Long-term health outcomes in older recipients of blood or marrow transplantation: a report from the BMTSS.

Introduction

Advancements in supportive care, greater donor availability, and use of nonmyeloablative conditioning regimens have contributed to a growing number of older (≥60 years) adults with hematologic malignancies being considered for blood or marrow transplant (BMT). 1 It is estimated that ∼30% of recipients of allogeneic BMT and 45% of recipients of autologous BMT will be ≥60 years old, and these proportions are expected to steadily increase in the coming years, contributing to a growing number of older survivors of BMT. 2 However, BMT carries substantial risk of morbidity and mortality, particularly in older patients who may have preexisting aging-related comorbidities. Implementation of risk-based supportive care strategies during BMT can decrease the burden of acute toxicities, but the long-term health and well-being of these older recipients of BMT has not been adequately characterized. 3 , 4 , 5

In younger survivors of BMT, chronic health conditions (CHCs) such as cardiopulmonary diseases and subsequent malignant neoplasms (SMNs) are leading causes of late mortality, with mortality rates exceeding those reported for the general population. 6 Understanding long-term health outcomes among older patients who have undergone BMT is essential. Comparing their burden of morbidity and mortality with that of the general population could inform shared decision-making, and guide the development of tailored, age-appropriate screening and intervention strategies to optimize outcomes long after the peri-BMT period. Previous studies have focused on general survival outcomes, or specific conditioning and graft-versus-host disease (GVHD) prophylaxis regimens, among older recipients of BMT, 7 , 8 but there has not been a comprehensive characterization of morbidity, mortality, and general health status in this older patient population. We addressed existing knowledge gaps for older survivors by leveraging data from the Blood or Marrow Transplant Survivor Study (BMTSS) to characterize the burden of cause-specific mortality, SMNs, CHCs, frailty, and overall health status in older survivors of BMT, and compared them with age-matched general population and sibling controls.

Methods

The BMTSS is a collaboration between City of Hope, University of Minnesota, and University of Alabama at Birmingham, with the goal of studying long-term outcomes in ≥2-year survivors of autologous or allogeneic BMT performed between 1974 and 2014, regardless of disease status at cohort entry or vital status thereafter. 9 Participants (BMT survivors and siblings) were asked to complete a 255-item BMTSS survey that included questions regarding sociodemographics (age at survey completion, sex, race, ethnicity, education, income, and health insurance), SMNs, CHCs and chronic GVHD (cGVHD) diagnosed by a health care provider, and health status (frailty, general health, and functional or activity limitations). Siblings were included as a nontransplant comparison group; however, they were not necessarily biologically related to the survivors of BMT in this study. For this analysis, siblings were frequency-matched to survivors of BMT based on age at survey completion and sex. Severe, life-threatening, or fatal (grade 3-5) CHCs were graded using the Common Terminology Criteria for Adverse Events (version 5.0). 10 The BMTSS survey also asked about participants’ health status (poor general health, functional impairment, activity limitation; supplemental Table 1 ). 11 Physiologic frailty was categorized using the modified Fried frailty criteria, as reported previously ( supplemental Table 2 ). 12 , 13 Participants endorsing ≥3 criteria were considered frail. 14 The reliability and accuracy of the BMTSS questionnaire have been previously established. 15 , 16 , 17 The National Death Index was used to determine date and cause of death through 31 December 2020. Cause of death was coded according to the International Classification of Diseases-10, and grouped into the following categories: recurrence, SMN, cardiovascular diseases, respiratory diseases, infection, renal diseases, neurologic diseases, other health-related causes, and external causes (homicide, accidents, and suicides). 18 A waiver of consent was granted by the institutional review board (IRB) for linking the cohort to National Death Index (NDI) and Accurint databases. Data regarding age at BMT, indication for BMT (primary diagnosis), BMT characteristics (type of BMT [autologous, allogeneic], stem cell source [bone marrow, peripheral blood stem cells, cord blood], conditioning agents [total body irradiation (TBI), chemotherapeutic agents], conditioning intensity [myeloablative, nonmyeloablative/reduced intensity]), pre-BMT therapeutic exposures, and disease status at BMT (high or standard risk for recurrence 19 ) were obtained from institutional transplant databases or medical records. The current report included individuals who were aged ≥60 years at the time of BMT and survived ≥2 years after BMT, and a comparison cohort consisting of siblings of recipients of BMT.

Statistical analysis

Survivors of BMT

Survival, SMNs, and grade 3 to 5 nonmalignant CHCs were evaluated for all 1581 eligible survivors. Kaplan-Meier techniques were used to calculate overall survival. The cumulative incidence of cause-specific mortality was estimated for the BMT cohort using competing risk methods. The standardized mortality ratio (SMRs; ratio of observed to expected number of deaths) was used to compare all-cause and cause-specific mortality experienced by the recipients of BMT with the age- (5-year interval), sex-, and calendar-specific (5-year interval) mortality of the general US population. Person-years at risk were computed from BMT to either the date of death or date of completing the questionnaire, whichever occurred first. The expected number of deaths was calculated by multiplying the person-years in each defined stratum by the corresponding US mortality rates, obtained from Centers for Disease Control and Prevention. 20 The 95% confidence interval (CI) of the SMR was calculated assuming Poisson distribution. 21 SMRs were calculated for the entire cohort, by BMT type, and by treatment era (1990-2004; 2005-2014).

Cumulative incidence rates for SMNs as well as grades 3 to 5 nonmalignant CHCs were calculated using competing risk methods. 22 , 23 , 24 The difference in cumulative incidence between groups was assessed using Gray’s test. Standardized incidence ratios (SIRs) quantified the excess risk of SMNs among recipients of BMT when compared with the general population. The person-years at risk was calculated for the BMT cohort. Age- and sex-specific incidence rates of SMNs were obtained from the Surveillance, Epidemiology, and End Results (SEER) Program using SEER∗Stat. 25 The expected number of cases was calculated by multiplying the person-years at risk in the BMT cohort by the general population incidence rates. SIR was calculated as the ratio of observed to expected cases. The exact 95% CI was estimated by assuming Poisson distribution for SIR, where the offset is the number of total person-years and the outcome is the number of SMNs. 26 Fine-Gray proportional subdistributional hazard models evaluated the association between potential risk factors and SMNs.

Survivors of BMT compared with siblings

We compared clinical and demographic characteristics of 812 survivors of BMT (CONSORT diagram; supplemental Figure 1 ) and 594 siblings who completed the BMTSS questionnaire. Univariate and multivariable analyses were performed to evaluate risk factors for the following outcomes: grade 3 to 4 nonmalignant CHCs, frailty, and adverse health status. First, we examined the association between each outcome of interest and risk factors selected a priori: age at BMT, sociodemographics, primary diagnosis, BMT characteristics, and disease status at BMT. Backward stepwise elimination was used to remove variables with P < .05, 1 at a time, starting with the least significant. This was repeated until no more variables could be removed. Logistic regression evaluated the risk of CHCs, frailty, and adverse health status between survivors of BMT and siblings; the associations were summarized as odds ratios (ORs) and 95% CIs. All statistical analyses were 2-sided, and P < .05 was considered statistically significant in the final multivariable models. All analyses were conducted using SAS 9.4 (SAS Institute Inc, Cary, NC).

The IRB at The University of Alabama at Birmingham (UAB) serves as the single IRB of record and approved the study. Participants provided informed consent according to the Declaration of Helsinki.

Results

BMT population

In this cohort of 1581 recipients of BMT, the median age at BMT was 64.0 years (range, 60.0-78.0), and median age at study participation was 70.1 years (range, 62.0-89.4; Table 1 ). The median time from BMT to questionnaire completion was 5 years (range, 2.0-18.0), and from BMT to death was also 5 years (range, 2.1-25.1). Most survivors were male (62.9%) and non-Hispanic White (78.2%). The most common underlying diagnosis was multiple myeloma (44.7%), followed by non-Hodgkin lymphoma (28.9%) and acute myeloid leukemia or myelodysplastic syndrome (20.4%). Most (78.1%) received BMT between 2005 and 2014 (78.1%), and 72.1% underwent autologous BMT. Nearly 60% (59.2%) received myeloablative conditioning without TBI, followed by nonmyeloablative/reduced intensity without TBI (24.4%). Compared with nonparticipants, a larger proportion of participants were non-Hispanic White, and received BMT between 1990 and 2004. Demographic characteristics of survivors who did and did not complete the BMTSS questionnaire are detailed in supplemental Table 3 . Table 1. Demographic characteristics of survivors and siblings Entire cohort of survivors of BMT, N = 1581 Survivors of allogeneic BMT, n = 442 Survivors of autologous BMT, n = 1139 Survivors who completed BMTSS survey, n = 812 Siblings, N = 594 Survivors of BMT vs siblings ∗ Age at study, n (%), y Median (range) 70.1 (62.0-89.4) 69.0 (62.7-89.0) 70.7 (62.0-89.4) 70.0 (62.0-89.0) 66.7 (60.0-90.5) Age at study <65 109 (6.9) 36 (8.1) 73 (6.4) 33 (4.1) 225 (37.9) <.0001 Age at study ≥65 1472 (93.1) 406 (91.9) 1,066 (93.6) 779 (95.9) 369 (62.1) Sex, n (%) <.0001 Female 587 (37.1) 170 (38.5) 417 (36.6) 318 (39.2) 348 (58.6) Male 994 (62.9) 272 (61.5) 722 (63.4) 494 (60.8) 246 (41.4) Race/ethnicity, n (%) .001 Non-Hispanic White 1237 (78.2) 378 (85.5) 859 (75.4) 658 (81.0) 525 (88.4) Black 122 (7.7) 7 (1.6) 115 (10.1) 50 (6.2) 16 (2.7) Hispanic 136 (8.6) 33 (7.5) 103 (9.0) 58 (7.1) 34 (5.7) Other 86 (5.4) 24 (5.4) 62 (5.4) 46 (5.7) 19 (3.2) Education, n (%) .02 High school or below 187 (11.8) 38 (8.6) 149 (13.1) 142 (17.5) 78 (13.1) Some college 331 (20.9) 117 (26.5) 214 (18.8) 27 6 (34.0) 199 (33.5) College or above 459 (29.0) 157 (35.5) 302 (26.5) 389 (48.0) 317 (53.4) Missing 604 (38.2) 130 (29.4) 474 (41.6) 4 (0.5) 0 Income, n (%) .06 <$50 000 283 (17.9) 73 (16.5) 210 (18.4) 231 (28.4) 137 (23.1) $50 000-$74 999 168 (10.6) 55 (12.4) 113 (9.9) 147 (18.1) 119 (20.0) ≥$75 000 362 (22.9) 133 (30.1) 229 (20.1) 314 (38.7) 270 (45.5) Missing 768 (48.6) 181 (41.0) 587 (51.5) 120 (14.8) 68 (11.4) Health insurance, n (%) .0004 Private 548 (34.7) 176 (39.8) 372 (32.7) 445 (54.8) 391 (65.8) Public 426 (26.9) 140 (31.7) 286 (25.1) 359 (44.2) 197 (33.2) None 9 (0.6) 0 9 (0.8) 7 (0.9) 6 (1.0) Missing 598 (37.8) 126 (28.5) 472 (41.4) 1 (0.1) 0 Primary cancer diagnosis, n (%) AML/MDS 322 (20.4) 304 (68.8) 18 (1.6) 197 (24.3) Non-Hodgkin lymphoma 457 (28.9) 66 (14.9) 391 (34.3) 244 (30.0) PCD 706 (44.7) 17 (3.8) 689 (60.5) 323 (39.8) Other 96 (6.1) 55 (12.4) 41 (3.6) 48 (5.9) Age at BMT, y Mean ± SD 64.7 ± 3.7 64.2 ± 3.5 64.9 ± 3.7 64.6 ± 3.6 Median (range) 64.0 (60.0-78.0) 63.0 (60.0-75.0) 64.0 (60.0-78.0) 64.0 (60.0-78.0) <65, n (%) 842 (53.3) 263 (59.5) 579 (50.8) 443 (54.6) ≥65, n (%) 739 (46.7) 179 (40.5) 560 (49.2) 369 (45.4) BMT year 1990-2004 346 (21.9) 62 (14.0) 284 (24.9) 97 (11.9) 2005-2014 1235 (78.1) 380 (86.0) 855 (75.1) 715 (88.1) Stem cell type, n (%) Bone marrow 20 (1.3) 17 (3.8) 3 (0.3) 7 (0.9) Cord blood 51 (3.2) 51 (11.5) 0 31 (3.8) PBSC 1,510 (95.5) 374 (84.6) 1,136 (99.7) 774 (95.3) Type of BMT/cGVHD, n (%) Autologous 1139 (72.0) N/A 1,139 (100.0) 553 (68.1) Allogeneic without cGVHD 140 (8.9) 140 (31.7) N/A 71 (8.7) Allogeneic with cGVHD 302 (19.1) 302 (68.3) 188 (23.2) Risk of relapse at BMT, n (%) Standard risk 550 (34.8) 229 (51.8) 321 (28.2) 329 (40.5) High risk 995 (62.9) 198 (44.8) 797 (70.0) 472 (58.1) Missing 36 (2.3) 15 (3.4) 21 (1.8) 11 (1.4) BMT count, n (%) 1 1440 (91.1) 379 (85.7) 1,061 (93.2) 750 (92.4) >1 141 (8.9) 63 (14.3) 78 (6.8) 62 (7.6) Pretransplant CHC, n (%) No 351 (22.2) 119 (26.9) 232 (20.4) 280 (34.5) Yes 633 (40.0) 197 (44.6) 436 (38.3) 531 (65.5) Missing 597 (37.8) 126 (28.5) 471 (41.4) 1 (0.1) TBI, n (%) No 1338 (84.6) 313 (70.8) 1,025 (90.0) 700 (86.2) Yes 239 (15.1) 128 (29.0) 111 (9.7) 112 (13.8) Missing, n (%) 4 (0.3) 1 (0.2) 3 (0.3) 0 Conditioning intensity + TBI, n (%) MAC with TBI 127 (8.0) 9 (2.0) 118 (10.4) 55 (6.8) MAC without TBI 936 (59.2) 28 (6.3) 908 (79.7) 482 (59.4) NMA/RIC with TBI 119 (7.5) 119 (26.9) 0 61 (7.5) NMA/RIC without TBI 386 (24.4) 281 (63.6) 105 (9.2) 213 (26.3) Missing information 13 (0.8) 5 (1.1) 8 (0.7) 0 AML, acute myeloid leukemia; MAC, myeloablative conditioning; MDS, myelodysplastic syndrome; NMA, nonmyeloablative; PBSC, peripheral blood stem cell; PCD, plasma cell dyscrasia; RIC, reduced-intensity conditioning; SD, standard deviation. ∗ Comparison of siblings vs survivors of BMT who completed the BMTSS survey.

Late mortality

The 10-year cumulative incidences of nonrelapse-related mortality and relapse-related mortality were 11.9% (95% CI, 10.4%-13.7%) and 21.2% (95% CI, 19.3%-23.4%), respectively ( supplemental Figure 2 ). Overall, recipients of BMT were at a fivefold higher risk of all-cause mortality (SMR, 5.3 [95% CI, 5.0-5.6]) when compared with the general population. Among the nonrelapse-related causes of death, the highest SMRs overall, and by BMT type were observed for infection (entire BMT cohort: n = 180; SMR, 35.2 [95% CI, 30.3-40.6]; recipients of autologous BMT: n = 117; SMR, 31.1 [95% CI, 25.8-37.1]; recipients of allogeneic BMT: n = 63; SMR, 46.6 [95% CI, 36.0-59.0]), followed by renal disease (entire BMT cohort: n = 67, SMR, 15.0 [95% CI, 11.7-18.9]; recipients of autologous BMT: n = 60, SMR = 18.1 [95% CI, 13.9-23.0]; recipients of allogeneic BMT: n = 7, SMR, 6.1 [95% CI, 2.6-11.9]). The SMRs for all other nonrelapse-related causes of death were comparable between recipients of autologous and allogeneic BMT, except for higher SMR for respiratory causes among recipients of allogeneic BMT (SMR, 2.5 [95% CI, 1.3-4.3]; Table 2 ). Trends for all-cause and cause-specific mortality were similar across treatment eras ( supplemental Table 4 ). Table 2. SMRs and excess absolute risk for entire cohort, and by blood or marrow transplant type Cause of death Entire cohort Autologous BMT Allogeneic BMT SMR (95% CI) EAR SMR (95% CI) EAR SMR (95% CI) EAR All-cause 5.3 (5.0-5.6) 0.635 5.4 (5.0-5.8) 0.668 5.0 (4.4-5.6) 0.551 RRM 12.0 (11.1-13.0) 0.411 12.4 (11.3-13.5) 0.416 11.1 (9.4-12.9) 0.398 Infection 35.2 (30.3-40.6) 0.150 31.1 (25.8-37.1) 0.126 46.6 (36.0-59.0) 0.225 Renal 15.0 (11.7-18.9) 0.038 18.1 (13.9-23.0) 0.050 6.1 (2.6-11.9) 0.001 SMN 3.0 (2.6-3.5) −0.051 3.2 (2.7-3.8) −0.046 2.6 (1.8-3.5) −0.067 Cardiovascular 2.1 (1.7-2.5) −0.042 2.1 (1.7-2.6) −0.043 2.1 (1.4-2.9) −0.037 Neurologic 1.8 (1.0-2.9) −0.072 1.5 (0.7-2.8) −0.074 2.6 (0.9-5.6) −0.066 Respiratory 1.7 (1.2-2.4) −0.065 1.5 (0.9-2.2) −0.070 2.5 (1.3-4.3) −0.051 External 0.9 (0.5-1.6) −0.031 1.0 (0.5-1.8) −0.031 0.8 (0.2-2.2) −0.031 EAR, excess absolute risk; RRM, relapse-related mortality.

Morbidity

The 10-year cumulative incidence of grade 3 to 5 CHCs was 59.4% (95% CI, 57.0%-61.9%); this was higher among recipients of allogeneic BMT (67.3% [95% CI, 63.0%-71.9%]) than autologous BMT (56.3% [95% CI, 53.5%-59.3%]; Figure 1 ). For the entire cohort, the 10-year cumulative incidence of SMNs was 28.6% (95% CI, 26.2%-31.4%; supplemental Figure 3 ). Recipients of BMT had a 3.8-fold higher risk (95% CI, 3.5-4.2) of developing an SMN relative to the general population; higher SMRs were observed for subsequent melanoma (entire BMT cohort: SIR, 7.4 [95% CI, 5.1-10.2]; recipients of autologous BMT: SIR, 6.1 [95% CI, 3.8-9.1]; recipients of allogeneic BMT: SIR, 11.6 [95% CI, 6.2-19.4]). Recipients of autologous BMT had an increased risk of myelodysplastic syndrome/acute myeloid leukemia (SIR, 6.0 [95% CI, 2.7-11.1]) and gastrointestinal cancers (SIR, 1.7 [95% CI, 1.1-2.4]), whereas recipients of allogeneic BMT had increased risk of oropharyngeal cancers (SIR, 5.2 [95% CI, 1.9-11.1]; Table 3 ). Figure 1. Cumulative incidence of grade 3 to 5 CHCs among the entire cohort of survivors of BMT and by BMT type. Allo, allogeneic; Auto, autologous. Table 3. SIRs of SMNs, overall and by transplant type SMN Entire cohort Survivors of autologous BMT Survivors of allogeneic BMT Expected Observed SIR (95% CI) P value Expected Observed SIR (95% CI) P value Expected Observed SIR (95% CI) P value GI 19 35 1.7 (1.2-2.4) .002 14.7 27 1.7 (1.1-2.4) .008 4.3 8 1.9 (0.9-3.5) .079 Melanoma 4.5 33 7.4 (5.1-10.2) <.0001 3.4 21 6.1 (3.8-9.1) <.0001 1 12 11.6 (6.2-19.4) <.001 Prostate (male) 29.3 31 1.1 (0.7-1.5) .76 22.5 25 1.1 (0.7-1.6) .593 6.8 6 0.9 (0.3-1.8) .746 Breast 13 17 1.3 (0.8-2.0) .27 9.9 12 1.2 (0.6-2.0) .503 3.1 5 1.6 (0.6-3.4) .299 Lung 24.6 16 0.7 (0.4-1.0) .09 18.8 13 0.7 (0.4-1.1) .186 5.8 3 0.5 (0.1 to 1.3) .254 Oropharyngeal 4.1 11 2.7 (1.4-4.6) .001 3.1 6 1.9 (0.8-3.9) .114 1 5 5.2 (1.9-11.1) .0002 NHL 7.4 10 1.3 (0.7-2.4) .35 5.7 6 1.1 (0.4-2.1) .890 1.7 4 2.3 (0.7-5.3) .098 MDS/AML 1.7 9 5.1 (2.5-9.2) <.0001 1.3 8 6.0 (2.7-11.1) <.0001 0.4 1 2.4 (0.1-10.6) .379 AML, acute myeloid leukemia; GI, gastrointestinal; MDS, myelodysplastic syndrome; NHL, non-Hodgkin lymphoma. Boldface values are statistically significant.

Burden of morbidity and adverse health status in survivors of BMT compared with siblings

The 812 survivors who were alive and responded to a questionnaire provided 4870 person-years of follow-up. Their median age at BMT was 64.0 years (range, 60.0-78.0). Survivors were more likely than siblings to be older (mean 70.0 vs 66.7 years, P < .001), male (60.8% vs 41.4%; P < .001), and of minority race/ethnicity (19.0% vs 11.6%; P = .001; Table 1 ).

In adjusted models, survivors had higher odds of developing any grade 3 to 4 CHC (OR, 2.9 [95% CI, 2.2-3.7]) when compared with siblings. Specifically, survivors of both autologous and allogeneic BMT had higher odds of sensorineural impairment (OR, 3.0 [95% CI, 2.3-3.9]), cardiovascular disease (OR, 1.8 [95% CI, 1.2-2.5]), and blood clots (OR, 3.8 [95% CI, 2.3-6.2]) compared with siblings. Survivors of allogeneic BMT also had higher odds of developing diabetes (OR, 3.9 [95% CI, 2.1-7.2]; Table 4 ). Table 4. Prevalence and adjusted ORs (aORs) of grade 3 to 4 CHCs and adverse health status among survivors compared with siblings, overall and by transplant type Cohort of survivors of BMT (n = 811) Survivors of autologous BMT (n = 552) Survivors of allogeneic BMT (n = 259) Prevalence aOR 95% CI P value Prevalence aOR 95% CI P value Prevalence aOR 95% CI P value Siblings All survivors of BMT Survivors of BMT Survivors of BMT Nonmalignant CHCs, n (%) Any condition 303 (51.0) 585 (72.0) 2.9 2.2-3.7 <.0001 389 (70.3) 2.3 1.8-2.9 <.0001 196 (75.7) 3.5 2.5-4.9 <.0001 Sensorineural 149 (29.1) 387 (47.7) 3.0 2.3-2.8 <.0001 263 (47.6) 3.0 2.3-3.9 <.0001 124 (47.9) 3.0 2.1-4.2 <.0001 Cardiovascular disease 48 (9.4) 136 (16.8) 1.8 1.2-2.5 .002 92 (16.7) 1.7 1.2-2.5 .005 44 (17.0) 1.9 1.2-2.9 .01 Blood clot 20 (3.9) 122 (15.0) 3.8 2.3-6.2 <.0001 75 (13.6) 3.3 2.0-5.5 <.0001 47 (18.1) ∗ ∗ ∗ Diabetes 16 (3.1) 63 (7.8) 2.1 1.2-3.7 .01 32 (5.8) ∗ ∗ ∗ 31 (12.0) 3.9 2.1-7.2 <.0001 Adverse health status, n (%) Frailty † 18 (3.3) 89 (13.3) 3.5 2.1-6.0 <.0001 59 (12.9%) 3.8 2.2-6.6 <.0001 30 (14.0) 4.7 2.5-8.8 <.0001 Poor general health 34 (6.0) 174 (21.6) 4.1 2.8-6.0 <.0001 122 (22.2) 4.1 2.7-6.1 <.0001 52 (20.2) 4.3 2.7-6.9 <.0001 Functional impairment 195 (32.9) 450 (55.9) 3.2 2.5-4.0 <.0001 314 (57.4) 3.3 2.5-4.3 <.0001 136 (52.7) 3.2 2.3-4.5 <.0001 Activity limitation 201 (33.8) 478 (59.1) 3.1 2.4-3.9 <.0001 332 (60.3) 3.3 2.5-4.2 <.0001 146 (56.6) 2.8 2.1-3.9 <.0001 Multivariable models were created for each outcome of interest using backward selection of the following variables: age at study, sex, race, education, and income. ∗ Numbers not large enough for multivariable analysis. † Multivariable model also adjusted for CHCs.

Compared with the siblings, survivors had higher odds of frailty (OR, 3.5 [95% CI, 2.1-6.0]), with similar magnitudes of risk by BMT type ( Table 4 ). Survivors of BMT were also significantly more likely to report poor general health (21.6% vs 6.0%; OR, 4.1 [95% CI, 2.8-6.0]), functional impairment (55.9% vs 32.8%; OR, 3.2 [95% CI, 2.5-4.0]), and activity limitation (59.1% vs 33.8%; OR, 3.1 [95% CI, 2.4-3.9]) compared with siblings ( Table 4 ). In multivariable models including survivors and siblings, and adjustment for age and sex, lower income and educational attainment were independently associated with poor general health and functional impairment ( supplemental Table 5 ). Trends were similar in subset analyses by age intervals ( supplemental Table 6 ), and race and ethnicity ( supplemental Table 7 ). Of note, in subset analysis by income, survivors and siblings with income <$75 000 had higher prevalences of all adverse health status measures than those with income ≥$75 000. However, the relative odds of adverse health status in survivors compared with siblings remained similar among the 2 income categories ( supplemental Table 7 ).

Discussion

BMT is increasingly performed in older patients who are expected to live for several years following transplant. 2 In these survivors, risk-based multidisciplinary surveillance and interventions may be needed due to high prevalence of aging-related risk factors and comorbidities at baseline. 27 This report from the BMTSS represents, to our knowledge, the first comprehensive evaluation of the burden of morbidity and mortality focused exclusively on older (aged ≥60 years at transplant) survivors. We found a higher risk of mortality and morbidity than for the general population, but the overall magnitudes of risks were less than what has been reported for younger patients undergoing BMT, likely reflecting the increased background risk of mortality and comorbidities in the general aging population as well as careful selection of which older patients were eligible for BMT. Surprisingly, the relative risks for cause-specific mortality, SMNs, CHCs, frailty, and health status were generally similar by BMT type, and there were no clear treatment-specific modifiers of health outcomes, suggesting that the higher burden of long-term health complications in these older recipients of BMT may be associated with dysregulation of broader mechanisms of aging. 28

The 5-fold excess risk of all-cause mortality in our study is lower than the previously reported 9- and 14-fold higher risk of mortality in younger survivors of allogeneic (median age at BMT, 33 years) 29 and autologous (median age at BMT, 48 years) 30 BMT, respectively. Similar to previous studies, 18 , 29 we found that infections and SMNs were the leading causes of nonrelapse-related mortality. The markedly increased risk of mortality due to infections in our study cohort may reflect diminished physiologic and immune reserves among older adult recipients of BMT, 31 compounded by a higher infection risk among survivors with SMNs or post-BMT disease relapse. For the most part, we found there was a decline in the magnitudes of risk of infection-related mortality for those who underwent BMT in more recent eras (2005-2014 vs 1990-2004), which may reflect better disease control over time, lower long-term SMN risk, and use of less myeloablative conditioning strategies among older patients who received allogeneic BMT. The absolute number of infection-related deaths (n = 180) limited our ability to conduct subgroup analyses; however, this would be an important focus for future studies. As the population of older recipients of BMT continues to grow, further studies of their immune reconstitution (eg, lymphocyte and immunoglobulin subsets, cytokine response), and identification of strategies to facilitate this, may help mitigate the high burden of infection-related mortality in this population.

In this study, survivors had notably higher risk for both hematologic and solid cancers relative to the general population, irrespective of BMT type. Contrary to previous studies, 32 , 33 we did not observe an association with TBI exposure, which is a well-established risk factor for solid SMNs after BMT. This may be due to the relatively low proportion of patients in our cohort who received TBI-based myeloablative conditioning, or the more limited duration of follow-up in this study (median 5 years). 18 Previous studies, including our own, have shown that the latency of SMNs associated with TBI is ∼10 to 20 years, with an increasing risk persisting decades after radiation exposure. 33 , 34 , 35 Longer follow-up of this aging cohort may be needed to further interrogate these treatment-specific associations. Studies in patients with cancer who were conventionally treated have similarly noted lower SIRs for SMNs among those who were older vs younger at diagnosis. 36 Among these older patients, there is not a clear delineation of cancer treatment-related modifiers of risk. 36 , 37 There is emerging evidence, for example, that the general mutagenic effects of cancer treatment exposures and shared etiologic factors, such as tobacco use and viral infections, may be more pronounced in older patients. 36 , 37 Although some of the SMNs we observed and their underlying mechanisms have been described previously in survivors of BMT (eg, associations between post-BMT immunosuppression and melanoma, 38 cGVHD and oropharyngeal cancer, 39 and alkylating agents and myelodysplastic syndrome/acute myeloid leukemia), 40 the nuances of their relationship to age-related somatic and epigenetic changes associated with aging and environmental exposures remain an active area of investigation. 41 , 42 , 43

We found that survivors of BMT had a 2.9-fold risk of severe or life-threatening CHCs compared with siblings. Similar to previous reports, 44 we also found that compared with siblings, survivors of allogeneic BMT had a higher risk of CHCs than survivors of autologous BMT. 9 Both survivors of autologous and allogeneic BMT had higher prevalences of aging-related conditions, including sensorineural impairment, diabetes, cardiovascular disease, and blood clots, than siblings. Individual chemotherapy exposures such as pre-BMT anthracycline or steroids, or cGVHD were surprisingly not associated with the overall risk of developing CHCs. This suggests that among older recipients of BMT, the etiology of CHCs may be more complex, and attributed to the disruption of healthy aging processes. 45 , 46 For example, chemotherapy and radiation may induce senescence among normal noncancerous cells, and these senescent cells release proinflammatory cytokines. 47 Both cellular senescence and inflammation are associated with CHCs such as cardiovascular disease and frailty. 47 , 48 , 49 Additional studies are needed to more accurately determine which patients are at risk of developing CHCs after BMT, and to establish biomarkers to facilitate early detection. This may ultimately guide post-BMT late effects guidelines, with screening frequency and diagnostic tests specifically tailored to the aging-related risks of this older patient population.

We found that survivors of BMT had more than threefold odds of frailty and adverse health status outcomes relative to siblings. Over half of the survivors of BMT in this study reported functional impairment and/or activity limitation, emphasizing the need for interventions to optimize musculoskeletal health and physical function in older recipients of BMT. 50 , 51 Prehabilitation with personalized exercise interventions and nutrition counseling before BMT is increasingly being considered to improve functional status before BMT and optimize outcomes in the peritransplant period. 52 , 53 However, as older recipients of BMT continue to live for many years after BMT, it may be necessary to leverage these approaches to develop sustainable and accessible programs to optimize their long-term health status. There is also a need to better characterize the impact of socioenvironmental risk factors on subsequent CHCs and frailty, given the strong association between lower income and educational attainment and self-reported health status in our study. In older adults with solid tumors, higher social vulnerability is associated with frailty and additional aging-related impairments (eg, functional impairment, cognitive deficits), which affect treatment decisions and risk of toxicity and mortality. 54 , 55 Socioenvironmental vulnerability has also been associated with decreased access to and poorer outcomes following allogeneic BMT. 56 , 57 It has been proposed that for older recipients of BMT, their ecosystem (caregiver support, social support system, financial resources, and living situation) should be included in comprehensive pre-BMT evaluations, allowing for the allocation and utilization of resources (eg, remote assessments and health care visits, transportation assistance) to minimize the burden on patients without compromising their quality of monitoring and follow-up. 27 Studies focused on patients’ ecosystems and feasible, relevant interventions are needed to determine optimal, scalable approaches to improve outcomes in this patient population. Our study highlights the importance of studying these factors well into survivorship, setting the stage for tailored resources to address aging-related comorbidities in older patients who received BMT.

The findings of this study should be considered in the context of its limitations. The study relied on self-reported data regarding health conditions and health status, which inherently carries potential risk for reporting and recall bias. By including ≥2-year survivors, there is also the potential for survival bias, given the possibility that there may be an overrepresentation of a more resilient subset of patients who received BMT. Different age cutoffs have been used to define “older adults.” To be inclusive of the older population who received BMT and ensure that the current report remains as informative as possible, we used the age cutoff of 60 years, which is similar to what has been used by previous studies focused on older recipients of BMT, 58 , 59 as this is representative of the age at which hematologic malignancies are more common. Further, the relatively short duration of follow-up (median 5 years) may have precluded a comprehensive evaluation of late-occurring events such as solid SMNs or cardiovascular complications. The BMTSS includes patients who received BMT between 1974 and 2014. This cohort does not include patients who received transplants using newer strategies, including haploidentical BMT, chimeric antigen receptor T-cell therapy, and novel regimens for GVHD prevention. 8 , 60 Nevertheless, our findings add to a growing body of literature regarding the necessity of multifaceted approaches to oncogeriatric care, 61 , 62 , 63 and specifically highlight key considerations for supportive management and late-effects screening in this cohort.

This study represents, to our knowledge, the first comprehensive evaluation of long-term health outcomes specifically among older recipients of BMT. We found that these survivors had increased risk for mortality, SMNs, CHCs, frailty, and adverse health status that extended beyond what is expected for their age. As the numbers of BMTs performed in older individuals increases, it is imperative to develop well-informed approaches to determine which patients would derive benefit from BMT in the context of their disease status, comorbidities, and functional status, recognizing that age alone provides an incomplete picture of their health status and anticipated outcomes. The findings from this study highlight potential opportunities to develop prevention, early detection, and intervention strategies to mitigate morbidity, mortality, and adverse health status in the growing population of older patients with hematologic malignancies.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

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Supplementary Material

Supplemental Figures and Tables

Acknowledgments

This work was supported, in part, by the National Cancer Institute (R01 CA078938 [S.B.]; U01 CA213140 [S.B.]; K12CA001727), and the Leukemia and Lymphoma Society (R6502-16 [S.B.]).

Authorship

Contribution: R. Bhandari contributed to conceptualization, study design, interpretation of results, and original draft writing, reviewing, and editing; Q.M. contributed to data analysis, interpretation of results, and manuscript reviewing and editing; L.H., L.F., E.S.R., N.B., and A.B. contributed to data acquisition and manuscript reviewing and editing; R. Bhatia and W.L. contributed to interpretation of results and manuscript reviewing and editing; D.J.W. contributed to data acquisition, interpretation of results, and manuscript reviewing and editing; F.L.W. contributed to study design, interpretation of results, and manuscript reviewing and editing; S.B. contributed to study design, data acquisition, data analysis, interpretation of results, and original draft writing, reviewing, and editing; and S.H.A. contributed to conceptualization, study design, data acquisition, data analysis, interpretation of results, and original draft writing, reviewing, and editing.

Presented in abstract form at the 66th annual meeting of the American Society of Hematology, San Diego, CA, 7 to 10 December 2024.

The data sets generated and/or analyzed during this study are available from the corresponding author, Rusha Bhandari ( rbhandari@coh.org ), on reasonable request.

The full-text version of this article contains a data supplement.