Haemophagocytic lymphohistiocytosis in children.

OBJECTIVE: To evaluate the clinical and diagnostic features of children presenting with haemophagocytic lymphohistiocytosis (HLH), evolution of the disease and outcomes in response to treatment. METHODOLOGY: The medical records of 12 children, aged 5 weeks to 13 years at diagnosis, with HLH managed at a single institution were reviewed. RESULTS: Presenting features were fever, hepatosplenomegaly, pancytopenia and hypertriglyceridemia or hypofibrinogenemia. Nine patients (75%) developed central nervous system (CNS) disease. Only one child with CNS disease survived. Five children had complete responses to therapy (42%), but all relapsed at a median of 1.5 months after starting treatment (range 2 weeks to 5 months). Two of the children treated are long-term survivors (17%), both after allogeneic bone marrow transplantation. All deaths occurred in the context of active disease. CONCLUSIONS: Haemophagocytic lymphohistiocytosis is a disease with a poor prognosis. Central nervous system complications are common and response to treatment usually is transient. This study provides support for the use of immunomodulatory therapy for remission introduction followed by consideration of allogeneic bone marrow transplantation.

Bone-marrow transplantation for haematological malignancy in childhood.

Twenty-three children with haematological malignancies and a poor prognosis underwent bone-marrow transplantation. Thirteen children had acute lymphoblastic leukaemia, eight had acute nonlymphoblastic leukaemia, one had chronic myeloid leukaemia and one had malignant histiocytosis. One child was in relapse at the time of transplant and 22 were in first or subsequent remission. Before transplantation all patients received cyclophosphamide (60 mg/kg) on two consecutive days followed by total body irradiation given as a single dose of 10 Gy at 0.18 Gy/min (one patient) or 0.07 Gy/min (three patients), or as a fractionated dose of 10-12 Gy at 0.07-0.1 Gy/min (19 patients). One child with malignant histiocytosis also received two doses of etoposide (5 mg/kg). Methotrexate was given after transplantation to prevent or modify graft-versus-host disease (GVHD). One patient who received a transplant in relapse died early from overwhelming bacterial sepsis. Twenty-two patients engrafted, and of these 11 developed acute GVHD; five developed chronic GVHD; seven developed interstitial pneumonitis, with four deaths; and five relapsed between three and 12 months after transplantation, with three deaths. Fifty-nine per cent (13/22) of patients who received a transplant during remission remain in continuous complete remission and 68% (15/22) have survived for a median of 18 months (range, four to 73 months). Bone-marrow transplantation that is undertaken during remission of disease offers a prolonged disease-free survival in selected childhood malignancies.

Determination of serum methotrexate and 7-hydroxymethotrexate concentrations. Method evaluation showing advantages of high-performance liquid chromatography.

The use of large doses of methotrexate (MTX), greater than 3 g/m2, for the treatment of some malignant disorders requires careful monitoring of serum concentrations. A simple and sensitive method for the separation of MTX and 7-hydroxymethotrexate (7-OH-MTX) by reversed-phase high-performance liquid chromatography (HPLC) is described. The method involves deproteinizing the serum sample on a Sep-Pak C18 cartridge, followed by separation on a C18 column and detection at 313 nm. The extraction efficiency of free MTX from serum is 70% and the maximum sensitivity is 2.2 X 10(-8) M. A high degree of correlation was obtained between the HPLC method of serum MTX determination and an enzyme multiplied immunoassay technique. The HPLC method separates MTX from its analogues, or drugs which may be administered concomitantly with MTX. Concentrations of MTX and 7-OH-MTX achieved over a 24-h period during high-dose therapy, (500-1000 mg/m2), and over 48 h for very-high-dose methotrexate therapy (8-12 g/m2) are described. A significant observation is the presence of 7-OH-MTX in sera of patients 6 h after commencement of infusion. This method was also utilized for monitoring cerebrospinal fluid MTX concentrations.