Bone marrow transplantation for severe aplastic anemia: has outcome improved?

Bone marrow transplants for severe aplastic anemia were first performed in the 1970s. Transplant regimens, supportive care, and patient selection have changed substantially since then. Our objective was to determine the impact of these changes on transplant outcome. We studied 1,305 recipients of HLA-identical sibling transplants for aplastic anemia between 1976 and 1992, reported to the IBMTR by 179 centers. We compared survival of transplants performed in three intervals (1976 through 1980 [n = 186], 1981 through 1987 [n = 648], and 1988 through 1992 [n = 471]) using Cox proportional hazards regression. Five-year survival (+/-95% confidence interval) increased from 48% +/- 7% in the 1976-1980 cohort to 66% +/- 6% in the 1988-1992 cohort (P < .0001). Risks of graft-versus-host disease (GVHD) and interstitial pneumonia decreased over time, but the risk of graft failure did not. Higher long-term survival resulted primarily from decreased mortality in the first 3 months posttransplantation. Late mortality risks were low and changed little over the intervals studied. In multivariate analysis, changes in transplantation strategies accounted for most but not all of the improved outcome. Use of cyclosporine to prevent GVHD was the most important factor. Changes in patient selection did not seem to explain improved survival. Survival after HLA-identical sibling bone marrow transplantations for aplastic anemia has improved since 1976. Changes in GVHD prophylaxis account for much of this improvement. Other changes may also operate.

Bone marrow transplants from HLA-identical siblings in advanced Hodgkin's disease.

PURPOSE: To determine the outcome of HLA-identical sibling bone marrow transplants in advanced Hodgkin's disease. PATIENTS AND METHODS: We reviewed the data on 100 consecutive patients with Hodgkin's disease who received HLA-identical sibling bone marrow transplants between April 1, 1982 and August 12, 1992, reported to the International Bone Marrow Transplant Registry (IBMTR). The median interval from diagnosis to transplant was 2.5 years (range, < 1 to 14). All had advanced disease. Eighty-nine of 100 patients were not in remission at the time of transplant. Fifty had pretransplant Karnofsky scores less than 90% and 27 had active infection in the week before transplant. Patients received a variety of conditioning regimens; 45 received total-body radiation. RESULTS: The 100-day probability of acute graft-versus-host disease (GVHD) was 35% (95% confidence interval [CI], 26% to 46%); the 3-year probability of chronic GVHD was 45% (95% CI, 31% to 59%). The 3-year probability of relapse was 65% (95% CI, 50% to 78%). The 3-year probability of survival was 21% (95% CI, 14% to 30%). The 3-year disease-free survival rate was 15% (95% CI, 9% to 24%). CONCLUSION: HLA-identical sibling bone marrow transplants have a limited role in advanced Hodgkin's disease.

Chemotherapy versus transplants for acute myelogenous leukemia in second remission.

The best therapy for persons with acute myelogenous leukemia (AML) in 2nd remission is unknown. Bone marrow transplants from an HLA-identical sibling are reported to be better than chemotherapy but this is controversial. The objective of the study was to compare 3-year leukemia-free survival (LFS) in comparable subjects receiving chemotherapy or a transplant. 485 persons with AML in 2nd remission were studied. The chemotherapy cohort included 244 persons treated on trials of the British Medical Research Council, Eastern Cooperative Oncology Group and MD Anderson Hospital. The transplant cohort included 257 persons transplanted worldwide and reported to the international Bone Marrow Transplant Registry (16 were also chemotherapy subjects.) Subjects were selected for comparable age and year of treatment. Preliminary analyses identified two factors correlated with LFS: age < or = or > 30 years and 1st remission duration < or = or > 1 year; subsequent analyses were partitioned accordingly. Three-year probabilities of treatment-related mortality with chemotherapy and transplants were 7% (95% confidence interval, 3-15%) vs 56% (49-63%). Three-year leukemia relapse probabilities were 81% (74-86%) vs 41% (33-49%). Three-year probabilities of LFS were 17% (12-23%) vs 26 (20-32%). Cohort analysis showed significantly higher LFS with transplants vs chemotherapy in persons < or = 30 years and 1st remissions > 1 year (41% (29-53%) vs 17% (7-32%); P = 0.017) and those in > 30 years with 1st remissions < or = 1 year (18% (9-29%) vs 7% (2-16%); P = 0.046). Others had comparable LFS with both treatments. These data indicate better LFS with HLA-identical sibling transplants than chemotherapy in some persons with AML in 2nd remission.

Risk factors for hepatic veno-occlusive disease following HLA-identical sibling bone marrow transplants for leukemia.

The objective was to analyze risk factors for veno-occlusive disease of the liver (VOD) after allogeneic bone marrow transplantation. A cohort of 1717 recipients of HLA-identical sibling transplants for leukemia between 1988 and 1990, in 200 transplant teams worldwide, was studied. Patients were scored as having VOD if liver tissue showed typical histologic features or if they had all three of the following: (1) jaundice; (2) hepatomegaly and right upper quadrant abdominal pain; and (3) ascites and/or unexplained weight gain. Patients surviving more than 7 days post-transplant without histologic or any of these clinical features of VOD were classified as not having VOD. Patient-, disease- and transplant-related characteristics of 95 patients with VOD were compared to those of 1514 without VOD. Variables correlated with an increased risk of VOD were: pretransplant conditioning with busulfan and cyclophosphamide compared to total body radiation (relative risk (RR) 2.8; P < 0.0001), pretransplant fungal infection (RR 4.1; P = 0.011), pretransplant Karnofsky performance score < 90% (RR 1.9; P = 0.012), prior liver disease (RR 1.9; P = 0.05) and age > 20 years (RR 1.8; P = 0.05). In patients receiving radiation for conditioning, intravenous immune globulin decreased VOD risk (RR 0.26; P = 0.003). This analysis identifies risk factors for VOD. The data suggest several strategies for modifying transplant regimens to reduce VOD risk and which patients might be suitable subjects for trials of strategies of VOD prevention.

Bone marrow transplantation for Fanconi anemia.

Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.

Bone marrow transplantation for Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a rare disorder usually diagnosed in the first year of life. Although most cases respond to corticosteroids, > 20% are, or become, steroid-resistant. We report 10 children with DBA who received a bone marrow transplant from an HLA-identical sibling (n = 8), maternal (n = 1) or unrelated (n = 1) donor and reported to the International Bone Marrow Transplant Registry. Among eight recipients of HLA-identical sibling transplants, six are alive 5-87 months after transplant with no evidence of DBA and with Karnofsky performance scores of 90-100%. The two recipients of non-HLA-identical sibling transplants died < 2 weeks after transplant. The actuarial 2-year probability of survival for the eight sibling transplants was 72 (37-92)% (95% confidence interval).

Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission.

BACKGROUND: It is unclear how best to treat children with acute lymphoblastic leukemia who are in a second remission after a bone marrow relapse. For those with HLA-identical siblings, the question of whether to perform a bone marrow transplantation or to continue chemotherapy has not been answered. METHODS: We compared the results of treatment with marrow transplants from HLA-identical siblings in 376 children, as reported to the International Bone Marrow Transplant Registry, with the results of chemotherapy in 540 children treated by the Pediatric Oncology Group. A preliminary analysis identified variables associated with treatment failure in both groups. We selected cohorts by matching these variables. A possible bias associated with differences in the interval between remission and treatment was controlled for by choosing matched pairs in which the duration of the second remission in the chemotherapy recipient was at least as long as the time between the second remission and transplantation in the transplant recipient. A total of 255 matched pairs were studied. RESULTS: The mean (+/- SE) probability of a relapse at five years was significantly lower among the transplant recipients than among the chemotherapy recipients (45 +/- 4 percent vs. 80 +/- 3 percent, P < 0.001). At five years the probability of leukemia-free survival was higher after transplantation than after chemotherapy (40 +/- 3 percent vs. 17 +/- 3 percent, P < 0.001). The relative benefit of transplantation as compared with chemotherapy was similar in children with prognostic factors indicating a high or low risk of relapse (the duration of the first remission, age, leukocyte count at the time of the diagnosis, and phenotype of the leukemic cells). CONCLUSIONS: For children with acute lymphoblastic leukemia in a second remission, bone marrow transplants from HLA-identical siblings result in fewer relapses and longer leukemia-free survival than does chemotherapy.

Identical-twin bone marrow transplants for leukemia.

OBJECTIVE: To compare outcomes of identical-twin with HLA-identical sibling bone marrow transplants for leukemia. DESIGN: Matched-pair analysis comparing relapse, treatment-related mortality, and leukemia-free survival in cohorts matched for disease and variables correlated with transplant outcome, with and without adjustment for graft-versus-host disease. SETTING: 163 institutions worldwide between 1978 and 1990, reporting to the International Bone Marrow Transplant Registry. PARTICIPANTS: 103 identical-twin transplants: 24 for acute lymphoblastic leukemia (ALL) in first remission, 45 for acute myelogenous leukemia (AML) in first remission, and 34 for chronic myelogenous leukemia (CML) in first chronic phase. Results were compared with those in 1030 concurrent HLA-identical sibling transplants matched for prognostic factors. RESULTS: Three-year probabilities of relapse after identical-twin compared with HLA-identical sibling transplants were as follows: ALL, 36% (95% CI, 17% to 55%) compared with 26% (CI, 20% to 32%); AML, 52% (CI, 37% to 67%) compared with 16% (CI, 12% to 20%); and CML, 40% (CI, 23% to 57%) compared with 7% (CI, 4% to 10%). Increased relapse risks in AML and CML persisted after adjusting for graft-versus-host disease (relative risk, 3.1 [CI, 1.9 to 5.1] and 5.5 [CI, 2.8 to 11.0], respectively). Although twins had less treatment-related mortality than HLA-identical siblings, leukemia-free survival was similar. Three-year leukemia-free survival probabilities after twin compared with HLA-identical sibling transplants were as follows: ALL, 57% (CI, 37% to 77%) compared with 58% (CI, 52% to 64%); AML, 42% (CI, 27% to 57%) compared with 55% (CI, 50% to 60%); and CML, 59% (CI, 42% to 76%) compared with 61% (CI, 56% to 66%). CONCLUSIONS: Identical-twin transplants in AML and CML are associated with increased relapse risk compared with HLA-identical sibling transplants. A similar trend was observed in ALL but was not statistically significant. Increased relapse in twin transplants is not explained by lack of graft-versus-host disease. Leukemia-free survival after twin and HLA-identical sibling transplants is similar because increased relapse in twins is offset by decreased treatment-related mortality.

Bone marrow transplantation in leukemia.

Bone marrow transplants are increasingly being used as treatment for leukemia. Several IBMTR studies have identified variables predicting outcome in allogeneic transplants. These studies have also identified factors like GVL that increase our understanding of leukemia treatment. Following the success of HLA-identical sibling transplants, allografts from related and unrelated donors are now performed frequently and achieve long-term LFS. The use of autologous transplants, with and without marrow treatment, is also increasing and continues to be investigated as an alternative therapy for leukemia.

1993 progress report from the International Bone Marrow Transplant Registry. Advisory Committee of the International Bone Marrow Transplant Registry.

The International Bone Marrow Transplant Registry is an organization devoted to scientific research in BMT. More than 230 transplant teams worldwide contribute detailed information about recipients of allogeneic and syngeneic BMT for study. Results of analyses are published in medical journals and presented at national and international scientific meetings (more than 60 publications and more than 500 presentations in the past 4 years). This collaborative research program has grown rapidly with more than 2000 cases reported annually. This report summarizes results of several recent investigations and reviews the state of BMT in leukemia and aplastic anemia.

Outcome after allogeneic bone marrow transplant for leukemia in older adults.

OBJECTIVE: To determine whether age over 40 years is associated with adverse outcome after allogeneic bone marrow transplantation for leukemia. DESIGN: A retrospective analysis of outcome after bone marrow transplants for leukemia reported to the International Bone Marrow Transplant Registry (IBMTR) among recipients 30 through 39 years, 40 through 44 years, 45 through 49 years, and 50 years of age and older. SETTING: Transplantations performed in 138 institutions worldwide and reported to the IBMTR. PATIENTS: A total of 2180 recipients of HLA-identical sibling bone marrow transplants for leukemia, divided into four cohorts based on age: 30 through 39 years (n = 1282), 40 through 44 years (n = 527), 45 through 49 years (n = 291), and 50 years and older (n = 80). MAIN OUTCOME MEASURES AND RESULTS: Incidence of leukemia-free survival, graft-vs-host disease, and relapse was comparable among the four age cohorts. Patients with advanced leukemia aged 45 years or older had a slightly higher risk of treatment-related mortality, and the 45- through 49-year-old cohort had a higher risk of interstitial pneumonia. CONCLUSIONS: These data indicate that among leukemia patients over 30 years of age at the time of allogeneic bone marrow transplantation, increasing age into the fifth decade does not adversely affect outcome after transplants from HLA-identical siblings.

Results of bone marrow transplants from human leukocyte antigen-identical sibling donors for treatment of childhood leukemias. A report from the International Bone Marrow Transplant Registry.

PURPOSE: Bone marrow transplantation is an effective treatment for leukemia. Cures are possible in 20-80% of transplant recipients depending on the stage of leukemia at the time of transplant. The antileukemia efficacy of transplants result from high-dose chemotherapy and/or radiation given pretransplant and from immune-mediated effects of the graft. RESULTS: Success of the procedure is limited by transplant-related complications, including graft rejection, graft-vs.-host disease and interstitial pneumonia. Five-year leukemia-free survival ranges from approximately 25% for children transplanted with advanced leukemia, to > 60% in those transplanted in first remission of acute leukemia or first chronic phase of chronic myeloid leukemia. CONCLUSIONS: Candidates for transplant include children failing conventional therapy and, possibly, those with early leukemia characterized by features predicting a poor response to conventional therapy.

The first official meeting of the International Society for Experimental Hematology.

In 1972, 85 scientists from 10 countries came to Milwaukee to participate in the first official meeting of the International Society for Experimental Hematology. We summarize here some of the events leading up to the meeting, fondly recollect the enthusiastic spirit of the meeting and reprint the program, which is not all that different in content from the program of the 21st meeting.

Report from the International Bone Marrow Transplant Registry and the North American Autologous Bone Marrow Transplant Registry.

The Statistical Center of the IBMTR/NAABMTR has expanded its role from collecting data on allogeneic and syngeneic transplants to the area of autologous bone marrow and blood cell transplantation given to support high-dose therapies for cancer. In diseases such as acute leukemia for which both allogeneic and autotransplants are performed, direct comparisons of outcomes of these therapies are now possible. The large number of cases that has accrued rapidly into the NAABMTR (over 9,000 since 1989) will allow us to use sophisticated statistical techniques to determine potential benefits and disadvantages in the rapidly growing area of autotransplantation.

Progress report from the International Bone Marrow Transplant Registry.

The International Bone Marrow Transplant Registry receives and analyses detailed information contributed by more than 200 transplant teams worldwide. This collaborative research program has grown rapidly; there are now more than 15,000 cases in the database. This progress report summarizes the current status of bone marrow transplantation, the results of recent investigations and studies planned for the coming year.

Changing trends in allogeneic bone marrow transplantation for leukemia in the 1980s.

OBJECTIVE: To identify changes in practice and outcome of bone marrow transplants for leukemia in the 1980s. DESIGN: Comparison of key explanatory and outcome variables in five 2-year cohorts, from 1980 through 1981 to 1988 through 1989, using a large database of detailed clinical information. PATIENTS: Recipients (7788) of bone marrow transplants for acute lymphoblastic, acute myelogenous, or chronic myelogenous leukemia reported to the International Bone Marrow Transplant Registry, Milwaukee, Wis, by 185 transplant teams worldwide. RESULTS: Linear increases occurred during the periods 1980 through 1981 to 1988 through 1989 as follows with 95% confidence intervals: (1) transplants for chronic myelogenous leukemia from 14% +/- 2% to 35% +/- 2%; (2) transplants from unrelated donors from 1% +/- 1% to 7% +/- 1%; (3) preparative regimens without radiation from 3% +/- 1% to 30% +/- 2%; and (4) use of methotrexate plus cyclosporine to prevent graft-vs-host disease from 2% +/- 1% to 55% +/- 2%. Among recipients of human lymphocyte antigen-identical sibling bone marrow, the 2-year probability of treatment-related mortality decreased by 6% to 22%. The probability of relapse decreased from 46% +/- 6% to 38% +/- 6% in intermediate leukemia but did not change appreciably in early or advanced leukemia. Probabilities of leukemia-free survival improved from 51% +/- 4% to 57% +/- 3% in early leukemia, from 28% +/- 4% to 36% +/- 5% in intermediate leukemia, and from 12% +/- 4% to 18% +/- 5% in advanced leukemia. A separate analysis of a homogenous population of patients indicated that improvements in outcome in the 1980s were due to improvements in transplant practice rather than improved patient selection. CONCLUSIONS: Modest increases in leukemia-free survival rates occurred after human lymphocyte antigen-identical sibling bone marrow transplants in the 1980s. Improvements were due primarily to reductions in treatment-related mortality with little or no change in relapse risk. More effective antileukemia strategies and continued reductions in treatment-related toxic effects are needed.

Should HLA-identical sibling bone marrow transplants for leukemia be restricted to large centers?

There is substantial evidence that the volume of medical procedures in a hospital has an inverse relationship with mortality. We analyzed data for 1313 recipients of HLA-identical sibling bone marrow transplants for early leukemia (acute leukemia in first remission or chronic myelogenous leukemia in first chronic phase) to determine whether transplant outcome differed in small and large centers. Transplants were performed in 86 bone marrow transplant centers active between the years 1983 and 1988, which participated in the International Bone Marrow Transplant Registry. Twenty-one (24%) centers performed five or fewer allogeneic transplants per year during the study period; five (6%) performed more than 40 per year. After adjustment for differences in patient and disease characteristics, the relative risks of treatment-related mortality (1.53, P less than .01) and treatment failure (1.38, P less than .04) were higher among patients who received transplants at centers doing five or fewer transplants per year than among those at larger centers. Among patients receiving transplants in centers performing more than five transplants a year, there was no statistically significant correlation between number of transplants and outcome.

Increasing utilization of allogeneic bone marrow transplantation. Results of the 1988-1990 survey.

OBJECTIVE: To determine the pattern and frequency of allogeneic bone marrow transplantation from related and unrelated donors from 1988 to 1990. DESIGN AND SETTING: Survey of 342 institutions in 47 countries. MEASUREMENTS: Numbers of patients receiving bone marrow transplantation for specific disease categories at institutions with active allogeneic bone marrow transplant programs. MAIN RESULTS: Patients (14,745) received allogeneic bone marrow transplantation between 1988 and 1990; of these, 1153 (8%) were from unrelated donors. Reasons for transplantation were acute leukemia (47%), chronic myelogenous leukemia (27%), lymphoma and other malignancies (10%), severe aplastic anemia (9%), and other nonmalignant diseases (7%). The number of allogeneic bone marrow transplants per million persons differed among countries, averaging 7.7 per million in North America and 5.7 per million in western Europe. CONCLUSIONS: The use of allogeneic bone marrow transplantation continued to increase at a rate of more than 600 additional patients and 25 new transplant teams annually. This rise is due in part to increasing use of unrelated volunteers as donors. Resources allocated for transplants vary widely among countries.