Bone Marrow Transplantation For Hematologic Malignancies Research Articles

Effect of body mass in children with hematologic malignancies undergoing allogeneic bone marrow transplantation

AbstractThe rising incidence of pediatric obesity may significantly affect bone marrow transplantation (BMT) outcomes. We analyzed outcomes in 3687 children worldwide who received cyclophosphamide-based BMT regimens for leukemias between 1990 and 2007. Recipients were classified according to age-adjusted body mass index (BMI) percentiles as underweight (UW), at risk of UW (RUW), normal, overweight (OW), or obese (OB). Median age and race were similar in all groups. Sixty-one percent of OB children were from the United States/Canada. Three-year relapse-free and overall survival ranged from 48% to 52% (P = .54) and 55% to 58% (P = .81) across BMI groups. Three-year leukemia relapses were 33%, 33%, 29%, 25%, and 21% in the UW, RUW, normal, OW, and OB groups, respectively (P < .001). Corresponding cumulative incidences for transplant-related mortality (TRM) were 18%, 19%, 21%, 22%, and 28% (P < .01). Multivariate analysis demonstrated a decreased risk of relapse compared with normal BMI (relative risk [RR] = 0.73; P < .01) and a trend toward higher TRM (RR = 1.28; P = .014). BMI in children is not significantly associated with different survival after BMT for hematologic malignancies. Obese children experience less relapse posttransplant compared with children with normal BMI; however, this benefit is offset by excess in TRM.

Primary human keratinocytes as targets in predicting acute graft-versus-host disease following HLA-identical bone marrow transplantation

Graft-versus-host-disease (GVHD) remains a major problem following allogeneic bone marrow transplantation (BMT) and manifests itself mainly by damage to epithelial cells of the skin, gut and bile ducts. Reliable tests to predict GVHD are lacking. We developed an assay in which donor T cells are stimulated by patient keratinocytes (KCs), compared that with stimulation by patient peripheral blood mononuclear cells (PBMCs) and studied the relationship to GVHD. In 27 patients undergoing HLA-identical BMT for haematological malignancies, donor T-cell reactivity was determined as the helper T-lymphocyte precursor (HTLp) frequency against host PBMCs (25 patient-donor pairs) and host KCs (20 patient-donor pairs). KCs were obtained by shave biopsies and cultured with interferon (IFN)-gamma to induce HLA class II expression. In assays using patient KCs and donor T cells, anti-CD28 antibody was added to compensate for the lack of co-stimulatory molecules on KCs. Results were related to the occurrence of GVHD. As BMTs were performed with partially T cell-depleted grafts, GVHD was limited to grade 0 (five patients), grade I (seven patients) and grade II (12 patients). No differences were found in donor T-cell reactivity to patient PBMCs, as expressed as HTLp frequency in patients with or without GVHD. However, significant differences (P < 0.01) were found in donor T-cell reactivity to patient KCs when comparing patients with and without GVHD. Donor HTLp frequencies against patient KCs give a better prediction of GVHD than those against patient haemopoietic cells following HLA-identical BMT, which may indicate that at least some minor non-HLA histocompatibility antigens present on KCs are different from those on haemopoietic cells.

Use of Recombinant Human Interleukin-2 in Conjunction With Syngeneic Bone Marrow Transplantation in Mice as a Model for Control of Minimal Residual Disease in Malignant Hematologic Disorders

AbstractUnlike allogeneic bone marrow transplantation (BMT), autologous BMT is not accompanied by immune-mediated graft- versus-leukemia (GVL) effects; hence, the relapse rate observed after autologous BMT in malignant hematologic disorders is higher than that observed after allogeneic BMT. Autologous BMT represents a much safer medical procedure available for many patients in need in situations where allogeneic BMT is not feasible or risky. The present experiments were designed to investigate whether it might be possible to combine the therapeutic benefits of autologous BMT with additional immunotherapy after BMT. The tumor model used for investigating GVL effects was the murine B-cell leukemia (BCL1), a spontaneous, nonimmunogenic, highly lethal leukemia of BALB/c origin. BALB/c mice inoculated with 103 BCL1 leukemia cells were treated on day -1 with cyclophosphamide 100 mg/kg and transplanted with normal syngeneic BM cells on day 0. High-dose recombinant interleukin-2 (rlL-2) (100,000 Cetus units × 3/day intraperitoneally × 5 consecutive days) was initiated on day +1, +7, or +21 after BMT. Kinetics of lymphocyte reconstitution after syngeneic BMT indicated a steep increase in the absolute number of peripheral blood lymphocytes on days 17 through 24. All experimental groups were observed for relapse. Mice receiving no rlL-2 therapy relapsed and died within 50 days after BMT, whereas mice receiving rlL-2 showed long-term disease-free survival. Optimal time for administration of rlL-2 was noted at 3 weeks post-BMT, with 90% of the mice surviving with no evidence of disease for more than 1 year. Similarly, when 104 BCL1 cells were given 1 day after syngeneic BMT to simulate minimal residual disease after syngeneic BMT, rlL-2 therapy administered at 14 days post- BMT seemed effective in prolonging disease-free survival in contrast to the same regimen given at 1 day after BMT. Our data suggest that immunotherapy with rlL-2 should be further investigated as a new immunotherapeutic tool for decreasing the relapse rate after BMT for hematologic malignancies.

Use of recombinant human interleukin-2 in conjunction with syngeneic bone marrow transplantation in mice as a model for control of minimal residual disease in malignant hematologic disorders

Unlike allogeneic bone marrow transplantation (BMT), autologous BMT is not accompanied by immune-mediated graft-versus-leukemia (GVL) effects; hence, the relapse rate observed after autologous BMT in malignant hematologic disorders is higher than that observed after allogeneic BMT. Autologous BMT represents a much safer medical procedure available for many patients in need in situations where allogeneic BMT is not feasible or risky. The present experiments were designed to investigate whether it might be possible to combine the therapeutic benefits of autologous BMT with additional immunotherapy after BMT. The tumor model used for investigating GVL effects was the murine B-cell leukemia (BCL1), a spontaneous, nonimmunogenic, highly lethal leukemia of BALB/c origin. BALB/c mice inoculated with 10(3) BCL1 leukemia cells were treated on day-1 with cyclophosphamide 100 mg/kg and transplanted with normal syngeneic BM cells on day 0. High-dose recombinant interleukin-2 (rIL-2) (100,000 Cetus units x 3/day intraperitoneally x 5 consecutive days) was initiated on day +1, +7, or +21 after BMT. Kinetics of lymphocyte reconstitution after syngeneic BMT indicated a steep increase in the absolute number of peripheral blood lymphocytes on days 17 through 24. All experimental groups were observed for relapse. Mice receiving no rIL-2 therapy relapsed and died within 50 days after BMT, whereas mice receiving rIL-2 showed long-term disease-free survival. Optimal time for administration of rIL-2 was noted at 3 weeks post-BMT, with 90% of the mice surviving with no evidence of disease for more than 1 year. Similarly, when 10(4) BCL1 cells were given 1 day after syngeneic BMT to simulate minimal residual disease after syngeneic BMT, rIL-2 therapy administered at 14 days post-BMT seemed effective in prolonging disease-free survival in contrast to the same regimen given at 1 day after BMT. Our data suggest that immunotherapy with rIL-2 should be further investigated as a new immunotherapeutic tool for decreasing the relapse rate after BMT for hematologic malignancies.