Impact of RLA matching and cyclosporine on long-term survival in transplanted rabbits.

In order to measure the impact on long-term survival of rabbit leukocyte antigen (RLA) matching and the administration of cyclosporine (CSP) in allogeneic marrow transplantation of irradiated adult rabbits, four groups of five rabbits each were studied. Group 1 consisted of RLA-mismatched animals that did not receive CSP following transplant. All five animals died of infectious complications or graft-versus-host disease (GVHD) (median survival 12 days, range 6-20 days).

Failure of anti-MHC antibodies to prevent GVHD in DLA mismatched unrelated canine marrow recipients.

Gene products of the major histocompatibility complex (MHC) have been shown to elicit lethal graft-versus-host disease (GVHD) in experimental animals. Antibodies specific for MHC cell surface determinants might therefore be expected to overcome histocompatibility barriers and influence survival of marrow graft recipients. GVHD can be consistently induced in dogs by transplanting donor marrow cells into lethally irradiated, unrelated, mismatched recipients.

Supportive care of the marrow transplant recipient: the Seattle Experience.

It is now almost 2 decades after the first successful human marrow transplants from HLA-identical siblings for the treatment of life-threatening hematologic diseases. Results have improved, especially for patients transplanted earlier in the course of disease. However, major problems remain in supporting patients through the transplant.

Bone marrow transplantation for acute nonlymphocytic leukemia (ANL).

When a patient less than age 55 presents with ANL, it can be recommended that the patient and his family be HLA typed prior to initial induction chemotherapy. The information gained may be of help for platelet support but, more importantly, if the patient fails to achieve a remission, transplantation can be carried out straight away. If the patient achieves a first complete remission, the therapeutic approach depends upon whether a donor is found.

Prevention of transfusion-induced graft-versus-host disease in dogs by ultraviolet irradiation.

Ten dogs were given 9.2 Gy of total body irradiation and autologous bone marrow infusion followed by ten daily transfusions of leukocytes for a total of 11.5 to 36.

Busulfan, cyclophosphamide and fractionated total body irradiation as a preparatory regimen for marrow transplantation in patients with advanced hematological malignancies: a phase I study.

Thirty-six patients with advanced hematologic malignancy were entered into a phase I study designed to define a tolerable dose of busulfan (BU) and cyclophosphamide (CY) combined with 12 Gy of fractionated total body irradiation (TBI) as preparation for marrow transplantation from HLA-identical siblings, 0-1 locus HLA-non-identical family members or autologous cryopreserved marrow. Five of 18 evaluable patients prepared with 8.7 mg/kg of BU and 69 mg/kg CY + TBI developed severe regimen related toxicity (RRT) while none of 15 patients treated with 6.

Specific marrow localization of an 131I-labeled anti-myeloid antibody in normal dogs: effects of a "cold" antibody pretreatment dose on marrow localization.

Tumor recurrence and regimen-related toxicity remain major obstacles in the successful use of marrow transplantation as therapy for hematologic malignancies. By attaching radionuclides to monoclonal antibodies (MoAbs) targeted at myeloid-associated antigenic determinants, a more effective and directed delivery of therapy may be possible without increasing toxicity. We investigated the biodistribution over time of an anti-myeloid antibody (DM-5) labeled with trace amounts of 131I in normal dogs.

High-dose cytosine arabinoside, total body irradiation and marrow transplantation for advanced malignant lymphoma.

Twenty-four patients with advanced malignant lymphoma including Hodgkin's disease (HD, n = 1), intermediate grade non-Hodgkin's lymphoma (IGL, n = 12) and high-grade non-Hodgkin's lymphoma (HGL, n = 11) were prepared for syngeneic (n = 2), allogeneic (n = 11) or autologous (n = 11) marrow transplantation with cytosine arabinoside, 3 g/m2 every 12h for 12 doses (HDAC) and total body irradiation, 200 cGy daily for 6 days (TBI) to determine toxicity and efficacy. Eight patients (33%) died from early regimen related toxicity and all eight had a Karnofsky performance score less than or equal to 80 at the start of treatment. The actuarial probability of disease-free survival was 17% with a 65% probability of relapse at 4 years after transplantation.

Regimen-related toxicity and early posttransplant survival in patients undergoing marrow transplantation for lymphoma.

Ninety-five patients transplanted for malignant lymphoma were retrospectively evaluated for regimen-related toxicity (RRT) and early posttransplant survival. Nineteen patients developed life-threatening (grade 3) or fatal (grade 4) RRT in one or more organs. Grade 3 or 4 RRT was more common in patients with advanced disease versus those transplanted earlier in their course (P = .

Stimulation of canine hematopoiesis by recombinant human granulocyte-macrophage colony-stimulating factor.

The effect of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on canine hematopoiesis was evaluated. rhGM-CSF stimulated granulocyte-macrophage colony formation of canine marrow depleted of accessory cells up to tenfold. Stimulation of colony formation was abrogated by anti-rhGM-CSF antiserum or heat inactivation.

Effect of recombinant human granulocyte colony-stimulating factor on hematopoiesis of normal dogs and on hematopoietic recovery after otherwise lethal total body irradiation.

This study was designed to test whether recombinant human G-CSF (rh G-CSF) affects hematopoiesis in normal dogs and, if so, to test the effects of G-CSF in dogs given otherwise lethal total body irradiation (TBI). Rh G-CSF given subcutaneously at 10 or 100 micrograms/kg/d for 14 days to two normal dogs increased peripheral blood neutrophils eight to tenfold and monocytes four to sixfold above controls. Lymphocyte counts remained unchanged at the lower dose and increased threefold at the higher dose of rh G-CSF.

Comparison of fractionated to single-dose total body irradiation in conditioning canine littermates for DLA-identical marrow grafts.

We explored the ability of fractionated total body irradiation (TBI) given at a rate of 7 cGy/min from opposing dual 60Co sources at otherwise lethal doses of 450, 600, 700, 800, and 920 cGy to condition dogs for marrow grafts from DLA-identical littermates. Results were compared with those of a previously reported study using single-dose TBI administered under otherwise identical conditions. Fractionated TBI was less immunosuppressive than single-dose TBI, as evidenced by a significantly higher rate of graft rejection (P = .

Graft-versus-host disease prevention by methotrexate combined with cyclosporin compared to methotrexate alone in patients given marrow grafts for severe aplastic anaemia: long-term follow-up of a controlled trial.

Forty-six patients with aplastic anaemia (median age 23 years) were given cyclophosphamide followed by infusion of marrow from an HLA-identical family member. To evaluate postgrafting prophylaxis for graft-versus-host disease (GVHD), the patients were entered into a randomized prospective trial comparing a combination of methotrexate and cyclosporin (n = 22) to methotrexate alone (n = 24). Methotrexate/cyclosporin significantly reduced the incidence and severity of acute GVHD and improved early survival.

Treatment of refractory non-Hodgkin's lymphoma with radiolabeled MB-1 (anti-CD37) antibody.

The biodistribution, toxicity, and therapeutic potential of anti-CD37 monoclonal antibody (MoAb) MB-1 labeled with iodine 131 (131I) was evaluated in ten patients with advanced-, low- or intermediate-grade non-Hodgkin's lymphomas who failed conventional treatment. Sequential dosimetric studies were performed with escalating amounts of antibody MB-1 (0.5, 2.

Use of trimetrexate for the prevention of graft-versus-host disease.

The effects of trimetrexate following marrow transplantation were studied in a dog model. Four animals were given 9.2 Gy total body irradiation (TBI), autologous marrow, and either trimetrexate alone (0.

The clinical use of hematopoietic growth factors.

Recombinant DNA technology has allowed for the production of large quantities of several hematopoietic growth factors as cloned gene products. Three of these factors--recombinant human erythropoietin (r-HuEPO), granulocyte macrophage colony-stimulating factor (GM-CSF), and granulocyte colony-stimulating factor (G-CSF)--are currently undergoing clinical trials and appear to offer considerable promise for the treatment of a variety of hematopoietic abnormalities. Therapy with r-HuEPO can raise the hematocrit levels of patients with end-stage renal disease.

Antibody-radionuclide conjugates as part of a myeloablative preparative regimen for marrow transplantation.

The behaviors of an anti-Ia antibody (7.2) and an antibody directed at a lymphocyte adhesion molecule (S.5) radiolabeled with 131I were studied in normal dogs.

Preliminary validation of the opposing view method for quantitative gamma camera imaging.

We perform gamma camera imaging to generate data for estimation of internal radiation dose in our radioimmunotherapy candidates. Because of the inability of single photon emission computed tomography (SPECT) to account for patient attenuation variability without serious error, quantitative planar imaging was performed to estimate the radioactive content of normal organs. We undertook the following studies to further validate this method.

Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial.

Patients with acute nonlymphoblastic leukemia (ANL) in first remission (n = 38) or chronic myelocytic leukemia (CML) (n = 55) were given cyclophosphamide and total body irradiation, followed by marrow infusion from HLA-identical siblings. To evaluate postgrafting prophylaxis for acute graft-versus-host disease (GVHD), the patients were randomized to receive either methotrexate and cyclosporine (n = 43) or cyclosporine alone (n = 50). Methotrexate/cyclosporine significantly reduced the incidence and severity of acute GVHD, and improved early survival.