Marrow transplantation from unrelated donors for patients with severe aplastic anemia who have failed immunosuppressive therapy.

Allogeneic marrow transplantation offers curative therapy for patients with aplastic anemia. We analyzed retrospective results in 141 patients with severe aplastic anemia who received transplants between 1988 and 1995 from an unrelated volunteer donor identified through the National Marrow Donor Program (NMDP). All patients had failed one or more courses of immunosuppressive therapy. Of the patients, 121 (86%) received a radiation-containing conditioning regimen, and 20 (14%) were given chemotherapy only. Based on serologic human leukocyte antigen (HLA) typing (class I and II), 105 patients (74%) received HLA-matched marrow, and 36 (26%) received marrow mismatched for at least one HLA-A, -B, or -DR antigen. Allele-level (molecular) typing for HLA-DRB1 was available in 108 donor-recipient pairs; 77 patients received DRB -matched and 31 DRB1-mismatched transplants. All but 13% of patients were given a cyclosporine-containing regimen for graft-vs.-host disease (GVHD) prophylaxis, and 45 patients (32%) received marrow that was T cell-depleted. Among 131 evaluable patients, 116 (89%) achieved sustained engraftment and 15 (11%) did not. Among patients with engraftment, acute GVHD of grades II-IV developed in 60 patients (52%) and extensive chronic GVHD in 24 patients at risk (31%). Currently, 51 patients (36%) are surviving at 11-94 months (median 36) after transplantation. All but five have Karnofsky scores > or =80. Patients who received a serologically matched transplant fared somewhat better than did patients given a serologically mismatched transplant p = 0.03). Patients with donors matched by both serology and allele-level DRB1 typing had significantly better survival than DRB1-mismatched patients with 56 vs. 15% surviving at 3 years p = 0.001). Outcome in patients transplanted within 3 years of diagnosis was superior to that among patients transplanted with greater delay. Major causes of death were graft failure, GVHD, and infections. These data suggest that unrelated marrow transplantation offers successful therapy for a proportion of patients who have failed immunosuppressive therapy.     

Unrelated donor bone marrow transplants for severe aplastic anemia with conditioning using total body irradiation and cyclophosphamide.

The outcome of unrelated donor bone marrow transplantation for aplastic anemia is inferior to that of sibling donor bone marrow transplantation because of a higher rate of transplant-related mortality (TRM), which is closely associated with the intensity of pretransplant conditioning to overcome graft rejection. We conducted a prospective trial with an intermediate to high dose of total body irradiation (TBI) in combination with a fixed dose of cyclophosphamide (120 mg/kg) to use for pretransplant conditioning for unrelated donor bone marrow transplantation in adult aplastic anemia. The number of patients who received doses of 1200, 1000, and 800 cGy of TBI were 5, 9, and 26, respectively. The corresponding probabilities of overall survival (OS) at 3 years were 40%, 44%, and 92%, respectively. The incidence of regimen-related toxicity with grade III-IV and graft rejection in the patients who received a dose of 800 cGy of TBI were 0 of 26 patients. The significant factors associated with OS were the TBI dose (800 cGy vs. >or=1000 cGy; P = .001), chronic graft-versus-host disease (less than or equal to limited vs. extensive; P = .013), the method of HLA typing for the donor-recipient matching (serologic typing vs. DNA-based typing; P = .006), and the transfusion amount before transplantation (90 units; P = .020).     

Subtotal body irradiation with linear accelerator as preparation for marrow engraftment in aplastic anemia.

Two cases of multitransfused severe aplastic anemia were retransplanted with bone marrow from the same HLA compatible sibling donors after subtotal body irradiation (800 r). Only minor non hematologic toxicity was observed. No permanent take was seen in relation to this procedure. During the survival time of the patients (78-120 days) no signs of interstitial pneumonia were observed.     

Fludarabine-based conditioning for marrow transplantation from unrelated donors in severe aplastic anemia: early results of a cyclophosphamide dose deescalation study show life-threatening adverse events at predefined cyclophosphamide dose levels

Excessive adverse events were encountered in a Phase I/II study of cyclophosphamide (CY) dose deescalation in a fludarabine-based conditioning regimen for bone marrow transplantation from unrelated donors in patients with severe aplastic anemia. All patients received fixed doses of antithymocyte globulin, fludarabine, and low-dose total body irradiation. The starting CY dose was 150 mg/kg, with deescalation to 100 mg/kg, 50 mg/kg, or 0 mg/kg. CY dose level 0 mg/kg was closed due to graft failure in 3 of 3 patients. CY dose level 150 mg/kg was closed due to excessive organ toxicity (n?=?6) or viral pneumonia (n?=?1), resulting in the death of 7 of 14 patients. CY dose levels 50 and 100 mg/kg remain open. Thus, CY at doses of 150 mg/kg in combination with total body irradiation (2 Gy), fludarabine (120 mg/m(2)), and antithymocyte globulin was associated with excessive organ toxicity.     

Surgical intervention in patients with aplastic anemia.

Eighteen surgical procedures have been performed on 14 cases of aplastic anemia (AA). Of the 10 major surgical procedures, 7 were emergency and 3 elective. The median duration from the diagnosis of AA to major surgery was 0.5 months (3 days-47.3 months), and the median survival after surgery was 12.3 months (4 days-38 months). The hematological status of AA at the time of major surgery were 3 in partial response (PR), 2 with no response (NR) and 5 at diagnosis, respectively; and those after major surgery were 2 with complete response (CR), 2 in PR, 1 with minimal response, and 2 in NR. Three postoperative complications were sepsis, pneumonia and atelectasis encountered in 2 cases. A total of 3 deaths were caused by infection and cancers. Considering the fact that surgery may not only control complications, but offer the opportunity to give effective therapy for AA and therefore improves chances for survival, it is strongly suggested that active surgical intervention should be performed if the patient's status is not terminal.     

Marrow transplantation for treatment of aplastic anemia. An analysis of factors associated with graft rejection.

Seventy-three consecutive patients with severe aplastic anemia were treated by marrow grafts from normal, HLA-identical siblings, and 68 lived long enough to demonstrate engraftment. In 21 patients the garft was rejected, and 19 of these patients died. This analysis, using a binary logistic regression model, was aimed at identifying factors that predicted marrow-graft rejection. Of the 24 factors entered into the analysis, only two strongly correlated with graft rejection: a positive relative response index in mixed leukocyte culture indicating sensitization of patient against donor (P less than 0.01); and a low number of marrow cells ( less than 3 X 10(8) cells per kilogram) used for transplantation (P less than 0.01). These findings suggest that more powerful immunosuppressive conditioning regimens should be used in patients who are sensitized, and that the greatest possible amount of donor marrow, perhaps supplemented by stem cells derived from the peripheral blood, should be obtained.     

Marrow versus blood-derived stem cell grafts for allogeneic transplantation from unrelated donors in patients with active myeloid leukemia or myelodysplasia

Peripheral blood stem cells (PBSCs) are increasingly used as the graft source in allogeneic hematopoietic cell transplantation. We compared long-term outcome after unrelated donor transplantation of 85 consecutive patients with acute myelogenous leukemia or myelodysplastic syndrome regarding disease status (early disease [CR1, refractory anemia); n = 25 and advanced/active disease [>CR1, >refractory anemia]; n = 60) who were treated with conventional conditioning regimens followed by bone marrow (BM) or PBSC grafts. Graft-versus-host disease prophylaxis consisted mainly of cyclosporine A, short-course methotrexate, and anti-T-lymphocyte globulin. After a median follow-up of 118?months (68-174), the 10-year event-free survival rate after peripheral blood stem cell transplantation (PBSCT) was 54.8% (95% confidence interval [CI], 39.7%-69.8%), and after bone marrow transplantation (BMT), it was 27.9% (14.5%-41.3%; P < .004). In the advanced/active disease group, the 10-year event-free survival rate after PBSCT was 50% (30.8%-69.2%), and after BMT, it was 23.5% (9.3%-37.8%; P < .007). Non relapse mortality was less after PBSCT than BMT (14.3% vs 30.2%), respectively. In multivariate Cox regression analysis, PBSCT showed a better overall survival (OS; hazard ratio [HR], 0.43; 95% CI, 0.23-0.79; P = .007) compared to BMT; unfavorable/unknown prognostic impact cytogenetic abnormalities were an adverse factor for all patients (HR, 2.202; 95% CI, 1.19-4.06; P = .011). In patients with advanced disease, the use of PBSCs showed a significant favorable outcome via multivariate analysis (HR, 0.49; 95% CI, 0.24-0.99; P = .046). Outcome of acute myelogenous leukemia/myelodysplastic syndrome after unrelated hematopoietic cell transplantation is adversely affected by cytogenetic abnormalities and state of remission at hematopoietic cell transplantation. PBSC as a graft source has a significant favorable influence on survival.     

Fludarabine-based reduced intensity conditioning for stem cell transplantation of Fanconi anemia patients from fully matched related and unrelated donors.

Reduced intensity conditioning has been suggested as a desirable therapeutic modality for the treatment of patients with malignant and nonmalignant indications, but it seems particularly attractive for patients with Fanconi anemia due to their increased sensitivity to chemoradiotherapy. Between November 1996 and September 2003, 7 patients (1 male and 6 female; age range, 3-31 years; median age, 9.5) were conditioned with a fludarabine-based protocol for stem cell transplantation without radiation. In vivo T-cell depletion was accomplished with anti-thymocytic globulin or Campath-1H (alemtuzumab). Graft-versus-host disease prophylaxis consisted of low-dose cyclosporine alone. Eight transplantations were carried out for 7 patients using bone marrow, peripheral blood, and/or cord blood as sources of stem cells. All patients received transplants from HLA-A, -B, -C, and -DR matched donors, 5 from family members and 2 from matched unrelated donors. One patient did not engraft her first matched unrelated donor and underwent a second transplantation from another matched unrelated donor, after which she engrafted well. All 7 patients are alive and well, fully reconstituted with donor cells, and with 100% performance status. In conclusion, fludarabine-based preparative protocols are well tolerated, facilitate rapid engraftment with minimal toxicity, and should be considered an essential component of choice for patients with Fanconi anemia.     

Outcomes of adults with acute myelogenous leukemia in remission given 550 cGy of single-exposure total body irradiation, cyclophosphamide, and unrelated donor bone marrow transplants.

On the basis of observations from dog models and human studies, we hypothesized that a low-dose (550 cGy), single-exposure total body irradiation (TBI)-based regimen would result in improved survival when given to adult patients with acute myelogenous leukemia (AML) who were undergoing unrelated donor bone marrow transplantation in complete remission (CR). The regimen consisted of single exposure (550 cGy) of TBI given at a high dose rate (30 cGy/min) and cyclophosphamide. Graft-versus-host disease prophylaxis consisted of cyclosporine, methotrexate, and corticosteroids. Thirty-two consecutive adult patients (median age, 47 years) with AML in CR (15 in CR 1 and 17 in CR > or =2) were treated. Sixteen patients (50%) were alive and in remission at last follow-up (median, 2.2 years; range, 0.6-4.0 years). Kaplan-Meier estimates of overall and leukemia-free survival at 3 years were 55% +/- 14% (mean +/- SE) and 57% +/- 14% in CR 1 patients and were both 39% +/- 12% in CR > or =2 patients. Transplant-related mortality was 13% for patients in CR 1 and 41% for those in CR > or =2. Only 1 patient (3%) experienced fatal regimen-related organ toxicity, and only 1 had grade III or IV acute graft-versus-host disease. Graft failure was not observed. Relapse occurred in 22% of patients. This low-dose (550 cGy), single-exposure TBI-based regimen resulted in good survival and a low risk of fatal regimen-related organ toxicity in adult patients with AML who underwent unrelated donor bone marrow transplantation in CR.     

肺屏蔽块对全身照射剂量分布的影响

目的：探讨全身照射（ＴＢＩ）中为控制肺剂量所采用肺屏蔽挡块对剂量分布的影响。方法：利用三维自动扫描水箱按实际ＴＢＩ照射条件测量三种厚度不同的肺铅挡块下，水模体中剂量分布情况。结果：加肺档块使纵膈区剂量减少，肺挡因子与测量的深度有关。结论：肺挡因子应在照射条件下测量。在全身照射总剂量与肺部限受剂量相差较大时，应注意纵膈剂量的修正。     

Long-term cultures of marrow cells from the patients with aplastic anemia

Long-term marrow cultures were established from 35 patients with aplastic anemia (AA) and the adherent stromal cell layers were assessed. Cultures from 23 of the 35 patients grew scanty stromal cell layers or did not produce any adherent cells. Long-term cultures from the remaining patients formed adherent cell layers that appeared to be morphologically normal. Cultures from 7 patients that grew apparently normal adherent cell layers were examined for expression of intermediate filament proteins using antibodies CGA-7 and HHF, which respectively recognize actin epitopes expressed in smooth muscle and normal marrow stromal cells. Cells from 4 of the 7 patients expressed vimentin (antibody 43 beta E8) but did not react with CGA-7 or HHF. It thus appears that most patients with AA have quantitative or qualitative abnormalities in the adherent cell layers from long-term marrow cultures, suggesting a defect in the hematopoietic microenvironment.