ALBERT

Description: The pathogenic effect of cytomegalovirus (CMV) infection on the hematopoietic recovery after bone marrow transplantation (BMT) was retrospectively studied in 87 recipients of (nonpurged) autologous BMT and in 56 recipients of allogeneic BMT from HLA-identical siblings. Indications for autologous BMT were lymphomas or acute leukemias and for allogeneic BMT various malignancies or aplastic anemia. Patients were divided for the study in two groups, CMV-positive and CMV-negative on the basis of the CMV status pretransplant, and CMV-negative patients were kept CMV-negative by the local transfusion policy. In allogeneic BMT recipients, platelet recovery was significantly slower in CMV- positive patients than in CMV-negative patients (platelets greater than 50,000 cells/microL after 41 days v 27 days, P = .007). This difference held true when patients with acute graft-versus-host disease above grade I were excluded (platelets greater than 50,000 cells/microL after 42 days v 24 days, P = .01). In autologous BMT, the negative effect on platelet recovery was present in patients with lymphomas, but absent in patients with acute leukemias. Patients with acute leukemias had a very delayed recovery of platelets and granulocytes after autologous BMT, irrespective of the CMV status, probably due to the original stem cell disorder. Platelet recovery was significantly slower in CMV-positive autologous BMT recipients with lymphomas than in those not infected (platelets greater than 50,000 cells/microL after 36 days v 24 days, P = .0002). The presence of CMV infection had no effect on the recovery of granulocytes in autologous or allogeneic BMT. These data show that CMV infection causes delayed platelet recovery after BMT; however, in autologous BMT, the underlying disease (ie, acute leukemia) is more determinant for hematopoiesis after BMT.

Description: Surface exposed membrane proteins of malignant cells may offer important clues about the differentiation stage of the cell or may contain proteins specific for the malignant state. We have studied the surface exposed membrane proteins of human acute myeloid leukemia cells employing the lactoperoxidase, periodate, or the neuraminidase/galactose oxidase ectolabeling procedures. One- dimensional membrane protein patterns were prepared from 20 patients, and from 19 patients, two-dimensional patterns were prepared according to OFarrell. No consistent differences in membrane proteins could be found between patients classified as M1, M2, M4, or M5 (FAB classification). A diagram of membrane proteins from acute myeloid leukemia cells subjected to two-dimensional electrophoresis could be composed from the results obtained. About 25 different membrane proteins can be indicated. Two-dimensional patterns, after the various ectolabeling procedures, were also prepared from mature myeloid cells, visualizing about 18 different membrane proteins. Comparison of these and the undifferentiated myeloid leukemia cell pattern reveals some maturation-linked or leukemia-associated differences. The most relevant proteins will be discussed, along with their association with a recently described “malignancy marker” with a molecular weight of 68,000 daltons.

Description: Fourteen patients with non-Hodgkin's lymphoma (NHL) of high-grade malignancy were treated with cyclophosphamide and total body irradiation followed by autologous bone marrow transplantation (ABMT). All patients were pretreated with conventional chemotherapy. Three of four patients with drug-resistant disease achieved complete remission (CR), but relapse occurred within six months. Four patients in partial remission (PR) achieved CR; one died because of sepsis, two relapsed within six months, and one is still in CR 28+ months later. Six were treated in CR, five in first CR, and one in second CR. From these six patients (who received this treatment as consolidation therapy), five are in unmaintained CR seven to 31+ months after ABMT (one patient died of a secondary illness). There were two therapy-related deaths, both in patients with a poor clinical condition. Toxicity of this treatment was mild for those receiving transplants who were in better condition. These preliminary results suggest that intensive cytoreductive therapy followed by ABMT may improve disease-free survival in patients in NHL of high-grade malignancy in CR.

Description: A 22-year-old man who underwent syngeneic bone marrow transplantation (BMT) for acute lymphoblastic leukemia acquired a human immunodeficiency virus (HIV) infection by transfusion of blood products from a donor at risk. The manifestations were acute encephalopathy together with immune thrombocytopenia in the early posttransplant period, and acquired immunodeficiency syndrome (AIDS) developed 20 months after BMT. Because he had a syngeneic donor, the possibility of reconstituting the immune system was investigated by repeated transfer of healthy syngeneic lymphocytes and by combining repeated transfer of syngeneic lymphocytes with the antiviral agent suramin to protect the infused leukocytes from being attacked by HIV. No improvement was observed clinically or in the patient's immune functions by these efforts.

Description: Allogeneic bone marrow transplantation (BMT) in humans is hampered mainly by graft-versus-host disease (GVHD). Ex vivo T-cell depletion of the marrow graft has decreased the incidence and severity of GVHD, but has resulted in a higher incidence of graft failure and of relapse of the disease. In order to find an optimal T-cell number that avoids the extreme risks on both sides, we performed BMTs with a fixed low number of T cells. Thirty-one patients received marrow grafts, containing 1 x 10(5) T cells per kilogram body weight, from their HLA-identical sibs. All patients, except one, received cyclosporin A. Engraftment of donor marrow cells occurred in all patients and (late) graft rejections are not observed to date. Eighteen of 30 (60%) evaluable patients had acute GVHD, grade I (10 patients) or grade II (8 patients), limited to the skin in all patients. Chronic GVHD, also limited to the skin, was found in 9 of 27 (33%) evaluable patients. Incidence but not severity of GVHD in our study seems similar to that observed in non-T-cell depleted marrow grafting. Relapse was observed in 1 of 13 leukemic patients transplanted in first (or second) remission or first chronic phase with a follow-up of at least 6 months. These results suggest that with a fixed low number of T cells severe GVHD and failure to engraft can be avoided. More patients and longer follow-up are necessary for conclusions regarding relapse rate and late graft failure.

Description: Fourteen patients with non-Hodgkin's lymphoma (NHL) of high-grade malignancy were treated with cyclophosphamide and total body irradiation followed by autologous bone marrow transplantation (ABMT). All patients were pretreated with conventional chemotherapy. Three of four patients with drug-resistant disease achieved complete remission (CR), but relapse occurred within six months. Four patients in partial remission (PR) achieved CR; one died because of sepsis, two relapsed within six months, and one is still in CR 28+ months later. Six were treated in CR, five in first CR, and one in second CR. From these six patients (who received this treatment as consolidation therapy), five are in unmaintained CR seven to 31+ months after ABMT (one patient died of a secondary illness). There were two therapy-related deaths, both in patients with a poor clinical condition. Toxicity of this treatment was mild for those receiving transplants who were in better condition. These preliminary results suggest that intensive cytoreductive therapy followed by ABMT may improve disease-free survival in patients in NHL of high-grade malignancy in CR.

Description: Lymphocyte function-associated antigen-1 (LFA-1) (CD11a/CD18) expression on bone marrow-derived plasma cells from normal individuals, patients with monoclonal gammopathies of undetermined significance (MGUS), and patients with multiple myeloma (MM) was studied by immunofluorescence microscopy and flow cytometry using a new monoclonal antibody (MoAb) F8.8. This MoAb recognizes the alpha-chain (CD11a) of LFA-1 as determined by immunoprecipitation, and inhibits T-cell-induced cytotoxicity. Although the F8.8 MoAb stains unstimulated peripheral blood T cells with the same mean fluorescence intensity as other anti- CD11a MoAbs, it proved to be superior in detecting CD11a on plasma cells as compared with reference MoAbs. Using the anti-CD11a MoAb F8.8, a strong correlation was found between LFA-1 expression and disease activity in MM, as defined by clinical performance and serum M-protein level. Hardly any LFA-1+ plasma cells were detected in normal individuals, patients with MGUS, and MM patients in a nonactive phase of their disease, while plasma cells of some MM patients with active disease and all patients with fulminant disease expressed LFA-1. Plasma cell LFA-1 expression correlated well with the labeling index (LI) of the tumors in the individual patients. The relation between LFA-1 expression and the tumor growth suggests an involvement of this adhesion molecule in cellular interactions resulting in plasma cell proliferation.

Description: A 22-year-old man who underwent syngeneic bone marrow transplantation (BMT) for acute lymphoblastic leukemia acquired a human immunodeficiency virus (HIV) infection by transfusion of blood products from a donor at risk. The manifestations were acute encephalopathy together with immune thrombocytopenia in the early posttransplant period, and acquired immunodeficiency syndrome (AIDS) developed 20 months after BMT. Because he had a syngeneic donor, the possibility of reconstituting the immune system was investigated by repeated transfer of healthy syngeneic lymphocytes and by combining repeated transfer of syngeneic lymphocytes with the antiviral agent suramin to protect the infused leukocytes from being attacked by HIV. No improvement was observed clinically or in the patient's immune functions by these efforts.

Description: Surface exposed membrane proteins of malignant cells may offer important clues about the differentiation stage of the cell or may contain proteins specific for the malignant state. We have studied the surface exposed membrane proteins of human acute myeloid leukemia cells employing the lactoperoxidase, periodate, or the neuraminidase/galactose oxidase ectolabeling procedures. One- dimensional membrane protein patterns were prepared from 20 patients, and from 19 patients, two-dimensional patterns were prepared according to OFarrell. No consistent differences in membrane proteins could be found between patients classified as M1, M2, M4, or M5 (FAB classification). A diagram of membrane proteins from acute myeloid leukemia cells subjected to two-dimensional electrophoresis could be composed from the results obtained. About 25 different membrane proteins can be indicated. Two-dimensional patterns, after the various ectolabeling procedures, were also prepared from mature myeloid cells, visualizing about 18 different membrane proteins. Comparison of these and the undifferentiated myeloid leukemia cell pattern reveals some maturation-linked or leukemia-associated differences. The most relevant proteins will be discussed, along with their association with a recently described “malignancy marker” with a molecular weight of 68,000 daltons.

Description: Despite prophylaxis with immunosuppressive drugs, severe acute graft- versus-host disease (GVHD) remains a major cause of morbidity and mortality in patients transplanted with unmodified bone marrow (BM) grafts from HLA-identical siblings. Although T-cell depletion of the BM graft has evolved as the most effective method to prevent severe acute GVHD, this beneficial effect is counterbalanced by an increased rate of graft failure and relapse of the disease. To find an approach to T-cell depletion that may avoid these extreme risks, we gave BM recipients a fixed low number of 1 x 10(5) donor T cells per kilogram of recipient's body weight in the graft. This corresponds with 99% T-cell depletion and is achieved by the addition of T cells to the graft that was previously depleted of T cells. A total of 70 patients with hematologic malignancies or aplastic anemia, including 40 patients with standard- risk leukemias, received BM grafts, depleted of T cells according to this approach, from HLA-identical siblings. The preparative regimen consisted of cyclophosphamide and total body irradiation. The patients also received a short course of cyclosporine posttransplant. Graft failure did not occur. Acute GVHD, only grade I or II, was seen in 70% of the patients and was limited to the skin in all patients. Chronic GVHD occurred in 31% of the patients and, with the exception of 1 patient, was limited to the skin as well. Relapse occurred in 3 of 40 (8%) patients with standard-risk leukemias, resulting in a projected survival at 5 years of 80%. Patients with standard-risk diseases had a procedure-related mortality of 11%. Quality of life, determined 1 year after BM transplant, was good in almost all patients with standard-risk diseases. Thus, this approach of T-cell depletion may be an approach that avoids the development of severe acute and chronic GVHD without damaging the function or antileukemic effect of the graft and that has a low transplant-related morbidity and mortality.