Search

Background: Successful allogeneic bone marrow transplantation relies on global immunosuppression or elimination of T cells. In contrast, the induction of anergy can inactivate specific sets of alloreactive T cells in the donor marrow. Previous work has shown that anergy can be induced by blocking the interaction of the B7 molecule on the surface of antigen-presenting cells with the CD28 molecule on the surface of T cells, thus preventing key signaling events essential for the activation of T cells. To investigate the feasibility of this approach with respect to transplantation of histoincompatible bone marrow, we undertook a clinical trial of ex vivo induction of anergy in T cells present in donor marrow to recipient alloantigens., Methods: Outcomes in 12 transplant recipients were evaluated. The recipients' peripheral-blood lymphocytes were collected before myeloablation and served as alloantigen-presenting cells. To induce alloantigen-specific anergy, bone marrow from a donor mismatched with the recipient for one HLA haplotype was cocultured with irradiated cells from the recipient for 36 hours in the presence of CTLA-4-Ig, an agent that inhibits B7:CD28-mediated costimulation. After conventional myeloablation and immunoprophylaxis, the treated donor cells were transfused into the recipient., Results: After the induction of anergy, the frequency of T cells capable of recognizing alloantigens of the recipient in donor marrow was sharply reduced (P<0.001), whereas the responsiveness to alloantigens from persons unrelated to the recipient or the donor was unaffected (P=0.51). In the 11 patients who could be evaluated, the haploidentical bone marrow cells engrafted. Of these 11 patients, 3 had acute graft-versus-host disease (GVHD) confined to the gastrointestinal tract. No deaths were attributable to GVHD. Five of the 12 patients were alive and in remission 4.5 to 29 months after transplantation., Conclusions: Donor bone marrow treated ex vivo to induce anergy to alloantigens from the recipient can reconstitute hematopoiesis in vivo with a relatively low risk of GVHD.

Antibody concentrations to vaccine-preventable diseases decline following BMT and an optimal schedule for vaccination after transplant has not been established. We examined antibody responses to tetanus toxoid (TT) and Haemophilus influenzae type b-conjugate (HIB) vaccines of BMT patients immunized at 6, 12 and 24 months (6 month group, n = 21) and compared them to those previously reported for patients immunized at 3, 6, 12 and 24 months (3 month group, n = 74) or at 12 and 24 months (12 month group, n = 17) following transplantation. Geometric mean total anti-HIB and IgG anti-TT concentrations were significantly higher after the 12 month dose in the 3 and 6 month immunization groups compared to the group who received their first dose at 12 months. Although HIB antibody concentrations were higher in the 3 month and 6 month groups 12 to 24 months after BMT, the proportion of patients with protective levels was not significantly different from the proportion protected in the 12 month group. Following the 24 month immunizations, geometric mean antibody concentrations to HIB and TT were similar for all three immunization groups. The proportion of patients in each group with protective levels of HIB antibody after the 24 month dose was > or = 80%. A two dose schedule of HIB and TT vaccines at 12 and 24 months after BMT should afford protection.

Therapy-related myelodysplasia (MDS) is a fatal marrow disorder distinct from primary MDS. We examined the efficacy of bone marrow transplantation (BMT) as a treatment for patients with therapy-related MDS. Eighteen patients with therapy-related MDS and twenty-five patients with primary MDS received an allogeneic, syngeneic, or unrelated donor BMT. Graft-versus-host disease prophylaxis included methotrexate, methotrexate plus cyclosporine, FK-506, or T cell depletion. Conditioning regimens consisted of cyclophosphamide/total body irradiation, with and without cytosine arabinoside, busulfan/cyclophosphamide, and cyclophosphamide/etoposide/carmustine. For patients with therapy-related MDS, the median age was 32 years and the actuarial disease-free survival was 24% (95% confidence interval 6, 42%) with a median follow-up of 3 years. For patients with primary MDS, the median age was 36 years and the actuarial disease-free survival at 3 years was 43% (95% confidence interval 22, 64%). Four of the therapy-related patients and two of the primary patients have relapsed. Three patients experienced graft failure; all three had received T cell-depleted marrow and two had marrow fibrosis. Our results suggest that patients with therapy-related MDS can be successfully transplanted. Transplantation should be considered early in the disease, since long-term disease-free survival is achievable.

Objective: To evaluate, in a pilot study, the use and efficacy of a gonadotropin-releasing hormone (GnRH)-agonist in inducing amenorrhea in women undergoing BMT., Study Design: We evaluated the use of the GnRH agonist leuprolide acetate (LA) for the induction of amenorrhea in 10 postmenarcheal women prior to BMT. If there was a contraindication to the use of the intramuscular (i.m.) formulation of LA, the subcutaneous (s.c.) formulation was given as a daily intravenous (i.v.) bolus. Once the subject's platelet count was > 50,000/microL, the LA was discontinued. Menstrual bleeding, time from initiation of therapy to amenorrhea, and liver function test results were monitored., Results: All subjects had induction of amenorrhea with the use of LA except for one subject with a large, myomatous uterus, who experienced light spotting. One subject who was thrombocytopenic at the prescribed time of the second dosage of i.m. LA received i.v. LA with documentation of continued pituitary/gonadal suppression. No adverse effects were determined to be directly related to either the i.m. or i.v. LA., Conclusion: LA is an option for the induction of amenorrhea in postmenarcheal women undergoing BMT. In thrombocytopenic subjects, administration of the s.c. formulation of LA by an i.v. route served as an alternative to i.m. injection and was documented to maintain gonadotropin suppression.

Severe aplastic anemia (SAA) is a frequent complication of orthotopic liver transplantation for non-typeable viral hepatitis. Allogeneic bone marrow transplantation (BMT) may successfully reconstitute hematopoiesis but the optimal conditioning regimen and graft-versus-host disease (GVHD) prophylaxis in such patients are unknown. Allogeneic BMT was undertaken in an 8-year-old male patient who developed SAA 6 weeks after cadaveric orthotopic liver transplantation for fulminant hepatic failure secondary to presumed non-typeable viral hepatitis. The preparative regimen for his HLA genotypically identical sibling BMT consisted of cytoxan and anti-thymocyte globulin. Tacrolimus (FK506) and prednisone, used to prevent liver graft rejection, were supplemented with methotrexate on post-BMT days, 1, 3, 6 and 11 for GVHD prophylaxis. Engraftment proceeded promptly and without complications. Transfusion dependence resolved 6 weeks after BMT. The patient is alive and well 1 year after his BMT on FK506 and prednisone without any signs of GVHD or liver allograft rejection. This case is the first demonstration of the feasibility of continuing FK506 used for prevention of liver graft rejection as GVHD prophylaxis for allogeneic BMT.

A case of isolated testicular relapse occurring 5 years after allogeneic bone marrow transplantation (BMT) for acute myelogenous leukemia (AML) is reported. The patient presented with M4 AML at age 13 and underwent allogeneic BMT in first remission, 5 months after diagnosis. He had no acute graft-versus-host disease (GVHD) but developed mild chronic GVHD 5 months following transplant and received immunosuppressive therapy for the next 2 years. Five years post-transplant he had an isolated testicular relapse that was treated with chemotherapy and testicular radiation. The patient remains in remission 17 months following relapse and more than 15 months following the cessation of therapy.

Immune reconstitution following autologous bone marrow transplantation (ABMT) is characterized by defects in B cell and T cell function and loss of specific antibody. In the late post-transplant period, patients are at risk for infections with polysaccharide encapsulated organisms and respond poorly to polysaccharide vaccines. We examined whether immunizing ABMT patients before bone marrow (BM) harvest enhanced the early recovery of specific antibody. Twelve patients were immunized before BM harvest with Haemophilus influenzae type b (HIB)-conjugate, tetanus toxoid and polysaccharide pneumococcal vaccines. Forty-one comparable ABMT patients not immunized prior to BM harvest were also studied. Following ABMT, both groups of patients were immunized with HIB-conjugate and tetanus toxoid vaccines at 3, 6, 12 and 24 months and with pneumococcal vaccine at 12 and 24 months. Patients immunized before BM harvest had higher HIB antibody concentrations during the first 2 years post-transplant, the differences reaching significance at 3 months (P = 0.0001) and following the 24-month dose (P = 0.048). Tetanus toxoid antibody concentrations were also significantly higher at 3 months (P = 0.001) and 6 months (P = 0.032) in patients immunized before BM harvest. There were no differences in pneumococcal antibody concentrations between the two groups. Immunization of patients before bone marrow harvest resulted in higher anti-HIB antibody concentrations following ABMT and may be an effective strategy to prevent infectious complications.

Bone marrow transplant patients are at increased risk for infections with polysaccharide encapsulated organisms and respond poorly to polysaccharide vaccines. We evaluated the effect of donor immunization with Haemophilus influenzae type b (HIB) polysaccharide-conjugate vaccine on recipient antibody responses following allogeneic bone marrow transplantation. Thirty-two allogeneic transplant patients and their donors were immunized before transplantation with HIB-conjugate, tetanus toxoid and 23-valent pneumococcal vaccines. Following transplantation, patients received HIB-conjugate and tetanus toxoid vaccines at 3, 6, 12, and 24 months and 23-valent pneumococcal vaccine at 12 and 24 months. Thirty-three patients with unimmunized donors were immunized following transplantation in an identical manner. Patients whose donors were immunized had significantly higher total anti-HIB antibody concentrations at 3 months (P = .0001), 6 months (P = .0001), 12 months (P = .0001), and 24 months (P = .002) after transplant compared with patients whose donors were unimmunized. Higher antitetanus toxoid antibody concentrations were also noted in patients with immunized donors, whereas donor immunization with pneumococcal vaccine had no effect on antibody concentrations following transplantation. Donor immunization with HIB-conjugate vaccine resulted in higher antibody concentrations in patients as early as 3 months after allogeneic transplantation and may be an effective strategy to prevent HIB infections.

Acute graft-versus-host disease (GVHD) that is resistant to therapy is a highly lethal complication of marrow transplantation. Inflammatory cytokines such as interleukin-1 (IL-1) may be critical mediators of this process. If so, specific inhibition of IL-1 activity with recombinant human IL-1 receptor antagonist (IL-1Ra), a naturally occurring competitive inhibitor of IL-1, may ameliorate acute GVHD. We performed an open-label, phase I/II trial to evaluate the safety and efficacy of IL-1Ra in 17 patients with steroid-resistant GVHD. The IL-1Ra was administered as a 24-hour continuous infusion over 7 days. The dose was escalated in cohorts of patients from 400 to 3,200 mg/d. Acute GVHD was evaluated in each affected organ and as an overall grade. Stage-specific improvement of acute GVHD occurred in the skin (8 of 14, 57%), gut (9 of 11, 82%), and liver (2 of 11, 18%). Overall, acute GVHD improved by at least one grade in 10 of 16 (63%) patients. Response to therapy was associated with a reduction of tumor necrosis factor-alpha (TNF-alpha) mRNA levels in blood mononuclear cells (P = .001). The only toxicity attributable to IL-1Ra was reversible transaminase elevation in two patients. Inhibition of IL-1 activity with IL-1Ra is safe and has demonstrable efficacy in acute GVHD that failed to respond to conventional treatment. These data provide further evidence that IL-1 is a mediator of GVHD.

Bone marrow transplant patients have impaired responses to pure polysaccharide (PS) vaccines and are at an increased risk for disease caused by PS encapsulated pathogens such as Haemophilus influenzae type B (HIB) and Streptococcus pneumoniae. We immunized 35 BMT patients (21 allogeneic and 14 autologous) ages 2-45 years with pure PS pneumococcal (Pnu-imune 23) HIB-conjugate (HibTITER), and tetanus toxoid vaccines. Patients were assigned to receive vaccines at either 12 and 24 months after transplantation or at 24 months only. Only 19% of all enrolled patients developed protective antibody concentrations (> or = 0.300 microgram antibody nitrogen/ml) to the 6 pneumococcal serotypes measured after the 24-month immunization. Poor response to pneumococcal vaccine was not different for the 2 study groups and was similar to previous studies. In contrast, HIB-conjugate vaccine elicited protective concentrations of antibody (> or = 1.0 microgram/ml) in 56% of patients after 1 dose and in 80% after 2 doses. The group that received 2 doses of HIB-conjugate vaccine had a significantly higher geometric mean antibody concentration of 14.5 micrograms/ml as compared with 1.43 micrograms/ml for those receiving only 1 dose (P = 0.012). Responses to tetanus toxoid vaccine were similar to HIB-conjugate vaccine, with a booster response documented after the second dose. In summary, 2 doses of HIB-conjugate vaccine given at 12 and 24 months after transplantation produced protective antibody concentrations in 80% of patients. While the response to pure PS pneumococcal vaccine was poor, the results with HIB-conjugate vaccine suggest that future pneumococcal conjugate vaccines may also benefit BMT patients.

Purpose: We examined a consecutive series of 78 patients with non-Hodgkin's lymphoma treated on prospective protocols with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (CBV) plus autotransplantation to determine prognostic factors for time to treatment failure., Patients and Methods: Patients with relapsed, refractory, or poor-risk intermediate- and high-grade non-Hodgkin's lymphoma were treated with CBV with autologous marrow or peripheral-blood progenitor cell support. Patient characteristics before transplantation were examined in univariate analyses by the log-rank test and simultaneously in a Cox proportional hazards regression analysis. A best-predictive model was determined from those variables significant (P < .10) in the univariate test., Results: In univariate analysis, intermediate-grade and immunoblastic lymphoma, responsiveness to pretransplant salvage chemotherapy, and transplantation after primary therapy (first complete response [CR] or partial response [PR]) were associated with prolonged time to treatment failure. In proportional hazards multiple regression analysis, intermediate-grade and immunoblastic histology, responsive disease, and autotransplantation in first CR or PR were positive prognostic factors, and these characteristics are the basis of the best-predictive model for prolonged time to failure. Actuarial 3-year failure-free survival of patients with stable or responding disease at autotransplant was 54%., Conclusion: CBV is an effective conditioning regimen in intermediate-grade and immunoblastic non-Hodgkin's lymphoma. Patients with these histologies transplanted while responding to primary therapy, or those with stable disease or disease responding to salvage therapy at the time of autotransplant, are most likely to benefit. Patients with lymphoblastic lymphoma or diffuse undifferentiated lymphoma did poorly with CBV and should be offered alternative therapy.

Twenty-three patients with primary myelodysplasia (MDS) or secondary myelodysplasia/acute nonlymphocytic leukemia (MDS/ANLL) were treated with allogeneic or syngeneic bone marrow transplantation (BMT). Only one patient was in a chemotherapy-induced hematologic remission. Graft-versus-host disease prophylaxis included methotrexate, methotrexate plus cyclosporine, cyclosporine, or T-cell depletion using one of two anti-CD5 monoclonal antibodies. For patients with primary MDS, the median age was 19 years (range, 11 to 41 years) and the actuarial disease-free survival was 56% +/- 21% (median follow-up, 2 years; range, 0.8 to 5 years). There were three graft failures (two with autologous recovery) and two early deaths. Outcome appeared to be related to French-American-British (FAB) classification. For patients with secondary MDS/ANLL, the median age was 28 years (range, 3 to 16 years) and the actuarial disease-free survival was 27% +/- 13% (median follow-up, 5 years; range, 2.5 to 8.5 years). There were no graft failures, two relapses, and four early deaths. The presence of marrow fibrosis per se did not predict for graft failure (P = .21); however, the use of T-cell depleted marrow in patients with marrow fibrosis resulted in graft failure in three of five individuals. Our results suggest that in patients with primary MDS or secondary MDS/ANLL, BMT should be considered early in the course of the disease, and that attempts at inducing a remission prior to BMT appeared to be unnecessary. In MDS patients with marrow fibrosis, T-cell depletion should be avoided.

Between 1980 and 1987, 59 children with acute lymphoblastic leukemia (ALL) or stage IV neuroblastoma (NB) underwent allogeneic or autologous bone marrow transplantation (BMT). Thirty-nine of these patients were alive and in remission 6 months post BMT and were evaluable for this analysis. Sixteen have developed renal dysfunction. Eight were transplanted for relapsed ALL and received an autologous transplant. Preparation included tenopiside (VM 26), cytosine arabinoside, and cyclophosphamide followed by total body irradiation (TBI). One patient received 850 cGy in a single fraction, while all other patients received fractionated TBI (1200-1400 cGy in 6-8 fractions over 3-4 days). Eight of 11 evaluable patients who received a BMT for NB have developed late renal problems (4-7 months after BMT). The preparation for neuroblastoma patients included VM 26, cis-platinum, melphalan, cyclophosphamide and fractionated TBI (1200-1296 cGy). All 8 neuroblastoma patients had received cis-platinum as induction treatment prior to transplantation. All patients presented with anemia, hematuria and elevations of BUN and creatinine. Renal biopsies were consistent with radiation nephropathy. In conclusion, a high incidence of renal dysfunction has occurred after BMT in children with neuroblastoma and ALL. The clinical and laboratory features are consistent with either radiation nephropathy or hemolytic-uremic syndrome. The relatively young age of these patients and conditioning with intensive multi-agent chemotherapy may decrease the tolerance of the kidney to radiation injury.

Renal disease has not been considered a major late complication of bone marrow transplantation. Of 31 evaluable pediatric patients undergoing allogeneic or autologous bone marrow transplantation for neuroblastoma or acute lymphoblastic leukemia, 14 developed a hemolytic anemia, microscopic hematuria, and renal insufficiency at a median of 5 months (range, 3 to 7 months) posttransplant. Renal biopsies were performed in two patients at the onset of kidney disease and showed mesangiolysis with intraglomerular capillary aneurysm formation, mesangial proliferation, and focal thickening and splitting of the glomerular basement membranes. The clinical presentation, time to onset of renal disease, and biopsy material are consistent with a diagnosis of radiation nephritis, a previously uncommon finding in this patient group. The high incidence of this syndrome in the current report may have been due to the combination of intensive chemotherapy and total-body irradiation in the conditioning regimens.

Therapeutic options for children with de novo or secondary myelodysplastic syndromes (MDSs) are limited. We report the outcome of eight pediatric patients (median age 12 years, range 3 to 19 years) with myelodysplasia who underwent allogeneic bone marrow transplantation between 1984 and 1987. Two of the eight children had developed secondary myelodysplasia after alkylating agent-based combination chemotherapy. Five patients had clonal chromosomal abnormalities, including four patients with monosomy 7. Seven of eight patients engrafted. Two of these seven subsequently died of complications of acute or chronic graft-v-host disease (GVHD), and a third patient died at 21 months of pulmonary fibrosis. None of the patients have had recurrence of disease. The four surviving patients remain in complete remission at a median follow-up of 19 months (range 10 to 44 months).

Between 1980 and 1986, 44 children with acute lymphoblastic leukemia (ALL) or Stage IV neuroblastoma (NB) underwent allogeneic or autologous bone marrow transplantation (BMT). Twenty-nine of these patients were alive and in remission 3 months post BMT and were evaluable for this analysis of whom eleven have developed renal dysfunction. Six of 17 (35%) evaluable ALL patients developed renal dysfunction (3.5 to 6 months post BMT). This group was transplanted for CALLA positive ALL and received an autologous transplant. Preparation included tenopiside (VM 26) cytosine arabinoside, and cyclophosphamide followed by total body irradiation (TBI). One patient received 850 cGy in a single fraction, while all other patients received fractionated TBI (1200-1400 cGy in 6-8 fractions over 3-4 days). Five of 7 (71%) evaluable patients who received a BMT for NB have developed late renal problems (4-7 months after BMT). The preparation for NB patients included VM 26, cis-platinum, melphalan, cyclophosphamide, and fractionated TBI (1200-1296 cGy). All seven NB patients had received cis-platinum as induction treatment prior to transplantation. All patients presented with anemia, hematuria, and elevations of BUN and creatinine. Two patients underwent renal biopsies which were consistent with radiation nephropathy or hemolytic uremic syndrome. In conclusion, a high incidence of renal dysfunction has occurred 3 to 7 months after BMT for children with NB and ALL. The clinical and laboratory features are consistent with either acute radiation nephropathy or hemolytic-uremic syndrome. These patients were prepared for BMT with multiple chemotherapeutic agents as well as TBI. The relatively young age of these patients and conditioning with intensive multi-agent chemotherapy may decrease the tolerance of the kidney to radiation injury.

Constitutional pure red cell aplasia (CPRCA) is a syndrome of failed erythropoiesis usually diagnosed within the first year of life. Four patients with CPRCA received transplants with marrow from their HLA-identical, mixed lymphocyte culture-nonreactive siblings. All patients were resistant to corticosteroid therapy and were dependent on regular red cell transfusions for at least 5 years. Three patients were conditioned with procarbazine, antithymocyte globulin, cyclophosphamide, and busulfan, and one was conditioned with antithymocyte serum, cyclophosphamide, and busulfan. Three patients promptly had successful engraftments with establishment of donor hematopoiesis. One patient initially rejected his graft but received a successful retransplant. All patients are currently alive with Karnofsky performance scores of 100 and normal erythropoiesis of donor origin. Despite a history of multiple transfusions, bone marrow transplantation is a potentially curative therapy for patients with CPRCA.

Presents a case of a patient with homozygous alpha-thalassemia diagnosed and treated in utero, who underwent successful hematopoietic stem cell transplantation. Medical history of the patient; Treatments received; Implication of the case for the treatment of the lethal disorder.