Carl Lenarsky

Treatment of Donor Bone Marrow with Monoclonal Anti-T-Cell Antibody and Complement for the Prevention of Graft-Versus-Host Disease: A Prospective, Randomized, Double-Blind Trial

The effects of ex-vivo depletion of T lymphocytes from donor bone marrow using a monoclonal anti-T-cell antibody (CT-2) and complement on the outcome of allogeneic bone marrow transplantation was evaluated in a prospective, randomized, double-blind study of 40 patients with leukemia. Patients receiving T-cell-depleted bone marrow had a lower incidence of acute graft-versus-host disease than control patients (3 of 20 compared with 13 of 20; p = 0.004), and mortality due to acute graft-versus-host disease was reduced. Five patients in the T-cell-depletion group developed graft failure; all control patients had sustained engraftment (p less than 0.05). Clinically apparent relapse of leukemia occurred in 7 patients from the T-cell-depletion group and in 2 controls (p, not significant). Cytogenetic evidence of residual leukemia was also detected in the 5 patients with graft failure without overt relapse. Infections and overall survival were similar in the two groups. The effects of T-cell depletion on engraftment and recurrence of leukemia require further evaluation.

Treatment of acute myelogenous leukemia. A prospective controlled trial of bone marrow transplantation versus consolidation chemotherapy.

In a prospective controlled trial, the relative effectiveness of allogeneic bone marrow transplantation and postremission chemotherapy was assessed for adult patients with acute myelogenous leukemia in first complete remission. Twenty-three patients, 15 to 45 years of age, who had an HLA-identical sibling donor were designated to receive bone marrow transplantation. Forty-four patients who either lacked an HLA-identical sibling or were over 45 years of age were designated to receive intensive consolidation chemotherapy. The actuarial rate of leukemia relapse was significantly lower in the transplantation group than in the chemotherapy group (40 +/- 25% [95% confidence interval] compared with 71 +/- 14%, p = 0.01). Actuarial survival at greater than 4 years was not significantly different (40 +/- 21% compared with 27 +/- 14%, p greater than 0.4). These data show that bone marrow transplantation is more effective than consolidation chemotherapy in preventing leukemia relapse, but overall survival was not improved in this study.

Comparison between bone marrow transplantation and antithymocyte globulin in treatment of young patients with severe aplastic anemia

Fifty-seven patients younger than 25 years with severe aplastic anemia underwent either bone marrow transplantation or antithymocyte globulin therapy (ATG) to ascertain which approach should be used in young patients. Thirty-five patients who had an HLA-identical sibling donor underwent bone marrow transplantation after conditioning with cyclophosphamide and low-dose total-body radiation. Twenty-two patients who did not have an HLA-identical donor received ATG. The 2-year actuarial survival of patients after transplant is 72% (95%, CI 64% to 80%), versus 45% (95%, CI 29% to 61%) in those given ATG therapy (P = 0.18). In those patients surviving 6 months after treatment, return of peripheral blood counts to normal values was more common in patients who received marrow transplant compared with those given ATG therapy (P less than 0.001). Furthermore, 24 of 26 transplant survivors had Karnofsky performance scores greater than 90%, compared with only five of 13 ATG survivors. These data suggest that bone marrow transplantation is the preferred therapy for severe aplastic anemia in young patients who have an HLA-identical sibling donor. ATG should be reversed for those young patients with severe aplastic anemia who do not have a histocompatible marrow donor.

Delayed surgery and bone marrow transplantation for widespread neuroblastoma.

From 1983 to 1986, 21 patients with poor prognosis neuroblastoma were treated with bone marrow transplantation. This regimen included induction chemotherapy, delayed surgical resection, local irradiation, and intensive chemoradiotherapy followed by infusion of allogeneic or autologous marrow. This therapeutic approach resulted in a 57% long-term survival rate (follow-up: 14–48 months), which appears to be approximately three times superior to conventional chemotherapy in a comparable group of children. In addition, complete resection was possible in 11 of 17 patients operated on after induction therapy. Recurrence in the primary site after bone marrow transplantation occurred in only one of 18 evaluable patients. Thus, this approach almost always eradicates primary tumor in patients with neuroblastoma with advanced disease.

Plasma inhibition of lymphocyte proliferation in nephrotic syndrome: correlation with hyperlipidemia.

Plasma-mediated inhibition of normal lymphoproliferation is an unexplained immunologic abnormality frequently observed in nephrotic syndrome. Since hyperlipidemia, also common in nephrotic syndrome, has been linked within vitro andin vivo immunodeficiency in other diseases, we have quantitated plasma-mediated inhibition of lymphoproliferation and related it to the degree of hyperlipidemia in 19 patients with nephrotic syndrome. Fifteen patients were hyperlipidemic; the plasma of 9 of these 15 caused >60% inhibition of antigen-specific proliferative responses of normal lymphocytes. None of the four normolipidemic plasmas, nor a hyperlipidemic plasma depleted of lipoproteins by ultracentrifugation, was inhibitory. A highly significant correlation between the degree of inhibition and the plasma triglyceride levels in patients with nephrotic syndrome was observed (P<0.001). The results suggest that elevated plasma lipids may be the cause of the plasma-mediated inhibition of lymphoproliferation in nephrotic syndrome.

Occurrence of neuroblastoma and asymmetric crying facies." Case report and review of the literature

responsible for thromboembolic phenomena in SLE. Histologic studies of patients with lupus with extremity, intestinal, or hepatic venous thrombosis have revealed an underlying endophlebitis, presumably mediated by immune complex deposition. 9-~ Specific antiendothelial cell antibodies have recently been discovered in patients with lupus2 ~ We believe that immune-mediated venulitis may be responsible for the cerebral venous sinus thrombosis in our patient. The treatment of this patient posed many questions. We elected not to use anticoagulation because of fear of a hemorrhagic intracerebral infarction. Ligation of the thrombosed internal jugular vein was another option considered to prevent intracardiac extension and subsequent pulmonary embolization. However, because pulmonary embolization is a rare complication of internal jugular vein thrombosis, the surgical literature recommends a conservative approach. ~2 Additionally, although ligation may prevent embolization, it compounds the problem of increased intracranial pressure. We decided that ligation of the internal jugular vein in our patient would be done only if pulmonary embolism developed. We elected conservative management with steroids and serial lumbar punctures. When these measures failed and concern for visual loss heightened, lumboperitoneal shunting was performed to provide permanent relief from increased intracranial pressure. In the past, it has been speculated that certain cases of pseudotumor cerebri may have been caused by unrecognized cerebral dural venous sinus obstruction. 6 This case demonstrates that internal jugular vein thrombosis may be a previously unsuspected accompaniment of these events.

Bone Marrow Transplantation for Children with Cancer

Bone marrow transplantation is a new, effective method for producing long-term disease-free survival in some cancer patients whose disease cannot be controlled by conventional treatments. The procedure is arduous and costly. The major problems which limit the usefulness of bone marrow transplantation are the effectiveness with which malignant disease can be eradicated and the control of graft-vs-host disease. As approaches to these problems are developed, it is likely that bone marrow transplantation will be more widely employed in the treatment of children with cancer. Careful followup of patients will be necessary in order to define the long-term effects of bone marrow transplantation, particularly as they are expressed in disorders of growth, development, learning, and psychosocial adaptation.

FOUR DRUG CHEMOTHERAPY, TOTAL BODY IRRADIATION |[lpar]|TBI|[rpar]| AND ALLOGENEIC OR AUTOLOGOUS BONE MARROW TRANSPLANTATION |[lpar]|EMT|[rpar]| FOR METASTATIC NEUROBLASTOMA

Intensive chemotherapy, TBI, and BMT may improve the outcome for children with metastatic neuroblastoma (August, et al, 1982). We are testing a new four drug chemotherapy and TBI pretransplant regimen for its toxicity and efficacy. Five patients received cis-platinum, VM26, doxorubicin, melphalan, and TBI (VAMP-TBI); and 3 received melphalan and TBI (M-TBI) because they could not tolerate the other agents or because their tumor was judged resistent. Allogeneic (allo) marrow was given to 5 and autologous (auto) marrow to 3 patients. They were 1 1/2 to 7 yrs old when transplanted (median 5 yrs) and were transplanted 5-13 mos after diagnosis (median 10 mos). Auto marrow had no neuroblastoma cells by immunoperoxidase staining for neuron specific enolase and cell surface antigens, which detects 1 tumor cell/105 normal cells. The most consistent acute toxicity from VAMP-TBI was severe mucositis, vomiting, and diarrhea; M-TBI also caused these complications but to a lesser extent. One acute toxic death occurred with each regimen. Of the 5 patients receiving VAMP-TBI, 3 have no evidence of disease (NED) at 60 (auto), 195 (allo), and 317 (allo) days; and 1 (auto) is 7 days post transplantation. One of 3 receiving M-TBI is NED at 45 days (auto), and another has progressive disease at 189 days (allo). We conclude that VAMP-TBI is a tolerable conditioning regimen. The survival of 3 of 4 evaluable patients receiving VAMP-TBI with NED suggests that this regimen should continue to be investigated.

941 PLASMA INHIBITION OF LYMPHOCYTE BLASTOGENESIS IN NEPHROTIC SYNDROME: CORRELATION WITH HYPERLIPIDEMIA

The plasma of patients with Nephrotic Syndrome suppresses in vitro lymphocyte blastogenesis, but the mechanism of this effect has not been defined. The frequent association of Nephrotic Syndrome with hypertriglyceridemia, and previous studies which demonstrate an immunoregulatory effect of lipids and lipoproteins, suggested the hypothesis that the immunosuppressive effect of Nephrotic Syndrome plasma was correlated with the hypertriglyceridemia. Plasma was obtained from 8 patients with Nephrotic Syndrome and tested for its effects on lymphocyte blastogenenic responses of normal peripheral blood lymphocytes. Triglyceride and cholesterol levels were also determined. The plasma of 5 Nephrotic Syndrome patients caused >90% suppression of normal lymphocyte blastogenesis to concanavalin A and SKSD. Furthermore, the degree of inhibition of lymphocyte blastogenesis was correlated with the severity of hypertriglyceridemia in all 8 patients (for concanavalin A, r=.905, p<.01; for SKSD, r=.775, p<.05).These results suggest that the in vitro plasma mediated immunosuppression in Nephrotic Syndrome may be due to the associated hypertriglyceridemia. Studies to further characterize the nature of plasma mediated in vitro immunosuppression in Nephrotic Syndrome are in progress.