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Biomedical subjects

A M Yeager

Publications and source records attributed to A M Yeager.

At least 37 records · Page 2Linked to original sources
PubMed1997

Sustained multilineage engraftment of allogeneic hematopoietic stem cells in NOD/SCID mice after in utero transplantation.

Substantial barriers exist to the engraftment of hematopoietic cells in mice after in utero transplantation. Although high levels of donor-derived hematopoiesis have been reported in SCID mice, the majority of chimeric recipients exhibit decreasing levels of donor cells over time. To directly test whether the natural killer cell and macrophage activity of the recipients represents a barrier to sustained engraftment, fetal NOD/SCID mice were injected on day 13.5 of gestation with an enriched congenic hematopoietic progenitor cell population. Forty-four percent of pups showed the presence of Ly5.1+ donor cells 4 weeks after transplantation. The mean number of donor-derived nucleated cells in the peripheral blood (PB) was 30%. Although the majority of circulating donor cells were lymphocytes, up to 15% expressed myelomonocytic markers. Serial PB samples from individual mice indicated that the percentage of circulating donor cells increased from 17% to 55% between 4 and 24 weeks. At 6 months posttransplantation, an increased frequency of multilineage, donor-derived cells was also observed in the bone marrow (BM) and the spleen of chimeric recipients. The engraftment of pluripotent hematopoietic stem cells was evaluated by transplanting BM from chimeric mice into irradiated congenic recipients. Irradiated secondary recipients also exhibited multilineage donor-derived hematopoiesis in the PB, BM, and spleen for up to 6 months. These results show that the in utero transplantation of lineage-depleted BM cells into NOD/SCID recipients produces a high frequency of sustained engraftment of allogeneic hematopoietic stem cells.

Animals↗
PubMed1997

Expression and regulation of Bcl-2, Bcl-xl, and Bax correlate with p53 status and sensitivity to apoptosis in childhood acute lymphoblastic leukemia.

Bcl-2 and its homologue, Bcl-x1, encode membrane-associated proteins that protect neoplastic cells from DNA damage-induced apoptosis, whereas Bax is a Bcl-2 antagonist that promotes cell death. In the present study, we examined the expression and regulation of these genes at both the mRNA and protein level in 22 pediatric acute lymphoblastic leukemia (ALL) cell lines, as well as their sensitivity to apoptosis after exposure to ionizing radiation (IR). Eleven of 22 lines expressed wild-type (wt) p53, 4 expressed mutant p53, and 7 did not express p53 (p53-null). Nine of 22 (41%) lines expressed Bcl-2; of these, 8 were wt-p53+ and 1 expressed mutant p53. Bcl-2 was not expressed in any p53-null lines. In contrast, all 22 lines were positive for Bcl-x1 and Bax, although expression level varied. Treatment with IR (10 Gy) induced both downregulation of Bcl-2 and upregulation of Bax at 2 to 5 hours post-IR in 5 of 8 (63%) wt-p53+ lines, leading to apoptosis. Conversely, lines that failed to both downregulate Bcl-2 and upregulate Bax after IR were resistant to apoptosis. Although levels of Bcl-x1 expression varied among the 22 lines, high levels of Bcl-x1 were observed in 5 of 7 (71%) p53- lines. There were no obvious changes in the expression of Bcl-x1 in these lines after IR. However, among the p53-null lines, resistance to IR was observed only in those expressing high levels of Bcl-x1. These results suggest that expression of Bcl-2 but not Bcl-x1 is p53-dependent and that IR-induced downregulation of Bcl-2 and upregulation of Bax occur in most wt-p53+ lines and are associated with radiosensitivity. Furthermore, high-level expression of Bcl-x1 occurs predominantly in p53-null lines and is associated with resistance to IR-induced apoptosis in these lines, indicating differential expression and regulation of Bcl-2 and Bcl-x1 in pediatric ALL.

Apoptosis↗
PubMed1997

Expression of interleukin-6 receptors by pediatric acute lymphoblastic leukemia cells with the t(4;11) translocation: a possible target for therapy with recombinant IL6-Pseudomonas exotoxin.

We have detected expression of interleukin-6 receptors (IL-6R) by primary leukemic cells from three of six patients with t(4;11)+ ALL. Scatchard analysis revealed from 960 to 2100 high-affinity IL-6R/cell on these cells (median, 1560; mean, 1540). All three IL-6R+ cases also expressed CD33, which was not expressed on IL-6R-negative cases. To determine if these receptors could serve as a target for a recombinant ligand-toxin, we examined the sensitivity of primary IL-6R+ ALL cells to a recombinant IL6-Pseudomonas exotoxin (IL6-PE4E) fusion protein, in which the toxicity and specificity of the chimeric toxin was enhanced by substitution of four glutamine residues for naturally occurring amino acids in PE domain I. Primary cells from IL-6R+ cases were sensitive to IL6-PE4E in a 48-h cytotoxicity assay, with ID50 values (concentrations causing 50% decrease in viability) ranging from 23 ng/ml to 92 ng/ml (median, 61; mean, 58). Furthermore, incubation of these cells with 10(3) ng/ml IL6-toxin for 24 h prevented their subsequent engraftment in SCID mice. Thus, IL6-PE4E may be useful for ex vivo purging of IL-6R+ leukemic cells in an autologous bone marrow transplantation setting and possibly for therapy of residual, chemotherapy-resistant disease.

ADP Ribose Transferases↗
PubMed1997

Cancers after stem cell transplantation in children: a cost of cure?

There have been many advances in the field of stem cell transplantation over the past few years. Newer preparative regimens and better supportive care measures are allowing more children to survive and lead long lives after stem cell transplantation. We are only now beginning to see what the cost of this success may be in regard to the long-term effects of this treatment. Most long-term follow up studies have been reported in the adult literature and there is very little information on the pediatric population. Children who undergo stem cell transplantation will have a long period of observation in which new and different complications can occur. This article looks at the current literature on secondary malignancies and lymphoproliferative disorders after stem cell transplantation in children, with particular focus on risk factors, possible strategies for prevention, and treatment.

Child↗
PubMed1996

Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. Pediatric Oncology Group.

BACKGROUND: The value of autologous bone marrow transplantation in the treatment of children with acute myeloid leukemia (AML) is unknown. We compared autologous bone marrow transplantation with intensive consolidation chemotherapy as treatments for children with AML in first remission. METHODS: We induced remission with one course of daunorubicin, cytarabine, and thioguanine, followed by one course of high-dose cytarabine (3 g per square meter of body-surface area for six doses). Patients in remission after the second course of induction therapy were eligible for randomization. Between June 1988 and March 1993, 552 of 649 enrolled patients who could be evaluated (85 percent) entered remission. A total of 209 patients were not eligible for randomization; of the remaining 343 patients, 232 were randomly assigned to receive six courses of intensive chemotherapy (117 patients) or autologous transplantation (115 patients). Of the original 649 patients, 189, including 21 with Down's syndrome, were nonrandomly assigned to receive intensive chemotherapy. RESULTS: The rates of event-free survival and overall survival for the entire group at three years were 34 +/- 2.5 percent and 42 +/- 2.6 percent, respectively. For patients who were randomly assigned to one of the two treatment groups, the mean (+/- SE) rates of event-free survival three years after randomization were not significantly different in the two groups when examined by intention-to-treat analysis: 36 +/- 5.8 percent for the intensive-chemotherapy group as compared with 38 +/- 6.4 percent for the autologous-transplantation group; and the relative risk of treatment failure for the chemotherapy group as compared with the autologous-transplantation group was 0.81 (P = 0.20 by the log rank test; 95 percent confidence interval, 0.58 to 1.12). Overall survival at three years followed a similar pattern. There was a lower relapse rate (31 percent vs. 58 percent, P < 0.001) but a higher rate of treatment-related mortality (15 percent vs. 2.7 percent, P = 0.005) in the group treated with autologous transplantation than in the intensive-chemotherapy group. The event-free survival at three years for the nonrandomized intensive-chemotherapy group was 39 +/- 5.1 percent, and for a contemporaneous group of patients each of whom received a histocompatible bone marrow transplant from a sibling, it was 52 +/- 8.0 percent. CONCLUSIONS: Treatment of children with AML in first remission with either autologous bone marrow transplantation or intensive chemotherapy prolongs event-free survival equally.

Acute Disease↗
PubMed1996

Engraftment potential of different sources of human hematopoietic progenitor cells in BNX Mice.

Human hematopoietic progenitor cells (HPCs) from mobilized peripheral blood mononuclear cells (PBMCs), adult bone marrow (ABM), and fetal bone marrow (FBM) were evaluated for their ability to produce multilineage human hematopoietic engraftment in vivo. Sublethally irradiated BNX (beige/nude/xid) mice were injected with either unfractionated cells or CD34+ cells purified from these sources. The presence of human cells in the mouse PB, BM, and spleen was evaluated by flow cytometry at either 6 to 8 weeks or 6 months postinjection. Recipients with > or = 1% human cells in any of these tissues were considered chimeric. Of 26 mice injected with FBM, 4 showed up to 73% human cells in the BM or spleen at 6 months. The phenotypes of these cells included CD13/33+ myelomonocytic cells (38%), CD19+ B cells (67%), and CD34+ progenitor cells (28%). In contrast, ABM gave rise to a mean of 5% human cells in the PB in 2 of 42 (4%) recipients at 6 to 8 weeks. These circulating human cells were predominantly CD3+, whereas CD13/33+ and CD34+ cells were detected in the BM for up to 6 months. A total of 18% of mice injected with PBMCs showed a mean of 36% human cells in the PB. Both the BM and spleens of PBMC-injected mice contained CD3+ cells in a proportion similar to that observed in the PB. These CD3+ cells were phenotypically mature CD4+,CD8- or CD4-,CD8+ T cells and coexpressed a variety of Vbeta T-cell receptor (TCR) genes. The percentage of CD3+ cells in the circulation of chimeric recipients injected with either FBM, ABM, or PBMCs correlated well with the input CD3+ cell dose for each of these HPC sources (r = .99). The high levels of engraftment of CD3+ cells in recipients of PBMCs and the long-term multilineage engraftment of FBM recipients have important implications for developing strategies to study the regulation of these human cells in vivo.

Adult↗
PubMed1995

Overexpression of the MDM2 gene by childhood acute lymphoblastic leukemia cells expressing the wild-type p53 gene.

The wild-type (wt) p53 tumor suppressor gene is commonly inactivated in human malignancies, either by mutations or by loss of expression. An additional proposed mechanism for inactivation of wt-p53 is amplification of the murine double minute 2 (MDM2) gene and overexpression of the MDM2 protein, which binds to p53 and eliminates its tumor suppressor function. To investigate a potential role for MDM2 in the inactivation of wt-p53 in pediatric acute lymphoblastic leukemia (ALL), we examined the expression of MDM2 and p53, as well as the occurrence of p53 mutations and possible amplification of the MDM2 gene, in 19 pediatric ALL cell lines and one pediatric acute myelogenous leukemia (AML) line. Although we did not find significant amplification of the MDM2 gene in any of the leukemic lines, we detected overexpression of MDM2 in all 10 lines that expressed wt-p53. Of the 10 lines without overexpression of the MDM2 gene, six (including the AML line) did not express p53, and four expressed mutant p53 with single point mutations in exons 7 and 8. To determine whether primary leukemic cells showed a similar correlation, we analyzed the original cryopreserved leukemic bone marrow cells from seven patients from whom cell lines were established. We obtained similar results from both the primary leukemic cells and the corresponding cell lines: overexpression of MDM2 was present in primary cells that expressed wt-p53 but not in cells that lacked expression of wt-p53. These findings suggest an important role for MDM2 in the pathogenesis of pediatric ALL in which leukemic cells express wt-p53.

Blotting, Southern↗
PubMed1995

Homozygous deletions of the CDKN2 (MTS1/p16ink4) gene in cell lines established from children with acute lymphoblastic leukemia.

Homozygous deletions of the CDKN2 (MTS1/p16ink4) gene have been found at high frequency in cell lines derived from a variety of adult solid tumors. In order to investigate the status of the CDKN2 gene in cell lines established from childhood acute lymphoblastic leukemia (ALL), we surveyed 25 lines representing the major pediatric ALL phenotypes for the presence of this gene by Southern blot analysis. Homozygous deletions of all or part of the CDKN2 gene were detected in 21 (84%) cell lines, including 11 of 14 (79%) early-pre-B-ALL, four of five (80%) pre-B-ALL, and six of six T-ALL lines. CDN2 mRNA was detected by Northern blotting in each of the four lines containing an intact CDKN2 gene. These data suggest an important role for CDKN2 deletion in the cause and/or progression of pediatric ALL.

Blotting, Northern↗
PubMed1994

The effects of bone marrow transplantation on pulmonary function in children.

The effects of current methods of bone marrow transplantation (BMT) on pulmonary function in children have not been extensively studied. We reviewed serial pulmonary function tests (PFTs) in 25 children (median age, 9 yr; range, 4-15) who received allogeneic (n = 14) or autologous (n = 11) BMT for neoplastic diseases at The Johns Hopkins Hospital. The PFTs were obtained before BMT and at 6 months (early) and 15 months (late) after transplant. In all but 6 patients, PFTs were normal before BMT. A mild transient decline in carbon monoxide diffusing capacity (DLCO) was observed early after BMT but returned to baseline levels in the late post-BMT period. A trend towards worsening of PFTs with increasing age of patients was observed. The presence of graft-versus-host disease (GVHD) and pretransplant seropositivity for cytomegalovirus (CMV) were associated with significant decrements in several measurements of pulmonary function in the early post-BMT period. Patients given bulsulfan-containing preparative regimens tended to have less impairment of PFTs than those given other regimens using other combination high-dose chemotherapeutic agents or total body irradiation. These findings suggest that abnormalities in PFTs are common in the first months after BMT in pediatric patients but are not consistently associated with impairment of lung function when studied 15 months post-transplant.

Adolescent↗
PubMed1993

Recent developments in experimental bone marrow transplantation.

Animal models have been a mainstay for the preclinical evaluation of the principles of bone marrow transplantation. In addition to evaluation of the therapeutic effectiveness of bone marrow transplantation in oncologic, hematologic, immunologic, and genetic diseases, experimental animal models provide insights into the immunobiology of bone marrow transplantation, including engraftment kinetics, tolerance, immune reconstitution, and graft-versus-host and graft-versus-tumor reactions. Many recent developments in experimental bone marrow transplantation resulted from not only the discovery of new spontaneously occurring models of human diseases but also the induction of neoplastic diseases, eg, chronic myelogenous leukemia, by transplantation of syngeneic marrow cells into which foreign genes were introduced and expressed. Murine bone marrow transplantation systems are an exemplary format for the study of clinically relevant basic aspects of hematopoiesis, including identification and elucidation of the biology of hematopoietic stem cells. Finally, the application of molecular biologic techniques in animal bone marrow transplantation models provides the preclinical foundations of gene-insertion therapy by transplantation of syngeneic or autologous marrow-derived stem cells into which functional genes were inserted.

Animals↗
PubMed1993

Hematopoietic cell transplantation in the twitcher mouse. The effects of pretransplant conditioning with graded doses of busulfan.

The effects of congenic hematopoietic cell transplantation (HCT; transplantation of bone marrow and spleen cells) after graded doses of busulfan (BU), a myeloablative but nonimmunosuppressive alkylating agent, were evaluated in the twitcher mouse model of human galactosylceramidase deficiency, a demyelinating sphingolipid storage disease. C57BL/6 twitcher mice (immunophenotype Ly-5.1) were given 10 to 50 mg/kg of BU or total-body irradiation (9.0 Gy) at age nine days and HCT from congenic Ly-5.2 donors 24 hr later. The 30-day post-HCT survival, an indicator of tolerance of the preparative regimen, was at least 83% in twitcher mice given 45 mg/kg or less of BU, was 50% in recipients of 50 mg/kg BU and 75% in TBI-conditioned twitchers. The lifespan of twitcher mice given HCT after 10 or 20 mg/kg of BU was similar to that of untreated twitchers (median survival, 42 days; range, 30-47). In contrast, mice transplanted after 35 to 50 mg/kg of BU had significantly prolonged survival (median, 82 days; range, 56-208) and stabilization of hindlimb paralysis, similar to TBI-conditioned recipients. Post-HCT repopulation by donor Ly-5.2 cells was determined by flow cytometry. Thirty days after HCT, only 11-15% of lymphohematopoietic cells in blood, bone marrow, and spleens were of Ly-5.2 donor origin in twitcher mice transplanted after 10 mg/kg of BU but 60-80% were of Ly-5.2 donor origin in mice transplanted after higher doses of BU. These levels further increased to 70-90% by 90 days after HCT, comparable to that seen after TBI. Levels of galactosylceramidase in livers, spleens, and brains of twitchers transplanted after 35-50 mg/kg of BU or after TBI increased to 30-116% of normal control values by 90 days after HCT. Conditioning for HCT with as little as 35 mg/kg of BU provides minimal peritransplant mortality, rapid and sustained establishment of donor lymphohematopoiesis, replacement of lysosomal hydrolase, and prolonged survival in this murine model of human sphingolipidosis.

Animals↗
PubMed1993

Cyclosporine-induced graft-versus-host disease after autologous bone marrow transplantation for acute myeloid leukemia.

Rodents given cyclosporine (CSP) for several weeks after autologous or syngeneic bone marrow transplantation develop a syndrome that mimics allogeneic graft-versus-host disease (GVHD). Autologous GVHD has also been reported after administration of CSP in patients who have received autologous bone marrow transplantation (ABMT) with untreated marrow for lymphoma or acute myeloid leukemia (AML). Our study was designed to determine whether CSP administration is associated with appearance of autologous GVHD in patients with AML receiving ABMT with 4-hydroperoxycyclophosphamide (4HC)-purged marrow and whether there was a dose-dependent effect of CSP on development of the syndrome. Thirty-three patients with AML (18 in first remission [CR1], 10 in CR2, and 5 in CR3) received intravenous CSP, beginning on the day of ABMT, after a preparative regimen of busulfan and cyclophosphamide and ABMT with 4HC-treated marrow. Skin biopsies were obtained weekly after ABMT or on appearance of rash and were graded for GVH changes. In the first phase of this study, groups of patients received CSP dosages of either 1 mg/kg/day (7 patients), 2.5 mg/kg/day (8 patients), or 3.75 mg/kg/day (6 patients) for 28 days. Sixteen of the 21 patients (76%) developed cutaneous histopathologic grade 2 GVHD at a median of 34 days (range, 14-49) after ABMT, and cutaneous manifestation were present at time of positive biopsy in 11 of the 16 patients. There was no apparent difference in frequency, time to onset, or duration of GVHD among the three CSP dosage groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

Optimization of busulfan dosage in children undergoing bone marrow transplantation: a pharmacokinetic study of dose escalation.

Busulfan (BU) is a widely used myeloablative and antineoplastic agent in clinical bone marrow transplantation (BMT). The lower incidence of BU-associated toxicities and lower therapeutic effectiveness in young children given BU doses based on body weight (ie, 16 mg/kg) is associated with altered pharmacokinetics of BU; the area under the curve (AUC) of BU concentration versus time is significantly less in these patients than those observed in older children and adults. To optimize BU dosage in young BMT recipients, we developed a dosage regimen based on body surface area (BSA) and determined BU pharmacokinetics and BU-associated toxicities. Seven children (median age, 3.9 years, range, 1.1 to 5.7) undergoing allogeneic or autologous BMT for leukemia received 40 mg/m2/dose BU every 6 hours for 16 doses; BU concentrations were measured in the plasma, and AUCs were determined for each patient after the first and 13th doses. Expressed as a function of body weight, the median BU dosage was 26.4 mg/kg (range, 24.3 to 28.2), a 60% increase over the BU dosage based on body weight. Four patients developed mucositis, and one of them also developed nonfatal hepatic veno-occlusive disease (VOD). No patients receiving 40 mg/m2 BU developed neurotoxicity (eg, seizures) or interstitial pneumonitis. Prompt and sustained engraftment was observed in the allogeneic BMT recipients, and late graft failure was not seen. The mean BU AUCs were 1,105 mumol/L.min (range, 790 to 2,080) after the first dose and 1,022 mumol/L.min (range, 632 to 1,860) after the 13th dose of BU, comparable to the AUCs in adults given 16 mg/kg of BU. These studies suggest that, in young children, BSA-based dosing of BU (40 mg/m2) provides drug exposures (AUCs) closer to adult values with acceptable toxicities and may improve therapeutic effects.

Bone Marrow Transplantation↗
PubMed1992

Induction of cutaneous graft-versus-host disease by administration of cyclosporine to patients undergoing autologous bone marrow transplantation for acute myeloid leukemia.

Cutaneous graft-versus-host disease (GVHD) has been reported after administration of cyclosporine (CSP) after autologous bone marrow transplantation (ABMT) with unpurged marrow in patients with lymphoma. To determine whether GVHD can be induced after ABMT with chemopurged marrow in acute myeloid leukemia (AML), we administered intravenous CSP for 28 days (beginning on the day of ABMT) to 19 patients with AML (12 in first remission [CR1], six in CR2, and one in CR3) who received busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg) and ABMT with 4-hydroperoxycyclophosphamide (4HC)-treated marrow. In this dose-escalation trial, CSP daily doses were 1 mg/kg in seven patients, 2.5 mg/kg in eight patients, or 3.75 mg/kg in four patients. Skin biopsies were obtained weekly after ABMT or on appearance of rash and were graded for GVH changes. Overall, 15 of 19 patients (79%) had cutaneous histopathologic grade 2 GVHD at a median of 33 days (range, 14 to 49) after ABMT; in 10, cutaneous manifestations were present at time of positive biopsy. The frequency, time to onset, and duration of GVHD were similar among the three CSP dosage groups. No patients had hepatic or gastrointestinal dysfunction attributable to GVHD or required specific therapy for GVHD. Positive biopsies for GVHD were seen in seven of eight patients who received full-course, full-dose CSP and 8 of 11 patients who had CSP discontinued or dosage reduced because of renal insufficiency. Three patients (one with positive biopsy) died with ABMT-related complications. Seven patients (four CR1, three CR2) relapsed with AML at a median of 411 days (range, 178 to 549) after ABMT; six of seven had positive biopsies for cutaneous GVHD. Nine patients (seven CR1, one CR2, and one CR3) are alive without relapse at a median of 501+ days (range, 252+ to 811+) after ABMT; eight of nine had cutaneous GVHD. Short-course CSP can induce autologous GVHD in recipients of chemopurged marrow autografts for AML, but randomized prospective trials are needed to determine whether this immunologic reaction is associated with alterations in leukemic relapse rate and disease-free survival after ABMT in AML.

Adolescent↗
PubMed1992

Growth in children after bone marrow transplantation: busulfan plus cyclophosphamide versus cyclophosphamide plus total body irradiation.

Growth was assessed during the first and second years following bone marrow transplantation (BMT) in 47 children treated by either busulfan plus cyclophosphamide (BU/CY) (n = 24) or cyclophosphamide plus fractionated total body irradiation (CY/TBI) (n = 23). Before transplant, the median height was only 0.2 SD below age- and sex-adjusted means (range, -2.5 to +3.0). Height was greater than 2.0 SD below normal in only three patients (6%). The pretransplant heights were comparable in the BU/CY and CY/TBI groups (-0.1 v -0.6 SD, P = .35). Following transplant, median 1- and 2-year heights were 0.7 and 0.9 SD below normal, respectively. Growth rates were 2.2 SD and 1.4 SD below normal during the first and second years, respectively. Growth rates were greater than 2.0 SD below normal in 24 of 47 (51%) at 1 year and in 12 of 31 (39%) at 2 years after transplant. Growth rates in patients treated with BU/CY were comparable to those treated with CY/TBI during both years: -2.5 versus -1.7 SD during the first year (P = .19, Wilcoxon), and -1.5 versus -1.1 SD during the second year (P = .61). Growth rates during the second year correlated with growth rates during the first year (r = .36, P = .046). Growth rates during the first year were lower in patients who had been given prior cranial irradiation, those who were near pubertal age at the time of transplant, and those who were transplanted for a disease other than acute lymphoblastic leukemia (ALL). During the second year, poor rates of growth were associated only with the use of corticosteroids after transplant.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Treatment of recurrent and refractory pediatric solid tumors with high-dose busulfan and cyclophosphamide followed by autologous bone marrow rescue.

PURPOSE: The purpose of this study was to determine the toxicities of and responses to high-dose busulfan and cyclophosphamide with autologous bone marrow transplant (ABMT) in patients with recurrent or refractory pediatric solid tumors. PATIENTS AND METHODS: We treated 18 patients (ages, 2 to 38 years; median, 14) who had tumors that were resistant to conventional chemotherapy and radiotherapy with busulfan 16 mg/kg and cyclophosphamide 200 mg/kg. Seventeen patients received bone marrow purged with 4-hydroperoxycyclophosphamide; one received unpurged marrow. RESULTS: Despite extensive prior treatment, including radiotherapy in 16 patients, toxicity generally was acceptable. For seven patients with measurable disease, there were three partial responses of 2, 10, and 20 months' duration, three patients with stable disease (SD), and one early, toxic death. Of the 11 patients with no measurable disease at the time of transplantation, one patient with osteosarcoma continues in remission at 57+ months and one third of the patients survived for at least 16 months. Mucositis was the predominant nonhematopoietic toxicity. CONCLUSION: Although the high-dose busulfan and cyclophosphamide combination showed modest activity, changes in the preparative regimen should be considered to improve the response rate in refractory tumors.

Adolescent↗
PubMed1992

Growth retardation and depigmentation of hair after high-dose busulfan and congenic hematopoietic cell transplantation in mice.

Busulfan, a myeloablative but non-immunosuppressive alkylating agent, is used extensively in clinical bone marrow transplantation (BMT), but the effects of high-dose administration have not been previously evaluated in preclinical BMT settings with young murine recipients. We compared the survival and growth of C57BL/6 mice given graded single doses of busulfan (10-100 mg/kg) or total body irradiation (TBI; 900 cGy) at age 9 days and hematopoietic cell transplantation (HCT; transplantation of congenic bone marrow and spleen cells) 24 h later. The 30-day survival was 87-100% in mice transplanted after 10-40 mg/kg busulfan and 79% after TBI, but fell to 54% and 33%, respectively, after 80 mg/kg and 100 mg/kg busulfan, suggesting that this latter dosage range represents the LD50 for single-dose busulfan in young C57BL/6 mice given stem cell rescue. The weights of 10-week-old mice given HCT after lower doses of busulfan ranged from 87% of control at 10 mg/kg to 64-69% of control in mice conditioned with 35-65 mg/kg busulfan or TBI. Impairment of weight gain was most striking (approximately 50% of control) in mice transplanted after 80-100 mg/kg busulfan. Despite retardation of somatic growth, the brain weights of busulfan-conditioned mice remained at least 90% of control, and there were no obvious neuropathological alterations in the brains of these animals. All mice treated with at least 20 mg/kg busulfan or TBI lost hair by 3-4 weeks after transplant.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗