Thomas Ed

Reconstitution of Cellular Immunity against Cytomegalovirus in Recipients of Allogeneic Bone Marrow by Transfer of T-Cell Clones from the Donor

BACKGROUND Cytomegalovirus (CMV) disease in immunocompromised patients correlates with a deficiency of CD8+ cytotoxic T lymphocytes specific for CMV. We evaluated the safety and immunologic effects of immunotherapy with clones of these lymphocytes in recipients of allogeneic bone marrow transplants. METHODS Clones of CD8+ cytotoxic T cells specific for CMV proteins were isolated from the blood of bone marrow donors. Fourteen patients each received four intravenous infusions of these clones from their donors beginning 30 to 40 days after marrow transplantation. The reconstitution of cellular immunity against CMV was monitored before and during the period of infusions and for up to 12 weeks after the final infusion. The rearranged genes encoding the T-cell receptor served as markers in evaluating the persistence of the transferred T cells. RESULTS No toxic effects related to the infusions were observed. Cytotoxic T cells specific for CMV were reconstituted in all patients. In vitro measurements showed that cytotoxic activity against CMV was significantly increased (P < 0.001) after the infusions in 11 patients who were deficient in such activity before therapy. The level of activity achieved after the infusions was similar to that measured in the donors. Analysis of rearranged T-cell-receptor genes in T cells obtained from two recipients indicated that the transferred clones persisted for at least 12 weeks. Cytotoxic-T-cell activity declined in patients deficient in CD4+ T-helper cells specific for CMV, suggesting that helper-T-cell function is needed for the persistence of transferred CD8+ T cells. Neither CMV viremia nor CMV disease developed in any of the 14 patients. CONCLUSIONS The transfer of CMV-specific clones of CD8+ T cells derived from the bone marrow donor is a safe and effective way to reconstitute cellular immunity against CMV after allogeneic marrow transplantation.

Antileukemic Effect of Graft-versus-Host Disease in Human Recipients of Allogeneic-Marrow Grafts

To determine whether allogeneic bone-marrow transplantation is associated with a graft-versus-leukemia effect, we examined the relation between relapse of leukemia and graft-versus-host disease in 46 recipients of identical-twin (syngeneic) marrow, 117 recipients of HLA-identical-sibling (allogeneic) marrow with no or minimal graft-versus-host disease, and 79 recipients of allogeneic marrow with moderate to severe or chronic disease. The relative relapse rate was 2.5 times less in allogeneic-marrow recipients with graft-versus-host disease than in recipients without it (P less than 0.01). This apparent antileukemic effect was more marked in patients with lymphoblastic than nonlymphoblastic leukemia, and in those who received transplants during relapse rather than during remission, and was most evident during the first 130 days after transplantation. Survival of all patients was comparable since the lesser probability of recurrent leukemia in patients with graft-versus-host disease was offset by a greater probability of other causes of death.

Regimen-related toxicity in patients undergoing bone marrow transplantation.

Bone marrow transplantation is associated with significant morbidity and mortality, some of which is due to high-dose chemoradiotherapy. In order to quantitate toxicity that was felt to be due to the preparative regimen (termed regimen-related toxicity [RRT]), a system was developed in which toxicities were graded from 0 (none) to 4 (fatal). One hundred ninety-five patients who underwent marrow transplantation for leukemia were studied retrospectively to determine whether toxicities that were clinically felt to be due to the preparative regimen were influenced by other factors such as disease status, graft-versus-host disease (GVHD) prophylaxis, and allogenicity. All patients developed grade I toxicity in at least one organ, and 30 developed grades III-IV (life-threatening or fatal) RRT. RRT was more common in relapsed patients v remission patients (P = .04), in those receiving 15.75 Gy total body irradiation (TBI) v 12.0 Gy TBI (P = .028), and in those receiving allogeneic marrow v autologous marrow (P = .0029). Autologous marrow recipients did not develop grades III-IV toxicity in this study. A multivariate analysis controlling for autologous marrow grafting showed that the dose of TBI was the only statistically significant predictor of grades III-IV RRT. Those patients who developed grade III RRT were unlikely to survive 100 days from transplant, though not all deaths could be attributed to RRT. Patients who developed grade II toxicity in three or more organs were more likely to die within 100 days than those developing grade II toxicity in two or less organs (P = .0027). This system was generally able to distinguish RRT from other toxicities observed in marrow recipients.

Marrow transplantation for acute nonlymphoblastic leukemia in first remission.

MARROW transplantation provides the opportunity for aggressive antileukemic therapy without regard to marrow toxicity.1 We have reported the application of this approach combined with intensive che...

Marrow Transplantation for the Treatment of Chronic Myelogenous Leukemia

One hundred ninety-eight patients with chronic myelogenous leukemia received marrow transplants after intensive chemotherapy and total body irradiation. Multivariate analysis showed disease status at time of transplantation to be the most powerful predictor of survival. The probability of long-term survival for allogeneic graft recipients was 49% for 67 patients in the first chronic phase, 58% for 12 in the second chronic phase, 15% for 46 in the accelerated phase, and 14% for 42 in the blastic phase. The major cause of death was interstitial pneumonia for patients in the chronic phase, and relapse for those in the blastic or accelerated phases. Factors favoring survival were early transplantation, age less than 30 years, and absence of severe graft-versus-host disease. Splenectomy or spleen size did not influence survival. For recipients of syngeneic grafts survival probability was 87% for 16 patients in the chronic phase, 27% for 7 in the accelerated phase, and 12% for 8 in the blastic phase. Of the 198 patients, 71 are alive without Philadelphia chromosomes 1 to 9 years after receiving their graft. All but 4 long-term disease-free survivors have Karnofsky performance scores of 80% or better.

Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia

To determine the incidence of secondary cancers after bone marrow transplantation, we reviewed the records of all patients at our center who received allogeneic, syngeneic, or autologous transplants for leukemia (n = 1926) or aplastic anemia (n = 320). Thirty-five patients were given a diagnosis of secondary cancer between 1.5 months and 13.9 years (median, 1.0 year) after transplantation. Sixteen patients had non-Hodgkins lymphomas, 6 had leukemias, and 13 had solid tumors (including 3 each with glioblastoma, melanoma, and squamous-cell carcinoma). There were 1.2 secondary cancers per 100 exposure-years during the first year after transplantation (95 percent confidence interval, 0.7 to 2.0). The rate declined to 0.4 (95 percent confidence interval, 0.2 to 0.7) after one year. The age-adjusted incidence of secondary cancer was 6.69 times higher than that of primary cancer in the general population. In a multivariate model, the predictors (and relative risks) of any type of secondary cancer were acute graft-versus-host disease treated with either antithymocyte globulin (relative risk, 4.2) or an anti-CD3 monoclonal antibody (13.6) and total-body irradiation (3.9). Two additional factors were associated with secondary non-Hodgkins lymphomas: T-lymphocyte depletion of donor marrow (12.4) and HLA mismatch (3.8). We conclude that recipients of bone marrow transplantation have a low but significant risk of a secondary cancer, particularly non-Hodgkins lymphoma.

Granulocyte Transfusions for the Prevention of Infection in Patients Receiving Bone-Marrow Transplants

Prophylaxis by granulocyte transfusions against infection associated with granulocytopenia was studied in 69 patients receiving bone-marrow transplants for the therapy of hematologic neoplasia or aplastic anemia. Patients were randomized to receive or not to receive granulocyte transfusions when their circulating granulocyte levels fell to less than 200 per cubic millimeter during the period between transplantation and the development of graft function. During the first 21 posttransplant days, there were two local infections and no septicemias in 29 transfused patients. Seven local infections and 10 septicemias developed among the 40 controls. This protection was afforded by granulocytes collected by reversible leukoadhesion as well as by cells collected by continuous-flow centrifugation.

Regimen-related toxicity and early posttransplant survival in patients undergoing marrow transplantation for lymphoma.

Ninety-five patients transplanted for malignant lymphoma were retrospectively evaluated for regimen-related toxicity (RRT) and early posttransplant survival. Nineteen patients developed life-threatening (grade 3) or fatal (grade 4) RRT in one or more organs. Grade 3 or 4 RRT was more common in patients with advanced disease versus those transplanted earlier in their course (P = .008), and was more common in patients with advanced disease conditioned with cytarabine (Ara-C)/total body irradiation (TBI) versus those prepared with cyclophosphamide (CY)/TBI (P = .033). There was no significant difference in the incidence of grade 3 or 4 toxicity in autologous, histocompatibility locus antigen (HLA)-identical, or HLA-mismatched marrow recipients. Grade 3 or 4 RRT tended to be more common and 100-day survival worse in patients with a Karnofsky performance status of less than 90 (P = .063 and .0002, respectively). Patients receiving 20 Gy or more of mediastinal irradiation before coming to transplant had more idiopathic or cytomegalovirus (CMV) interstitial pneumonitis than those who received less than 20 Gy (30% v 9%, P = .027). The probability of survival decreased with the number of organs in which toxicity was observed (P = .0001). Severe or fatal toxicities directly related to the preparative regimen are a significant problem in the treatment of patients with advanced malignant lymphoma and can be reduced by carrying out transplantation earlier in the course of the disease.

Prophylactic use of human leukocyte interferon after allogeneic marrow transplantation

STUDY OBJECTIVE To determine the efficacy of prophylactic interferon for prevention of cytomegalovirus infection and relapse of leukemia after allogeneic marrow transplantation. DESIGN Randomized trial with intermittent interferon administration to day 80 after transplantation. SETTING Marrow transplantation units of a cancer research center. PATIENTS Consecutive patients with acute lymphocytic leukemia in remission at the time of transplantation. Thirty-nine patients received interferon, and 40 were control patients. INTERVENTIONS Partially purified human leukocyte interferon given every 3 days beginning after marrow engraftment and continuing to day 80 after transplantation. After initial safety testing, the starting and minimum dose was 6 X 10(4) units/kg of body weight, with dose escalations determined by the circulating neutrophil count. Transplant conditioning and post-transplantation prophylaxis of graft-versus-host disease with methotrexate followed standard procedures. MEASUREMENTS AND MAIN RESULTS No difference was observed in the probability or severity of cytomegalovirus infection or in the probability or severity of graft-versus-host disease. Relapse of leukemia occurred in 9 interferon recipients and 21 control patients, with a minimum follow-up of 4 years among surviving patients. The probability of relapse among all interferon recipients was 0.36 (95% confidence interval [Cl], 0.56 to 0.17) and among all control patients was 0.74 (95% Cl, 0.91 to 0.58) (p = 0.04 by log-rank test). Among patients who received transplants in first or second remission, the probability of relapse among interferon recipients was 0.19 (95% Cl, 0.37 to 0.02) compared with 0.71 (95% Cl, 0.97 to 0.51) among control patients (p = 0.008 by log-rank test). Survival rates did not differ between interferon recipients and control patients. Transient decreases in leukocyte count and anorexia and nausea occurred among interferon recipients. Six interferon recipients, all of whom had received chemoradiotherapy of the central nervous system before transplantation, developed leukoencephalopathy after transplantation. CONCLUSIONS These data suggest that interferon given after transplantation reduces the risk for subsequent relapse of leukemia. The effect of longer administration and of administration in patients with other underlying diseases will require additional trials. No effect was observed on cytomegalovirus infection, either because interferon was not initiated until a median of 18 days after transplantation or because of a lesser effect among marrow allograft recipients.

Profound hypomagnesemia and renal magnesium wasting associated with the use of cyclosporine for marrow transplantation

We prospectively studied 41 marrow transplant patients to evaluate the possible association of hypomagnesemia with cyclosporine immunosuppressive therapy. During the 3 months posttransplant the mean nadir serum magnesium level was 1.06±0.16 mEq/L in 24 patients treated with cyclosporine and 1.33±0.13 in 14 patients treated with methotrexate (P<0.0001). Eleven of 24 patients receiving cyclosporine versus 1 of 14 patients receiving methotrexate had magnesium levels <1 mEq/L, or were begun on replacement therapy for presumed symptomatic hypomagnesemia (P<0.02). Agents known to be associated with hypomagnesemia, aminoglycosides and amphotericin B, were given in both lesser quantity and frequency to cyclosporine-treated patients than to methotrexate-treated patients. Hypomagnesemic patients treated with cyclosporine had inappropriately elevated urine magnesium excretion. Renal magnesium wasting may be added to the spectrum of nephrotoxicity resulting from cyclosporine. Several adverse reactions previously attributed to cyclosporine may be secondary to magnesium deficiency.