No abstract

Fifty-one patients with acute nonlymphocytic leukemia (16 with end-stage disease, 17 in second or third remission or in early relapse, and 18 in first remission) were given infusions of HLA-identical sibling marrow after cytoreduction with high doses of busulfan and cyclophosphamide. Actuarial two-year survival rates were 0 per cent, 29 per cent, and 44 per cent, respectively. Twelve patients are still alive and in remission after 327 to 1488 days, with 10 surviving beyond two years. Acute graft-versus-host disease and viral pneumonia were the major causes of death. Leukemic cells failed to clear in one patient with end-stage disease, and a relapse with meningeal leukemia occurred in another. Only one other relapse was seen--in a patient given a transplant during a third remission. Survival was favorably affected by younger age and transplantation during first remission. We conclude that high-dose chemotherapy with busulfan and cyclophosphamide, followed by allogeneic-marrow transplantation, can produce long-term remission of acute leukemia. Chemotherapy with high-dose busulfan and cyclophosphamide before transplantation provides an effective alternative to cyclophosphamide and total-body irradiation before transplantation for the treatment of acute nonlymphocytic leukemia.

Fifty-three recipients of bone marrow transplants were monitored prospectively for urinary excretion of human polyomaviruses by enzyme-linked immunosorbent assays of urinary supernatants and DNA hybridization assays of urinary cells. Excretion of BK virus was demonstrated in 47 percent of the transplant recipients and was the result of the reactivation of latent virus. Hemorrhagic cystitis of long duration (greater than or equal to 7 days) was associated with BK viruria. The disease occurred four times more frequently in patients who excreted BK virus than in those who did not, and the virus was identified in 55 percent of the urine specimens during episodes of cystitis as compared with 8 to 11 percent of the specimens during cystitis-free periods. BK viruria often preceded or coincided with the onset of the disease. Among 19 patients with BK viruria lasting seven days or longer, hemorrhagic cystitis occurred in 15. Occurrence of the disease was related to the source of marrow. The disease occurred in 50 percent of 38 recipients of allogeneic marrow and in 7 percent of 15 recipients of syngeneic or autologous marrow. Among recipients of allogeneic marrow, the disease was observed in 71 percent of the 21 patients excreting BK virus and in 24 percent of the 17 not excreting the virus. An association of BK virus with hemorrhagic cystitis was demonstrated in 16 of the 18 cases of the disease that were adequately characterized. We conclude that reactivation of BK virus may account for a substantial proportion of late-onset, long-lasting hemorrhagic cystitis in recipients of bone marrow transplants.

Busulfan is an alkylating agent that is widely used in preparative regimens for bone marrow transplantation (BMT). We developed a high-performance liquid chromatographic (HPLC) assay for the determination of plasma busulfan concentrations in 30 patients who received oral doses of 1 mg/kg. Concentrations were fit by a one-compartment pharmacokinetic model with first-order absorption. The pattern of absorption and elimination varied widely between patients, with peak concentrations ranging from 1.2 to 10.4 mumol/l (mean, 4.25 +/- 2.49). The elimination half-life ranged from 58 to 433 min (harmonic mean, 140 min). The AUC contributed by a single oral dose ranged from 606 to 5,144 mumol-min/l (mean, 2,012 +/- 1,223). Patients were evaluated for the development of veno-occlusive disease (VOD), a treatment complication that occurs in 20% of patients undergoing BMT and causes 10% of transplantation-related deaths. All six patients who developed VOD had an AUC greater than the mean, and five of them had an AUC that was greater than 1 SD above the mean. The occurrence of VOD was highly correlated with an increased AUC (greater than 1 SD above the mean) (X2 = 18; P less than 0.0001). Using multivariate logistic regression, no other statistically significant pharmacokinetic predictor of VOD was found. The tenfold variability in the busulfan AUC and the statistical association of increased AUC with the development of VOD suggest a possible role for therapeutic monitoring in this setting.

In this preliminary trial, thalidomide appeared to be safe and effective for the treatment of chronic GVHD. A trial comparing thalidomide with prednisone in patients with newly diagnosed chronic GVHD will be required to demonstrate its relative efficacy.

A prospective randomized trial of therapy for severe aplastic anemia was designed to compare early bone marrow transplantation with conventional treatments. All patients with a sibling matched at the major histocompatibility region were transplanted. Transplantation was performed with 17–100 (median 33) days of original diagnosis. Conventional treatments included transfusion support with or without androgens. Twenty-four of 36 patients intered on the transplant arm are alive after 4–20 (median 9) mo with full marrow reconstitution. Only two are limited by chronic graft-versus-host disease. In contrast only 12 of 31 conventionally treated patients are alive. Six of these survivors have improved, five incompletely. The 19 nontransplant deaths have occurred within 1–11 (median 3) mo of diagnosis. Compared to nontransplant regimens, early transplantation more effectively restores normal marrow function and decreases the acute mortality of severe marrow aplasia (p = 0.006). Pending longer follow-up, early marrow transplantation appears to be the most effective available treatment for severe aplastic anemia.

No abstract

Cyclosporin A (CsA) ~ is a potent reversible immunosuppressive agent which is able to suppress allograft rejection and acute allogeneic graft-versus-host disease (GVHD) (1-7). Although CsA dramatically improves survival after allogeneic marrow transplantation, rats treated with a short course of CsA develop delayed onset GVHD after CsA withdrawal. This paper presents new evidence which indicates that GVHD may develop upon CsA withdrawal following not only allogeneic but also syngeneic and even autologous bone marrow reconstitution. Materials and MethodsRats. Lewis female RT1 ~ rats, 6-8 wk old, were purchased from Harlan Sprague Dawley, Inc., Indianapolis, IN.Radiation. Lewis rats were irradiated on day -1 (1,020 rad) at 120 rad/min from a dual source Cs ~3~ small animal irradiator (Atomic Energy of Canada Ltd., Ottawa, Ontario). Leg-shielded rats were then anesthetized with chloral hydrate, their right tibias shielded with a lead doughnut 1.5 cm thick and 2.5 cm long, and irradiated with 1,020 rad.Marrow Transplantation. Donor marrow from tibias, femurs, and humeri was sus-7 pended at 6 × 10 nucleated cells/ml in Hanks' solution supplemented with 50 U/ml penicillin and 50 ng/ml streptomycin. On day 0 rats received 1 ml via the tail vein.Antibiotics. Rats received medicated drinking water supplemented with bactrim, neomycin, and polymyxin B and were given 2.5 mg/kg gentamycin per day subcutaneously for 20 d. Rats that developed overt clinical infections were routinely sacrificed and excluded from the study.Cyclosporin A. CsA was the generous gift of Sandoz, Inc., Hanover, NJ. Emulphor EL-620 was obtained from GAF Corp., New York. Powdered CsA was dissolved in absolute ethanol, added to emulphor, and mixed with water to yield a final emulphor concentration of 5%. Rats were weighed daily and received 1 ml/100 g body weight per day subcutaneously from day 0 to 40 or as indicated.Assessment of GVHD. Rats were examined daily for signs of clinical GVHD such as red ears, dermatitis, or diarrhea. Skin biopsies were taken at frequent intervals. When rats developed severe clinical GVHD characterized by weight loss, hunched appearance, and extensive dermatitis they were sacrificed and autopsied. Previously described criteria were