Mixed chimerism after allogeneic bone marrow transplantation for leukemias.
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Biomedical subjects
Publications and source records attributed to D Blaise.
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Forty-seven patients with high risk acute lymphoblastic leukemia (ALL) received an allogeneic (allo) or autologous (auto) bone marrow transplant (BMT). Patients in both groups were comparable in terms of age, initial presentation of ALL and induction chemotherapy. Allo patients were transplanted earlier (median 3 months after CR) than auto patients (median 6.5 months after CR). Auto patients received more consolidation chemotherapy before BMT. All patients received total body irradiation 2.2 Gy/day x 5 days after cyclophosphamide 60 mg/kg x 2 (18 allo and five auto) or melphalan 140 mg/m2 (seven allo and 17 auto). Prevention of graft-versus-host disease (GVHD) was by conventional immunosuppression in 17 patients and T cell depletion in eight. Seven patients (28%) developed moderate to severe acute GVHD. Auto marrow was treated in vitro in each case. Seven patients died in CR from BMT complications (five allo and two auto). The probability of relapse was 9% for patients receiving allo BMT and 52% for patients receiving auto BMT (p less than 0.01). The disease-free survival was 71% for allo BMT and 40% for auto BMT (p = NS). Early BMT is an effective form of consolidation for high risk patients with ALL in first CR. An allogeneic anti-leukemia effect was demonstrated in this study.
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From March 1982 to December 1986, 32 patients with standard risk leukaemia were conditioned for allogeneic bone marrow transplantation (BMT) with low dose fractionated total body irradiation (TBI) after infusion of alkylating agents. This series includes six children and 26 adults. Minimal follow-up was 24 months. The total dose of 11 Gy, given in 5 daily fractions of 2.20 Gy, was given in the lateral position, following chemotherapy with either melphalan or cyclophosphamide. Lungs were shielded for 2 out of the 5 fractions. All patients had in vivo dosimetry. The death rate is 25% without relapse or rejection. Disease-free survival is 73% at 5 years. Toxic deaths are detailed: 2 from sepsis and veino-occlusive disease of the liver, 3 from severe graft versus host disease (GVHD), 2 from GVHD associated with virus pneumonitis and one from HIV infection. Fractionated low dose rate TBI is discussed regarding its decreased toxicity and its efficiency for disease control.
Twenty-five adult patients, 19 males, six females, age 16-43 years (median 23), with lymphoblastic lymphoma received allogeneic or autologous bone marrow transplantation in first complete remission. Twelve patients were Murphy stage IV with bone marrow and/or CNS involvement and 13 were stage III of whom nine had thoracic involvement. Complete remission was achieved with an intensive anthracycline containing multiagent chemotherapy protocol. Twelve patients with an HLA identical sibling received an allogeneic marrow and 13 without a donor received their own marrow harvested a median of 2 months (0-4 months) after complete remission and purged in vitro with either mafosfamide (eight patients) or anti T-cell monoclonal antibodies and complement (three patients). Bone marrow transplantation was performed 1-7 months (median 3 months) after achieving first complete remission. The conditioning regimen consisted of cyclophosphamide or high dose melphalan and total body irradiation. The actuarial 4-year disease-free survival is 68% (+/- 9% SE). The actuarial probability of relapse was 26% (+/- 3% SE) with a median follow up to 22 months. There was no difference between allogeneic and autologous transplantation with eight out of 12 allo patients in first continuous complete remission 26-45 months after transplant and nine out of 13 auto in continuous complete remission 15-75 months after transplant. These results compare favourably with those achieved with the best chemotherapeutic regimen used for such patients.
The feasibility of marrow cryopreservation for autologous bone marrow transplantation after 7 d in liquid culture was assessed in 10 leukaemic patients. A median of 0.17 x 10(8) nucleated cells/kg and 0.4 x 10(4) CFU-GM/kg could be collected after the complete procedure, with overall a consistent cell loss. Long-term cultures could be established from these cultured and frozen marrows, showing the persistance of precursors of haematopoietic and stromal cells. In vitro a significant decrease in the proportion of leukaemic cells could be observed in only one out of nine evaluable patients. This patient, with refractory AML, received an autologous transplant and is alive in continuous complete remission after 600 d. One patient with chronic myeloid leukaemia in acute phase underwent an autologous BMT with a marrow collected and cultured while in chronic phase and failed to engraft. These results show the feasibility of cryopreservation of cultured marrow cells for autologous bone marrow transplantation. The procedure is associated with poor cell recovery and must be improved to have a more general clinical application. This technology may have a major application with the emergence of modulators of growth and differentiation of haematopoietic cell lines.
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The aplasia which follows bone marrow transplantation is extremely deep and characterized by disruption of all cutaneous and mucosal barriers and by major immunodepression. It is complicated in 30 to 40 per cent of the cases by septicaemia usually caused by Gram-positive organisms. Because the natural defence mechanisms have been suppressed an empirical broad-spectrum antibiotic therapy is usually instituted before microbiological results are available, and this has proved effective in reducing the immediate mortality due to infection. However, nephrotoxic drugs such as cyclosporin A and amphotericin B are also used in this context, and clinicians are looking for antibiotics that have minimal noxious effect on the kidneys. Ceftazidime administered alone or combined with another antibiotic is currently being investigated from this point of view in several clinical trials.
Twenty-six patients (median age 33 years) with poor-risk malignancies were treated with high-dose combination chemotherapy associating BCNU-etoposide-cytosine arabinoside and melphalan (BEAM) followed by autologous bone marrow transplantation (ABMT). Twenty-one patients had malignant lymphomas, three, acute lymphoblastic leukemia (ALL), and two, malignant thymomas. Eleven patients (group 1) were not in complete remission (CR) at the time of BEAM, and fifteen patients (group 2) were in CR. Hematological recovery occurred in all patients. The duration of aplasia and the non-hematological toxicities were similar in both groups. Ten of the eleven patients (group 1) evaluable for response achieved CR and one achieved partial remission (PR). Five patients relapsed, and five are in continuous CR with a short follow-up (median 8 months). Among the fifteen patients in CR at the time of BEAM (group 2), four patients relapsed and ten patients are in unmaintained continuous CR with a median follow-up of 15 months (one patient died in CR). The disease-free survival is 53%, with 29% for patients receiving BEAM while in relapse (group 1) and 65% for patients receiving BEAM while in CR (group 2). These data indicate that BEAM followed by ABMT can produce a high antitumor response with an acceptable toxicity in patients with poor-risk malignancies.
From February 1986 to July 1987, 87 patients who underwent an autologous or allogeneic bone marrow transplantation were randomized to receive ticarpen tobramycin or ticarpen moxalactam for their first febrile episode. Forty received ticarpen tobramycin and 47 ticarpen moxalactam. The two groups were similar according to age, sex, conditioning regimen, underlaying pathology and duration of granulocytopenia. We observed 58.6% of fever unknown origin and 37% of bacteremia. A similar number of clinical and bacteriological successes occurred in the two groups. Hepatic and renal toxicities were similar in the two groups. Vancomycin was widely used in these patients without particular justification. We conclude that the use of two beta lactam is a possible antibiotherapy in marrow transplantation where renal function should be preserved from additional toxicity.
Eleven children between the ages of 1 and 16 years with acute non-lymphoblastic leukemia (ANLL) in first remission were included in a study of double unpurged autologous bone marrow transplantation (ABMT). Prior to each ABMT patients received massive chemotherapy with melphalan at a dosage of 140 mg/m2. The first ABMT was done within a median of 4 months after the achievement of complete remission. As soon as the children had adequate hematologic recovery, a second marrow collection was done, followed by a second course of melphalan and a second ABMT. The duration of aplasia was significantly longer after the second ABMT than after the first, but the non-hematologic toxicity was relatively mild in each case and no patient died from the procedure. Four patients relapsed and seven are alive in unmaintained complete remission with a median duration of leukemia-free survival of 29 months (range 15-56 months) after the first ABMT. These data demonstrate the feasibility of repeating ABMT after melphalan in children with ANLL. The eventual impact of such therapy needs to be demonstrated in prospective randomized studies.
We evaluated retrospectively the incidence and prognosis of bacteremias after bone marrow transplantation treated in protected environment with intestinal decontamination. Bacteremias are more frequent during the extreme granulopenia (55% of the patients) than during recovery of granulocyte counts greater than 500/mm3 (35% of the patients). Gram + organisms are more frequently responsible of bacteremias (80%), mainly Staphylococcus epidermidis and Streptococci. Mortality is low (7%) and related to additional factors like GVH, resistant leukemia. These data invite to develop new approaches of prevention of bacterial infection, with measures possibly efficient on Gram + organisms.
We prospectively evaluated after randomization in 60 consecutive recipients of bone marrow transplantation the efficiency of a short administration of vancomycin (10 mg/kg I.V. q 6 H, day -5 to +1). Thirty-three patients were randomized as controls and 27 were designed to receive vancomycin. Both groups were similar in terms of age, diagnosis, status, allogeneic or autologous graft, in vitro marrow treatment or not. Eighteen patients (30%) experienced bacteremias: 15/18 bacteremias were due to Gram positive organisms, including 11 streptococci. These infections occurred with a similar frequency in both groups, the relatively low incidence of bacteremias in this study needs further evaluation in new patients to insure the prophylactic effects of a course of vancomycin in bone marrow transplant recipients.
We evaluated serially by cytogenetics the blood and marrow chimerism of 38 leukemic recipients of HLA-matched bone marrow transplants (BMT) who were prepared by high doses of alkylating agents and fractionated total-body irradiation (2.2 Gy X 5). Donor or host mitoses were identified by examination of sex chromosomes in 32 patients or by evaluation of the polymorphism of other chromosomes after specific banding in six patients. Twenty-four patients were recipients of untreated BMT, and 14 were recipients of T-cell-depleted BMT. In the 24 patients who received untreated BMT, all showed successful engraftment, and only three had a transient mixed chimera. In the 14 recipients of T-cell-depleted BMTs, four rejected their grafts, and seven had mixed chimeras; these mixed chimeras were more frequent in blood lymphocytes than in marrow cells and could be detected up to 26 months after BMT. This high frequency of partial chimerism after T-cell-depleted BMT by comparison with a control group suggests that the donor's T cells play an important role in the eradication of host residual hematopoiesis after allogeneic BMT.
71 leukaemic patients having HLA-matched bone-marrow transplants (BMT) were randomised to receive whole marrow (group A) or marrow depleted of T cells by treatment with monoclonal antibodies (anti CD4-CD5-CD8, group B; anti CD2-CD5-CD7, group C) plus complement. All patients received cyclophosphamide and total body irradiation before transplantation and cyclosporin after BMT. Marrow treatment removed 97% of T cells (median) in group B and 99% in group C. Although both serious and mild graft-versus-host disease (GVHD) were reduced in T-cell depleted patients, graft failure and relapse were increased. Graft failure was caused by GVHD and transplant complications in the controls and by rejection and relapse in the T-cell depleted groups; relapse-free survival did not differ between the groups. Without better control of host immunity and of the residual leukaemia T-cell depletion of the marrow, BMT should not be pursued in standard-risk patients.
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Twenty-six children with acute leukemia were treated with allogeneic marrow transplantation from HLA identical siblings after a conditioning regimen with Cyclophosphamide-total body irradiation (19 patients), Melphalan-total body irradiation (6 patients) or Busulfan-cyclophosphamide (1 patient). Eighteen were transplanted in complete remission (4 with acute non lymphoblastic leukemia in first remission, 14 with acute lymphoblastic leukemia: 6 in first, 6 in second and 2 in subsequent remission): 2 died of cytomegalovirus pneumoniae, 1 relapsed and 15 survive in continuous complete remission from 5 to 42 months after transplantation (median = 22 months). Eight were transplanted in relapse, 7 achieve complete remission, 5 of them relapsed, 1 died of G.V.H. and 1 survives in continuous complete remission 46 months after transplantation. Actuarial analysis shows a disease free survival rate at 3 years of 82% for patients transplanted in remission and 12% for patients transplanted in relapse (p less than 0.01).
We describe five patients receiving long-term hemodialysis (mean duration of 6.4 years) in whom eight renal carcinomas were found. In four patients, the carcinoma was confirmed by tissue pathology, while the fifth patient had multiple (four) areas of neovascularity on selective renal arteriography. Two patients died of metastases. In four patients the diagnosis was initially made with selective renal arteriography and in the remaining one, with sonography and computerized tomography. In three of the four arteriography showed diffuse cystic degeneration; pathologic findings revealed renal carcinoma and the changes of "end-stage" disease. Two patients had brief pharmacologic immunosuppression during unsuccessful renal transplantation six years earlier. These cases demonstrate an apparently increased risk of renal carcinomas in end-stage renal disease, a risk that appears to be independent of pharmacologic immunosuppression.