[Allogenic transplantation of hematopoietic stem cells in the treatment of children with high-risk acute leukemia]. / Alogenní transplantace kmenových bunek krvetvorby v lécbe detí s vysoce rizikovou akutní leukémií.

BACKGROUND: Most children with acute lymphoblastic leukemia (ALL) and increasing number of children with acute myelogenous leukemia (AML) are currently cured with conventional chemotherapy. Despite of this success there is a subset of patients with high-risk features at diagnosis who are predisposed to a very high risk of relapse. Relapse of AML and early bone marrow relapse of ALL can not be cured by conventional chemotherapy. Allogeneic hematopoietic stem cell transplantation (HSCT) is therapeutic option in these children with very high-risk acute leukemia. METHODS AND RESULTS: Between XI/1989-XII/1996 33 children with acute leukemia (ALL: 22, AML: 11) underwent an allogeneic HSCT from HLA identical related donors (HLA-identical sibling: 30, twin: 1, other HLA-identical relative: 2) at the 2nd Dept. of Pediatrics, University Hospital Motol. Median age of our group was 9 years (1.5-19 y.), boys (n = 23) clearly dominated over the girls (n = 10). The resource of stem cells was bone marrow in 31 children, bone marrow and peripheral blood progenitor cells (PBPC) and PBPC in one child respectively. Myeloablative conditioning regimen varied, consisting of total body irradiation and chemotherapy in 21 children and chemotherapy in 12 children. HSCT was performed in first complete remission of acute leukemia in 9 children (AML: 7, ALL: 2), in second remission in 14 children (AML: 2, ALL: 12), in third remission in 4 children (ALL: 4). Six children underwent HSCT in first partial remission (n = 1) and in second (n = 4) or third (n = 1) chemoresistant relapse. Seven (21%) children died due to post-transplant complications. Nine (28%) children suffered from clinically significant acute graft-versus-host reaction (GVH) and 15% (4/27) children who survived 100 days post-transplant suffered from chronic GVH disease. Relapse of leukemia was diagnosed in 39% (12/31) children. Fourteen (42%) children are alive and well in continuous remission with median follow-up 42 months. CONCLUSIONS: Allogeneic HSCT can cure children with very high-risk acute leukemia in the situations where conventional chemotherapy fails. Relapse of leukemia and GVH reaction are most important causes of post-transplant morbidity and mortality.

Busulphan kinetics and limited sampling model in children with leukemia and inherited disorders.

Busulphan pharmacokinetics were investigated in 20 children, who underwent bone marrow transplantation for either leukemia or inherited disorders. Busulphan (1.90-6.02 mg/kg/day) was administered orally as a single dose or twice daily. Busulphan kinetics were found to be linear within the studied range. Children with inherited disorders eliminated busulphan significantly faster after the first and the last dose with half-lives (t1/2) of 1.93 and 1.71 h, respectively compared to children with leukemia (3.16 and 2.70 h, respectively). The area under plasma concentration curves (AUCs, corrected for mg/kg) as an expression for the systemic exposure of busulphan were significantly higher in children with leukemia, 22.4 and 19.04 mumol/l.h (5527 and 4690 ng.h.ml-1) after the first and the last dose, respectively, compared to 11.2 and 8.2 mumol/l.h (2768 and 2029 ng.h.ml-1) found in children with inherited disorders. The present results confirm those reported by others, ie busulphan pharmacokinetics can be influenced by the underlying disease and its status. Our population pharmacokinetic analysis showed a negative correlation between the weight corrected clearance and the age in both groups of children. However, clearance was about 42% higher in children with inherited disorders compared to those with leukemia. To estimate AUC for the first dose, we evaluated a limited sampling model based on three concentrations (1, 3 and 6 h). A high correlation (r = 0.998, P < 0.0001, n = 40) between the estimated and the determined AUC was found. The present model is reliable and adequate for studying more patients, with a long-term follow-up combined with drug monitoring in correlation with drug efficacy and toxicity to define the optimal busulphan dosage required.

Infection-associated hemophagocytic syndrome complicated by infectious lymphoproliferation: a case report.

The case of a 7-year-old boy with virus-associated hemophagocytic syndrome (VAHS) and serologically proven parvovirus B-19 infection is described. The patient with VAHS presented with fever, hepatosplenomegaly, pancytopenia, and hyperlipidemia type IV. After induction therapy with VP-16 and prednisone, partial remission was achieved. Despite maintenance therapy, reinductions, and the addition of cyclosporine A for 3 months, several relapses occurred. The therapy was stopped because of life-threatening complications (Klebsiella sepsis, neutropenic enterocolitis, and stercoral peritonitis). The complications were treated successfully. The patient status was stabilized after splenectomy. However, hepatomegaly progressed slowly and the hyperlipidemia endured. Ten months after the diagnosis leukocytosis with absolute T lymphocytosis appeared. Reactivation of VAHS was suspected and intravenous immunoglobin and then antilymphocyte immunoglobulin ALG therapy were started. The resultant decrease in leukocytosis was prompt, but lymphopenia did not occur. Virostatic treatment with foscarnet was introduced based on human herpesvirus-6 seroconversion. Twenty-six months after the diagnosis, the patient is well, without any sign of VAHS or lymphoproliferation.

[Allogenic transplantation of bone marrow in childhood]. / Alogenní transplantace kostní drene v detském veku.

BACKGROUND: Bone marrow transplantation has become the therapeutic method in some forms of malignant haemotopoietic diseases, malignant tumours, inborn errors of metabolism and immunodeficiency states. The objective of the presented work is the analysis of 40 allogenic bone marrow transplantations in children made in 1989-1994. METHODS AND RESULTS: Bone marrow transplantation was made in 40 children (26 boys and 14 girls), mean age 10.5 years (range 1.5-17.5 years). Indications were acute lymphoblastic leukaemia in 11, acute myeloid leukaemia in 10, chronic myeloid leukaemia in 6, myelodysplastic syndrome in 2, aplastic anaemia and Fanconi's anaemia in 7, non-Hodgkin lymphoma in 2 and inborn errors in 2 children. The donor was in 33 patients in HLA identical sibling and in seven instances a monozygotic twin, HLA non-identical sibling or relative or unrelated matched donor. Bone marrow engraftment was achieved in 35 (87.5%) patients, in one instance the bone marrow was rejected (2.5%) and in four patients (10%) early death occurred before the bone marrow engraftment. On Aug. 15, 1995 20 patients (50%) survived, a relapse developed in 7 (17.5%) and 13 patients died in conjunction with the transplantation (32.5%). The most frequent cause of death were infectious complications (9 children) either in conjunction with the development of graft versus host reaction (6x) or without signs of this reaction (3x). As a prophylaxis of graft versus host disease 24x Cyclosporine A with corticosteroids was used, 16x with methotrexate. A chronic graft versus host disease developed in 6 of 28 children surviving 100 days after transplantation. The greatest problem are infectious (bacterial and mycotic) complications in the phase of bone marrow aplasia before engraftment of the transplanted bone marrow or in conjunction with a graft versus host reaction which cannot be completely avoided by preventive measures. CONCLUSIONS: Bone marrow transplantation is also in children an effective therapeutic method of some forms of malignant haematopoietic diseases, malignant tumours and immunodeficiency states. The correct indication, suitable donor, preventive measures against the graft versus host reaction and protection against infectious complications are essential for the success of this pretentious treatment.

Busulfan bioavailability.

Busulfan is widely used as a component of the myeloablative therapy in bone marrow transplantation. Recent studies have shown that the drug disposition is altered in children and is associated with less therapeutic effectiveness, lower toxicities, and higher rates of engraftment failure. We have evaluated the bioavailability of the drug in two groups of patients: eight children between 1.5 and 6 years of age and eight older children and adults between 13 and 60 years. Oral bioavailability showed a large interindividual variation. In children, the bioavailability ranged from 0.22 to 1.20, and for adults, it was within the range 0.47 to 1.03. The elimination half-life after intravenous administration in children (2.46 +/- 0.27 hours; mean +/- SD) did not differ from that obtained for adults (2.61 +/- 0.62 hours). However, busulfan clearance normalized to body weight was significantly higher in children (3.62 +/- 0.78 mL.min-1.kg-1) than that in adults (2.49 +/- 0.52 mL.min-1.kg-1). Also, the distribution volume normalized for body weight was significantly higher in children (0.74 +/- 0.10 L.kg-1) compared with 0.56 +/- 0.10 L. kg-1 in adults. The difference in clearance between children and adults was not statistically significant when normalized to body surface area, which most probably shows that busulfan dosage should be calculated on the basis of surface area rather than body weight. However, to avoid drug-related toxicities, drug monitoring and an individual dose adjustment should be considered because of the variability in busulfan bioavailability.