggests that the absolute risk depends on the tumor type, the stage or extent of the cancer, and treatment with antineoplastic agents. Furthermore, age, surgery, immobilization, and other comorbid features will also influence the overall likelihood of thrombotic complications, as they do in patients without cancer. The role of hereditary thrombophilia in patients with cancer and thrombosis is still unclear, and screening for this condition in cancer patients is not indicated. The most common malignancies associated with thrombosis are those of the breast, colon, and lung, reflecting the prevalence of these malignancies in the general population. When adjusted for disease prevalence, the cancers most strongly associated with thrombotic complications are those of the pancreas, ovary, and brain. Idiopathic thrombosis can be the first manifestation of an occult malignancy. However, intensive screening for cancer in patients with VTE often does not improve survival and is not generally warranted. Independently of the timing of cancer diagnosis (before or after the VTE), the life expectancy of cancer patients with VTE is relatively short, because of both deaths from recurrent VTE and the cancer itself. Patients with cancer and acute VTE who take anticoagulants for an extended period are at increased risk of recurrent VTE and bleeding. A recent randomized trial, the Randomized Comparison of Low Molecular Weight Heparin versus Oral Anticoagulant Therapy for Long-Term Anticoagulation in Cancer Patients with Venous Thromboembolism (CLOT) study, showed that low molecular weight heparin may be a better treatment option for this group of patients. The antineoplastic effects of anticoagulants are being actively investigated with promising preliminary results.

Venous Thromboembolism and Cancer: Risks and Outcomes

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of severe hyperinflammation caused by the uncontrolled proliferation of activated lymphocytes and histiocytes secreting high amounts of inflammatory cytokines. Cardinal signs and symptoms are prolonged fever, hepatosplenomegaly and pancytopenia. Characteristic biochemical markers include elevated triglycerides, ferritin and low fibrinogen. HLH occurs on the basis of various inherited or acquired immune deficiencies. Impaired function of natural killer (NK) cells and cytotoxic T-cells (CTL) is shared by all forms of HLH. Genetic HLH occurs in familial forms (FHLH) in which HLH is the primary and only manifestation, and in association with the immune deficiencies Chediak-Higashi syndrome 1 (CHS 1), Griscelli syndrome 2 (GS 2) and x-linked lymphoproliferative syndrome (XLP), in which HLH is a sporadic event. Most patients with acquired HLH have no known underlying immune deficiency. Both acquired and genetic forms are triggered by infections, mostly viral, or other stimuli. HLH also occurs as a complication of rheumatic diseases (macrophage activation syndrome) and of malignancies. Several genetic defects causing FHLH have recently been discovered and have elucidated the pathophysiology of HLH. The immediate aim of therapy in genetic and acquired HLH is suppression of the severe hyperinflammation, which can be achieved with immunosuppressive/immunomodulatary agents and cytostatic drugs. Patients with genetic forms have to undergo stem cell transplantation to exchange the defective immune system with normally functioning immune effector cells. In conclusion, awareness of the clinical symptoms and of the diagnostic criteria of HLH is crucial in order not to overlook HLH and to start life-saving therapy in time.

Familial and acquired hemophagocytic lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) is probably a genetically transmitted disease affecting infants and very young children. Cardinal symptoms are fever, hepatosplenomegaly, and pancytopenia. Frequently meningeal involvement is seen, manifested by neurologic symptoms and a lymphohistocytic pleocytosis with increased protein levels in the cerebrospinal fluid. Characteristic laboratory findings in FHL are hypertriglyceridemia and hypofibrinogenemia, which are reversible with treatment. The disease has been rapidly fatal in most patients, but recently longterm remissions have been achieved with cytotoxic agents.

https://www.hemonc.theclinics.com/article/S0889-8588(05)70520-7/pdf

Familial hemophagocytic lymphohistiocytosis

Lymphohistiocytic reticulosis with phagocytosis is a rare, familial disorder affecting infants and children. It is characterized by fever, pancytopenia, hepatosplenomegaly, and a rapidly fatal course. Prior attempts to treat this disease have been unsuccessful. We describe two patients with lymphohistiocytic reticulosis with phagocytosis and hyperlipidemia. A sibling of one patient had died of the same disease. One patient also had abnormal lymphocyte response to mitogens. Both patients who were treated with epipodophyllotoxin VP 16-213 (VP-16) had remission of their disease and resolution of hyperlipidemia. VP-16 appears to be an effective agent for treating lymphohistiocytic reticulosis with phagocytosis.

Successful treatment of lymphohistiocytic reticulosis with phagocytosis with epipodophyllotoxin VP 16–213

A syndrome of thrombosis and hemorrhage complicating L-asparaginase therapy for childhood acute lymphoblastic leukemia.

The incidence and possible clinical relevance of immune complexes in sera from children with acute leukemias was investigated. Determinations were made in sera obtained at three-month intervals from individual patients over a two-year period. Two tests, the C1q binding and the polyethylene glycol precipitation assays, were employed. At time of diagnosis, immune complexes were found in sera from 6 of 41 patients (15%) with acute lymphoblastic leukemia (ALL). Three of 6 patients with T-cell leukemia had immune complexes at diagnosis as compared to 3 of 35 with null-cell leukemia. Only 1 of the 6 patients with T-cell leukemia had a white blood cell count of less than 50,000/μl3. Of the patients followed for six months or more, 34% had immune complexes during therapy and the incidence of relapse was unrelated to the presence or absence of immune complexes. Fifty-two percent of patients that remained in remission during the period of study and 5 of 8 patients that relapsed (63%) had immune complexes at one time or another suggesting that the presence of immune complexes by themselves did not portend either a favorable or an unfavorable prognosis. Sera taken at the time of diagnosis from children with acute non-lymphoblastic leukemia (ANLL) had a higher incidence (36%) of immune complexes than similar sera from ALL patients (15%). Antibodies in sera from leukemia patients at diagnosis had a lower capacity to bind a BCG antigen than did sera from control subjects. Eleven of 17 patients that had BCG immunotherapy had a humoral antibody response to BCG. There was no relation between an antibody response to BCG and a favorable clinical response.

Immune complexes in children with leukemia: relationship to disease characteristics and to antibody response to Mycobacterium bovis (BCG) in patients receiving BCG immunotherapy.

Splenomegaly is usually the result of systemic disease. The differential diagnosis can logically be subdivided into infectious, hematologic, metabolic, vascular, and neoplastic diseases which result in abnormalities of the lymphoid, reticuloendothelial, or vascular components of the spleen. Splenic enlargement increases the risk of traumatic rupture of the spleen. Splenectomy, although indicated in some conditions, does not always relieve the hypersplenic state, and its benefit must be weighed against the hazard of life-threatening episodes of sepsis.

David G. Tubergen

Papers

Successful treatment of lymphohistiocytic reticulosis with phagocytosis with epipodophyllotoxin VP 16–213

A syndrome of thrombosis and hemorrhage complicating L-asparaginase therapy for childhood acute lymphoblastic leukemia.

Immune complexes in children with leukemia: relationship to disease characteristics and to antibody response to Mycobacterium bovis (BCG) in patients receiving BCG immunotherapy.

Splenomegaly in children. Identifying the cause.

Study CD2+CD19+ Acute Lymphoblastic Leukemia: A Children's Cancer Group Clinical Features and Treatment Outcome of Children With Biphenotypic