Bone marrow transplantation in auto-immune disease.
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Animals↗
Biomedical subjects
J C Biggs
Publications and source records attributed to J C Biggs.
Improved specificity of ribozyme-mediated cleavage of bcr-abl mRNA.
Ribozyme-mediated cleavage of bcr-abl mRNA has been shown to be associated with the concomitant cleavage of bcr mRNA. The possible role of this ribozyme as a clinical therapeutic constrained us to improve its target specificity. Consequently, three modified ribozymes (Rz7-9) were created, each carrying a single base mismatch in the sequence immediately 5' of the cleavage site, while a fourth ribozyme (Rz10) was targeted to a nearby site. Each was compared with the parent ribozyme for its ability to cleave synthetic bcr-abl and bcr substrates, and it was shown that alteration of the second base 5' of the cleavage site created a ribozyme with significantly improved specificity for its substrate. Rz10 was shown to exclusively act on bcr-abl, but the efficiency of cleavage was reduced compared to that shown by ribozymes 6, 8, and 9.
Base Sequence↗
Prospective randomised double-blind trial of the in vivo use of recombinant human erythropoietin in bone marrow transplantation from HLA-identical sibling donors. The Australian Bone Marrow Transplant Study Group.
Ninety one patients between the ages of 17 and 58 years undergoing histocompatible allogeneic transplants from sibling donors were entered into a double-blind randomised trial to evaluate the effect of human erythropoietin (rhu EPO) at a dose of 300 units per kg/day given thrice weekly by intravenous injection on erythropoiesis and on erythrocyte and platelet transfusion requirements. Dose was ceased when the haemoglobin exceeded 12g/dL and recommenced if the haemoglobin fell below 12 g/dL, at 150 units/kg/day. If the haemoglobin exceeded 12 g/dL on a further occasion, the dose of rhu EPO was not given. Patients received two units of erythrocytes when the haemoglobin dropped below 8.5g/dL and received platelet transfusions when the count dropped below 20 x 10(9)/L. Univariate analysis revealed a significantly higher reticulocyte count, haemoglobin concentration and bone marrow erythropoiesis after day 14 in the group receiving rhu EPO but this was not reflected in decreased erythrocyte transfusion (7 +/- 5 in controls versus 6 +/- 5 in rhu EPO group) or in platelet transfusions (11 +/- 7 in controls versus 11 +/- 9 in rhu EPO group). Hospitalisation in each group was the same (29 +/- 8 in the control group and 28 +/- 8 in the rhu EPO group). However, in the multivariate analysis, the administration of rhu EPO was associated with an 18% reduction in erythrocyte transfusion requirement when other variables were taken into account. No side-effects due to rhu EPO were detected in this study.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Characterization of a novel leucocyte surface membrane antigen recognized by the monoclonal antibody WM65.
WM65 is a murine mAb which recognizes a novel surface membrane antigen present on leukaemic and normal leucocytes. The present study further investigates the nature of this antigen, especially those features which relate to the possible therapeutic applications of the WM65 antibody. There are 1-3 x 10(4) molecules of this antigen present on normal leucocytes, and the same or greater numbers of antigen molecules are present on a variety of leukaemic cells. In vitro data showed that the WM65 antibody is internalized following interaction with its antigen on normal leucocytes. The affinity of this antibody was calculated using an ELISA method which required neither labelling of the antibody nor purification of the antigen and the affinity constant was found to be 3 x 10(7) +/- 2 x 10(7) (mol/L)-1. Further data are presented which suggest that this antigen is a differentiation antigen and an integral membrane protein. Despite the relatively low affinity of the WM65 antibody, a number of characteristics of the antigen suggest the antibody may possibly have therapeutic applications. These characteristics include its cellular distribution, the number of antigen molecules expressed on the cell surface and its ability to internalize in vitro.
Antibodies, Monoclonal↗
Assessment of proliferative responses to granulocyte-macrophage colony-stimulating factor (GM-CSF) in acute myeloid leukaemia using a fluorescent ligand for the nucleoside transporter.
Nucleoside transporter expression has been linked to proliferation in a variety of haemopoietic cell types. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was given for 72 h before commencing chemotherapy in 15 patients with relapsed or refractory acute myeloid leukaemia (AML) and in 11 patients serial bone marrows were taken for measurement of [3H]thymidine labelling index, Ki-67 positivity and maximal binding of 5-(SAENTA-x8)-fluorescein, a flow cytometry ligand which enumerates nucleoside transporter sites. GM-CSF caused proliferation of marrow myeloblasts in eight of 11 patients, while in three patients there was no change in proliferative indices. The expression of nucleoside transporters increased up to 4-fold in the myeloblasts from the patients showing a proliferative response to GM-CSF but there was no increase in transporters on the myeloblasts from the three non-responding patients. A close correlation was found between the fold increase in nucleoside transporter expression and the fold increase in labelling index of marrow myeloblasts (r = 0.86, n = 9, p < 0.01). In one patient with acute megakaryoblastic leukemia, GM-CSF caused parallel increases in labelling index, Ki-67 positivity and numbers of nucleoside transporters on peripheral blood blast cells. Thus induction of proliferation by cytokine increases the expression of nucleoside transporters on leukaemic myeloblasts studied in serial samples from the same source (bone marrow or blood). The suitability of 5-(SAENTA-x8)-fluorescein for two colour flow cytometric analysis allows the rapid enumeration of nucleoside transporters in the myeloblast compartment of heterogeneous marrow samples.
Acute Disease↗
Cytokine priming of acute myeloid leukemia may produce a pulmonary syndrome when associated with a rapid increase in peripheral blood myeloblasts.
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Adult↗
Outcome after allogeneic bone marrow transplant for leukemia in older adults.
OBJECTIVE: To determine whether age over 40 years is associated with adverse outcome after allogeneic bone marrow transplantation for leukemia. DESIGN: A retrospective analysis of outcome after bone marrow transplants for leukemia reported to the International Bone Marrow Transplant Registry (IBMTR) among recipients 30 through 39 years, 40 through 44 years, 45 through 49 years, and 50 years of age and older. SETTING: Transplantations performed in 138 institutions worldwide and reported to the IBMTR. PATIENTS: A total of 2180 recipients of HLA-identical sibling bone marrow transplants for leukemia, divided into four cohorts based on age: 30 through 39 years (n = 1282), 40 through 44 years (n = 527), 45 through 49 years (n = 291), and 50 years and older (n = 80). MAIN OUTCOME MEASURES AND RESULTS: Incidence of leukemia-free survival, graft-vs-host disease, and relapse was comparable among the four age cohorts. Patients with advanced leukemia aged 45 years or older had a slightly higher risk of treatment-related mortality, and the 45- through 49-year-old cohort had a higher risk of interstitial pneumonia. CONCLUSIONS: These data indicate that among leukemia patients over 30 years of age at the time of allogeneic bone marrow transplantation, increasing age into the fifth decade does not adversely affect outcome after transplants from HLA-identical siblings.
Adult↗
Methotrexate, cyclosporine, or both to prevent graft-versus-host disease after HLA-identical sibling bone marrow transplants for early leukemia?
Optimal prophylaxis of graft-versus-host disease (GVHD) is controversial. We compared efficacy of three posttransplant immune suppressive regimens in 2,286 recipients of HLA-identical sibling bone marrow transplants for acute lymphoblastic leukemia (ALL) in first remission, acute myelogenous leukemia (AML) in first remission, or chronic myelogenous leukemia (CML) in first chronic phase. Six hundred forty received methotrexate, 977 received cyclosporine, and 669 received combined cyclosporine and methotrexate. In children, the three regimens resulted in similar outcomes. In adults, cyclosporine and methotrexate had comparable risks of acute and chronic GVHD. Compared with methotrexate, cyclosporine was associated with less interstitial pneumonia (relative risk [RR] = 0.6; P < .001), less treatment-related mortality (RR = 0.6; P < .001), more relapses (RR = 1.6; P < .05), and less treatment failure (relapse or death from any cause; RR = 0.7; P < .001). Different effects were observed in different leukemias. In ALL, the rate of leukemia relapse was increased with cyclosporine versus methotrexate, with no effect on other outcomes. In AML and CML, interstitial pneumonia, treatment-related mortality, and treatment failures were decreased with cyclosporine, with no increase in relapse. Similar analyses comparing cyclosporine plus methotrexate with cyclosporine alone showed that adults receiving the combination had less acute GVHD (RR = 0.5; P < .001), less chronic GVHD (RR = 0.7; P < .01), and less interstitial pneumonia (RR = 0.7; P < .001). Treatment failure (RR = 0.8; P < .05) was marginally reduced. Separate analyses in ALL and AML showed less acute GVHD with combined therapy, but no significant effect on other outcomes. In CML, acute GVHD, interstitial pneumonia, treatment-related mortality, and treatment failure were decreased with combined therapy.
Adolescent↗
Clinical analysis of 125 patients with the lupus anticoagulant.
A retrospective analysis of 125 consecutive lupus anticoagulant (LA) positive patients and 125 age, sex matched lupus anticoagulant negative controls is reported with the aims of defining further the clinical spectrum of disease, determining at-risk subgroups and management strategies. There was no significant difference in the incidence or pattern of complications in those with systemic lupus erythematosus (SLE) and related disorders, and those without SLE. Venous thromboembolism, immune thrombocytopenia, foetal loss, depression and hypertension were statistically more common in the LA group than in the control group. In contrast to previous reports, children aged ten years or less with the LA developed significantly more complications than controls. Patients with the LA secondary to drugs also developed complications, a finding which is also at variance with previous reports. There was a significant difference in the outcome of arterial disease (p < 0.04) and venous thromboembolism (p < 0.001) when long term anticoagulation was part of the treatment regimen.
Adolescent↗
Changing results of HLA-identical sibling bone marrow transplantation in patients with haematological malignancy during the period 1981-1990.
During the years 1981-90 inclusive 227 patients with haematological malignancy received an HLA-identical sibling first transplant at St Vincent's Hospital, Sydney. Recipients with acute leukaemia in first remission or chronic myeloid leukaemia in first chronic phase were analysed as good risk, and those beyond these stages, as poor risk patients. Good risk patients transplanted in the years 1986-90 (n = 52) showed improved actuarial survival (74%) compared to those (n = 58) transplanted during 1981-85 (37%, p = 0.01). There was a suggestion that leukaemia-free survival was also improved in those transplanted during the later time period (62% versus 36%, p = 0.07). In contrast, poor risk patients transplanted during 1986-90 (n = 55) appeared to have worse leukaemia-free survival (15%) compared to those transplanted during 1981-85 (n = 62) (22%, p = 0.09). The incidence of acute graft-versus-host disease (GVHD) grades I-IV in all patients was 94% in those transplanted during 1981-85 (n = 120) and 86% in those transplanted during 1986-90 (n = 107) (p = 0.002). The incidence of acute GVHD grades II-IV was 37% during 1981-83, 20% during 1984-86, and 28% during 1987-90 (p = 0.1). The decrease in incidence and severity of acute GVHD correlated with the introduction of the cyclosporin/short methotrexate regimen in our practice. The incidence of cytomegalovirus (CMV) pneumonitis was 18% in 1981-85, and 11% in 1986-90 (p = 0.09). In 1989 and 1990 no cases of CMV pneumonitis occurred.(ABSTRACT TRUNCATED AT 250 WORDS)
Acute Disease↗
Treatment of chronic myelogenous leukemia with allogeneic bone marrow transplantation after preparation with busulfan and cyclophosphamide (BuCy2): an update.
Allogeneic bone marrow transplantation (BMT) has been shown to result in long-term disease-free survival in patients with leukemia. However, the utility of this treatment approach is limited by treatment-related morbidity and mortality. We present an update of a study in which a BMT preparative regimen consisting of a 4-day course of busulfan and a 2-day course of cyclophosphamide (BuCy2) was used in patients with chronic myelogenous leukemia. Patient survival depended on disease stage, with a 58% survival rate for patients in first chronic phase, 41% for those in accelerated phase, and 25% for those in the blast transformation stage. There was a significant difference in patient survival between those who received transplants within 1 year of diagnosis and those who received transplants more than 1 year after diagnosis (70% v 40%). This difference appeared to be due to the extent of previous exposure to busulfan. The overall mortality rate in this study was 46%. We conclude that the BuCy2 preparative regimen is similar in effectiveness to regimens that include total body irradiation and results in comparable levels of transplant-related mortality. Our results strongly indicate that patients with chronic myelogenous leukemia who receive BMT within the first year after diagnosis have a significantly better clinical outcome than those who receive BMT later in the course of the disease.
Adolescent↗
Allogeneic bone marrow transplantation for acute myelogenous leukemia, acute lymphocytic leukemia, and multiple myeloma following preparation with busulfan and cyclophosphamide (BuCy2).
The combination of busulfan (Bu) and cyclophosphamide (Cy) has been found to be effective preparative therapy for patients treated with allogeneic bone marrow transplantation (BMT). We developed the BuCy2 regimen, which contains a lower dose of cyclophosphamide than the original BuCy regimen, in the hope of reducing regimen-related toxicities. We have studied the use of BuCy2 as preparation for allogeneic BMT in patients with acute myelogenous leukemia, acute lymphocytic leukemia, and multiple myeloma. In patients with acute myelogenous leukemia, the leukemia-free survival and regimen-related toxicity rates obtained in our study appear similar to those achieved with other preparative regimens, including those containing Cy and total body irradiation (TBI). BuCy2 is also an effective BMT preparative regimen in patients with acute lymphocytic leukemia and multiple myeloma. Treatment with BuCy2 results in a lower incidence of severe stomatitis and probably of interstitial pneumonia than does treatment with Cy/TBI, but hepatic veno-occlusive disease occurs more frequently in BuCy-treated patients. The incidence of veno-occlusive disease appears to be affected by agents used as prophylaxis for graft-versus-host disease. Compared with Cy/TBI regimens, BuCy treatment is likely to result in fewer delayed effects of treatment, such as impairment of fertility and second malignancies. Current clinical efforts are focusing on ways to improve the antileukemic activity of the BuCy preparative regimen and to reduce regimen-related toxicities.
Antineoplastic Combined Chemotherapy Protocols↗
Apparent cure of rheumatoid arthritis by bone marrow transplantation.
We describe the induction of sustained remissions and possible cure of severe erosive rheumatoid arthritis (RA) by bone marrow transplantation (BMT) in 2 patients. BMT was used to treat severe aplastic anemia which was caused by gold in one case and D-penicillamine in the other. In the 8 and 6 years since the transplants (representing 8 and 4 years since cessation of all immunosuppressive therapy, respectively), the RA in each case has been completely quiescent. Although short term remission of severe RA following BMT has been reported, these are the first cases for which prolonged followup has been available. This experience raises the question of the role of BMT itself as a therapeutic option for patients with uncontrolled destructive synovitis.
Adult↗
Production of a functional single-chain Fv fragment from the pan-leukocyte antibody WM65 using splicing by asymmetric PCR.
A method of assembly of a single-chain Fv fragment is described, whereby asymmetric polymerase chain reactions (APCR) and primer extension were used to join immunoglobulin heavy and light chain variable region genes via a linker sequence. In this procedure heavy and light chain genes, together with a linker gene containing complementary sequences, were amplified by APCR to generate single-stranded products. The single stranded heavy or light chain genes were hybridized to the relevant single-stranded link product, and extended to produce double-stranded heavy-link and link-light genes. These genes then underwent another round of APCR, resulting in two single-stranded genes (heavy-link and link-light) containing extensive overlapping sequences. Hybridization and extension of these two single-stranded products allowed the formation of the complete heavy chain-link-light chain double-stranded product. Using this method, a functional single-chain Fv fragment based on the pan-leukocyte antibody WM65 was expressed and purified from E. coli. This method of immunoglobulin gene assembly by polymerase chain reaction (PCR) offers an alternative to the current methods of the genetic engineering of antibody fragments.
Antibodies↗
Treatment of chronic myeloid leukemia with allogeneic bone marrow transplantation after preparation with BuCy2.
One hundred fifteen patients with chronic myelocytic leukemia (CML) were administered busulphan 4 mg/kg for 4 days and cyclophosphamide 60 mg/kg on each of 2 days (BuCy2) followed by allogeneic bone marrow transplantation from histocompatible sibling donors. For 62 patients in chronic phase, 26 in accelerated phase, and 27 in blast transformation, the actuarial survival at 3 years was 58%, 41%, and 25%, respectively. Actuarial probability of relapse was 3%, 12%, and 27%, respectively. Only two patients in chronic phase showed a transient cytogenetic relapse and one of these died from subsequent transplant-related complications, whereas the other remains cytogenetically normal 697 days posttransplant. Patients who were transplanted within 1 year of diagnosis in chronic phase had a survival of 70% compared with 40% when transplanted beyond 1 year from diagnosis. This significant difference in survival was due to transplant-related complications and was correlated with previous exposure to high doses of busulphan. This study indicates that BuCy2 is a useful conditioning regimen for marrow transplantation in patients with CML and results in similar survival statistics and transplant-related mortality as would be expected with conditioning regimens containing total body irradiation. It is possible that relapse after BuCy2 may be lower than expected with regimens containing total body irradiation, but larger analyses are required.
Adolescent↗
Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy.
About 30% of adults with acute lymphoblastic leukemia (ALL) and 20% to 40% of children and adults with acute myelogenous leukemia (AML) never achieve remission, even with intensive chemotherapy. Most die of resistant leukemia, often within 6 months or less. In this study of 126 patients with resistant ALL or AML, allogeneic bone marrow transplants from HLA-identical siblings produced remissions in 113 of 115 (98%) evaluable patients. The 3-year probability of leukemia-free survival was 21% (95% confidence interval, 15% to 29%). Leukemia-free survival was similar in ALL (23%, 12% to 40%) and AML (21%, 14% to 31%). Only 3 of 27 patients at risk relapsed more than 2 years posttransplant.
Adolescent↗
Bone marrow transplantation for severe aplastic anemia: influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome.
Data for 595 patients with severe aplastic anemia receiving HLA-identical sibling bone marrow transplants were analyzed to determine the effect of pretransplant conditioning and graft-versus-host disease (GVHD) prophylaxis on outcome. Transplants were performed between 1980 and 1987 and reported to the International Bone Marrow Transplant Registry. Three conditioning regimens (cyclophosphamide alone, cyclophosphamide plus limited field radiation, and cyclophosphamide plus total body radiation) were studied; none was associated with superior long-term survival. Three GVHD prophylaxis regimens (methotrexate, cyclosporine, and methotrexate plus cyclosporine) were studied. Recipients of cyclosporine with or without methotrexate had a significantly higher probability of 5-year survival (69%, 95% confidence interval 63% to 74%) than patients receiving methotrexate only (56%, 49% to 62%, P less than .003). Higher survival with cyclosporine resulted from decreased risks of interstitial pneumonia (P less than .0002) and chronic GVHD (P less than .005). Additional risk factors adversely associated with survival included infection pretransplant (P less than .004), use of parous or transfused female donors (P less than .005), older patient age (P less than .005), and 20 or more pretransplant transfusions (P less than .006). These data may prove useful in planning randomized clinical trials and in identifying patients at high-risk of treatment failure.
Adolescent↗
The bcr breakpoint and chronic phase duration in chronic myeloid leukemia.
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Adult↗