Antileukemic, autologous bone marrow transplantation in childhood acute lymphoblastic leukemia.
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Biomedical subjects
Publications and source records attributed to R J Haas.
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Samples of bone marrow from 32 leukaemic children were removed during remission and stored in liquid nitrogen for retransplantation during relapse. Subsequently two children in advanced stages of common acute lymphoblastic leukaemia (cALL) were transplanted with their own cryopreserved marrow cells, after intensive combination chemotherapy and high doses of radiation therapy. Before grafting, the marrow cells were treated with purified heterologous antibodies prepared against cALL antigens, to remove any residual tumour cells. The antibodies showed high cytotoxic activity against leukaemic cells of cALL type without interfering with normal haemopoietic stem cells. Evidence of take was obtained in one patient, who died on day 7 with cardiac failure. In the other patient the dose of nucleated marrow cells grafted was 1.9 x 10(8)/kg (86 000 CFU-C/kg). The patient achieved complete haematological recovery on day 27 and a normal platelet count after day 50 and is now in complete remission. Marrow cells collected during remission and treated with antileukaemic antibodies can repopulate bone marrow after conditioning of the recipient with high doses of radiation.
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An in vitro incubation of incompatible donor bone marrow by xenogenic anti-T-cell globulin (ATG) suppressed an otherwise lethal GvH reaction in animal models. An application of this principle to clinical bone marrow transplantation was successfully tried in three patients with acute lymphoblastic leukemia. Preparation of the specific anti-human T-cell globulin (ATCG-H) was carried out by absorption of anti-human thymocyte globulin with liver-kidney homogenate, chronic lymphocytic leukemia cells of B-cell type, and erythrocytes. Subsequent testing revealed that the serum still reacted with human T-cells but no longer reduced the number of colony-forming units in culture (CFU-C). All three bone marrow recipients were treated by chemotherapeutic conditioning and total body irradiation followed by grafting of in vitro treated bone marrow from HLA-identical siblings. The transplantation of the bone marrow was well tolerated and no major side effects were encountered. No patient so far (24, 7, 6 months) has shown any signs of GvHD. The in vitro pretransplantation treatment of bone marrow with anti T-globulin may be a new approach to the prevention for GvHD in man.
Investigation was done in children with acute leukemia in complete hematological remission. It was tested whether out-patient treatment by intramuscular administration of arabinosylcytosine (Ara-C) may obviate the continuous intravenous Ara-C regimen. Every therapy cycle lasted 5 days. Changes in peripheral blood cell counts after 5 days of continuous intravenous. Ara-C infusion against 5 days of intramuscular Ara-C application given every 12 h were tested. 129 cycles of intramuscular application and 11 cycles of intravenous application were evaluated. Evaluation was done by the Friedmanntest. There was a significant decrease in blood cell counts after intramuscular Ara-C treatment. When administered intramuscularly during the first cycle Ara-C was effective for at least 3 weeks, whereas after repeated cycles the decline of blood cells was only demonstrable for 14 days. A comparison of the effect between intravenous and intramuscular routes revealed similar results. No local side effects were noted when Ara-C was given intramuscularly.
Close cooperation of pediatric surgeons and pediatric oncologists with radiotherapists, using coordinated treatment schedules conformable to the stage of the disease, and combining tumor nephrectomy, postoperative irradiation and the treatment with AMD and Vincristine, has increased the 3-year survival rate from 27% (13 of 49) up to 67% (14 of 21) for children with Wilm's tumor.
A patient with severe combined immunodeficiency received three transplants of bone marrow from the HLA-B- and -D-identical mother. The first transplantation led to a severe graft-versus-host reaction followed by immunological reconstitution. A split chimerism was found with engraftment only of the maternal lymphocytes. Five months after the transplantation an autoimmune hemolytic anemia was observed which was due to rhesus incompatibility as well as polyspecific antibodies. At the same time agranulocytosis developed and 9 mth after the first transplantation the child suffered from aplastic anemia. Two further attempts failed to engraft the maternal hematopoiesis. The child died during the treatment with cyclophosphamide as conditioning for a third transplantation.
The number of childhood malignancies in West Germany amounts to 1500 per year. The relative success of the treatment requires a therapy concept with curative intention. Diagnosis and treatment during the intensive phase should be centralized in special pediatric oncology departments to guarantee the best possible results. It is emphasized that the patients must be treated after the intensive phase on an outpatient basis. Unavoidable side effects of the treatment demand a "life long" follow-up of the patients in pediatric tumor centers.
In 22 patients with osteogenic sarcoma, treated with 103 high-dose methotrexate infusions (6-8.5 g/m2 in 4-6 h) plasma methotrexate levels were measured with a specific and rapid radioimmunoassay. Nontoxic infusions were associated with methotrexate concentrations below 8.0 X 10(-6) mol/l at 24 h, 8.0 X 10(-7) mol/l at 48 h and 4.25 X 10(-7)/mol/1 at 72 h. All patients with 48 h methotrexate levels above 1 X 10-6 mol/l manifested severe toxicity with myelosuppression and stomatitis due to delayed methotrexate excretion. Rise of serum creatinine was not reliable to predict oxicity. Determination of 48- and 72-h methotrexate concentrations proved to be a valuable method for identifying patients at high risk for toxic side effects. Additional citrovorum factor may thus be given in time.
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A series of 66 children with acute lymphoblastic leukemia (ALL) at diagnosis were investigated (simultaneously) for various surface markers. For this purpose the reaction of specific antisera against ALL antigens and T cell antigens was analysed in every case by several test systems, namely immunofluorescence, microcytotoxicity and complement fixation. A clearly defined classification in 6 subgroups of ALL emerged. The clinical data at presentation and possible correlations with the immunological subgroups were demonstrated.
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Acute lymphatic leukaemia (ALL) in infants is a very heterogeneous disease from the immunological point of view. Phaenotyping of leukaemic cells in 138 patients via different immunmarkers has so far allowed subdivision into 6 subgroups. Clinical risk factors and correlations with the immunologically defined subgroups, as well as their significance for prognosis, are demonstrated with the help of 61 examined ALL patients. 90-95% of all acute lymphatic leukaemias can presently be identified via heterologous antisera. After corresponding absorption, these antisera show high cytotoxicity against ALL cells without displaying any aggressivity towards normal haemopoetic stem cells. The authors make therapeutic use of anti-T cell and anti-common ALL (cALL) globulin in autologous bone marrow transplantation. This method involves withdrawal of bone marrow from patients with ALL in complete remission, the marrow being then fractionated, treated with antiserum to destroy residual leukaemic cells, and then cryopreserved. The leukaemia-free bone marrow will thus be available for transplantation in relapse.
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