Search PubMed⌕ Search

Biomedical subjects

F R Appelbaum

Publications and source records attributed to F R Appelbaum.

At least 199 records · Page 11Linked to original sources
PubMed1995

Trisomy 11: an association with stem/progenitor cell immunophenotype.

The clinicopathological features and the prognostic significance of acute myeloid leukaemia (AML) with trisomy 11 are currently unknown. In this study we describe 15 adult AML cases with trisomy 11. Trisomy 11 was the sole chromosomal anomaly in eight cases; the remaining seven cases were characterized by +11 in association with other karyotypic aberrations. Patients ages ranged from 34 to 79 years. 12 patients were male; three were female. Although there was no correlation of trisomy 11 with any specific FAB subgroup [M2 (n = 7), M1 (n = 5), M4/5 (n = 2), M3 (n = 1)] less mature forms predominated. Immunologically, the leukaemic blasts showed a strikingly consistent stem cell phenotype with expression of HLA-DR, CD34 and the myeloid antigens (CD15, CD33 and/or CD13). In addition, two cases expressed the B-cell associated antigen CD19. The presence of trilineage dysplasia, suggesting the presence of an underlying myelodysplasia (MDS), was observed at presentation in five cases; in another case MDS was evident at relapse only. Unexpectedly, MLL gene rearrangements were observed in two of four cases characterized by trisomy 11 as the sole karyotypic abnormality; however, MLL aberrations were not identified in three cases with trisomy 11 accompanied by other karyotypic anomalies. The majority of patients in each subgroup (i.e. those with and without additional cytogenetic abnormalities) achieved a short first complete remission (CR) (mean 8 months) and failed to obtain a second CR. Only one patient in each trisomy 11 subgroup is in a continuous CR for > 34 months. These findings suggest that trisomy 11 leukaemia is characterized by a stem/progenitor cell immunophenotype with poor response to standard chemotherapeutic regimens and an unfavourable prognosis.

Acute Disease↗
PubMed1995

Peripheral-blood stem-cell collections after paclitaxel, cyclophosphamide, and recombinant human granulocyte colony-stimulating factor in patients with breast and ovarian cancer.

PURPOSE: Here we evaluate Taxol (paclitaxel; Bristol-Myers Squibb, Princeton, NJ) and cyclophosphamide (CY) with recombinant human granulocyte colony-stimulating factor (rhG-CSF) for mobilization of peripheral-blood stem cells (PBSCs) for autologous stem-cell transplantation in patients with breast and ovarian cancer. PATIENTS AND METHODS: PBSCs were collected from 17 patients with breast (n = 11), ovarian (n = 5), and gastric (n = 1) cancer after administration of Taxol (170 mg/m2 x 1) and CY (4 g/m2 x 1) followed by rhG-CSF (10 micrograms/kg/d). PBSC collections after Taxol and CY were compared with PBSC collections from nine patients with stage IV breast (n = 8) or stage III ovarian (n = 1) cancer who had received CY (4 g/m2 x 1) followed by rhG-CSF (16 micrograms/kg/d) for mobilization. RESULTS: Mean WBC and platelet counts on the first day of apheresis were 6.3 x 10(9)/L (range, 1.9 to 22.1) and 35 x 10(9)/L (range, 19 to 77), respectively. The median numbers of CD34+ cells, peripheral-blood mononuclear cells (PBMNC), and peripheral-blood total nucleated cells (PBTNC) collected were 13.02 x 10(6)/kg (range, 5.4 to 57.8; mean, 16.02), 6.86 x 10(8)/kg (range, 1.9 to 51.2), and 17.41 x 10(8)/kg (range, 2.4 to 106.6), respectively. In the comparison group, the median yield of CD34+ cells was 6.39 x 10(6)/kg (range, 0.2 to 28; mean, 10.01; P = .01). The mean daily yield of CD34+ cells/kg/collection was 3.5 (range, 0.8 to 28.9) after Taxol and CY, as compared with 1.3 (range, 0.1 to 7.0) for patients who received CY alone (P = .01). All patients who received CY and Taxol reached a target level of 5 x 10(6) CD34+ cells/kg, as compared with five of nine patients (55.5%) who received CY alone (P = .03). CONCLUSION: These data suggest that Taxol and CY followed by rhG-CSF mobilizes PBSCs in patients with advanced breast and ovarian cancer more effectively than this regimen without Taxol.

Adult↗
PubMed1995

An update on allogeneic marrow transplantation for myelodysplastic syndrome.

Ninety-three patients with myelodysplastic syndrome with either excess blasts or life-threatening cytopenia received cyclophosphamide and total body irradiation (88 patients) or busulfan (5 patients) followed by allogeneic (90 patients) or syngeneic (3 patients) marrow infusion. Thirty-eight patients are disease-free survivors between 1.8 and 11.3 years (median 6.1 years) after transplantation. The median Karnofsky performance status of the survivors is 100%, and only 2 have a performance status of < 80%. Eighteen patients relapsed and the remaining 37 died without evidence for relapse. The 5-year actuarial disease-free survival, relapse, and non-relapse mortality rates are 40%, 29%, and 44%, respectively. The actuarial relapse rate was higher among patients with excess blasts at the time of transplantation compared to those without excess blasts (49% vs. 4%, p = 0.0001), resulting in a lower disease-free survival (31% vs. 54%, p = 0.07). Increasing age was associated with a lower disease-free survival (p = 0.02). In a multivariate analysis, younger age, shorter disease duration, and absence of excess blasts were associated with improved outcome. We recommend that patients with myelodysplasia with appropriate marrow donors, especially patients less than age 40, undergo marrow transplantation early during the disease course, before the disease progresses or life-threatening complications develop.

Adolescent↗
PubMed1995

Influence of total nucleated cell dose from marrow harvests on outcome in patients with acute myelogenous leukemia undergoing autologous transplantation.

This retrospective study was conducted to determine whether the total number of nucleated cells (TNC)/kg collected at marrow harvest was associated with outcome in 151 patients with acute myelogenous leukemia (AML) who received an autologous purged (n = 67) or non-purged (n = 84) marrow transplant. At the time of transplant 33 patients were in first complete remission (CR), 47 in second CR, 54 in first relapse and 17 beyond second CR. Ninety patients received busulfan (BU) 16 mg/kg and cyclophosphamide (CY) 120 or 200 mg/kg, 51 patients received CY 120 mg/kg and total body irradiation (TBI) 12-15.75 Gy and 10 patients received BU 8 mg/kg, CY 60 mg/kg and TBI 12 Gy as conditioning regimens. Patients whose marrow harvest yielded < 2 x 10(8) TNC/kg did not undergo purging with 4-hydroperoxycyclophosphamide (4HC). This group of patients (n = 28) had a 100 day mortality of 50% and only 54% achieved a granulocyte levels of > 0.5 x 10(9)/l and 29% achieved platelet transfusion independence. Patients whose marrow harvest yielded 2-4 x 10(8) TNC/kg and did not undergo marrow purging had a 20% mortality by day 100, 91% recovered granulocytes to > 0.5 x 10(9)/l and 61% became platelet independent. Patients whose marrow harvest yielded 2-4 x 10(8) TNC/kg and underwent marrow purging with 4HC had a 50% mortality by day 100 and 58% achieved a granulocyte levels of > 0.5 x 10(9)/l and 42% became platelet transfusion independent.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1995

Rapid engraftment after autologous transplantation utilizing marrow and recombinant granulocyte colony-stimulating factor-mobilized peripheral blood stem cells in patients with acute myelogenous leukemia.

This study was performed to determine whether peripheral blood stem cells (PBSCs) mobilized with recombinant granulocyte-colony stimulating factor (rhG-CSF) increase the tempo of granulocyte and platelet recovery when added to marrow in patients with acute myelogenous leukemia (AML) undergoing autologous bone marrow transplantation (BMT). Twenty six patients with AML had bone marrow harvested in first (n = 16) or second (n = 10) complete remission (CR) and cryopreserved. Patients received rhG-CSF alone (n = 20) or rhG-CSF following chemotherapy (n = 6). PBSCs were collected from 24 of the 26 patients a median of 7 (range 3-2130) days after marrow harvest. Two patients presumed to be in second CR did not have PBSCs collected because of early relapse. Fourteen patients in first CR (n = 3), second CR (n = 8) or first relapse (n = 3) proceeded to autologous BMT utilizing marrow + rhG-CSF-mobilized PBSCs. Engraftment parameters were compared with a historical group of 158 patients with AML who had received purged (n = 67) or unpurged (n = 91) autologous BMT without PBSCs. The median number of peripheral blood total nucleated and CD34+ cells collected from 24 patients was 19.55 x 10(8)/kg (range 1.83-54.83) and 5.59 x 10(6)/kg (1.23-34.79), respectively. All patients transplanted achieved a granulocyte level of > 0.5 x 10(9)/l with a median of 13 days (range 11-27 days) and platelets to 20 x 10(9)/l median 14 days (range 9-83 days).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1995

Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics.

We have determined the relationships between busulfan average concentration at steady-state and (1) rejection of graft, and (2) regimen-related toxicity, and have evaluated the dependence of busulfan clearance/F on body size and age. Patients received 16-30 mg/kg of busulfan followed by cyclophosphamide in doses of 120, 150, 174, or 200 mg/kg or 8 g/m2 in preparation for autologous, syngeneic or allogeneic grafts varying in compatibility from HLA-matched siblings to HLA-partially-matched unrelated donors. In a multivariate Cox time-to-rejection analysis, only busulfan concentration remained a significant determinant of rejection, P = 0.0154. An average concentration of busulfan at steady-state of at least 200 ng/ml was needed to avoid rejection of a matched-sibling graft, while 600 ng/ml was needed to avoid rejection of HLA-partially-matched related or HLA-matched unrelated donor grafts. The toxicity of the cytoreductive regimen correlated with busulfan average concentration at steady-state (rs = 0.717). Busulfan clearance/F expressed relative to body weight, ideal body weight or surface area declined with age during the first decade of life. Over the entire span of age, the coefficient of variation in clearance/F for all ages was similar when clearance/F was expressed in absolute terms (ml/min) and when adjusted for body surface area; the coefficient of variation was greater for clearance/F when expressed relative to total or ideal body weight. We conclude that busulfan concentration in plasma is an important determinant of graft survival and regimen-related toxicity, and that the variability of busulfan pharmacokinetics with age precludes the use of a fixed dose for all ages and indications.

Adolescent↗
PubMed1995

Impact of patient weight on non-relapse mortality after marrow transplantation.

We hypothesized that severely overweight patients were at an increased risk of transplant-related toxicity and that this might be reflected in increased mortality soon after transplant. All patients transplanted between January 1985 and January 1992 were included in the analysis; data were complete for 2238 (1662 adults, 576 children ( > 18 years). Since we were interested primarily in acute post-transplant toxicity, survival through day 150 was the primary end-point analyzed. Children and adults were analyzed separately since the decision to transplant or not to transplant may differ between the two populations. Log rank statistics and multivariable Cox regression analyses showed that adults at 95% to > 145% of ideal body weight (BW) experienced comparable non-relapse mortality and survival. In contrast, survival among patients at 85-95% or < 85% of ideal BM was significantly worse (P = 0.004 and P = 0.0001, respectively) than in the 95-145% weight category. Results in children were similar except that the differences were less prominent (comparisons of < 85%, 85-95% and > 145% categories vs. 95-145% category showed P values of 0.22, < 0.01 and 0.66, respectively). The observed weight effect was not explainable in terms of the composition of the lower weight categories in regards to nine other known or suspected risk factors. In addition to weight, patient age, diagnosis, type of transplant, year of transplant, graft-versus-host disease (GVHD) prophylaxis and GVHD grades II-IV were also significantly associated with outcome. Thus, the present analysis shows that underweight patients are at an increased risk of death in the early period after transplant.

Adolescent↗
PubMed1995

Carboplatin infusion in relapsed and refractory acute myeloid leukemia--a Southwest Oncology Group trial.

Carboplatin (CBDCA) is an active agent in the treatment of acute leukemia and is associated with limited extramedullary toxicity. Simultaneous phase II trials were conducted by the Southwest Oncology Group in adult patients with relapsed or refractory acute myeloid leukemia (AML). CBDCA was given as a continuous infusion at a dose of 300 mg/m2 daily for 5 days. Three (8%) of the 37 eligible patients in the relapsed group achieved complete remissions (CRs) lasting 3, 4, and 26 months. Entry of patients was stopped early in the refractory group due to slow accrual and in the relapsed group due to low CR rate. For both groups combined, the CR rate was 3/45 or 7% (95% confidence interval 3-18%). There were 12 fatal toxicities. Four patients died of intracerebral hemorrhage, three of infection, and five of hepatic and/or renal failure. Nonhematologic grade 4 toxicity included diarrhea in three patients, hyperbilirubinemia in four, and mucositis and renal toxicity in one each. These results suggest that CBDCA should not be considered for treatment of relapsed or refractory AML patients with prior high-dose therapy.

Acute Kidney Injury↗
PubMed1995

Bone marrow transplantation for chronic myelogenous leukemia.

Based on our understanding of CML, we recommend that patients age 65 or less with newly diagnosed CML should be evaluated to determine the stage of their disease and should be human lymphocyte antigen-typed along with their siblings. Patients age 55 years and younger who have matched or single antigen mismatched siblings should be advised to undergo BMT as soon as possible and patients up to age 65 should be considered for BMT early in their disease course if in good health. Patients age 55 years or younger without appropriately matched family member donors should have a search for an unrelated donor initiated and should be offered BMT if an appropriate donor is found. Patients for whom no donor is found and older patients without family matches can be considered for entry onto clinical trials evaluating autologous BMT or other experimental approaches.

Aged↗
PubMed1995

Effects of rhIL-11 on normal dogs and after sublethal radiation.

The effects of recombinant human interleukin-11 (rhIL-11) were studied in normal dogs and dogs given otherwise sublethal total-body irradiation (TBI) without marrow transplantation. Ten normal dogs were given rhIL-11 subcutaneously, twice daily for 14 days at varying doses, two dogs at 30 micrograms/kg/day, four dogs at 60 micrograms/kg/day, two dogs at 120 micrograms/kg/day, and two dogs at 240 micrograms/kg/day. Peripheral blood platelet counts increased in all dogs. The increase in platelet counts ranged from 1.4 to 3.1 times the pre-treatment level. The greater increases of platelets were associated with higher doses (p = 0.01). No change in platelet size was evident except at the dose of 240 micrograms/kg/day. There were no changes in the total white blood cell (WBC) count or differential. A higher proportion of megakaryocytes with a DNA content of 32N/64N was observed in dogs treated with rhIL-11 at day 7 (n = 6) than for control dogs that did not receive rhIL-11 (n = 7; p = 0.01). In both peripheral blood and marrow, significantly increased hematopoietic progenitors (i.e, colony-forming unit granulocyte/macrophage [CFU-GM]) were present 7 and 14 days after the start of treatment. Concentrations of serum fibrinogen increased by a median of 155 mg/dL at day 7 of rhIL-11 (p < 0.01). Cholesterol also increased by a median of 52 mg/dL at day 14 (p < 0.01). There was a single death of a non-irradiated dog from pneumonitis on day 15 after the start of rhIL-11 administration at a dose of 120 micrograms/kg/day. All other non-irradiated dogs tolerated rhIL-11 without any significant adverse effects. Five dogs were given 200 cGy TBI without marrow grafting, followed by 240 micrograms/kg/day rhIL-11 subcutaneously in two divided doses for 28 days starting within 2 hours of TBI. The results in this group were compared with 10 dogs that had previously or concurrently been given 200 cGy without marrow grafting or hematopoietic growth factors. Two of the five treatment dogs died of pneumonitis on day 13 compared to one death among 10 control dogs on day 24. Among dogs that survived to hematologic recovery, the rhIL-11 dogs had decreased platelet counts (< 150,000) for a median of 24 days (range = 24 to 41) compared to a median of 28 days (range = 21-40) for the control group. Treatment with rhIL-11 increased platelet counts, platelet size, ploidy number of megakaryocytes, and marrow and peripheral blood CFU-GM in normal dogs.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Phase II study of busulfan, cyclophosphamide and fractionated total body irradiation as a preparatory regimen for allogeneic bone marrow transplantation in patients with advanced myeloid malignancies.

A previous phase I dose escalation study determined that the maximum tolerated doses of busulfan and cyclophosphamide that could be combined with 12.0 Gy of total body irradiation were 7 mg/kg and 50 mg/kg, respectively. A phase II study of these three agents was carried out in 56 patients with advanced myeloid malignancies receiving allogeneic bone marrow transplants from HLA-identical donors. Cyclosporine with methotrexate or with prednisone was administered for prophylaxis against graft-versus-host disease. Grade 3 (n = 8) and 4 (n = 3) regimen-related toxicity occurred in 20% of patients, which was the maximum predicted from the phase I study. The 2-year actuarial probabilities of non-relapse mortality and relapse were 0.52 and 0.55, respectively. Fourteen patients survive, 12 in remission, 581-1761 days post-transplant. The actuarial probabilities of disease-free survival for patients with recurrent acute myeloid leukemia and advanced chronic myeloid leukemia at 2 years were 20% and 23%, respectively. When compared with our historical experience in patients receiving other treatment regimens, there was no apparent improvement in disease-free survival.

Adolescent↗
PubMed1995

Engraftment of patients with lymphoid malignancies transplanted with autologous bone marrow, peripheral blood stem cells or both.

Forty six patients with lymphoid malignancies receiving autologous transplants using three different sources of hematopoietic stem cells were compared for engraftment parameters. Thirteen patients (five with multiple myeloma, seven with non-Hodgkin's lymphoma and one with Hodgkin's lymphoma) received autologous marrow with post-transplant growth factors (group 1). During the same time interval, 14 patients (five with multiple myeloma, six with non-Hodgkin's lymphoma and three with Hodgkin's lymphoma) were transplanted with autologous marrow plus recombinant granulocyte colony-stimulating factor (rhG-CSF)-mobilized peripheral blood stem cells (PBSC) and post-transplant growth factors (group 2). Nineteen patients (seven with multiple myeloma and 12 with non-Hodgkin's lymphoma) received rhG-CSF mobilized PBSC and post-transplant growth factors (group 3). All PBSC were collected after G-CSF mobilization (16 micrograms/kg/day s.c. for 6 days) without prior chemotherapy. After high-dose myeloablative chemotherapy or chemoradiotherapy, the median days to recovery of neutrophils to levels of 0.5 and 1.0 x 10(9)/l were 12 vs. 9 vs. 9 days (P = 0.0003 (group 1 vs. group 2) and P = 0.53 (group 2 vs. group 3)) and 13 vs. 10 vs. 10 days (P = 0.0003 (group 1 vs. group 2) and 0.92 (group 2 vs. group 3)) for groups 1, 2 and 3, respectively. The median day to platelet transfusion independence was 22 vs. 11 vs. 11 days (P = 0.001 (group 1 vs. group 2) and P = 0.50 (group 2 vs. group 3)) for groups 1, 2 and 3, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

DLA-identical bone marrow grafts after low-dose total body irradiation: the effect of canine recombinant hematopoietic growth factors.

Previous studies found that bone marrow (BM) allografts from DLA-identical littermates resulted in survival of two thirds of recipient dogs after otherwise lethal doses of 450 to 600 cGy of total body irradiation (TBI) because of successful allografts or autologous recovery after rejection of the allografts. The current study asked whether survival could be further improved by treating allograft recipients with recombinant canine granulocyte colony-stimulating factor (G-CSF), stem cell factor (SCF), or G-CSF/SCF. Of 21 dogs, 14 (67%) receiving allografts but no growth factors survived, 10 with successful allografts (including 5 mixed chimeras) and 4 with autologous recovery; whereas 7 animals died, 5 from infections during BM aplasia and 2 from acute graft-versus-host disease. By comparison, 30 of 34 dogs (88%) receiving hematopoietic growth factors in addition to the BM graft survived, 17 with successful allografts (including 10 mixed chimeras) and 13 with autologous recovery; whereas 4 died, all with infection related to BM aplasia after rejection of the allograft. Survival was similar for recipients of G-CSF, SCF, or the combination of G-CSF and SCF. Logistic regression analyses, which accounted for possible effects of TBI dose, showed a trend for improved survival in dogs receiving growth factors (P = .09), no change in allogeneic engraftment (P = .74), and a slight increase in autologous recovery (P = .22). In agreement with previous data, we found that grafts of BM from DLA-identical littermates improved survival of recipient dogs exposed to low but otherwise lethal doses of TBI. A further improvement in survival could be achieved by additional treatment with G-CSF, SCF, or G-CSF/SCF. Results suggest that treatment by hematopoietic growth factors along with BM grafts should be considered for victims of radiation accidents.

Animals↗
PubMed1994

Availability and appropriateness of allogeneic bone marrow transplantation for chronic myeloid leukemia in 10 countries.

BACKGROUND: Allogeneic bone marrow transplantation, a sophisticated and expensive procedure, is the only curative therapy for chronic myeloid leukemia (CML). We examined the availability and appropriateness of allogeneic bone marrow transplantation for CML in 10 economically advanced countries with diverse health care systems. For each country we obtained data on the likelihood of transplantation to treat CML in patients under the age of 55 years, the length of time from diagnosis to transplantation, and the stage of disease at the time of transplantation. METHODS: Data were collected on 9873 allogeneic bone marrow transplantations performed at 208 centers in 10 countries from 1989 through 1991. Data were acquired from transplantation registries and by means of a mailed survey of all centers and teams that did not contribute data to registries. Data on the incidence of disease were drawn from national and regional cancer registries. RESULTS: Among the 10 countries there was a twofold difference between the lowest and highest rates of transplantation to treat CML (0.26 to 0.54 per 100,000 population per year); Swedish patients were the most likely to receive a transplant, and German patients the least likely. The median length of time from diagnosis to transplantation ranged from 6.8 to 15.4 months. In all countries, most transplantations were performed in the chronic phase of the disease, but as many as a third of patients received transplants in the less favorable accelerated or blast phase. The values for the United States fell near the middle of those for the 10 countries on all measures. CONCLUSIONS: Our findings challenge the assumption that the United States is unique in providing broad access to high-technology treatments. On no measure of the availability or appropriateness of transplantation for CML did it surpass the other nine countries studied.

Adolescent↗
PubMed1994

Treatment of acute graft-versus-host disease with humanized anti-Tac: an antibody that binds to the interleukin-2 receptor.

Humanized anti-Tac is a genetically engineered human IgG1 monoclonal antibody specific for Tac, the alpha subunit of the interleukin-2 (IL-2) receptor, and blocks IL-2-dependent activation of human T lymphocytes. The safety, pharmacokinetics, and immunosuppressive activity of humanized anti-Tac were evaluated in 20 patients who developed acute graft-versus-host disease (GVHD) after allogeneic marrow transplantation. Patients had developed acute GVHD at 5 to 26 (median, 14) days after transplantation and had failed to respond to primary therapy with glucocorticoids. Sequential groups of 4 patients each received a single 1-hour infusion of antibody in escalating doses of 0.5, 1.0, or 1.5 mg/kg; 8 additional patients were then treated with 1.5 mg/kg. A second infusion of antibody was administered after 11 to 48 (median, 16) days in 8 patients who had transient improvement of GVHD after the first infusion. Acute side effects, limited to chills in 1 patient and diaphoresis in another, were observed during or shortly after the antibody infusion. Overall improvement of acute GVHD occurred in 8 patients, 6 of whom were treated with a single antibody infusion and 2 with two infusions. Four responses were complete and 4 were partial. Three additional patients had improvement in one organ but progression in another. Responses occurred in 9 of 16 cases with skin disease, 3 of 15 with liver disease, and 6 of 12 with gastrointestinal disease. Two patients survive at 529 and 645 days after antibody treatment. Two patients died after relapse of leukemia. Sixteen patients died of infection or organ failure between 5 and 211 (median, 55) days. The terminal elimination half-life of the antibody was 44 to 363 hours, with a harmonic mean of 79, 88, and 94 hours, respectively, for the three doses studied. Absolute peripheral blood T-lymphocyte counts remained unchanged during the 56 days after infusion of the antibody. A fraction of circulating T cells expressed the alpha chain of the IL-2 receptor that, in some patients, was bound by antibody in vivo up to 28 days after treatment. No patient developed a measurable antibody response to humanized anti-Tac. Humanized anti-Tac has a long half-life after intravenous injection in humans, superior to any rodent monoclonal antibody specific for human T cells, and does not appear to induce antibody formation in recipients of marrow transplants. Improvement of steroid-refractory GVHD in 40% of patients after only one or two antibody infusions indicates that humanized anti-Tac is immunosuppressive.

Adult↗
PubMed1994

In vivo synergy between recombinant human stem cell factor and recombinant human granulocyte colony-stimulating factor in baboons enhanced circulation of progenitor cells.

Recombinant human stem cell factor (rhSCF) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) are synergistic in vitro in stimulating the proliferation of hematopoietic progenitor cells and their precursors. We examined the in vivo synergy of rhSCF with rhG-CSF for stimulating hematopoiesis in vivo in baboons. Administration of low-dose (LD) rhSCF (25 micrograms/kg) alone did not stimulate changes in circulating WBCs. In comparison, administration of LD rhSCF in combination with rhG-CSF at 10 micrograms/kg or 100 micrograms/kg stimulated increases in circulating WBCs of multiple types up to twofold higher than was stimulated by administration of the same dose of rhG-CSF alone. When the dose of rhG-CSF is increased to 250 micrograms/kg, the administration of LD rhSCF does not further increase the circulating WBC counts. Administration of LD rhSCF in combination with rhG-CSF also stimulated increased circulation of hematopoietic progenitors. LD rhSCF alone stimulated less of an increase in circulating progenitors, per milliliter of blood, than did administration of rhG-CSF alone at 100 micrograms/kg. Baboons administered LD rhSCF together with rhG-CSF at 10, 100, or 250 micrograms/kg had 3.5- to 16-fold higher numbers per milliliter of blood of progenitors cells of multiple types, including colony-forming units granulocyte/macrophage (CFU-GM), burst-forming unit-erythroid (BFU-E), and colony-forming and burst-forming units-megakaryocyte (CFU-MK and BFU-MK) compared with animals given the same dose of rhG-CSF without rhSCF, regardless of the rhG-CSF dose. The increased circulation of progenitor cells stimulated by the combination of rhSCF plus rhG-CSF was not necessarily directly related to the increase in WBCs, as this effect on peripheral blood progenitors was observed even at an rhG-CSF dose of 250 micrograms/kg, where coadministration of LD rhSCF did not further increase WBC counts. Administration of very-low-dose rhSCF (2.5 micrograms/kg) with rhG-CSF, 10 micrograms/kg, did not stimulate increases in circulating WBCs, but did increase the number of megakaryocyte progenitor cells in blood compared with rhG-CSF alone. LD rhSCF administered alone for 7 days before rhG-CSF did not result in increased levels of circulating WBCs or progenitors compared with rhG-CSF alone. Thus, the synergistic effects of rhSCF with rhG-CSF were both dose- and time-dependent. The doses of rhSCF used in these studies have been tolerated in vivo in humans.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia.

Graft rejection has been a problem after marrow grafts for patients with aplastic anemia who were conditioned with cyclophosphamide (CY). Rejection lessened when patients were given the marrow donor's peripheral blood buffy-coat cells in addition to the marrow, but this result was achieved at the price of more chronic graft-versus-host disease (GVHD). Results with second transplants suggested that CY alternating with antithymocyte globulin (ATG) was more immunosuppressive than CY alone. Therefore, the current study explored CY and ATG without buffy-coat cell transfusions in 39 patients with aplastic anemia given marrow transplants from HLA-identical family members (siblings in 38 cases, father in 1 case). We hoped both to minimize the risks of graft rejection and of chronic GVHD and to improve survival. Patients were 2 to 52 years of age (median, 24.5); 87% had received previous transfusions, and 41% had therapy with immunosuppressive agents before transplant. They were administered four daily doses of CY (total, 200 mg/kg) alternating with three doses of ATG (total, 90 mg/kg) followed by an HLA-identical marrow graft. Methotrexate and cyclosporine were administered to prevent GVHD. Two patients rejected their grafts (5%), and both were successfully retransplanted. Acute (grade 2 or 3) GVHD occurred in 15% and chronic GVHD in 34% of patients. The actuarial survival rate at 3 years was 92%, which compares favorably to the 72% survival rate in 39 historical patients who were matched with current patients for age and risk factors for rejection and GVHD. CY/ATG is a well-tolerated and effective conditioning program for marrow grafting in aplastic anemia that, when combined with GVHD prevention by methotrexate/cyclosporine, results in excellent survival.

Adult↗