Effect of cyclosporin A on immunological recovery after bone marrow transplantation.
Explore the source record for details and available documents.
Biomedical subjects
Publications and source records attributed to A Gratwohl.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Renal function was studied prospectively in 6 patients with rheumatoid arthritis and non-prospectively in 5 patients after bone marrow transplantation. Both groups were treated with cyclosporin A. Functionally and histologically the results suggest tubulotoxicity of cyclosporin A which seems to be dose-related and reversible. Also found in the urine of these patients were yellow, as yet undescribed crystalline bodies often included in casts.
Experience with a total of 49 plasma exchanges in 14 patients is reported. All exchanges were performed with the Aminco cellseparator in an attempt to remove documented or suspected antibodies completely. Indications were ABO-barrier before bone marrow-transplantation (6), acute rejection following renal transplantation (3), autoimmune diseases (3), Moschowitz disease, antithrombocytic antibodies and hepatic coma (1 each). The technique was modified to make it possible routinely to exchange 121 of plasma in 4 hours with no major untoward side effects even in anuric or thrombopenic patients. Complete removal of circulating antibodies was possible and often followed by impressive clinical benefit.
Explore the source record for details and available documents.
Experience with 17 allogeneic bone marrow transplantation (BMT) patients with refractory acute leukemia is reported. The authors show that it is extremely difficult to cure patients with end stage disease by this procedure. Based on experience that, if performed early, BMT can bring about over 50% potential cures, it is postulated that marrow grafts should be performed much earlier than is done at present. From the results in 45 patients with severe aplastic anemia it is concluded that the majority do not have a defect at the pluripotent stem cell itself. There is disturbed maturation to functional end cells which can be corrected in most instances by ALG, infusion of allogeneic marrow and low dose androgens. BMT between HLA-identical siblings need not cause major problems, but it involves a considerable risk of fatal complications such as irreversible marrow rejection and GvH.
A 56-year-old patient with severe acquired myasthenia gravis refractory to conventional therapy underwent a series of plasma exchanges. Three single exchanges did not improve her status. A series of intensive plasma exchanges of 6 liters each on 4 consecutive days reduced her anti-acetylcholine receptor antibodies to one-tenth of the initial value. The reduction was accompanied by an impressive clinical improvement. This study confirms that antibodies can be removed by plasma exchange. It further shows that the clinical improvement appears to be closely related to the quantity of antibodies removed.
18 patients with severe aplastic anemia (SAA) but without an HLA-identical sibling were treated by antilymphocyte globulin (ALG) followed by infusion of marrow cells from a semi-compatible family donor. 13 of these received low dose androgens after ALG: 11 (85%) achieved stable remission without transfusion requirement. One patient relapsed after 4 months, one patient with only partial remission died from infection. None of the 4 patients who did not receive androgens after ALG achieved remission. ALG, marrow and low-dose androgens represent a promising therapy for SAA and can be favorably compared with allogeneic bone marrow transplantation.
Lymphocytes of rabbits can be separated from small quantities of heparinized whole blood using a simple density gradient of Ficoll-Ronpacon 1.09. This separation technique yields a pure suspension of viable cells allowing reproducible results from cultures stimulated either with PHA or allogeneic lymphocytes isolated by the same technique.
Explore the source record for details and available documents.
Much progress has been made in allogeneic bone marrow transplantation for severe aplastic anemia (SAA) and acute leukemia (AL). In SAA it was shown that hemopoietic chimerism and apparently permanent cures can be achieved in the majority of patients by conditioning with cyclophosphamide followed by bone marrow transplantation (BMT) from an HLA-identical sibling. The previous transfusion history is crucial for failure or success: untransfused patients do very well while graft rejection is an enormous problem in most polytransfused ones. We have shown that most patients without HLA-identical sibling donors can be adequately helped as well. After conditioning with ALG followed by transfusion of haploidentical marrow and low dose androgens there is partial to complete autologous hemopoietic reconstitution in virtually all patients. This points to the fact that most of these patients have pluripotent hemopoietic stem cells that are intact, but apparently unable to differentiate to mature cells, because they are inhibited by autoimmune mechanisms. The results of BMT in patients with endstage leukemia are modest. New pilotstudies with early marrow grafts, i.e. for ANLL in first remission and for ALL in second remission indicate that with this type of approach potentially over 50% of all patients with HLA-identical siblings can be cured. We recommend that HLA-typing should be performed early in families with SAA and AL and that the possibility of a marrow graft should be seriously considered before the patients have endstage disease. Marrow grafts are technically simple but they may pose enormous problems such as graft versus host reaction (GvH), interstitial pneumonia, graft rejection and leukemic recurrence. Therefore, the procedure should only be performed in highly specialized centers with much knowledge and experience in the immunobiology of bone marrow transplantation.
We are reporting our experience with 13 patients suffering from end stage acute leukemia that were prepared for allogeneic bone marrow transplantation by combined chemotherapy followed by high dose cyclophosphamide (Cy) and total body irradiation (TBI). Only one patient became a long term survivor. Of the evaluable 12 patients, 6 died of interstitial pneumonia, 4 of GvH and 1 of recurrent leukemia. We conclude that adding combined chemotherapy to the standard conditioning program with Cy and TBI probably increases the risk of developing fatal interstitial pneumonia without eliminating the risk of recurrent leukemia. We suggest that allogenic marrow grafts should be performed earlier in the course of refractory acute leukemias, because in patients with end stage disease its chances of being curative are small.
Twenty-four patients with multiple myeloma received an allogeneic bone-marrow graft from HLA-compatible sibling donors (n = 23), or a twin donor (n = 1). Eighteen patients are alive, 1-36 months post bone-marrow transplantation (median 14 months). Ten of these patients had no signs of multiple myeloma as judged by immunoglobulins in serum, light chains in urine, or the percentage of plasma-cells in bone-marrow aspirate. Bone lesions on X-ray were mainly unchanged. Six patients died from transplant-related complications 3 weeks to 5 months post transplantation. One of these patients had severe acute graft-versus-host disease (aGVHD). In other patients aGVHD was a minor problem. Allogeneic bone-marrow transplantation appears to be a promising method for treatment of a selected group of patients with multiple myeloma.
Of 229 consecutive patients receiving allogeneic blood or bone marrow stem cell transplants for acute myeloid leukemia, chronic myeloid leukemia, or myelodysplastic syndrome between 1974 and 1996, 52 patients relapsed. The original tumor recurred as granulocytic sarcoma (chloroma) in three patients (1.3%). Chloroma was found in the ovary in two patients and in the central nervous system in one patient. None of these three patients had experienced > or = grade II acute or more than limited chronic graft-versus-host disease. The intervals between transplantation and recurrence with chloroma were 2, 6, and 13 years. Two patients received a second transplant, and all three died of treatment sequelae.
Autologous and allogeneic blood or marrow transplants are currently under intensive discussion as therapeutic option for patients with severe autoimmune disorders. Preclinical data as well as case reports from patients with transplants for other indications and concommitant autoimmune disorders support such concepts. In order to advance in a coordinated way the European League against Rheumatism EULAR and the European Group for Blood and Marrow Transplantation EBMT prepared common guide lines on how to proceed. They are presented and summarised. Clear clinical data are still missing. Preliminary data are promising and protocols for prospective studies are being prepared. They should allow a better evaluation of the procedures in a few years from now.
16 patients of studies AML-BFM-83 and -87 with allogeneic bone marrow transplantation (BMT) in first complete remission (CR) were compared with matched controls with postremission chemotherapy (CT-MC). CT-MC were selected from 250 non-grafted patients with a minimum of remission duration corresponding to the median interval between remission and allogeneic BMT (7.3 and 3.6 months in studies BFM-83 and BFM-87). Matched pair criteria according to prognostic significance were: blast cell reduction day 15 in bone marrow, FAB subtypes, white blood cell count, age, and time to CR. Therapy results in BMT and CT-MC groups were comparable: 2 relapses and 2 treatment-related deaths after BMT vs. 5 relapses. The probability for event-free interval of 9 years was: .73 (SD .12) in the BMT group vs. .67 (SD .12) in the CT-MC group. Early and late toxicity was higher in the BMT group. 3 children of the BMT group had tolerable or severe sequelae (convulsive seizures, hemiparesis). Currently, there is no advantage for allogeneic BMT in first CR according to our results. Only high risk patients should be grafted as soon as possible after achieving CR.
Patients receiving cytoreductive therapy and bone marrow transplantation (BMT) are known to develop marked protein catabolism. To assess the contribution of whole body protein breakdown, amino acid oxidation and incorporation into proteins, plasma leucine kinetics (1-13C-leucine infusion technique) were determined in six patients five times within 14 days before and after cytoreductive therapy (Cyclophosphamide and total body irradiation) and marrow transplantation. Nitrogen balance became negative (-0.20 +/- 0.04 g/Kg/24 hr) after cyclophosphamide (p less than 0.01) and was -0.25 +/- 0.05 g/Kg/24 hr 7 days after BMT in spite of total parenteral nutrition. Plasma leucine concentration increased after BMT by 67% (p less than 0.0015). Leucine plasma appearance was 1.20 +/- 0.15 mumol/kg/min before treatment, it increased slightly and transiently after cyclophosphamide, and increased again from day 5 to day 7 after BMT (p less than 0.01), suggesting increased protein break-down. Leucine oxidation increased from 0.27 +/- 0.07 before therapy to 0.97 +/- 0.16 mumol/kg/min (p less than 0.02) after cyclophosphamide and BMT. Nonoxidative leucine disappearance rate decreased slightly from 0.92 +/- 0.08 to 0.75 +/- 0.16 mumol/kg/min after BMT (ns). Leucine metabolic clearance rate decreased from 11.8 +/- 1.65 before therapy to 6.9 +/- 0.70 ml/kg/min (p less than 0.02) after cytoreductive therapy. After BMT it increased again to 9.9 +/- 1.5 ml/kg/min (p less than 0.02). The results demonstrate that patients undergoing cytoreductive therapy and bone marrow transplantation develop negative nitrogen balance due to increased protein breakdown associated with increased leucine oxidation and increased metabolic clearance rate.(ABSTRACT TRUNCATED AT 250 WORDS)
Explore the source record for details and available documents.