Summary:involving the developing central nervous system, endocrine system and skeletal system, can be avoided. Busulfan pharmacokinetics have been studied since We analyzed plasma pharmacokinetics of busulfan in 64 children and young adults (age 2.8-26; median 11Ehrsson and Hassan 1 developed a gas chromatographic assay for plasma in 1983. In a preliminary study we have years) with homozygous ␤-thalassemia transplanted with bone marrow from HLA-identical sibling donors.shown previously that variations in plasma pharmacokinetics may be age-dependent, with children younger than 5 A uniform conditioning regimen was employed, using busulfan 14 or 16 mg/kg in 12 divided doses, and cycloyears having a shorter elimination half-life than adults. 2 Several other studies reported the relationship between high phosphamide 120 or 200 mg/kg. Three sets of parameters were examined in this homogenous patient popubusulfan plasma levels and drug-related toxicities, namely hepatic veno-occlusive disease (VOD) and seizures. 3,4 An lation: (1) factors that affect the plasma kinetics of busulfan, such as age and pre-transplant liver status inverse correlation was seen between steady-state busulfan plasma concentration and graft rejection in unrelated donor defined by liver function tests, ferritin levels and liver biopsy; (2) busulfan-related toxicity: occurrence of BMT in patients with multiple diagnosis. 5 However, all previous studies were conducted analyzing veno-occlusive disease, seizures and idiopathic interstitial pneumonitis; and (3) the relationship between heterogeneous patient populations. There has been no study in a large, uniform group of patients with a single disease, busulfan exposure and transplant outcome: engraftment delay or rejection, aplasia, occurrence of mixed without pre-transplant chemotherapy. We analyzed plasma pharmacokinetics of busulfan in 64 chimeras and mortality. Kinetic analysis of first and 10th dose (using area under the curve (AUC), maximum children and young adults with homozygous ␤-thalassemia transplanted with histocompatable sibling bone marrow. A and minimum concentration) as comparable, showing no sign of accumulation or decline in busulfan plasma uniform conditioning regimen was employed, using busulfan 14 or 16 mg/kg and CY 120 or 200 mg/kg. Busulfan levels over time. Age and liver status did not influence busulfan metabolism. No relationship was found clearance in relation to age and pre-transplant liver status was assessed and the relationship of busulfan exposure to between busulfan exposure and toxicities or transplant outcome. We conclude that busulfan monitoring is not engraftment, graft rejection and toxicities was studied. predictive in children and young adults with homozygous ␤-thalassemia receiving busulfan and high-dose cyclophosphamide along with histocompatable sibling Materials and methods donor marrow.

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Cryopreservation has been used extensively in autologous marrow transplantation (BMT), but there has been limited use in allogeneic BMT. We describe here 6 cases of successful engraftment following allogeneic BMT with cryopreserved marrow. Patients suffered from Wiscott-Aldrich syndrome, osteopetrosis, aplastic anemia, and acute lymphocytic, acute non-lymphocytic, and chronic myelogenous leukemia, and ranged in age from 5 mos to 35 yrs. Marrow was collected using standard techniques. In one case T-cells were removed to prevent graft-vs-host disease. Marrow was frozen for a variety of reasons. Buffy coat cells were frozen at controlled rate in 10% DMSO, and stored in liquid nitrogen for 6 to 49 d. Engraftment (WBC greater than 1000/uL x 3 d) occurred from 13 to 37 d post BMT. In 4 of 4 cases in which data are available, donor origin of engraftment was documented, 1 with cytogenetics, 2 with red cell typing, and 4 with restriction fragment length polymorphisms. 3 patients are alive and well 21, 21, and 42 months post BMT. These results suggest frozen marrow can be successfully used for allogeneic BMT.

Based on the recent reports that recombinant human granulocyte/macrophage colony-stimulating factor (rhGM-CSF) accelerates the rate of engraftment in a variety of autologous bone marrow transplantation settings, we have investigated its effects on hematopoietic recovery of patients with acute lymphoblastic leukemia (ALL) undergoing autologous bone marrow transplantation. Our studies, which involved 25 autologous ALL recipients who received rhGM-CSF and 27 controls similar for disease status (remission or relapse) and disease type (B- or T-lineage) differed from previous studies in one important aspect: the bone marrows were purged with 4- hydroperoxcyclophosphamide (4HC) and anti-T or anti-B-cell lineage- specific antibodies before transplantation. Such treatments frequently lead to a reduction in the CFU-GM content of the transplanted marrow. Eighteen of 25 patients completed the entire course of rhGM-CSF. Of the 16 patients who received greater than or equal to 64 micrograms/M2/d for at least eight days, there were five patients who had an apparent rhGM-CSF response and 11 patients who did not respond. Of the parameters analyzed, only the number of CFU-GM progenitor cells infused per kilogram was significantly associated with an rhGM-CSF response. All patients receiving greater than or equal to 1.2 x 10(4) CFU-GM progenitors per kilogram achieved an absolute neutrophil count (ANC) greater than or equal to 1,000/microL by day 21 and had a greater than 50% decrement in ANC within 48 to 72 hours of discontinuing rhGM-CSF, as contrasted to none of the patients receiving less than or equal to 7.2 x 10(3) CFU-GM progenitors per kilogram.(ABSTRACT TRUNCATED AT 250 WORDS)

Leukemic relapse following bone marrow transplant (BMT) is generally due to the recurrence in recipient cells, but may rarely occur as a result of donor cell transformation. Donor cell relapse is generally identified using cytogenetic markers such as the sex chromosomes. Recently, molecular techniques have been used to identify the origin of bone marrow cells by their DNA restriction fragment length polymorphisms. We describe the case of a male pediatric patient who had a leukemic relapse 30 months following BMT from his sister. Both cytogenetic and molecular techniques were used to identify the origin of the leukemic relapse. Cytogenetic analyses indicated the absence of the Y chromosome and the presence of a donor cell type 9qh polymorphism, suggesting a donor cell relapse. Molecular analyses also indicated the absence of the Y chromosome but demonstrated the recurrence of recipient DNA markers from three other chromosomes, suggesting a recipient cell relapse. While the leukemic cell lineage cannot be definitively assigned in this case, our results suggest that caution must be exercised when assigning leukemic cell lineage following post-BMT relapse.

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