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Background and Methods It is uncertain whether mortality rates among patients who have undergone bone marrow transplantation return to the level of the mortality rates of the general population. We analyzed the characteristics of 6691 patients listed in the International Bone Marrow Transplant Registry. All the patients were free of their original disease two years after allogeneic bone marrow transplantation. Mortality rates in this cohort were compared with those of an age-, sex-, and nationality-matched general population. Cox proportional-hazards regression was used to identify risk factors for death more than two years after transplantation (late death).
Results Among patients who were free of disease two years after transplantation, the probability of living for five more years was 89 percent (95 percent confidence interval, 88 to 90 percent). Among patients who underwent transplantation for aplastic anemia, the risk of death by the sixth year after transplantation did not differ significantly from that of a normal population. Mortality remained significantly higher than normal throughout the study among patients who underwent transplantation for acute lymphoblastic leukemia or chronic myelogenous leukemia and through the ninth year among those who underwent transplantation for acute myelogenous leukemia. Recurrent leukemia was the chief cause of death among patients who received a transplant for leukemia, whereas chronic graft-versus-host disease was the chief cause among those who received a transplant for aplastic anemia. Advanced, long-standing disease before transplantation and active chronic graft-versus-host disease were important risk factors for late death.
Conclusions In patients who receive an allogeneic bone marrow transplant as treatment for acute myelogenous or lymphoblastic leukemia, chronic myelogenous leukemia, or aplastic anemia and who are free of their original disease two years later, the disease is probably cured. However, for many years after transplantation, the mortality among these patients is higher than that in a normal population.
Many transplant recipients survive acute complications of the procedure and remain free of their original disease for several years, but little information is available about their long-term survival. It is unknown when, or even whether, the mortality rate among these survivors returns to that of an age- and sex-matched general population.
In this study of 6691 patients who were free of their original disease for at least two years after transplantation, we determined the rate of death more than two years after allogeneic marrow transplantation (late death), compared that rate with the death rate in the general population, and identified risk factors for late death among patients who received allografts for acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), CML, or aplastic anemia.
Methods
Patients
We studied the records of 6691 patients who received an allogeneic bone marrow transplant or a bone marrow transplant from an identical twin between January 1980 and December 1993 for AML, ALL, CML, or acquired aplastic anemia and who were free of their primary disease for at least two years after transplantation (i.e., who were long-term survivors). Data on these patients had been reported to the International Bone Marrow Transplant Registry by 221 transplantation centers worldwide. An additional 8889 patients received transplants at these centers during the study period but were ineligible for these analyses: 8533 died or had a relapse within two years after transplantation; 256 (<4 percent of the final study population) were alive at the last contact but were lost to follow-up within two years after transplantation; 94 received a second transplant less than two years after the initial transplantation; and 6 survived for more than two years but no information was on record regarding the status of their primary disease. The median duration of follow-up was 80 months. Of the 6691 patients in the study, 4346 were followed for at least 5 years after transplantation, 2742 were followed for at least 7 years, and 1116 were followed for at least 10 years.
The main characteristics of the patients, their diseases, and their transplantations are summarized in Table 1. In this analysis, early-stage leukemia included acute leukemia in first remission and CML in the first chronic phase; intermediate-stage leukemia included acute leukemia in a second or subsequent remission and CML in a second or subsequent chronic phase or accelerated phase; and advanced-stage leukemia included acute leukemia not in remission and CML in blast phase.
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The International Bone Marrow Transplant Registry is a group of more than 300 transplantation centers worldwide that contribute detailed data on all the allogeneic bone marrow transplantations they perform to the Statistical Center at the Medical College of Wisconsin. Approximately two thirds of all active transplantation centers worldwide report data to the registry. The registry data base includes information on 40 to 45 percent of all patients who have received an allogeneic transplant since 1970, with annual updates. Computerized checks for errors, review of submitted data by physicians, and on-site audits of participating centers are used to monitor the quality of the data. To participate in this study, centers had to be able to provide follow-up on at least 90 percent of all eligible patients.
Statistical Analysis
Because of differences in the biologic features of disease, risk of recurrence, age, pretransplantation treatment, and conditioning regimens, we analyzed data on patients with AML, ALL, CML, and aplastic anemia separately. Reported causes of death were reviewed and categorized. Patients who died as a result of a relapse after transplantation were considered to have died of their original disease, even if this was not the recorded proximate cause of death. Similarly, patients who died of active chronic graft-versus-host disease (GVHD) were considered to have died of this complication even if other complications (e.g., infection or bleeding) were recorded as the proximate cause. Deaths due to infection included only those among patients without GVHD.
Data were analyzed as of December 31, 1996. Late deaths were defined as all deaths occurring more than two years after transplantation. Relapse-related deaths were defined as deaths in patients who had a relapse at any time after transplantation; deaths not related to relapse were those that occurred during a continuous complete remission. In analyses of the time to relapse-related death, data were censored at the time of death during a complete remission or at the time of last contact; in analyses of the time to death not related to relapse, data were censored at the time of a relapse-related death or the last contact. The probabilities of survival, of relapse-related death, and of death not related to relapse were estimated by the Kaplan–Meier method.
Estimates of the hazard rate for all the patients and of the hazard rates according to the type of disease were obtained with the use of the Nelson–Aalen estimator.10 The hazard rate provides a measure of the rate at which survivors die: it is the probability at any point in time that a patient who survives to that point will die at that time. A hazard rate of 0.02 at three years, for example, implies that 20 of 1000 patients who are alive three years after transplantation are expected to die shortly after that time.
We calculated estimates of relative mortality as described by Andersen and Vaeth,11 taking into account differences among patients with regard to age, sex, race, and nationality. Relative mortality with respect to a transplant recipient is the relative risk of dying at a given time after transplantation as compared with a person of similar age, sex, and nationality in the general population. Relative mortality rates with 95 percent confidence intervals that included 1.0 were not considered to indicate a significant difference from the rates in a normal population. To calculate relative mortality, we used age-, sex-, and nationality-specific rates for all countries and political regions from which transplantations were reported except Croatia, the Czech Republic, Hong Kong, Hungary, Israel, Jordan, Russia, Saudi Arabia, Taiwan, and Venezuela, for which data were not available. These areas accounted for only 5 percent of the study population.
Potential risk factors for late death were analyzed with the use of Cox regression models. All potential risk factors were checked, with time-dependent covariates, to ensure that assumptions of proportionality were met. Factors were then tested for their association with late death by means of forward stepwise selection of variables.10 End points were the time to death from any cause, the time to relapse-related death, and the time to death not related to relapse. All comparisons reaching the 0.05 level of significance are presented, but because multiple comparisons were made, those with P values greater than 0.01 should be interpreted with caution.
Results
Table 1 summarizes the characteristics of the study population. Most patients received transplants to treat early-stage leukemia. Among patients with CML, 10 percent had undergone splenectomy before transplantation. Most donors were HLA-identical siblings. Total-body irradiation was used in the conditioning regimens of 4460 patients (67 percent of the entire group). Acute GVHD developed in 25 percent of patients, and in 43 percent chronic GVHD developed within two years after transplantation. Of the 6691 patients, 1839 (27 percent) still had active chronic GVHD two years after transplantation.
Among the 6691 patients who were free of their primary disease two years after transplantation, the probability of surviving for five more years was 89 percent (95 percent confidence interval, 88 to 90 percent). Patients who underwent transplantation for treatment of aplastic anemia had a significantly lower probability of late death than those who underwent transplantation for leukemia; the probabilities were 6 percent (95 percent confidence interval, 4 to 7 percent) and 12 percent (95 percent confidence interval, 11 to 13 percent) at seven years (P<0.001). Among patients with leukemia who were disease-free two years after transplantation, the probability of relapse five years later was 11 percent (95 percent confidence interval, 10 to 12 percent) and the probability of relapse-related death was 6 percent (95 percent confidence interval, 6 to 7 percent). The probability of death due to other causes was 6 percent (95 percent confidence interval, 5 to 7 percent). For the whole cohort, the probability of new cancer appearing seven years after transplantation was 2 percent (95 percent confidence interval, 1.6 to 2.4 percent).
Overall hazard rates (i.e., instantaneous risks of death) were between 0.02 and 0.03 during the third and fourth years after transplantation and then decreased to between 0.01 and 0.02.
The primary causes of late death are summarized in Table 2. Recurrent leukemia was the most frequent cause of late death after transplantation for leukemia, and chronic GVHD was the second most frequent cause. Chronic GVHD was the most frequent cause of late death after transplantation for aplastic anemia.
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Results of multivariate analyses of risk factors for late death are summarized in Tables 3, 4, 5, and 6. Patients who had advanced-stage leukemia before transplantation were at a significantly higher risk of late death, whether death was related or not related to a relapse, than patients who had early-stage leukemia. Among patients who underwent transplantation for AML, those who had active chronic GVHD two years after transplantation had a risk of late death not related to relapse that was more than three times the risk for patients without GVHD (Table 3). Among patients who received a transplant for ALL, older age was usually associated with an increased risk of late death due to relapse or other causes; a transplant from a female donor to a male recipient and conditioning regimens that included single-dose total-body irradiation of 10 Gy or more were associated with higher risks of deaths not related to relapse (Table 4). Among patients who received a transplant for CML, those who received a T-cell–depleted transplant had a higher risk of relapse-related death than those whose grafts were not T-cell–depleted; patients with active chronic GVHD or previous acute GVHD had higher risks of death not due to relapse (Table 5). Finally, among patients who underwent transplantation for aplastic anemia, transplantation more than a year after diagnosis, acute GVHD, and active chronic GVHD two years after transplantation were independent risk factors for late death (Table 6).
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Discussion
Allogeneic bone marrow transplantation is associated with a substantial risk of death within the first two years after the procedure,1,12,13 whereas after two years survival curves often reach a plateau. This study of data on 6691 patients who were disease-free two years after transplantation shows that such patients have an excellent prognosis. The probability of surviving for seven years after transplantation was 89 percent for the whole cohort. Nevertheless, the risk of late death is not negligible. Our objective was to identify survivors with a high risk of late death who might be candidates for innovative methods of surveillance or intervention trials.
A study by the European Group for Blood and Marrow Transplantation (EBMT) that involved approximately 800 patients who survived for more than five years could not evaluate the mortality rates among subgroups of patients with different primary diseases because of the limited numbers of patients.14 Our study included 4346 patients who survived for at least five years after transplantation, 54 percent of whose data had been reported by European centers. We did not have access to information that would enable us to identify patients who were included in both studies; however, by analyzing the eligibility criteria and population description published by the EBMT, we estimate that about 550 patients at most (less than 10 percent of the current study population) were included in both studies. In both the present study and the EBMT study, the actuarial mortality of patients who survived for five years after transplantation was about 8 percent five years later, a rate higher than that in the general population. In contrast, among patients who underwent transplantation for aplastic anemia, the mortality rate about six years after transplantation did not differ significantly from that in the general population, and among those who underwent transplantation for AML, the mortality rate was normal after nine years. In the other groups, a persistent risk of recurrent leukemia kept the relative mortality high. The risk of relapse among the patients we studied, though important, is substantially less than that reported among patients treated with conventional chemotherapy, for whom late relapse is the leading cause of death.15,16,17,18,19,20 Patients treated with conventional chemotherapy may have a relapse as late as 10 years after the first complete remission.21,22
Chronic GVHD is the chief cause of death not related to relapse. It may lead to late death as a direct complication (e.g., bronchiolitis obliterans) or by the associated immunodeficiency that increases susceptibility to infections.23,24 Deeg et al. also found that chronic GVHD was the leading cause of disease and death among long-term survivors after transplantation for aplastic anemia.25
Notably, 6 percent of late deaths were due to infection in patients who did not have GVHD. Nearly half of these infections were bacterial and probably reflect long-lasting immunodeficiency after transplantation.24 Recipients of transplants from HLA-mismatched or unrelated donors had risks of late death similar to those of recipients of transplants from HLA-identical siblings, even though as recipients of alternative-donor transplants their risk of early transplantation-related mortality was higher. However, recipients of transplants from mismatched related donors or unrelated donors made up only 11 percent of the study population, and their follow-up tended to be shorter. Similarly, late mortality among recipients of transplants from their identical twins was close to that among recipients of HLA-identical allografts from siblings, but the numbers of such patients were too small to allow us to draw firm conclusions.
New cancers accounted for 6 percent of the late deaths. The incidence of cancer among survivors of transplantation is significantly higher than that in the general population.26 Some of these cancers may be related to the use of irradiation in the conditioning regimen26; others may result from previous therapy for leukemia.20 Another 6 percent of late deaths occurred as a result of organ failure (due to liver, cardiac, pulmonary, and renal diseases). It is likely that some of these deaths also resulted from pretransplantation treatment, since these kinds of late effects are known to occur in patients who receive only chemotherapy.
We found that patients who underwent transplantation for advanced leukemia or long-standing aplastic anemia had relatively high risks of late death. For ALL, an age greater than 40 years at transplantation was associated with an increased risk of death due to relapse. Among patients who received a transplant for CML, there was an increased risk of relapse among patients who received T-cell–depleted grafts. Careful monitoring of such patients may be important, since infusions of donor lymphocytes can control relapse of CML after transplantation.27,28
Our results should be interpreted with caution because protocols for transplantation, treatment of complications, and follow-up were not uniform among patients in this cohort. Transplantation techniques have changed over the three decades since the first patient was enrolled in the international registry. Prevention of some post-transplantation complications, such as acute GVHD, has improved, and treatment of relapsed CML is now more effective. Moreover, transplantation is now used more often in older patients and in patients whose donors are not HLA-identical siblings. The influence of these developments on the status of future long-term survivors is unknown. The data reported to the International Bone Marrow Transplant Registry suggest that functional status is good to excellent — as evidenced by Karnofsky scores of 80 to 100 — in most patients, but the Karnofsky score is an insensitive indicator of the quality of life, and studies with more sensitive instruments are needed.29
In conclusion, in patients who are disease-free two years after allogeneic marrow transplantation, the probability of cure is high. However, for years after transplantation mortality rates remain higher than those expected in the general population. To prevent and treat life-threatening late events, we recommend prolonged follow-up of patients who receive transplants.
Supported by Public Health Service grants (P01-CA-40053 and U24-CA-76518) from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung, and Blood Institute; by a contract (N01-CP-51028) with the National Cancer Institute; and by grants from Alpha Therapeutic, Amgen, Baxter Healthcare, Bayer, Berlex Laboratories, the Blue Cross–Blue Shield Association, the Lynde and Harry Bradley Foundation, Bristol-Myers Squibb, CellPro, Centeon, the Center for Advanced Studies in Leukemia, Chimeric Therapies, Chiron Therapeutics, the Charles E. Culpeper Foundation, the Eleanor Naylor Dana Charitable Trust, the Eppley Foundation for Research, Genentech, Glaxo Wellcome, ICN Pharmaceuticals, Immunex, the Kettering Family Foundation, Kirin Brewery, the Robert J. Kleberg, Jr., and Helen C. Kleberg Foundation, Herbert H. Kohl Charities, Nada and Herbert P. Mahler Charities, the Milstein Family Foundation, the Milwaukee Foundation–Elsa Schoeneich Research Fund, NeXstar Pharmaceuticals, the Samuel Roberts Noble Foundation, Novartis Pharmaceuticals, Ortho Biotech, the John Oster Family Foundation, the Jane and Lloyd Pettit Foundation, Alirio Pfiffer Bone Marrow Transplant Support Association, Pfizer, Pharmacia & Upjohn, Principal Mutual Life Insurance, RGK Foundation, Roche Laboratories, Rockwell Automation Allen-Bradley, SangStat Medical Corporation, Schering-Plough Oncology, Searle, the Stackner Family Foundation, the Starr Foundation, the Joan and Jack Stein Foundation, SyStemix, United Resource Networks, Wyeth–Ayerst Laboratories, and an anonymous donor.
Source Information
From the Service d'Hématologie–Greffe de Moelle, Hôpital Saint Louis, Paris (G.S.); the International Bone Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee (J.V.S., P.A.R., J.P.K.); the College of Medicine, University of Florida, Gainesville (J.R.W.); the Division of Hematology, Oncology, and Transplantation, University of Minnesota, Minneapolis (D.W.); the Division of Transplantation Medicine, University of South Carolina, Columbia (P.J.H.-D.); the Department of Medicine, University of Ottawa, Ottawa, Ont., Canada (C.B.); the Service d'Hématologie, Centre Hospitalier Universitaire de Besançon, Besançon, France (J.-Y.C.); the Department of Medicine, Kantonsspital Basel, Basel, Switzerland (J.R.P.); the Department of Internal Medicine, University Hospital, Maastricht, the Netherlands (H.C.S.); and the Department of Hematology, Klinikum Grosshadern, Munich, Germany (H.-J.K.). Other authors were Christine Bender-Götze, M.D., Department of Hematology–Oncology, Kinderpoliklinik, University of Munich, Munich, Germany; Bruce M. Camitta, M.D., Department of Pediatrics, Medical College of Wisconsin, Milwaukee; Kamar Godder, M.D., Division of Transplantation Medicine, University of South Carolina, Columbia; Mary M. Horowitz, M.D., International Bone Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee; and Alan S. Wayne, M.D., Division of Pediatric Hematology–Oncology, University of Miami School of Medicine, Miami.
Address reprint requests to Dr. Mary M. Horowitz at the International Bone Marrow Transplant Registry, Medical College of Wisconsin, 8701 Watertown Plank Rd., P.O. Box 26509, Milwaukee, WI 53226, or at marymh{at}mcw.edu.
References
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Related Letters:
Long-Term Survival after Bone Marrow Transplantation
Oki Y., Kami M., Muto Y., Lounici A., Salmi L. R., Socié G., Klein J. P., Horowitz M. M., The Late Effects Working Committee of the International Bone Marrow Transplant Registry
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Full Text
N Engl J Med 1999;
341:1394-1395, Oct 28, 1999.
Correspondence
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