FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 341:14-21 July 1, 1999 Number 1 Next

Abstract PDF Editorial by Thomas, E. D. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

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.

View this table: [in this window] [in a new window]   Table 1. Characteristics of 6691 Recipients of Allogeneic Bone Marrow Transplants Who Were Disease-free Two Years after Transplantation.

 
The International Bone Marrow Transplant Registry

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.

View this table: [in this window] [in a new window]   Table 2. Primary Causes of Death among Patients Who Were Disease-free Two Years after Transplantation.

 
Relative mortality rates were calculated for each disease category as a way of comparing transplant recipients with a sex-, age-, and nationality-matched general population. Among patients who underwent transplantation for AML, the relative mortality rate was 19.2 (95 percent confidence interval, 12.7 to 25.7) two years after transplantation and 10.2 (95 percent confidence interval, 7.0 to 13.4) five years after transplantation; it decreased to 4.5 (95 percent confidence interval, 1.0 to 8.0) nine years after transplantation. Among patients who received a transplant for ALL, the relative mortality rate was 20.1 (95 percent confidence interval, 9.6 to 30.6) 2 years after transplantation, 25.9 (95 percent confidence interval, 17.9 to 34.0) 5 years after transplantation, and 15.4 (95 percent confidence interval, 1.1 to 29.8) 10 years after transplantation. The relative mortality rate among patients with CML was 11.2 (95 percent confidence interval, 7.1 to 15.3) 2 years after transplantation, 11.2 (95 percent confidence interval, 8.2 to 14.1) 5 years after transplantation, and 19.1 (95 percent confidence interval, 8.8 to 29.4) 10 years after transplantation. Two years after transplantation, patients who underwent transplantation for aplastic anemia had a relative mortality rate of 30.8 (95 percent confidence interval, 17.3 to 44.5), which decreased to 3.9 (95 percent confidence interval, 0.5 to 7.2) six years after transplantation.

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).

View this table: [in this window] [in a new window]   Table 3. Relative Risk of Late Death among Patients with Acute Myelogenous Leukemia in Continuous Complete Remission Two Years after Transplantation.

 

View this table: [in this window] [in a new window]   Table 4. Relative Risk of Late Death among Patients with Acute Lymphoblastic Leukemia in Continuous Complete Remission Two Years after Transplantation.

 

View this table: [in this window] [in a new window]   Table 5. Relative Risk of Late Death among Patients with Chronic Myelogenous Leukemia in Continuous Complete Remission Two Years after Transplantation.

 

View this table: [in this window] [in a new window]   Table 6. Relative Risk of Late Death among Patients Alive Two Years after Transplantation for Aplastic Anemia.

 
Among the 6012 patients who were alive at the last contact, Karnofsky performance scores were available for 4201 (70 percent). Among these 4201 patients, the Karnofsky score was 100 for 64 percent, 90 for 21 percent, 80 for 9 percent, 70 for 4 percent, and less than 70 for 2 percent. This distribution of scores was relatively constant over time; that is, the proportions of patients with scores greater than 80 at 2 years and 10 years after transplantation were similar. A Karnofsky score of less than 90 was reported by 14 percent of patients with AML, 11 percent of those with ALL, 19 percent of those with CML, and 12 percent of those with aplastic anemia (P=0.001 for the comparison according to disease). Among the 3448 patients with leukemia for whom Karnofsky scores were reported, there was no relation between the score and the stage of the disease before transplantation. Patients with active chronic GVHD two years after transplantation were significantly more likely to have a Karnofsky score of less than 90 (32 percent) than were those without chronic GVHD or with chronic GVHD that had resolved within two years after transplantation (7 percent and 13 percent, respectively; P<0.001 for both comparisons).

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

1. Horowitz MM, Rowlings PA. An update from the International Bone Marrow Transplant Registry and the Autologous Blood and Marrow Transplant Registry on current activity in hematopoietic stem cell transplantation. Curr Opin Hematol 1997;4:395-400. [Medline]
2. Zittoun RA, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Engl J Med 1995;332:217-223. [Free Full Text]
3. Barrett AJ, Horowitz MM, Pollock BH, et al. Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission. N Engl J Med 1994;331:1253-1258. [Free Full Text]
4. Goldman JM. Optimizing treatment for chronic myeloid leukemia. N Engl J Med 1997;337:270-271. [Free Full Text]
5. Young NS, Barrett AJ. The treatment of severe acquired aplastic anemia. Blood 1995;85:3367-3377. [Free Full Text]
6. Passweg JR, Socié G, Hinterberger W, et al. Bone marrow transplantation for severe aplastic anemia: has outcome improved? Blood 1997;90:858-864. [Free Full Text]
7. Kernan NA, Bartsch G, Ash RC, et al. Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. N Engl J Med 1993;328:593-602. [Free Full Text]
8. Henslee-Downey PJ, Abhyankar SH, Parrish RS, et al. Use of partially mismatched related donors extends access to allogeneic marrow transplant. Blood 1997;89:3864-3872. [Free Full Text]
9. Gluckman E, Rocha V, Boyer-Chammard A, et al. Outcome of cord-blood transplantation from related and unrelated donors. N Engl J Med 1997;337:373-381. [Free Full Text]
10. Klein JP, Moeschberger ML. Survival analysis: techniques for censored and truncated data. New York: Springer-Verlag, 1997.
11. Andersen PK, Vaeth M. Simple parametric and nonparametric models for excess and relative mortality. Biometrics 1989;45:523-535. [CrossRef][Medline]
12. Armitage JO. Bone marrow transplantation. N Engl J Med 1994;330:827-838. [Free Full Text]
13. Beatty PG. Clinical and managed care issues in blood and marrow transplantation for hematologic diseases: report of a symposium, 14 March 1996, Washington, D.C. Exp Hematol 1997;25:1195-1208. [Medline]
14. Duell T, van Lint MT, Ljungman P, et al. Health and functional status of long-term survivors of bone marrow transplantation. Ann Intern Med 1997;126:184-192. [Free Full Text]
15. Hudson MM, Jones D, Boyett J, Sharp GB, Pui CH. Late mortality of long-term survivors of childhood cancer. J Clin Oncol 1997;15:2205-2213. [Free Full Text]
16. Nicholson HS, Fears TR, Byrne J. Death during adulthood in survivors of childhood and adolescent cancer. Cancer 1994;73:3094-3102. [CrossRef][Medline]
17. Robertson CM, Hawkins MM, Kingston JE. Late deaths and survival after childhood cancer: implications for cure. BMJ 1994;309:162-166. [Free Full Text]
18. Green DM, Zevon MA, Reese PA, Lowrie GS, Michalek AM. Factors that influence the further survival of patients who survive for five years after the diagnosis of cancer in childhood or adolescence. Med Pediatr Oncol 1994;22:91-96. [Erratum, Med Pediatr Oncol 1996;26:72.] [Medline]
19. Hawkins MM, Kingston JE, Kinnier Wilson LMK. Late deaths after treatment for childhood cancer. Arch Dis Child 1990;65:1356-1363. [Free Full Text]
20. de Lima M, Strom SS, Keating M, et al. Implications of potential cure in acute myelogenous leukemia: development of subsequent cancer and return to work. Blood 1997;90:4719-4724. [Free Full Text]
21. Freireich EJ, Keating MJ. Conclusions regarding leukemia long-term survival. Cancer 1997;80:Suppl:2215-2217. [CrossRef][Medline]
22. Appelbaum FR, Kopecky KJ. Long-term survival after chemotherapy for acute myeloid leukemia: the experience of the Southwest Oncology Group. Cancer 1997;80:Suppl:2199-2204. [CrossRef][Medline]
23. Sullivan KM. Graft-versus-host disease. In: Forman SJ, Blume KG, Thomas ED, eds. Bone marrow transplantation. Cambridge, Mass.: Blackwell Scientific, 1994:339-62.
24. Storek J, Gooley T, Witherspoon RP, Sullivan KM, Storb R. Infectious morbidity in long-term survivors of allogeneic marrow transplantation is associated with low CD4 T cell counts. Am J Hematol 1997;54:131-138. [CrossRef][Medline]
25. Deeg HJ, Leisenring W, Storb R, et al. Long-term outcome after marrow transplantation for severe aplastic anemia. Blood 1998;91:3637-3645. [Free Full Text]
26. Curtis RE, Rowlings PA, Deeg HJ, et al. Solid cancers after bone marrow transplantation. N Engl J Med 1997;336:897-904. [Free Full Text]
27. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995;86:2041-2050. [Free Full Text]
28. Collins RH Jr, Shpilberg O, Drobyski WR, et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997;15:433-444. [Free Full Text]
29. Cella DF, Bonomi AE. Measuring quality of life: 1995 update. Oncology (Huntingt) 1995;9:Suppl:47-60. [Medline]

Abstract PDF Editorial by Thomas, E. D. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

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
Extract | Full Text  
N Engl J Med 1999; 341:1394-1395, Oct 28, 1999. Correspondence

This article has been cited by other articles:

• Olivieri, A., Locatelli, F., Zecca, M., Sanna, A., Cimminiello, M., Raimondi, R., Gini, G., Mordini, N., Balduzzi, A., Leoni, P., Gabrielli, A., Bacigalupo, A. (2009). Imatinib for refractory chronic graft-versus-host disease with fibrotic features. Blood 114: 709-718 [Abstract] [Full Text]  
• Pidala, J., Anasetti, C., Jim, H. (2009). Quality of life after allogeneic hematopoietic cell transplantation. Blood 114: 7-19 [Abstract] [Full Text]  
• Savani, B. N., Goodman, S., Barrett, A. J. (2009). Can Routine Posttransplant HPV Vaccination Prevent Commonly Occurring Epithelial Cancers after Allogeneic Stem Cell Transplantation?. Clin. Cancer Res. 15: 2219-2221 [Abstract] [Full Text]  
• Socie, G., de Latour, R. P., McDonald, G. B. (2009). Hepatitis C virus and allogeneic stem cell transplantation still matters!. haematol 94: 170-172 [Full Text]  
• Armenian, S. H., Sun, C.-L., Francisco, L., Steinberger, J., Kurian, S., Wong, F. L., Sharp, J., Sposto, R., Forman, S. J., Bhatia, S. (2008). Late Congestive Heart Failure After Hematopoietic Cell Transplantation. JCO 26: 5537-5543 [Abstract] [Full Text]  
• Armenian, S. H., Bhatia, S. (2008). Cardiovascular disease after hematopoietic cell transplantation - lessons learned. haematol 93: 1132-1136 [Full Text]  
• Fujii, H., Cuvelier, G., She, K., Aslanian, S., Shimizu, H., Kariminia, A., Krailo, M., Chen, Z., McMaster, R., Bergman, A., Goldman, F., Grupp, S. A., Wall, D. A., Gilman, A. L., Schultz, K. R. (2008). Biomarkers in newly diagnosed pediatric-extensive chronic graft-versus-host disease: a report from the Children's Oncology Group. Blood 111: 3276-3285 [Abstract] [Full Text]  
• Howard, D. H., Meltzer, D., Kollman, C., Maiers, M., Logan, B., Gragert, L., Setterholm, M., Horowitz, M. M. (2008). Use of Cost-Effectiveness Analysis to Determine Inventory Size for a National Cord Blood Bank. Med Decis Making 28: 243-253 [Abstract]  
• Lee, S. J., Flowers, M. E. D. (2008). Recognizing and Managing Chronic Graft-Versus-Host Disease. ASH Education Book 2008: 134-141 [Abstract] [Full Text]  
• Majhail, N. S. (2008). Old and New Cancers after Hematopoietic-Cell Transplantation. ASH Education Book 2008: 142-149 [Abstract] [Full Text]  
• Bhatia, S., Francisco, L., Carter, A., Sun, C.-L., Baker, K. S., Gurney, J. G., McGlave, P. B., Nademanee, A., O'Donnell, M., Ramsay, N. K. C., Robison, L. L., Snyder, D., Stein, A., Forman, S. J., Weisdorf, D. J. (2007). Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study. Blood 110: 3784-3792 [Abstract] [Full Text]  
• Svegliati, S., Olivieri, A., Campelli, N., Luchetti, M., Poloni, A., Trappolini, S., Moroncini, G., Bacigalupo, A., Leoni, P., Avvedimento, E. V., Gabrielli, A. (2007). Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease. Blood 110: 237-241 [Abstract] [Full Text]  
• Shankar, S. M., Carter, A., Sun, C.-L., Francisco, L., Baker, K. S., Gurney, J. G., Weisdorf, D. G., Forman, S. J., Robison, L. L., Grant, M., Bhatia, S. (2007). Health Care Utilization by Adult Long-term Survivors of Hematopoietic Cell Transplant: Report from the Bone Marrow Transplant Survivor Study. Cancer Epidemiol. Biomarkers Prev. 16: 834-839 [Abstract] [Full Text]  
• Sakoda, Y., Hashimoto, D., Asakura, S., Takeuchi, K., Harada, M., Tanimoto, M., Teshima, T. (2007). Donor-derived thymic-dependent T cells cause chronic graft-versus-host disease. Blood 109: 1756-1764 [Abstract] [Full Text]  
• Socie, G. (2006). Chronic GVHD and health status in long-term survivors. Blood 108: 2503-2504 [Full Text]  
• Fraser, C. J., Bhatia, S., Ness, K., Carter, A., Francisco, L., Arora, M., Parker, P., Forman, S., Weisdorf, D., Gurney, J. G., Baker, K. S. (2006). Impact of chronic graft-versus-host disease on the health status of hematopoietic cell transplantation survivors: a report from the Bone Marrow Transplant Survivor Study. Blood 108: 2867-2873 [Abstract] [Full Text]  
• Rovo, A., Tichelli, A., Passweg, J. R., Heim, D., Meyer-Monard, S., Holzgreve, W., Gratwohl, A., De Geyter, C. (2006). Spermatogenesis in long-term survivors after allogeneic hematopoietic stem cell transplantation is associated with age, time interval since transplantation, and apparently absence of chronic GvHD. Blood 108: 1100-1105 [Abstract] [Full Text]  
• Couriel, D. R., Hosing, C., Saliba, R., Shpall, E. J., Anderlini, P., Rhodes, B., Smith, V., Khouri, I., Giralt, S., de Lima, M., Hsu, Y., Ghosh, S., Neumann, J., Andersson, B., Qazilbash, M., Hymes, S., Kim, S., Champlin, R., Donato, M. (2006). Extracorporeal photochemotherapy for the treatment of steroid-resistant chronic GVHD. Blood 107: 3074-3080 [Abstract] [Full Text]  
• Pene, F., Aubron, C., Azoulay, E., Blot, F., Thiery, G., Raynard, B., Schlemmer, B., Nitenberg, G., Buzyn, A., Arnaud, P., Socie, G., Mira, J.-P. (2006). Outcome of Critically Ill Allogeneic Hematopoietic Stem-Cell Transplantation Recipients: A Reappraisal of Indications for Organ Failure Supports. JCO 24: 643-649 [Abstract] [Full Text]  
• Chalandon, Y., Degermann, S., Villard, J., Arlettaz, L., Kaiser, L., Vischer, S., Walter, S., Heemskerk, M. H. M., van Lier, R. A. W., Helg, C., Chapuis, B., Roosnek, E. (2006). Pretransplantation CMV-specific T cells protect recipients of T-cell-depleted grafts against CMV-related complications. Blood 107: 389-396 [Abstract] [Full Text]  
• Pavletic, S. Z., Carter, S. L., Kernan, N. A., Henslee-Downey, J., Mendizabal, A. M., Papadopoulos, E., Gingrich, R., Casper, J., Yanovich, S., Weisdorf, D., for the members of the National Heart, Lung, and B, (2005). Influence of T-cell depletion on chronic graft-versus-host disease: results of a multicenter randomized trial in unrelated marrow donor transplantation. Blood 106: 3308-3313 [Abstract] [Full Text]  
• Syrjala, K. L., Langer, S. L., Abrams, J. R., Storer, B. E., Martin, P. J. (2005). Late Effects of Hematopoietic Cell Transplantation Among 10-Year Adult Survivors Compared With Case-Matched Controls. JCO 23: 6596-6606 [Abstract] [Full Text]  
• Ness, K. K., Bhatia, S., Baker, K. S., Francisco, L., Carter, A., Forman, S. J., Robison, L. L., Rosenthal, J., Gurney, J. G. (2005). Performance Limitations and Participation Restrictions Among Childhood Cancer Survivors Treated With Hematopoietic Stem Cell Transplantation: The Bone Marrow Transplant Survivor Study. Arch Pediatr Adolesc Med 159: 706-713 [Abstract] [Full Text]  
• Tomas, L. H. S., Loberiza, F. R. Jr, Klein, J. P., Layde, P. M., Lipchik, R. J., Rizzo, J. D., Bredeson, C. N., Horowitz, M. M. (2005). Risk Factors for Bronchiolitis Obliterans in Allogeneic Hematopoietic Stem-Cell Transplantation for Leukemia. Chest 128: 153-161 [Abstract] [Full Text]  
• Lee, S. J. (2005). New approaches for preventing and treating chronic graft-versus-host disease. Blood 105: 4200-4206 [Abstract] [Full Text]  
• Bhatia, S., Robison, L. L., Francisco, L., Carter, A., Liu, Y., Grant, M., Baker, K. S., Fung, H., Gurney, J. G., McGlave, P. B., Nademanee, A., Ramsay, N. K. C., Stein, A., Weisdorf, D. J., Forman, S. J. (2005). Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study. Blood 105: 4215-4222 [Abstract] [Full Text]  
• Lee, S., Kim, Y.-J., Min, C.-K., Kim, H.-J., Eom, K.-S., Kim, D.-W., Lee, J.-W., Min, W.-S., Kim, C.-C. (2005). The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 105: 3449-3457 [Abstract] [Full Text]  
• Stewart, B. L., Storer, B., Storek, J., Deeg, H. J., Storb, R., Hansen, J. A., Appelbaum, F. R., Carpenter, P. A., Sanders, J. E., Kiem, H.-P., Nash, R. A., Petersdorf, E. W., Moravec, C., Morton, A. J., Anasetti, C., Flowers, M. E. D., Martin, P. J. (2004). Duration of immunosuppressive treatment for chronic graft-versus-host disease. Blood 104: 3501-3506 [Abstract] [Full Text]  
• Oeffinger, K. C., Hudson, M. M. (2004). Long-term Complications Following Childhood and Adolescent Cancer: Foundations for Providing Risk-based Health Care for Survivors. CA Cancer J Clin 54: 208-236 [Abstract] [Full Text]  
• Syrjala, K. L., Langer, S. L., Abrams, J. R., Storer, B., Sanders, J. E., Flowers, M. E. D., Martin, P. J. (2004). Recovery and Long-term Function After Hematopoietic Cell Transplantation for Leukemia or Lymphoma. JAMA 291: 2335-2343 [Abstract] [Full Text]  
• Leger, C. S., Nevill, T. J. (2004). Hematopoietic stem cell transplantation: a primer for the primary care physician. CMAJ 170: 1569-1577 [Abstract] [Full Text]  
• Ades, L., Mary, J.-Y., Robin, M., Ferry, C., Porcher, R., Esperou, H., Ribaud, P., Devergie, A., Traineau, R., Gluckman, E., Socie, G. (2004). Long-term outcome after bone marrow transplantation for severe aplastic anemia. Blood 103: 2490-2497 [Abstract] [Full Text]  
• Peffault de Latour, R., Levy, V., Asselah, T., Marcellin, P., Scieux, C., Ades, L., Traineau, R., Devergie, A., Ribaud, P., Esperou, H., Gluckman, E., Valla, D., Socie, G. (2004). Long-term outcome of hepatitis C infection after bone marrow transplantation. Blood 103: 1618-1624 [Abstract] [Full Text]  
• Vincent, F., Costa, M.-A., Rondeau, E., Socie, G., Tichelli, A. (2003). Chronic renal failure: a nonmalignant late effect of allogeneic stem cell transplantation. Blood 102: 2695-2695 [Full Text]  
• Antin, J. H. (2003). A 41-Year-Old Woman With Chronic Myelogenous Leukemia. JAMA 290: 1083-1090 [Full Text]  
• Seaton, E. D., Szydlo, R. M., Kanfer, E., Apperley, J. F., Russell-Jones, R. (2003). Influence of extracorporeal photopheresis on clinical and laboratory parameters in chronic graft-versus-host disease and analysis of predictors of response. Blood 102: 1217-1223 [Abstract] [Full Text]  
• Akpek, G., Lee, S. J., Flowers, M. E., Pavletic, S. Z., Arora, M., Lee, S., Piantadosi, S., Guthrie, K. A., Lynch, J. C., Takatu, A., Horowitz, M. M., Antin, J. H., Weisdorf, D. J., Martin, P. J., Vogelsang, G. B. (2003). Performance of a new clinical grading system for chronic graft-versus-host disease: a multicenter study. Blood 102: 802-809 [Abstract] [Full Text]  
• Chang, G., McGarigle, C., Koby, D., Antin, J. H. (2003). Symptoms of Pain and Depression in Related Marrow Donors: Changes After Transplant. Psychosomatics 44: 59-64 [Abstract] [Full Text]  
• Lee, S. J., Klein, J. P., Barrett, A. J., Ringden, O., Antin, J. H., Cahn, J.-Y., Carabasi, M. H., Gale, R. P., Giralt, S., Hale, G. A., Ilhan, O., McCarthy, P. L., Socie, G., Verdonck, L. F., Weisdorf, D. J., Horowitz, M. M. (2002). Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse. Blood 100: 406-414 [Abstract] [Full Text]  
• Min, D., Taylor, P. A., Panoskaltsis-Mortari, A., Chung, B., Danilenko, D. M., Farrell, C., Lacey, D. L., Blazar, B. R., Weinberg, K. I. (2002). Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood 99: 4592-4600 [Abstract] [Full Text]  
• Okamoto, Y., Douek, D. C., McFarland, R. D., Koup, R. A. (2002). Effects of exogenous interleukin-7 on human thymus function. Blood 99: 2851-2858 [Abstract] [Full Text]  
• D'Andrea, A. D., Dahl, N., Guinan, E. C., Shimamura, A. (2002). Marrow Failure. ASH Education Book 2002: 58-72 [Abstract] [Full Text]  
• Maloney, D. G., Sandmaier, B. M., Mackinnon, S., Shizuru, J. A. (2002). Non-Myeloablative Transplantation. ASH Education Book 2002: 392-421 [Abstract] [Full Text]  
• Wingard, J. R., Vogelsang, G. B., Deeg, H. J. (2002). Stem Cell Transplantation: Supportive Care and Long-Term Complications. ASH Education Book 2002: 422-444 [Abstract] [Full Text]  
• Storek, J., Joseph, A., Espino, G., Dawson, M. A., Douek, D. C., Sullivan, K. M., Flowers, M. E. D., Martin, P., Mathioudakis, G., Nash, R. A., Storb, R., Appelbaum, F. R., Maloney, D. G. (2001). Immunity of patients surviving 20 to 30 years after allogeneic or syngeneic bone marrow transplantation. Blood 98: 3505-3512 [Abstract] [Full Text]  
• Chung, B., Barbara-Burnham, L., Barsky, L., Weinberg, K. (2001). Radiosensitivity of thymic interleukin-7 production and thymopoiesis after bone marrow transplantation. Blood 98: 1601-1606 [Abstract] [Full Text]  
• Weinberg, K., Blazar, B. R., Wagner, J. E., Agura, E., Hill, B. J., Smogorzewska, M., Koup, R. A., Betts, M. R., Collins, R. H., Douek, D. C. (2001). Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation. Blood 97: 1458-1466 [Abstract] [Full Text]  
• Leung, W., Hudson, M. M., Strickland, D. K., Phipps, S., Srivastava, D. K., Ribeiro, R. C., Rubnitz, J. E., Sandlund, J. T., Kun, L. E., Bowman, L. C., Razzouk, B. I., Mathew, P., Shearer, P., Evans, W. E., Pui, C.-H. (2000). Late Effects of Treatment in Survivors of Childhood Acute Myeloid Leukemia. JCO 18: 3273-3279 [Abstract] [Full Text]  
• Marr, K. A., Seidel, K., Slavin, M. A., Bowden, R. A., Schoch, H. G., Flowers, M. E. D., Corey, L., Boeckh, M. (2000). Prolonged fluconazole prophylaxis is associated with persistent protection against candidiasis-related death in allogeneic marrow transplant recipients: long-term follow-up of a randomized, placebo-controlled trial. Blood 96: 2055-2061 [Abstract] [Full Text]  
• Roux, E., Dumont-Girard, F., Starobinski, M., Siegrist, C.-A., Helg, C., Chapuis, B., Roosnek, E. (2000). Recovery of immune reactivity after T-cell-depleted bone marrow transplantation depends on thymic activity. Blood 96: 2299-2303 [Abstract] [Full Text]  
• Meyerson, M. (2000). Role of Telomerase in Normal and Cancer Cells. JCO 18: 2626-2634 [Abstract] [Full Text]  
• Kulkarni, S., Powles, R., Treleaven, J., Riley, U., Singhal, S., Horton, C., Sirohi, B., Bhagwati, N., Meller, S., Saso, R., Mehta, J. (2000). Chronic graft versus host disease is associated with long-term risk for pneumococcal infections in recipients of bone marrow transplants. Blood 95: 3683-3686 [Abstract] [Full Text]  
• Nietert, P. J., Abboud, M. R., Silverstein, M. D., Jackson, S. M. (2000). Bone marrow transplantation versus periodic prophylactic blood transfusion in sickle cell patients at high risk of ischemic stroke: a decision analysis. Blood 95: 3057-3064 [Abstract] [Full Text]  
• Oki, Y., Kami, M., Muto, Y., Lounici, A., Salmi, L. R., Socie, G., Klein, J. P., Horowitz, M. M., The Late Effects Working Committee of the Internat, (1999). Long-Term Survival after Bone Marrow Transplantation. NEJM 341: 1394-1395 [Full Text]  
• Thomas, E. D. (1999). Does Bone Marrow Transplantation Confer a Normal Life Span?. NEJM 341: 50-51 [Full Text]