Showing papers by "Eliane Gluckman published in 1989"

Hematopoietic reconstitution in a patient with fanconi's anemia by means of umbilical-cord blood from an hla-identical sibling

Abstract: The clinical manifestations of Fanconi’s anemia, an autosomal recessive disorder, include progressive pancytopenia, a predisposition to neoplasia, and nonhematopoietic developmental anomalies [1-3]. Hypersensitivity to the clastogenic effect of DNA-cross-linking agents such as diepoxybutane acts as a diagnostic indicator of the genotype of Fanconi’s anemia, both prenatally and postnatally [3-6]. Prenatal HLA typing has made it possible to ascertain whether a fetus is HLA-identical to an affected sibling [7]. We report here on hematopoietic reconstitution in a boy with severe Fanconi’s anemia who received cryo-preserved umbilical-cord blood from a sister shown by prenatal testing to be unaffected by the disorder, to have a normal karyotype, and to be HLA-identical to the patient. We used a pretransplantation conditioning procedure developed specifically for the treatment of such patients [8]; this technique makes use of the hypersensitivity of the abnormal cells to alkylating agents that cross-link DNA [9,10] and to irradiation [11] In this case, the availability of cord blood obviated the need for obtaining bone marrow from the infant sibling. This use of cord blood followed the suggestion of one of us that blood retrieved from umbilical cord at delivery, usually discarded, might restore hematopoiesis – a proposal supported by preparatory studies by some of us [12] and consistent with reports on the presence of hematopoietic stem and multipotential (CFU-GEMM), erythroid (BFU-E), and granulocyte-macrophage (CFU-GM) progenitor cells in human umbilical-cord blood (see the references cited by Broxmeyer et al. [12]).

Allogeneic bone marrow transplantation for children with acute lymphoblastic leukemia in first remission: a cooperative study of the Groupe d'Etude de la Greffe de Moelle Osseuse.

Abstract: Thirty-two children ranging in age from 1.5 to 16 years with poor-prognosis acute lymphoblastic leukemia (ALL) were treated with myeloablative immunosuppressive therapy consisting of cyclophosphamide (CPM) and total body irradiation (TBI) followed by allogeneic bone marrow transplantation (BMT) while in first complete remission (CR). The main reasons for assignment to BMT were WBC count greater than 100,000/microL, structural chromosomal abnormalities, and resistance to initial induction therapy. All children were transplanted with marrow from histocompatible siblings. Twenty-seven patients are alive in first CR for 7 to 82 months post-transplantation (median, 30 months). The actuarial disease-free survival rate is 84.4% (confidence interval, 7.2% to 29%) and the actuarial relapse rate is 3.5% (confidence interval, 0.9% to 13%). Four patients died of transplant-related complications, 16 developed low-grade acute graft-v-host disease (GVHD), and six developed chronic GVHD. The very low incidence of relapse...

Donor bone marrow treatment with T101 Fab fragment-ricin A-chain immunotoxin prevents graft-versus-host disease.

Abstract: Thirty-eight patients with haematological malignancies were treated with bone marrow transplantation using histocompatible immunotoxin T cell-depleted marrow siblings. All patients received conventional postgraft immunosuppression (methotrexate and/or cyclosporin A). Donor bone marrow was treated ex vivo with T101 Fab fragment coupled to ricin A-chain (T101 Fab-RTA) at a concentration of 10(-8) M of A-chain in association with NH4Cl (2 x 10(-2) M) in pH adjusted (7.8) incubation medium. A median cytoreduction of 99.5% (91-99.5) was obtained. The median of follow-up was 300 days. Only three patients developed grade II acute graft-versus-host disease (GVHD) (actuarial rate of acute GVHD: 9.1%). No chronic GVHD occurred. All patients but one engrafted. Six out of the 37 patients developed a documented bone marrow rejection (actuarial rate of graft failure: 18%). Ten patients relapsed (actuarial rate of relapse: 36.9%). These findings demonstrate that treatment of donor marrow with T101 Fab-RTA in association with NH4Cl at critical pH value can achieve a high level of mature T cell depletion and greatly reduce the incidence of bone marrow rejection and relapse after T cell-depleted allogeneic bone marrow transplantation.

Phenotype and function of T lymphocytes infiltrating the skin during graft-versus-host disease following allogeneic bone marrow transplantation.

Abstract: Seven lymphocyte populations were expanded from skin samples of patients with acute or chronic GVHD following allogeneic genotypically identical BMT. After amplification without in vitro antigenic stimulation or addition of mitogens, 5 of the 7 cell lines showed a large majority of mature CD4+ T cells (in contrast to published immunopathological data). One cell line showed an equal number of CD4+ and CD8+ cells, and another a predominance of CD4+ cells along with a large number of cells with a phenotype suggestive of non-MHC-restricted CTLs. After in vitro antigenic stimulation, various cytotoxicity patterns were seen: specific antihost cytotoxicity was seen in half the cell lines, NK activity was seen in 5 of the 7 lines, and a strong LAK activity was seen in 1 of the 7 cell lines. These results point to a diversity of cytotoxic effectors involved locally in GVHD and emphasize the need for further study of these local events. The cell lines established now constitute basic functional material for the in vitro study of cellular and humoral interactions at the site of GVHD lesions.

Long‐term study of chimaerism in bone marrow transplantation recipients for severe aplastic anaemia

Abstract: We used minisatellite probes to analyse by DNA fingerprints the long-term engraftment (median 4.3 years, range 1-2) of 21 bone marrow transplantation recipients for severe aplastic anaemia. Patients received their graft from histocompatible siblings. They were conditioned with cyclophosphamide (150 mg/kg) and a 6GY thoracoabdominal irradiation and did not have ex-vivo T cell depletion of marrow donor. DNA was extracted peripheral mononuclear cells and analysed by Southern blotting with 32P-labelled single-stranded RNA probes. Seven out of 21 donor-recipient pairs were sex-mismatched and additionally studied with a probe detecting a male specific repeated sequence on the Y chromosome. Red cell surface phenotype was also used as marker of engraftment in most cases. Long-term engraftment appeared complete for all patients studied with respect to the three methods.

Pediatric bone marrow transplantation for leukemia and aplastic anemia. Report of 222 cases transplanted in a single center.

Abstract: We report a single center experience of 222 patients (pts) less than 18 years old transplanted from 1973 to 1987. The median age was 11 years (1-18). The donor was a monozygotic twin (9 pts), an HLA-id sibling (193 pts), an HLA-id, parent (9 pts), a mismatched related donor (9 pts) and a matched unrelated donor (1 pt). Ninety-six pts were transplanted for SAA. Conditioning varied with time but the majority (59 pts) received CY 150 mg/kg and 6 Gy TAI. The long term actuarial survival is 66% with a median follow-up of 3 years. The group who received CY 200 mg/kg and MTX had a 33% long term survival (LTS). GVH was the main complication with 40% acute and 37% chronic GVHD. Chronic GVHD tended to improve with time after 2 to 4 years of evolution. Ninety pts were transplanted for leukemia (35 AML, 45 ALL and 11 CGL), 20 pts were in relapse. Pts in CR had a LTS of 40%, in pts in relapse, it was 12%. The main causes of death were: interstitial pneumonitis (30%), relapse (27%), GVH (15%). Thirty-five pts were transplanted for constitutional disease: Fanconi anemia (FA) (26 pts), Dyskeratosis congenita (2 pts), Blackfan-Diamond erythroblastopenia (2 pts), Glanzmann thrombasthenia (1 pt), osteopetrosis (1 pt) and Gaucher's disease (1 pt). In FA, the LTS is 70% with a CY 20 mg/kg, 5 Gy TAI regimen. In all disease categories, we did not find any influence of donor's sex on GVH and survival.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized study comparing ciclosporin A and antithymocyte globulin for treatment of severe aplastic anemia.

Abstract: UNLABELLED This report summarizes results of the treatment of SAA with ciclosporin A (CSA) or antithymocyte globulin (ATG) in 82 patients (pts) randomized since January 1986 from 28 centers. STUDY DESIGN at diagnosis, pts with established international criteria of SAA and without an HLA identical sib donor were randomized between 2 groups: CyA 4 to 6 mg/kg/d orally for 6 months, or H. ATG 15 mg/kg IV for 5 days associated with Methyl-Prednisolone 5 mg/kg for 5 days then gradually tapered off until day 60. At 3 months follow up, pts with a complete response (CR) or a partial response (PR) received no further therapy, pts with a failure (F) or minimal response (MR) were switched in the other group. All patients were followed regularly for at least 1 year. RESULTS at 3 months, all pts with CyA were alive (36 pts) and only 26/35 in the ATG group because of 9 early deaths due to severe infection. In the CyA group, 5 were in CR or PR and 31 in MR or F. Subsequently, 5 received a mismatched BMT and died, 8 remained on CyA, 20 had ATG with, at 1 year, 3 F and 11 PR + CR, 5 pts are too early to evaluate. In the ATG group, 26 pts were alive at 3 months, 6 had a CR or PR, 20 failed. Two pts received a mismatched BMT and died. Fifteen received CyA with, at 1 year, 1 failure and 7 responses (7 pts are too early to evaluate at 1 year).(ABSTRACT TRUNCATED AT 250 WORDS)

Transient cyclic neutropenia following GM-CSF in a patient with chronic granulocytic leukemia transplanted with HLA-identical T cell-depleted donor bone marrow.

Abstract: Treatment with GM-CSF or G-CSF is becoming widely used in patients with chronic neutropenia, or who are aplastic following chemotherapy or autologous or allogeneic bone marrow transplantation. Recently, some authors have described a phenomenon analogous to cyclic agranulocytosis following treatment with G-CSF in a patient with chronic neutropenia. We wish to describe the same phenomenon in a patient with chronic granulocytic leukemia who received GM-CSF (Sandoz) after T cell depletion in order to accelerate hematological reconstitution.

Role of immunosuppressive drugs for prevention of graft-v-host disease after bone marrow transplantation.

Abstract: In a series of 198 patients we compared various methods of prevention of GVHD. One hundred and thirty-three patients were treated with CSA alone, 44 with the combination of CSA and MTX, and 21 with CSA after marrow T cell depletion. The incidence of GVHD greater than or equal to II was 35% in the CSA group, 22% in the CSA+MTX group and 14% in the T depleted group. The actuarial survival was 55.4%, 52.3% and 55.1% respectively. These results show that the improvement of methods of prevention of GVHD did not affect significantly long term survival after BMT.

French national bone marrow donor registry and interaction with foreign files.

Abstract: A program to obtain volunteer bone marrow donors has been developed. A total of 33.000 HLA-A, B typings were performed. A search for 527 patients has been initiated. Among these, 44% are suffering from chronic myelogenous leukemia. For 23% of the patients no HLA-A, B identical donor has been identified. Out of the 401 patients who had HLA-A, B identical donor 35% (139/401) had one or more HLA-A, B, DR identical donors. In one of the transplant center, when the mixed lymphocyte culture (MLR) was carried out between 219 donors and 79 patients, a transplantation for 20/79 patients has been proposed. Up to now, transplantation has been carried out in 31 patients whom donor searches were initiated.