Key Points
Question
What are the trends in life expectancy and cause-specific late mortality after allogeneic blood or marrow transplantation over a 40-year period?
Findings
This cohort study of 4741 individuals 2 years after allogeneic blood or marrow transplantation performed between 1974 and 2014 found that, although late mortality declined, life expectancy was not fully restored to expected rates in the general US population. However, the decline in late mortality appeared to be limited to transplants performed in childhood or with bone marrow as a stem cell source, without meaningful declines for older patients or for those who received peripheral blood stem cell transplant.
Meaning
The findings of this study suggest that efforts to mitigate causes may be useful to reduce late mortality after blood or marrow transplantation.
Abstract
Importance
The past 4 decades have seen substantial changes in allogeneic blood or marrow transplantation (BMT) practice, with the overarching goal of expanding the eligible patient pool while optimizing disease-free survival.
Objective
To determine trends in life expectancy and cause-specific late mortality after allogeneic BMT performed over a 40-year period.
Design, Setting, and Participants
A retrospective cohort study of 4741 individuals who lived 2 or more years after allogeneic BMT performed between January 1, 1974, and December 31, 2014, was conducted at City of Hope, University of Minnesota, or University of Alabama at Birmingham. The end of follow-up was March 23, 2020.
Exposures
Allogeneic BMT performed in 3 eras: 1974-1989, 1990-2004, and 2005-2014.
Main Outcomes and Measures
All-cause, recurrence-related, and nonrecurrence-related mortality and projected reduction in life expectancy. Information regarding vital status and cause of death was obtained from the National Death Index Plus and Accurint databases.
Results
Of the 4741 individuals included in the study, 2735 (57.7%) were male; median age at BMT was 33 years (range, 0-75 years). The cumulative incidence of recurrence-related mortality plateaued at 10 years, reaching 12.2% (95% CI, 11.0%-13.4%) at 30 years from BMT. In contrast, the incidence of nonrecurrence-related mortality continued to increase and was 22.3% (95% CI, 20.4%-24.3%) at 30 years. Leading causes of nonrecurrence-related mortality included infection (30-year cumulative incidence, 10.7%; standardized mortality ratio [SMR], 52.0), subsequent malignant neoplasms (30-year cumulative incidence, 7.0%; SMR, 4.8), cardiovascular disease (30-year cumulative incidence, 4.6%; SMR, 4.1), and pulmonary disease (30-year cumulative incidence, 2.7%; SMR, 13.9). Compared with the general population, the relative mortality remained higher at 30 or more years after BMT (SMR, 5.4; 95% CI, 4.0-7.1). The cohort experienced a 20.8% reduction in life expectancy (8.7 years of life lost). Compared with 1974-1989 (reference), the adjusted 10-year hazard ratio (HR) of all-cause mortality declined over the 3 eras (1990-2004: HR, 0.67; 95% CI, 0.53-0.85; 2005-2014: HR, 0.52; 95% CI, 0.39-0.69; P < .001 for trend), as did years of life lost (1974-1989: 9.9 years [reference]; 1990-2004: 6.5 years; and 2005-2014: 4.2 years). The reduction in late mortality was most pronounced among individuals who underwent transplantation at ages younger than 18 years (1990-2004: HR, 0.62; 95% CI, 0.40-0.96; 2005-2014: HR, 0.30; 95% CI, 0.16-0.54; reference: 1974-1989; P < .001 for trend) and those who received bone marrow (1990-2004: HR, 0.70; 95% CI, 0.54-0.90; 2005-2014: HR, 0.45; 95% CI, 0.29-0.69; reference: 1974-1989; P < .001 for trend).
Conclusions and Relevance
This cohort study noted that late mortality among recipients of allogeneic BMT has decreased over the past 40 years; however, life expectancy was not restored to expected rates compared with the general US population. Furthermore, the reduction in risk of late mortality appeared to be confined to those who underwent transplantation at a younger age or those who received bone marrow. Further efforts to mitigate disease recurrence, infections, subsequent neoplasms, cardiovascular disease, and pulmonary disease may be useful in this population.
This cohort study examines changes in late mortality and life expectancy in individuals who received blood or bone marrow transplantation from 1974 to 2014.
Introduction
Allogeneic blood or marrow transplantation (BMT) is an established therapeutic option for patients with hematologic malignant neoplasms and other life-threatening illnesses; an estimated 10 000 patients receive allogeneic BMT in the US annually.1,2 The practice of BMT has changed in notable ways over the past 40 years. These changes include older age at BMT; use of alternative stem cell sources, such as peripheral blood stem cells (PBSCs) and cord blood; and use of nonmyeloablative or reduced-intensity conditioning. Early transplant-related mortality has decreased owing to improved strategies in supportive care and management of acute graft-vs-host disease (GVHD), resulting in an increasing number of survivors.3
Allogeneic BMT recipients carry a substantial burden of late-onset morbidity, such as subsequent malignant neoplasms (SMNs) and cardiovascular disease (CVD).4,5,6,7,8,9,10,11,12,13,14 Mortality rates of BMT recipients have exceeded those of the general population for several years after BMT due to recurrence of primary disease and the high burden of nonrecurrence-related morbidity (NRM).15,16,17,18,19,20 However, the cumulative effects of morbidity and premature mortality on life expectancy after allogeneic BMT remains unknown. Furthermore, it is unknown whether late mortality risk and life expectancy have changed with modifications in transplant practice. We addressed these gaps using the resources offered by the Blood or Marrow Transplant Survivor Study (BMTSS).
Methods
Study Participants and Data Collection
The BMTSS is a cohort study designed to examine the long-term outcome of individuals who have lived 2 years or more after BMT performed between January 1, 1974, and December 31, 2014, at City of Hope, University of Minnesota, or University of Alabama at Birmingham. Data on primary diagnosis, conditioning intensity (myeloablative, nonmyeloablative, or reduced-intensity conditioning),21 type of donor stem cells (related or unrelated), stem cell source (bone marrow, PBSCs, or cord blood), disease status at transplantation (high or standard risk for recurrence), and history of chronic GVHD were obtained from institutional transplant databases. We excluded patients who received a second BMT. National Death Index Plus22 provided data regarding the date and cause of death through December 31, 2017. Additional data from Accurint databases23 were used to extend the vital status information through March 23, 2020. The institutional review board (IRB) at the University of Alabama at Birmingham served as the single IRB of record; a waiver of consent was granted by the IRB for linking the cohort to the National Death Index and Accurint databases. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Two of us (S.B. and J.W.) independently assigned a cause of death. In the event of discrepant assignment, those investigators collectively adjudicated a final cause of death. Suicides, homicides, and motor vehicle crashes were categorized as an external cause of death. A cause of death matching the pretransplant diagnosis was classified as recurrence-related mortality (RRM). All other causes of death were classified as NRM. Deaths due to malignant diseases differing from the pretransplant diagnosis were classified as SMN related. Deaths due to heart failure, coronary artery disease, arrhythmia, stroke, or other cardiovascular causes were classified as CVD related. Deaths due to sepsis or other infectious causes were classified as infection related.
We used sex-specific US life-table data from the Centers for Disease Control and Prevention24 to calculate expected population mortality rates and life expectancy (eMethods in the Supplement).17 We chose the 2003 US life-table data because the median year of BMT for the cohort in this study was 2003.
Statistical Analysis
We obtained smoothed estimates of mortality rates and associated 95% CIs by fitting a Poisson regression model to the observed counts using cubic spline terms for time. The standardized mortality ratio (SMR), which is the ratio of observed to expected number of deaths, compared the mortality experienced by this cohort with age-, sex- and calendar-specific mortality of the US population.24 The Poisson regression method was used to calculate 95% CIs of the SMR.
Kaplan-Meier techniques were used to calculate overall survival, and Cox proportional hazards regression analysis with time from BMT as the time axis was used for identifying factors associated with all-cause mortality. Cumulative incidence rates for cause-specific mortality were calculated using competing risk methods. A proportional subdistribution hazards (Fine-Gray) model for competing risk was used to identify factors associated with cause-specific mortality. Factors examined for their association with all-cause and cause-specific mortality included age at BMT, sex, primary disease, disease status at BMT, donor type, stem cell source, conditioning intensity, use of total body irradiation, history of chronic GVHD, and BMT era. Race and ethnicity (self-reported or obtained from medical records) were included in the analysis because of previous evidence for racial and ethnic disparities in survival.25 We examined trends in all-cause and cause-specific mortality across 3 BMT eras (1974-1989; 1990-2004; and 2005-2014) based on changes in transplant practices.1 The comparison across the 3 eras was restricted to 10 years of follow-up to ensure adequate follow-up for the most recent era (2005-2014) evaluated.
All analyses were conducted using SAS, version 9.4 (SAS Institute Inc). Findings noted with 2-sided tests were considered statistically significant at P < .05.
Results
Patient Characteristics
Overall, 4741 individuals had undergone allogeneic BMT between 1974 and 2014 and survived 2 years or longer. As summarized in Table 1, the median age at BMT was 33 years (range, 0-75 years), 2735 patients were male (57.7%), 2006 were female (42.3%), 3231 were non-Hispanic White (68.2%), and 2204 individuals (46.5%) had undergone transplantation between 2005 and 2014. Median follow-up after BMT was 12 years (range, 2.0-44.0 years). Acute myeloid leukemia was the most common indication for BMT (1246 [26.3%]), 2806 individuals (59.2%) received related donor transplants, and 2253 patients (47.5%) received bone marrow as the source of stem cells. Conditioning regimens were myeloablative in 2632 patients (55.5%), and 2285 patients (48.2%) developed chronic GVHD.
Table 1. Patient Characteristics.
| Characteristica | No. (%) | P value | |||
|---|---|---|---|---|---|
| Entire cohort (n = 4741) | 1974-1989 (n = 582) | 1990-2004 (n = 1955) | 2005-2014 (n = 2204) | ||
| Age at BMT, median (range), y | 33.0 (0-75.0) | 19.5 (0-47.0) | 31.0 (0-75.0) | 43.0 (0-75.0) | <.001 |
| Age at BMT categories, y | |||||
| <18 | 1343 (28.3) | 254 (43.6) | 588 (30.1) | 501 (22.7) | <.001 |
| 18-45 | 1958 (41.3) | 322 (55.3) | 972 (49.7) | 664 (30.1) | |
| >45 | 1440 (30.4) | 6 (1.0) | 395 (20.2) | 1039 (47.1) | |
| Race and ethnicity | |||||
| African American | 196 (4.1) | 22 (3.8) | 87 (4.5) | 87 (3.9) | <.001 |
| Asian | 348 (7.3) | 22 (3.8) | 139 (7.1) | 187 (8.5) | |
| Hispanic | 846 (17.8) | 83 (14.3) | 343 (17.5) | 420 (19.1) | |
| Missing | 51 (1.1) | 1 (0.2) | 17 (0.9) | 33 (1.5) | |
| Non-Hispanic White | 3231 (68.2) | 447 (76.8) | 1347 (68.9) | 1437 (65.2) | |
| Otherb | 69 (1.5) | 7 (1.2) | 22 (1.1) | 40 (1.8) | |
| Sex | |||||
| Female | 2006 (42.3) | 251 (43.1) | 803 (41.1) | 952 (43.2) | .35 |
| Male | 2735 (57.7) | 331 (56.9) | 1152 (58.9) | 1252 (56.8) | |
| Primary diagnosis | |||||
| AML | 1246 (26.3) | 162 (27.8) | 413 (21.1) | 671 (30.4) | <.001 |
| ALL | 845 (17.8) | 122 (21.0) | 318 (16.3) | 405 (18.4) | |
| CML | 714 (15.1) | 121 (20.8) | 509 (26.0) | 84 (3.8) | |
| MDS | 431 (9.1) | 10 (1.7) | 122 (6.2) | 299 (13.6) | |
| NHL | 413 (8.7) | 14 (2.4) | 145 (7.4) | 254 (11.5) | |
| SAA | 310 (6.5) | 92 (15.8) | 111 (5.7) | 107 (4.9) | |
| Other | 782 (16.5) | 61 (10.5) | 337 (17.2) | 384 (17.4) | |
| Disease statusc | |||||
| High risk | 1352 (28.5) | 104 (17.9) | 508 (26.0) | 740 (33.6) | <.001 |
| Standard risk | 3020 (63.7) | 350 (60.1) | 1227 (62.8) | 1443 (65.5) | |
| Missing | 369 (7.8) | 128 (22.0) | 220 (11.3) | 21 (1.0) | |
| BMT donor type | |||||
| Related | 2806 (59.2) | 554 (95.2) | 1275 (65.2) | 977 (44.3) | <.001 |
| Unrelated | 1935 (40.8) | 28 (4.8) | 680 (34.8) | 1227 (55.7) | |
| Stem cell source | |||||
| Cord blood | 646 (13.6) | 1 (0.2) | 187 (9.6) | 458 (20.8) | <.001 |
| PBSCs | 1842 (38.9) | 0 | 547 (28.0) | 1295 (58.8) | |
| Bone marrow | 2253 (47.5) | 581 (99.8) | 1221 (62.5) | 451 (20.5) | |
| Conditioning intensity | |||||
| Myeloablative | 2632 (55.5) | 490 (84.2) | 1343 (68.7) | 799 (36.3) | <.001 |
| RIC/NMA | 2079 (43.9) | 84 (14.4) | 594 (30.4) | 1401 (63.6) | |
| Missing | 30 (0.6) | 8 (1.4) | 18 (0.9) | 4 (0.2) | |
| Total body irradiation | |||||
| No | 1806 (38.1) | 134 (23.0) | 598 (30.6) | 1074 (48.7) | <.001 |
| Yes | 2905 (61.3) | 440 (75.6) | 1339 (68.5) | 1126 (51.1) | |
| Missing | 30 (0.6) | 8 (1.4) | 18 (0.9) | 4 (0.2) | |
| Chronic GVHD | |||||
| No | 2080 (43.9) | 308 (52.9) | 878 (44.9) | 894 (40.6) | <.001 |
| Yes | 2285 (48.2) | 242 (41.6) | 962 (49.2) | 1081 (49.0) | |
| Missing | 376 (7.9) | 32 (5.5) | 115 (5.9) | 229 (10.4) | |
| Length of follow-up, median (range), y | 12 (2.0-44.0) | 31 (2.0-44.0) | 18 (2.0-29.0) | 8 (2.0-14.0) | <.001 |
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BMT, blood or marrow transplantation; CML, chronic myelogenous leukemia; GVHD, graft-vs-host disease; MDS, myelodysplastic syndrome; NHL, non-Hodgkin lymphoma; NMA, nonmyeloablative conditioning; PBSCs, peripheral blood stem cells; RIC, reduced-intensity conditioning; SAA, severe aplastic anemia.
Missing data: race and ethnicity (n = 51; 15 died), disease status (n = 369; 115 died), chronic GVHD (n = 376; 62 died), total body irradiation (n = 30; 2 died), and conditioning intensity (n = 30; 2 died).
Other included 69 individuals who were multiracial (n = 33), Native American/Alaska Native (n = 29), and Pacific Islander (n = 7) patients. For 1974-1989 (n = 7): multiracial (n = 1), Native American/Alaska Native (n = 6), and Pacific Islander (n = 0) patients; 1990-2004 (n = 22): multiracial (n = 10), Native American/Alaska Native (n = 12), and Pacific Islander (n = 0) patients; and 2005-2014 (n = 40): multiracial (n = 22), Native American/Alaska Native (n = 11), and Pacific Islander (n = 7) patients.
Patients who underwent allogeneic BMT in the first or second complete remission after ALL, AML, Hodgkin lymphoma, or NHL or in the first chronic phase of CML, as well as all patients with SAA, were considered at standard risk for relapse at transplantation. All other patients were considered at high risk.
Across the 3 eras, the median age at BMT increased (from 19.5 to 43.0 years), as did the proportion of patients receiving unrelated donor BMT (from 4.8% to 55.7%) and receiving BMT for high-risk disease (from 17.9% to 33.6%). There was a decrease in the proportion of patients conditioned with total body irradiation (from 75.6% to 51.1%), those receiving myeloablative conditioning (from 84.2% to 36.3%), and those receiving bone marrow stem cells (from 99.8% to 20.5%). There was an increase in the prevalence of patients with chronic GVHD (from 41.6% to 49.0%) (Table 1).
Mortality Rates and Life Expectancy
The cohort was at an 8.8-fold higher risk for all-cause mortality (95% CI, 8.4-9.3) compared with the general population. Relative mortality was highest in the 2- to 5-year period post-BMT (SMR, 34.3; 95% CI, 31.7-36.9) and decreased thereafter but remained significantly elevated at 30 or more years post-BMT (SMR, 5.4; 95% CI, 4.0-7.1). Relative mortality decreased from 1974-1989 (SMR, 23.4) to 2005-2014 (SMR, 5.8) (P < .001) (eTable 1 in the Supplement).
Mortality rates exceeded expected population rates from 2 to 35 years post-BMT (eFigure 1A in the Supplement), showing a U-shaped curve, with greater divergence from expected rates among individuals with the shortest follow-up (2 years post-BMT: 39.4 deaths/1000 person-years) and the longest follow-up (35 years post-BMT: 31.0 deaths/1000 person-years). Mortality rates increased with age at BMT and remained higher than expected in the general population across all ages (eFigure 1B in the Supplement).
Life Expectancy
Conditional on surviving 2 or more years after allogeneic BMT, patients experienced a 20.8% decrease in their life expectancy (8.7 years of life lost). The years of life lost were greatest for the youngest survivors (age 10 years: 21.5 years; 31% reduction in life expectancy) and least for the oldest survivors (age 70 years: 1 year; 8.4% reduction in life expectancy) (eFigure 1C and D in the Supplement). A greater than 25% reduction in life expectancy was observed in patients older than 45 years at BMT, those who underwent transplantation for acute lymphocytic leukemia, those who underwent transplantation between 1974 and 1989, those with high-risk disease who underwent transplantation, and those with chronic GVHD (eTable 2 in the Supplement). In the analysis restricted to 10 years of follow-up, the years of life lost decreased across the 3 eras (from 9.9 to 4.2 years) (Table 2).
Table 2. Multivariable Analysis of Risk Factors for All-Cause Mortalitya.
| Variable | Hazard ratio (95% CI) | P value | Reduction in life expectancy | |
|---|---|---|---|---|
| % | Years | |||
| Age at transplantation, y | ||||
| <18 | 1 [Reference] | 8.5 | 2.1 | |
| 18-45 | 1.42 (1.14-1.76) | .001 | 13.3 | 3.0 |
| >45 | 2.37 (1.87-3.01) | <.001 | 24.8 | 5.8 |
| Race and ethnicity | ||||
| Non-Hispanic White | 1 [Reference] | 16.2 | 6.3 | |
| Hispanic | 0.99 (0.83-1.18) | .90 | 16.1 | 6.3 |
| Asian | 0.76 (0.58-0.99) | .05 | 12.9 | 5.0 |
| African American | 1.27 (0.92-1.75) | .14 | 17.2 | 7.8 |
| Otherb | 0.96 (0.56-1.67) | .90 | 16.3 | 6.8 |
| Sex | ||||
| Female | 1 [Reference] | 15.0 | 6.3 | |
| Male | 1.24 (1.09-1.42) | .001 | 17.5 | 7.3 |
| Diagnosis | ||||
| SAA | 1 [Reference] | 5.6 | 2.7 | |
| ALL | 2.69 (1.65-4.39) | <.001 | 19.3 | 8.2 |
| AML | 2.36 (1.46-3.81) | <.001 | 19.1 | 6.8 |
| MDS | 1.89 (1.13-3.18) | .02 | 20.7 | 5.8 |
| CML | 1.78 (1.08-2.91) | .02 | 16.0 | 5.9 |
| NHL | 1.74 (1.03-2.94) | .04 | 18.6 | 5.3 |
| Otherc | 2.96 (1.79-4.87) | <.001 | 16.1 | 7.8 |
| Disease status | ||||
| Standard risk | 1 [Reference] | 13.4 | 5.6 | |
| High risk | 1.44 (1.24-1.67) | <.001 | 23.6 | 8.4 |
| Transplant yeard | ||||
| 1974-1989 | 1 [Reference] | 17.8 | 9.9 | |
| 1990-2004 | 0.67 (0.53-0.85) | <.001 | 16.0 | 6.5 |
| 2005-2014 | 0.52 (0.39-0.69) | <.001 | 11.7 | 4.2 |
| Transplant type | ||||
| Related | 1 [Reference] | 16.5 | 6.7 | |
| Unrelated | 1.13 (0.98-1.32) | .10 | 15.7 | 6.8 |
| Stem cell source | ||||
| Bone marrow | 1 [Reference] | 14.1 | 7.1 | |
| Cord blood | 1.11 (0.85-1.47) | .44 | 12.1 | 6.6 |
| PBSCs | 1.30 (1.07-1.58) | .008 | 21.1 | 7.9 |
| Conditioning intensity | ||||
| Myeloablative | 1 [Reference] | 17.1 | 7.6 | |
| Nonmyeloablative | 0.94 (0.78-1.14) | .55 | 14.5 | 5.9 |
| Total body irradiation | ||||
| No | 1 [Reference] | 14.6 | 4.7 | |
| Yes | 1.08 (0.89-1.31) | .43 | 17.1 | 6.3 |
| Chronic GVHD | ||||
| No | 1 [Reference] | 9.7 | 4.4 | |
| Yes | 2.11 (1.80-2.49) | <.001 | 25.0 | 9.6 |
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myelogenous leukemia; GVHD, graft-vs-host disease; MDS, myelodysplastic syndrome; NHL, non-Hodgkin lymphoma; PBSCs, peripheral blood stem cells; SAA, severe aplastic anemia.
Cohort was censored at 10 years after blood or marrow transplantation or death.
Other included multiracial, Native American/Alaska Native, and Pacific Islander patients.
Included histiocytic disorders (n = 9), inborn errors of metabolism (n = 254), inherited abnormalities of erythrocyte differentiation/function (n = 183), inherited abnormalities of skin (n = 13), immune disorders (n = 73), solid tumors (n = 9), and other (n = 34).
P < .001 for trend.
Hazard of All-Cause Late Mortality
Conditional on surviving the first 2 years after BMT, the 30-year overall survival was 57.8% for the entire cohort, ranging from 80.6% for severe aplastic anemia to 52.5% for chronic myelogenous leukemia (eFigure 2 in the Supplement). Risk factors associated with 10-year, all-cause late mortality included older age at BMT (18-45 years: hazard ratio [HR], 1.42; 95% CI, 1.14-1.76; >45 years: HR, 2.37; 95% CI, 1.87-3.01; reference, <18 y), male sex (HR, 1.24; 95% CI, 1.09-1.42), high-risk disease (HR, 1.44; 95% CI, 1.24-1.67), use of PBSCs as the stem cell source (HR, 1.30; 95% CI, 1.07-1.58; reference: bone marrow), and history of chronic GVHD (HR, 2.11; 95% CI, 1.80-2.49) (Table 2). Follow-up of patients to the date of the last contact yielded similar patterns of association (eTable 2 in the Supplement). Stratified analysis by chronic GVHD status revealed that the association between PBSCs and risk of all-cause late mortality was present in both groups (with chronic GVHD: HR, 1.50; 95% CI, 1.15-1.71; without chronic GVHD: HR, 2.09; 95% CI, 1.58-2.76).
Adjusting for all relevant demographic and clinical variables showed a decrease in the HR of 10-year, all-cause mortality over the 3 eras (reference: 1974-1989; 1990-2004: HR, 0.67; 95% CI, 0.53-0.85; and 2005-2014: HR, 0.52; 95% CI, 0.39-0.69; P < .001 for trend) (Figure 1, Table 2). We performed mediation analysis by adding each risk factor to examine the association between transplant era and mortality in separate models to examine whether the HRs changed with the addition of the respective risk factor. A risk factor mediated the association between transplant era and mortality if the addition of the factor resulted in a change in the HR.
Figure 1. Trends in Hazard of All-Cause and Cause-Specific Late Mortality After Allogeneic Blood or Marrow Transplantation (BMT) by Transplant Era.
The follow-up was truncated at 10 years post-BMT to allow comparison across the 3 eras. The models were adjusted for age at transplantation, sex, race and ethnicity, primary diagnosis, disease status at BMT, transplant type, stem cell source, conditioning intensity, use of total body irradiation, and presence of chronic graft-vs-host disease. Adjustment showed a decrease for all-cause mortality, recurrence-related mortality, and nonrecurrence-related mortality. The vertical line at 1.0 indicates the reference era (1974-1989). Data markers indicate hazard ratios; whiskers, 95% CIs.
The unadjusted hazard of 10-year, all-cause mortality was comparable across all eras (1990-2004: HR, 1.02; 95% CI, 0.83-1.25; 2005-2014: HR, 1.08; 95% CI, 0.88-1.32; reference: 1974-1989) (eTable 3 in the Supplement). Adjustment for age at BMT reduced the hazard of late mortality (1990-2004: HR, 0.80; 95% CI, 0.65-0.99; 2005-2014: HR, 0.68; 95% CI, 0.55-0.85). In a separate model, adjustment for stem cell source also reduced the hazard of mortality (1990-2004: HR, 0.76; 95% CI, 0.61-0.95; 2005-2014: HR, 0.63; 95% CI, 0.50-0.80). Adjustment for both age at transplant and stem cell source resulted in a further reduction (1990-2004: HR, 0.71; 95% CI, 0.56-0.88; 2005-2014: HR, 0.54; 95% CI, 0.43-0.72). Inclusion of the remaining risk factors did not result in any further reduction in the hazard of all-cause mortality (eTable 3 in the Supplement). Analysis stratified by age at BMT (<18, 18-45, and >45 years) revealed that the decrease in late mortality by transplant era was statistically significant only among individuals who underwent transplantation when younger than 18 years (1990-2004: HR, 0.62; 95% CI, 0.40-0.96; 2005-2014: HR, 0.30; 95% CI, 0.16-0.54; reference: 1974-1989; P < .001 for trend) (Figure 2A) but not so among those at older ages (eTable 4, eFigure 3 in the Supplement). Analysis stratified by stem cell source revealed that the decrease in late mortality by transplant era was statistically significant only among individuals who received bone marrow (1990-2004: HR, 0.70; 95% CI, 0.54-0.90; 2005-2014: HR, 0.45; 95% CI, 0.29-0.69; reference: 1974-1989; P < .001 for trend) (Figure 2B) but not so among those who received PBSCs or cord blood (eTable 5, eFigure 4 in the Supplement).
Figure 2. Overall Survival by Transplant Era.
A, Overall survival by transplant era for patients younger than 18 years at blood or marrow transplantation (BMT). B, Overall survival by transplant era for patients who received bone marrow. Shaded areas indicate 95% CIs.
Hazard of Cause-Specific Mortality
A cause of death was available for 1175 of the 1409 patients who died (83.4%) and included RRM (473 [40.3%]), NRM (675 [57.4%]), and external causes (27 [2.3%]). The 30-year cumulative incidence for RRM was 12.2% (95% CI, 11.0%-13.4%) (Figure 3A) and, for NRM, 22.3% (95% CI, 20.4%-24.3%) (Figure 3B). Factors associated with RRM included male sex (HR, 1.28; 95% CI, 1.05-1.57), older age at BMT (>45 years: HR, 1.99; 95% CI, 1.40-2.81), key primary diagnoses (acute lymphoblastic leukemia: HR, 3.95; 95% CI, 1.66-9.37; acute myeloid leukemia: HR, 3.22; 95% CI, 1.37-7.53; reference: severe aplastic anemia), high-risk disease (HR, 1.52; 95% CI, 1.21-1.90), and chronic GVHD (HR, 2.28; 95% CI, 1.76-2.96) (eTable 6 in the Supplement). Factors associated with NRM included older age at BMT (18-45 years: HR, 1.51; 95% CI, 1.07-2.13; >45 years: HR, 2.54; 95% CI, 1.77-3.66), diagnosis of acute lymphoblastic leukemia (HR, 2.24; 95% CI, 1.10-4.56), high-risk disease (HR, 1.37; 95% CI, 1.09-1.72), and chronic GVHD (HR, 2.20; 95% CI, 1.72-2.83) (eTable 6 in the Supplement).
Figure 3. Cumulative Incidence of Mortality.
A, Cumulative incidence of recurrence-related mortality (RRM), conditional on surviving the first 2 years after allogeneic blood or marrow transplantation (BMT). B, Cumulative incidence of nonrecurrence-related mortality (NRM), conditional on surviving the first 2 years after allogeneic BMT. Shaded areas indicate 95% CIs.
The adjusted hazard of 10-year RRM (1990-2004: HR, 0.68; 95% CI, 0.47-0.98; 2005-2014: HR, 0.56; 95% CI, 0.37-0.85; P = .02 for trend) and 10-year NRM (1990-2004: HR, 0.86; 95% CI, 0.60-1.22; 2005-2014: HR, 0.47; 95% CI, 0.31-0.72; P < .001 for trend) also decreased across the 3 eras (Figure 1; eTable 6 in the Supplement). The unadjusted hazard of 10-year RRM was comparable across all eras (1990-2004: HR, 1.02; 95% CI, 0.74-1.40; 2005-2014: HR, 1.09; 95% CI, 0.80-1.50; reference: 1974-1989). Adjustment for both age at transplantation and stem cell source resulted in a reduction in RRM (1990-2004: HR, 0.74; 95% CI, 0.52-1.04; 2005-2014: HR, 0.59; 95% CI, 0.40-0.86) (eTable 7 in the Supplement). The unadjusted hazard of 10-year NRM was comparable across all eras (1990-2004: HR, 1.27; 95% CI, 0.93-1.74; 2005-2014: HR,1.01; 95% CI, 0.73-1.37; reference: 1974-1989). Adjustment for both age at transplantation and stem cell source resulted in a reduction in late NRM only in the most recent era (2005-2014: HR, 0.47; 95% CI, 0.32-0.68; reference: 1974-1989) (eTable 8 in the Supplement). Furthermore, analyses stratified by age at BMT and stem cell source revealed that the decrease in RRM and NRM by transplant era was statistically significant only among individuals who underwent transplantation when younger than 18 years or among those who received bone marrow as the stem cell source (eFigures 5-8 in the Supplement).
Leading causes of NRM included infection (30-year cumulative incidence: 10.7%; SMR, 52.0), SMNs (30-year cumulative incidence: 7.0%; SMR, 4.8), CVD (30-year cumulative incidence: 4.6%; SMR, 4.1), and pulmonary disease (30-year cumulative incidence: 2.7%; SMR, 13.9) (eTable 9, eFigure 9 in the Supplement). Infection-related mortality was associated with older age at BMT (>45 years: HR, 1.94; 95% CI, 1.26-2.99), diagnosis of acute lymphocytic leukemia (HR, 2.51; 95% CI, 1.07-5.86), high-risk disease (HR, 1.34; 95% CI, 1.03-1.75), chronic GVHD (HR, 2.82; 95% CI, 2.06-3.86), and PBSC transplant (HR, 1.39; 95% CI, 1.00-1.92). Factors associated with SMNs included older age at BMT (>45 y: HR, 3.42; 95% CI, 1.68-6.93) and chronic GVHD (HR, 1.88; 95% CI, 1.10-3.19). Cardiovascular disease mortality was associated with older age at BMT (>45 y: HR, 3.68; 95% CI, 1.39-9.73), and pulmonary mortality was associated with chronic GVHD (HR, 3.89; 95% CI, 1.67-9.07), PBSCs (HR, 7.32; 95% CI, 2.54-21.99), male sex (HR, 1.90; 95% CI, 1.04-3.40), and African American race (HR, 2.89; 95% CI, 1.17-7.11) (eTable 10 in the Supplement). The higher risk of mortality among those with chronic GVHD was primarily infection-related (31% in individuals with chronic GVHD vs 21% in those without chronic GVHD) and pulmonary (8% in individuals with chronic GVHD vs 4% in those without chronic GVHD) deaths. The decrease in the hazard of late mortality was statistically significant for infection (1990-2004: HR, 0.82; 95% CI, 0.53-1.27; 2005-2014: HR, 0.50; 95% CI, 0.31-0.83; reference: 1974-1989; P = .001 for trend) and SMN (1990-2004: HR, 0.92; 95% CI, 0.44-1.94; 2005-2014: HR, 0.31; 95% CI, 0.12-0.78; reference: 1974-1989; P = .001 for trend) but not for CVD (1990-2004: HR, 0.87; 95% CI, 0.31-2.42; 2005-2014: HR, 0.55; 95% CI, 0.18-1.75; reference: 1974-1989; P = .31 for trend) or pulmonary disease (1990-2004: HR, 0.57; 95% CI, 0.12-2.31; 2005-2014: HR, 0.32; 95% CI, 0.06-1.68; reference: 1974-1989; P = .26 for trend) (eTable 10 in the Supplement).
Discussion
Mortality rates in this study’s cohorts remained increased at 30 or more years after BMT compared with the general US population. The excess mortality translated into 8.7 years of life lost. The leading causes of death included disease recurrence, infections, SMNs, CVD, and pulmonary disease. Although the rate of RRM plateaued with time from BMT, NRM continued to increase. The hazard of all-cause mortality, RRM, and NRM decreased significantly, with a concomitant improvement in life expectancy. This decrease in mortality was most pronounced among patients who underwent transplantation when younger than 18 years and those who received bone marrow as a stem cell source; there was no meaningful decrease in mortality among patients who underwent transplantation at older ages or those who received PBSCs.
Several studies have described the risk of late mortality after BMT (summary in eTable 11 in the Supplement).15,16,17,18,19,20,26 The composition of the cohorts has varied across studies, as has the time between BMT and cohort entry and disease status at cohort entry. In addition, previous cohorts have covered differing transplant eras, and the methods used to determine vital status have differed. This heterogeneity between previous studies has precluded meaningful comparisons. Nonetheless, all studies suggested elevated risk of mortality compared with the general population and most reported the risk to remain increased for at least 15 years after BMT. In our study, the mortality risk remained increased for 30 years or more after BMT. The SMR was highest for patients with acute lymphocytic leukemia and severe aplastic anemia (younger age with low expected rates) and lowest for patients with myelodysplastic syndrome and non-Hodgkin lymphoma (older age with high expected rates).
We found that cumulative incidence of RRM plateaued at 10 years and was 12.2% at 30 years after BMT. In contrast, the cumulative incidence of NRM continued to increase, exceeding 20% by 30 years post-BMT. Similar to other studies,15,16,17 the leading causes of NRM in our study included infections, SMNs, CVD, and pulmonary disease. Older age and chronic GVHD were associated with higher hazards of all-cause mortality, RRM, and NRM. The higher risk of mortality among patients with chronic GVHD was associated with infection-related and pulmonary deaths. We found a previously unreported association between PBSCs and all-cause, infection-related, and pulmonary mortality independent of the presence of chronic GVHD. A previous trial (CTN-0201) had randomized patients to unrelated donor bone marrow vs PBSCs27 and reported similar treatment-related mortality, as well as overall and disease-free survival, between the 2 groups. The association between PBSCs and a higher hazard of all-cause mortality observed in the BMTSS differs from CTN-0201 likely because of differences in the characteristics of the cohorts (BMTSS cohort includes patients who survived ≥2 years and CTN-0201 included patients from the time of transplant). Furthermore, the BMTSS followed up patients for a median of 12 years, and CTN-0201 followed up patients for a median of 3 years. The higher risk of mortality among patients who received PBSCs deserves further attention with respect to the incidence of specific late-occurring morbidities to inform clinical practice.
Overall, conditional on surviving the first 2 years after BMT, the life expectancy of patients who receive allogeneic BMT was 20.8% lower than expected, translating into 8.7 years of life lost. To our knowledge, the only prior study to examine life expectancy did so in the setting of a single institution cohort of allogeneic and autologous BMT recipients who were free of primary disease for 5 or more years, with Martin et al17 reporting a reduction in life expectancy of 30% across all attained ages. However, we found that reduction in life expectancy was highest for the youngest survivors and decreased with attained age. The lower life expectancy among BMT recipients compared with the US population may reflect the cumulative effects of pretransplant and transplant-related therapeutic exposures as well as posttransplant events, such as chronic GVHD, infections, SMNs, CVD, and pulmonary disease.
Transplant strategies have evolved over the past 4 decades, with the overarching goal of improving disease control and expanding the population of patients who could benefit from BMT. In particular, there is an increase in age at BMT in patients receiving transplants from donors other than human leukocyte antigen–matched siblings and in the use of PBSCs as a stem cell source. There is also an increase in the use of reduced-intensity conditioning. Taking these changes in transplant strategies into account, we observed a decrease in the hazard of all-cause mortality, RRM, and NRM (infection and SMN related) and a decrease in relative mortality, as well as improvement in life expectancy. The comparable unadjusted hazard of mortality across the 3 eras may reflect the increasing use of BMT in older populations and increasing use of PBSCs, and the reduction in mortality emerged only after adjustment for age at transplantation and stem cell source. The decline in all-cause mortality, RRM, and NRM (particularly infection related) across the 3 transplant eras was most pronounced among those who underwent transplantation at a younger age (<18 years) and those who received bone marrow as a stem cell source, with no meaningful decreases in late mortality observed among the older patients or those who received PBSCs (eTable 12 in the Supplement).
Limitations
The study has limitations; one of these may be reliance on data from the National Death Index Plus for cause of death. We mitigated the risk for misclassification by deploying 2 independent reviewers to adjudicate cause of death using predeveloped algorithms. When examining trends in late mortality, we were unable to capture changes in supportive care strategies that could have resulted in improvement in outcome. In addition, donor characteristics, degree of human leukocyte antigen match, and cytomegalovirus status were not available. We could not assess whether the cause of death was due to chronic GVHD because National Death Index Plus does not include GVHD as a discrete cause of death.
Conclusions
To our knowledge, this is the first large, multi-institutional study with mature follow-up, inclusion of both adults and children, and use of rigorous methods to evaluate vital status in patients who undergo BMT. The data showed an improvement in outcomes over 4 decades of allogeneic transplantation among individuals who underwent transplantation at a younger age and those who received bone marrow. There is a need to address the causes of late mortality among the older BMT recipients as well as those who receive PBSCs to improve outcomes.
eMethods. Calculation of Life Expectancy
eTable 1. Excess Risk of All-Cause Late Mortality Among BMT Recipients
eTable 2. Multivariable Analysis of Risk Factors for All-Cause Mortality—Cohort Followed Until Date of Last Contact/Death
eTable 3. Mediation Analysis of the Impact of Era of BMT on 10-Year All-Cause Mortality
eTable 4. Impact of Transplant Era on All-Cause Late Mortality—by Age at BMT
eTable 5. Impact of Transplant Era on All-Cause Late Mortality—by Source of Stem Cells
eTable 6. Risk Factors for Cause-Specific Late Mortality
eTable 7. Mediation Analysis of the Impact of Era of BMT on Recurrence-Related Late Mortality
eTable 8. Mediation Analysis of the Impact of Era of BMT on Nonrecurrence-Related Late Mortality
eTable 9. Excess Risk of Nonrecurrence-Related Late Mortality Among BMT Recipients
eTable 10. Risk Factors for Specific Nonrecurrence-Related Causes of Late Mortality—Multivariable Analysis
eTable 11. Summary of Previous Studies Describing Late Mortality After BMT
eTable 12. 10-Year Cumulative Incidence of All-Cause and Cause-Specific Late Mortality Stratified by Stem Cell Source and Age at BMT
eFigure 1. Mortality Rates and Life Expectancy
eFigure 2. Overall Survival by Diagnosis
eFigure 3. Overall Survival by Transplant Era by Age
eFigure 4. Overall Survival by Transplant Era by Stem Cell Source
eFigure 5. Cumulative Incidence of Recurrence-Related Late Mortality by Age
eFigure 6. Cumulative Incidence of Nonrecurrence-Related Late Mortality by Age
eFigure 7. Cumulative Incidence of Recurrence-Related Late Mortality by Stem Cell Source
eFigure 8. Cumulative Incidence of Nonrecurrence-Related Late Mortality by Stem Cell Source
eFigure 9. Cumulative Incidence of Disease-Related Late Mortality
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eMethods. Calculation of Life Expectancy
eTable 1. Excess Risk of All-Cause Late Mortality Among BMT Recipients
eTable 2. Multivariable Analysis of Risk Factors for All-Cause Mortality—Cohort Followed Until Date of Last Contact/Death
eTable 3. Mediation Analysis of the Impact of Era of BMT on 10-Year All-Cause Mortality
eTable 4. Impact of Transplant Era on All-Cause Late Mortality—by Age at BMT
eTable 5. Impact of Transplant Era on All-Cause Late Mortality—by Source of Stem Cells
eTable 6. Risk Factors for Cause-Specific Late Mortality
eTable 7. Mediation Analysis of the Impact of Era of BMT on Recurrence-Related Late Mortality
eTable 8. Mediation Analysis of the Impact of Era of BMT on Nonrecurrence-Related Late Mortality
eTable 9. Excess Risk of Nonrecurrence-Related Late Mortality Among BMT Recipients
eTable 10. Risk Factors for Specific Nonrecurrence-Related Causes of Late Mortality—Multivariable Analysis
eTable 11. Summary of Previous Studies Describing Late Mortality After BMT
eTable 12. 10-Year Cumulative Incidence of All-Cause and Cause-Specific Late Mortality Stratified by Stem Cell Source and Age at BMT
eFigure 1. Mortality Rates and Life Expectancy
eFigure 2. Overall Survival by Diagnosis
eFigure 3. Overall Survival by Transplant Era by Age
eFigure 4. Overall Survival by Transplant Era by Stem Cell Source
eFigure 5. Cumulative Incidence of Recurrence-Related Late Mortality by Age
eFigure 6. Cumulative Incidence of Nonrecurrence-Related Late Mortality by Age
eFigure 7. Cumulative Incidence of Recurrence-Related Late Mortality by Stem Cell Source
eFigure 8. Cumulative Incidence of Nonrecurrence-Related Late Mortality by Stem Cell Source
eFigure 9. Cumulative Incidence of Disease-Related Late Mortality