Cyclosporine-induced graft vs host disease in two patients receiving syngeneic bone marrow transplants.
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Bone Marrow Transplantation↗
Biomedical subjects
K Atkinson
Publications and source records attributed to K Atkinson.
Cytokine activity after human bone marrow transplantation. II. Production of macrophage procoagulant activity and the cytokine regulating its production, macrophage procoagulant inducing factor.
The production of procoagulant activity by circulating monocytes and its regulation by a cytokine secreted by mitogen-stimulated peripheral blood mononuclear cells was investigated in recipients of HLA-identical sibling bone marrow transplants. Blood monocyte numbers reached the normal range within 3 weeks of transplant. After stimulation with lipopolysaccharide, macrophage procoagulant activity was found to be within the normal range in all patients at all times post transplant. It did not appear to correlate with the presence or absence of graft-versus-host disease. Surprisingly, and in marked contrast to our previously documented severe depression of interleukin 2 production by transplant recipients' peripheral blood mononuclear cells, the mitogen-induced production of the cytokine that induces procoagulant activity production (macrophage procoagulant inducing factor, MPIF) was also normal in the majority of patients when assayed using the responsive myelomonocytic cell line RC-2A. These findings suggest firstly that monocyte differentiation and function normalize rapidly post transplant; and secondly, when taken together with previous studies, that the ability of peripheral blood mononuclear cells to synthesize cytokines post transplant varies greatly according to the specific cytokine involved.
Adolescent↗
High incidence of early leukemic relapse in patients given cyclosporin and T cell depleted HLA-identical sibling marrow transplants for acute leukemia in first remission.
Twelve patients with acute nonlymphoblastic leukemia (ANL, n = 6) or acute lymphoblastic leukemia (ALL, n = 6) in first complete remission received cyclophosphamide 120 mg/kg and total body irradiation (TBI) 12 Gy followed by HLA-identical sibling marrow that had been depleted of T cells by incubation with anti-CD2 (with or without anti-CD8) monoclonal antibody and rabbit complement. These 12 patients were compared historically to 25 patients with ANL (n = 15) or ALL (n = 10) in first remission given cyclophosphamide 120 mg/kg and TBI 12 Gy followed by non-T cell depleted HLA-identical sibling marrow for parameters of relapse and survival. Thirty-six of the 37 patients received cyclosporin as post transplant prophylaxis for graft-versus-host disease (GVHD). All surviving patients have been followed for a minimum of one year from transplant. The actuarial rate of leukemic relapse in the T-depleted group was 62% compared to 37% in the non-depleted group (p less than 0.02). Additionally, relapse occurred significantly earlier post transplant in the T-depleted recipients (p = 0.012). Actuarial survival at two years post transplant was 24% for the T-depleted recipients and 41% at six years post transplant for the non-depleted recipients (not significant, p = 0.37). We have previously shown that GVHD is less severe in patients given T cell depleted transplants. Taken together, these findings suggest that (under the protocol conditions used) a graft-versus-leukemia effect is not separable from a GVHD effect in man.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
A prospective randomised trial of cyclosporin versus methotrexate after HLA-identical sibling marrow transplantation for patients with acute leukemia in first remission: analysis 2.5 years after last patient entry.
The results of a prospective randomised trial comparing cyclosporin (CSP) with methotrexate (MTX) as immunosuppressive therapy after HLA-identical sibling marrow transplantation for patients with acute leukemia in first remission were analysed 2.5 years after entry of the last patient into the trial. Patients given cyclosporin showed a faster rate of marrow engraftment, less oro-pharyngeal mucositis, more azotemia and more diastolic hypertension than those receiving methotrexate. Actuarial four-year survival was 69% for patients receiving MTX and 43% for those receiving cyclosporin (not significant). Actuarial four-year survival in continuous complete remission from the time of transplant was 69% and 38% respectively (not significant, p = 0.09). While there was no difference in the incidence or severity of acute or chronic graft-versus-host disease, the actuarial rate of leukemic recurrence was 0% in the MTX and 36% in the GSP group (p = 0.02). This finding emphasises the importance of long-term follow up for the full assessment of new therapeutic protocols of marrow transplantation in the treatment of hematological malignancy.
Adolescent↗
The clinical diagnosis of acute graft-versus-host disease: a diversity of views amongst marrow transplant centers.
The diagnosis and grading of acute graft-versus-host disease (AGVHD) is based on a spectrum of clinical and laboratory features. To evaluate the reliability of current diagnostic and scoring criteria, six clinical vignettes were evaluated by 49 transplant physicians from 42 bone marrow transplant center worldwide. Responses were analysed to determine: (1) the degree of concordance among transplanters in diagnosing, scoring and treating AGVHD, and (2) the degree of concordance in assigning primary and contributing causes of death in patients with multiple complications of bone marrow transplantation. Concordance for the diagnosis of AGVHD ranged from 24 to 76%; concordance for grading AGVHD was 55%. Concordance for the decision to treat for AGVHD ranged from 43 to 55%; concordance for assigning the primary cause of death ranged from 71 to 100%. The findings demonstrate the need for (1) improved uniformity of reporting complications of bone marrow transplantation; (2) periodic revision and validation of diagnostic and grading criteria, and (3) methods of analysis that allow for multiple causes of death.
Acute Disease↗
Expression of messenger RNA for GM-CSF by blood mononuclear cells after allogeneic bone marrow transplantation.
We examined blood mononuclear cells from six recipients of HLA-identical sibling marrow transplants for their ability to express messenger (m) RNA for granulocyte-macrophage colony stimulating factor (GM-CSF). Cells were cultured for 48 hours with the stimulus of ionomycin and phorbol myristate acetate. mRNA specific for GM-CSF was detectable in stimulated cell cultures from all six patients. In two patients at days 31 and 40 post transplant respectively, mRNA for GM-CSF was just detectable; in a third at day 38 post transplant it was readily detectable, and in the three others at days 42, 165 and 185 respectively, it was easily detectable. These results indicate that maintenance of haemopoiesis post transplant may, at least in part, be due to the elaboration of GM-CSF by blood mononuclear cells.
Antineoplastic Combined Chemotherapy Protocols↗
The development of the acquired immunodeficiency syndrome after bone-marrow transplantation.
Since bone-marrow transplant recipients receive considerable quantities of packed-cell, platelet and sometimes leukocyte transfusions, as well as the donor marrow infusion, it would be predictable that acquired immunodeficiency syndrome (AIDS) by blood-product transfusion would occur in this patient population. We report here two patients who received HLA-identical sibling bone-marrow transplants for acute non-lymphoblastic leukaemia during their first remission. Both developed category-A AIDS at days 342 and 546 after transplantation, respectively. Neither patient belonged to any known high-risk group for AIDS, other than having received a blood-product transfusion. One of the two patients is now known to have received blood from a donor who was human immunodeficiency virus (HIV) seropositive. Both patients developed Pneumocystis carinii pneumonia and other opportunistic infections, and both have died of AIDS without evidence of recurrence of their leukaemia. One patient had no chronic graft-versus-host disease (GVHD) and the other had mild chronic GVHD of the mouth. Since severe opportunistic infections are rare after transplantation in the absence of GVHD, their late occurrence after transplantation should raise the suspicion of AIDS. This complication is likely to have an adverse impact on the long-term survival of patients who received bone-marrow transplants between 1981 and the introduction of effective screening tests for HIV infection in blood donors.
Acquired Immunodeficiency Syndrome↗
A comparative study of T-cell depleted and non-depleted marrow transplantation for hematological malignancy.
Sixteen patients with hematological malignancy received cyclophosphamide (120 mg/kg), fractionated total body irradiation (12 Gy), oral cyclosporin, and an HLA-identical sibling marrow transplant depleted of T cells by incubation with the monoclonal antibody anti-HuLy-m1 (CD2) and rabbit complement with (five patients) or without (11 patients) anti-HuLy-m8). These 16 patients were compared historically to 84 patients with hematological malignancy receiving cyclophosphamide (120 mg/kg), fractionated total body irradiation (12 or 14 Gy), oral cyclosporin, and unmanipulated HLA-identical sibling marrow, for parameters of engraftment and graft-versus-host disease (GVHD). Graft failure occurred in one of the 16 T-cell depleted recipients and in one of the 84 nondepleted recipients. Engraftment was slightly but significantly slower in the T-cell depleted group and bacterial infections significantly more frequent and severe than in the unmanipulated group. There was a suggestion that the severity of acute GVHD was reduced in those receiving T depleted marrow. Randomized trials will be necessary to determine if marrow T-cell depletion results in superior long-term leukemia-free survival.
Acute Disease↗
T cell depletion of bone marrow for clinical marrow allografting: optimalization of conditions for depletion by anti-CD2 and anti-CD8 monoclonal antibodies with rabbit complement, and for detection of residual T cell content.
Normal bone marrow obtained at harvest for bone marrow transplantation was passed over a Ficoll density gradient to obtain the mononuclear cell fraction. These cells were incubated with anti-T cell monoclonal antibodies (MAb) anti-HuLym-1 and anti-HuLym-8 plus rabbit complement, washed, and the degree of T cell depletion was assessed by culture in phytohemagglutinin, by flow cytometry and by limiting dilution analysis. The optimal protocol for T cell depletion was found to be a 2-stage incubation with 2 cycles of complement treatment, using a bone marrow cell concentration as low as possible. The precise conditions of complement dilution and incubation temperature depended on the batch of complement used, and had to be assessed for each batch. Of the 3 methods used for assessing T cell contamination, culture in PHA was found to be inappropriate due to large variation in background proliferation of treated and untreated bone marrow cells. Flow cytometry was accurate for residual T cell content of greater than 1% (corresponding to a 90-95% depletion of T cells) but could not detect lower levels of T cell contamination. The limit dilution assay was found to be by far the most sensitive, being capable of detecting a T cell contamination of 1 in 10,000 cells. When combined with flow cytometry on untreated marrow for calculation of the cloning efficiency, it gave very accurate determinations of residual T cell content of marrow.
Animals↗
CD4+ T cells appear capable of initiating graft-versus-host disease across non-major histocompatibility complex (MHC) barriers in man.
Twelve patients with haematological malignancy received cyclophosphamide 120 mg/kg, fractionated total body irradiation 12 Gy, oral cyclosporin and an HLA-identical sibling marrow transplant depleted of T cells by incubation with monoclonal antibodies directed against the CD2 and CD8 antigens and rabbit complement. The phenotype of the residual T cells in the donor marrow inocula was CD3+, CD4+, CD8-. To exclude the possibility that this represented modulation or blocking of the CD8 antigen, T-depleted and non-depleted marrow aliquots from these donors were bulk-cultured for 10 days with phytohaemagglutinin and interleukin-2. Even after this attempted expansion, only a small proportion of cultured T cells from the depleted aliquots (in contrast to the non-depleted aliquots) expressed the CD8 antigen. Since all patients receiving CD3+, CD4+, CD8- marrow developed mild or moderate acute graft-versus-host disease (GVHD), we conclude that CD4+ T cells are capable of initiating acute GVHD across non-MHC barriers in man.
Antigens, Differentiation, T-Lymphocyte↗
Mechanisms of tolerance in canine radiation chimeras.
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Animals↗
Both class I and class II responsive T cell subsets can separately initiate lethal graft-versus-host disease in H-2-incompatible murine radiation chimeras.
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Animals↗
T4+ cells can initiate human graft-versus-host disease.
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Acute Disease↗
Cyclosporin in bone marrow transplantation.
Cyclosporin, the first truly selective immunosuppressive agent, has a useful role in HLA-identical sibling bone marrow transplantation for haematological malignancy and severe aplastic anaemia. Specifically, it has been shown to minimise graft-versus-host disease, particularly when used in combination with methotrexate, and to reduce the risk of marrow graft rejection. Its mode of action, pharmacology, clinical utility and toxicology in the marrow transplant setting are described.
Bone Marrow Transplantation↗
Human marrow T cell dose correlates with severity of subsequent acute graft-versus-host disease.
Sixteen patients with haematological malignancy received high-dose chemotherapy or chemotherapy and total body irradiation followed by an HLA-identical sibling marrow transplant from which the T lymphocytes had been depleted prior to infusion by incubation with an anti-CD2 anti-T cell antibody with (seven patients) or without (nine patients) an anti-CD8 anti-T cell antibody together with rabbit complement. Additionally, all patients received cyclosporin. The number of T cells present in the donor marrow was determined by limiting dilution analysis, and was found to correlate with the subsequent incidence and severity of acute graft-versus-host disease (GVHD). The number of T cells infused into patients with no acute GVHD or with minimal acute GVHD of the skin (skin rash present for 14 days or less) was 1.3 +/- 1.0 x 10(5)/kg, while the number infused into those with moderate acute GVHD or with skin acute GVHD present for 15 days or more was 12.3 +/- 11.5 x 10(5)/kg (p less than 0.001). Thus a dose of 10(5) (or less) T cells/kg was associated with minimal or no acute GVHD, while 10(6) T cells/kg (or more) caused significant disease.
Bone Marrow Cells↗
Invasive Trichosporon cutaneum infection: an increasing problem in immunosuppressed patients.
Trichosporon cutaneum (syn. T. beigelii), a saprophytic fungal organism normally found in the soil, is increasingly being recognized as a cause of life-threatening systemic illness in immunosuppressed patients. Of 42 cases reported in the literature, 27 (64%) have died, including all four occurring after bone marrow transplantation. We report here a 44-year-old man who developed an invasive pulmonary infection and fungemia with T. cutaneum following bone marrow transplantation. The infection was manifest by severe respiratory distress and hypoxemia despite a clear chest X-ray, and was diagnosed by the identification of fungal hyphae on a percutaneous lung aspirate and by culture of the organism from the blood. Despite the previous reports indicating that there is a high mortality rate in this situation, the patient recovered following treatment with amphotericin B, miconazole and ketoconazole. T. cutaneum needs to be recognized as a potentially serious but treatable pathogen in severely immunosuppressed patients, including bone marrow transplant recipients.
Adult↗
Preparative regimens for marrow transplantation containing busulphan are associated with haemorrhagic cystitis and hepatic veno-occlusive disease but a short duration of leucopenia and little oro-pharyngeal mucositis.
One-hundred-and-forty-three patients with haematological malignancy or severe aplastic anaemia received HLA-identical sibling bone marrow transplants. In 111 of these patients who had haematological malignancy and who were prepared for transplant with cyclophosphamide 120 mg/kg and fractionated total body irradiation 12-14 Gy, the incidence of haemorrhagic cystitis and hepatic veno-occlusive disease was 13% and 3%, respectively. In contrast, the incidence in 15 leukaemic patients prepared for transplant with chemotherapy regimens containing high-dose busulphan was 47% and 20%, respectively (p less than 0.001). Two patients in this latter group who developed fatal veno-occlusive disease had chronic myeloid leukaemia and had received long-term low-dose busulphan pre-transplant. Neither complication occurred in 26 patients prepared by cyclophosphamide alone (20 patients with severe aplastic anaemia) or with cyclophosphamide and melphalan (six patients with leukaemia). The regimen of busulphan 16 mg/kg in combination with cyclophosphamide 120 mg/kg was associated with a short duration of total leucopenia with a significantly higher leucocyte count on the day of marrow transplant compared to other regimens. Furthermore, oro-pharyngeal mucositis was not severe even when methotrexate was utilised as post-transplant prophylaxis for graft-versus-host disease. Thus, while the busulphan-cyclophosphamide regimen appeared useful, we suggest that (1) high-dose busulphan should not be used as a preparative regimen for patients previously exposed to busulphan, and (2) bladder irrigation (as well as intravenous hydration) is necessary to minimise haemorrhagic cystitis in patients given regimens that incorporate high-dose busulphan.
Anemia, Aplastic↗
Avascular necrosis of the femoral head secondary to corticosteroid therapy for graft-versus-host disease after marrow transplantation: effective therapy with hip arthroplasty.
Of 50 patients surviving 2 years or longer after HLA-identical sibling bone marrow transplantation for haematological malignancy or severe aplastic anaemia, five developed avascular necrosis of the femoral head. All had previously received corticosteroid therapy post-transplant for graft-versus-host disease. Median day of onset of symptoms was 545 days post-transplant (range 249-731). Clinical, radiological and radionuclide findings were typical of osteonecrosis. One patient has had bilateral hemiarthroplasties and one total hip replacements performed, both with excellent results. Bilateral arthroplasties are planned for a third patient but, interestingly, the disease process in the other two patients has been relatively mild with no progression over a period of greater than 256 and greater than 825 days, respectively. Since one patient had as little as 14 days treatment with prednisone, this complication should be borne in mind when designing prophylactic regimens for minimisation of GVHD that include corticosteroids.
Adrenal Cortex Hormones↗