David Emanuel

BACKGROUND: Lymphoma associated with Epstein-Barr virus (EBV) is a complication of bone marrow transplantation that responds poorly to standard forms of therapy. The lymphoma is usually of donor origin. We hypothesized that treatment with infusions of donor leukocytes, which contain cytotoxic T cells presensitized to EBV, might be an effective treatment. METHODS: We studied five patients in whom EBV-associated lymphoproliferative disorders developed after they received a T-cell-depleted allogeneic bone marrow transplant. Biopsy specimens were immunophenotyped, subjected to the polymerase chain reaction to determine the origin of the lymphoma (donor or host) and to detect the presence of EBV, and analyzed by Southern blotting for the presence of the clonal EBV genome and immunoglobulin-gene rearrangement. Patients were treated with infusions of unirradiated donor leukocytes at doses calculated to provide approximately 1.0 x 10(6) CD3+ T cells per kilogram of body weight. RESULTS: Histopathological examination of biopsy specimens from all five patients demonstrated monomorphic, malignant lymphomas of B-cell origin. Each of the four specimens that could be evaluated was of donor-cell origin. Evidence of clonality was found in two of the three samples adequate for study. EBV DNA was detected by the polymerase chain reaction in all five samples. In all five patients there were complete pathological or clinical responses. The responses were first documented histologically within 8 to 21 days after infusion. Clinical remissions were achieved within 14 to 30 days after the infusions and were sustained without further therapy in the three surviving patients for 10, 16, and 16 months. CONCLUSIONS: In a small number of patients, infusions of unirradiated donor leukocytes were an effective treatment for EBV-associated lymphoproliferative disease that arose after allogeneic bone marrow transplantation.

STUDY OBJECTIVE: To assess the efficacy of the combination of the antiviral agent ganciclovir (9-1,3 dihydroxy-2-propoxymethylguanine) and high-dose intravenous immune globulin for treating cytomegalovirus interstitial pneumonitis after allogeneic bone marrow transplantation. DESIGN: Nonrandomized prospective trial of combined treatment with two drugs; findings in these patients were compared with those in control patients treated with either of the two drugs alone. SETTING: Medical, pediatric, and intensive care units of a tertiary-care cancer treatment center. PATIENTS: Consecutive cases of 10 patients in the study group and of 11 patients in a historical control group with evidence of cytomegalovirus pneumonia after bone marrow transplantation for treatment of leukemia or congenital immune deficiency. INTERVENTIONS: Study Group (10 patients): ganciclovir, 2.5 mg/kg body weight, three times daily for 20 days, plus intravenous immune globulin, 500 mg/kg every other day for ten doses. Patients were then given ganciclovir, 5 mg/kg.d three to five times a week for 20 more doses, and intravenous immune globulin, 500 mg/kg twice a week for 8 more doses. Control Group (11 patients): ganciclovir alone (2 patients), 5 mg/kg twice a day for 14 to 21 days; cytomegalovirus hyperimmune globulin (5 patients), 400 mg/kg.d for 10 days; and intravenous immune globulin (4 patients), 400 mg/kg.d for 10 days. MEASUREMENTS AND MAIN RESULTS: Responses were observed in all patients treated with combination therapy; 7 of 10 patients were alive and well, and had no recurrence of disease at a median of 10 months after therapy. No therapeutic benefit was observed, and none of the 11 patients treated with either ganciclovir or intravenous immune globulin alone survived (P = 0.001 by Fisher exact test). CONCLUSIONS: Ganciclovir, when combined with high-dose intravenous immune globulin, appears to have significantly altered the outcome of patients with cytomegalovirus pneumonia after allogeneic bone marrow transplantation.

Ninety-seven children with either acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML) received HLA-identical bone marrow transplants from sibling donors, after preparation with 1320 cGy of hyperfractionated total-body irradiation and high-dose cyclophosphamide. Kaplan-Meier product-limit estimates (means +/- SE) of disease-free survival at five years among patients with ALL in second remission, third remission, and fourth remission or relapse were 64 +/- 9, 42 +/- 14, and 23 +/- 11 percent, respectively, with probabilities of relapse of 13 +/- 7, 25 +/- 13, and 64 +/- 16 percent. Among patients with AML in first remission, second remission, and third remission or relapse, five-year disease-free survival estimates were 66 +/- 10, 75 +/- 15, and 33 +/- 19 percent, with respective relapse probabilities of 0, 13 +/- 12, and 67 +/- 19 percent. The most frequent cause of death in patients in early remission (ALL in second or third remission or AML in first or second remission) was bacterial sepsis, fungal sepsis, or both, most often in the presence of acute or chronic graft-versus-host disease. Among patients with ALL who received transplants while in second remission, the duration of the initial remission had no effect on the probability of relapse after transplantation. The only pretransplantation factor that significantly affected outcome was the disease status at the time of transplantation; patients in early remission had better disease-free survival. We conclude that transplantation after preparation with hyperfractionated total-body irradiation and cyclophosphamide is an effective mode of therapy in children with refractory forms of acute leukemia.

Unrelated cord blood (UCB) is being used as a source of alternative hematopoietic stem cells for transplantation with increasing frequency. From November 1994 to February 1999, 30 UCB transplant procedures were performed for both malignant and nonmalignant diseases in 27 children, aged 0.4 to 17.1 years. Patients received either HLA-matched (n = 3) or 1- or 2-antigen-mismatched (n = 27) UCB following 1 of 2 standardized preparative and graft-versus-host disease regimens (hyperfractionated total body irradiation, cyclophosphamide, and antithymocyte globulin [ATG] with cyclosporine A and methotrexate; or busulfan, melphalan, and ATG with cyclosporine A and prednisone). The median time to neutrophil and platelet engraftment was 27 days (12-60 days) and 75 days (33-158 days) posttransplantation, respectively. No correlation was noted between neutrophil and platelet engraftment and nucleated cells per kilogram, CD34(+) cells per kilogram infused, or cytomegalovirus status of recipient. The cumulative probability of acute grade 2 or greater graft-versus-host disease (GVHD) was 37.2%, and of grade 3 or greater GVHD was 8.8%. No patients developed chronic GVHD. CD4, CD19, and natural killer cell recovery was achieved at a median of 12, 6, and 2 months, respectively. CD8 recovery was delayed at a median of 9 months. Normal mitogen response was achieved at 6 to 9 months. The probability of survival, disease-free survival, and event-free survival at 1 year was 52.3% (34.1%-70.5%), 54.7% (34.5%-74.9 %) and 49.6% (29.9%-69.4%), respectively. This series of 30 UCB transplants suggests that although CD8 cell recovery is delayed, the pattern of immune reconstitution with UCB is similar to that reported for other stem cell sources. (Blood. 2000;96:2703-2711)

Bronchoalveolar lavage material from 54 immunocompromised patients with interstitial pneumonia was examined by immunofluorescence with cytomegalovirus-specific monoclonal antibodies. Twelve patients (22%) had cytomegalovirus detected in their lavaged cells, and 9 of these patients (17%) had proven cytomegalovirus pneumonitis. This assay detected all samples with cytomegalovirus when the virus was detected by established methods either at the time of lavage or after any other procedure in the subsequent 2 months; that is, it had a sensitivity of 100%. Cytomegalovirus could be detected within 3 hours of the lavage, and a clear correlation was seen between the number of fluorescent cells and the presence of cytomegalovirus pneumonia. All 9 patients with pneumonitis had more than 0.5% fluorescent cells, whereas the 3 patients in whom cytomegalovirus was detected without pneumonia had significantly fewer fluorescent cells. This method provides a sensitive, rapid, and quantifiable system for detection of cytomegalovirus, facilitating the early diagnosis and treatment of cytomegalovirus pneumonia.