Long-Term Health Outcomes in Older (≥60 Years) Blood or Marrow Transplantation (BMT) Recipients: A Report from the Blood or Marrow Transplant Survivor Study (BMTSS)

Background: Better conditioning approaches and supportive care have increasingly allowed older (≥60y) patients with hematologic malignancies to undergo BMT. Patients >60y currently account for >30% of allogeneic and >40% of autologous BMT recipients in the US and represent a fast-growing demographic. Studies conducted primarily in younger (<60y) BMT recipients suggest long-term survivors exhibit signs of accelerated aging, attributed to therapeutic exposures and comorbidities related to BMT. Yet, comprehensive evaluation of the burden of aging-related health complications among older patients treated with BMT remains largely unknown. We addressed this gap by evaluating late mortality, subsequent malignant neoplasms (SMNs), chronic health conditions (CHCs), and health status in older BMT patients using the BMTSS.

Methods: Patients were eligible if they underwent an allogeneic or autologous BMT for a hematologic malignancy between 1990 and 2014 at one of 3 BMT centers in the US and survived for ≥2y after BMT (regardless of disease status at study entry and vital status after study entry). The cohort was linked with the National Death Index. This analysis was restricted to those who were ≥60y at BMT (n=1,581). Those alive at study participation (n=812) and an unaffected sibling comparison group (n=594) completed a 255-item BMTSS survey that included questions regarding sociodemographics, subsequent malignant neoplasms (SMNs) and chronic health conditions (CHCs) diagnosed by a healthcare provider, and health status (general health and functional or and activity limitations). CHC scoring was based on Common Terminology Criteria for Adverse Events ([CTCAE] v 5.0). US population age-, sex-, and calendar year-matched standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) for SMNs were calculated for the entire cohort. Multivariable logistic regression analysis was used to compare the risk of severe/life-threatening CHCs (grade 3-4), physiologic frailty (modified Fried criteria, JAMA Oncol, 2016), and adverse health status between survivors and siblings.

Results: Median age at BMT was 64.0y (range 60.0-78.0y); 62.9% were male and 78.2% were non-Hispanic White. The most common diagnosis was myeloma (44.7%); 78.1% underwent BMT between 2005 and 2014 and 72.1% received autologous BMT. Late mortality: BMT recipients had a 5.3-fold greater risk of all-cause mortality (95%CI 5.0-5.6) compared to the general population. The 10y cumulative incidence of non-relapse mortality (NRM: 21.2%) exceeded relapse-related mortality (RRM: 11.9%). Excess risk of death was observed for infection (SMR 35.2, 95%CI 30.3-40.6) and renal disease (SMR 15.0, 95%CI 11.7-18.9). SMNs: The 10y cumulative incidence of SMNs was 28.6% (95%CI 26.2-31.4%), representing a 3.8-fold greater risk (95% CI 3.5-4.2) relative to the general population. SIRs were highest for the following SMNs: Hodgkin lymphoma (SIR 18.5, 95%CI 7.4-37.5), melanoma (SIR 7.4, 95%CI 5.1-10.2), and cervical cancer (SIR 6.4, 95% CI 1.1-19.9). Chronic health conditions: Compared to siblings, survivors had higher odds of developing severe/life-threatening CHCs (OR 2.9, 95% CI 2.2-3.7), and the odds were significantly higher for blood clot (OR 3.8, 95% CI 2.3-6.2), sensorineural impairment (OR 3.0, 95% CI 2.3-3.9), diabetes (OR 2.1, 95% CI 1.2-3.7), and cardiovascular disease (OR 1.8, 95% CI 1.2-2.5). Physiologic frailty and health status: Survivors had higher odds of physiologic frailty (OR 3.5, 95%CI 2.1-6.0), and were more likely to report poor general health (OR 4.1, 95%CI 2.8-6.0), functional impairment (OR 3.2, 95% CI 2.5-4.0), and activity limitation (OR 3.1, 95%CI 2.4-3.9) compared to siblings. Overall, these risks for late mortality, SMNs, CHCs, physiologic frailty, and adverse health status were similar across BMT types.

Conclusion: This study provides a global assessment of long-term health outcomes in older patients treated with BMT and finds that, compared to the general population and sibling controls, older survivors of both allogeneic and autologous BMT are at substantially higher risk of mortality and of developing SMNs, severe/life-threatening complications, and physiologic frailty. These findings reinforce the need for multi-disciplinary management of older patients who undergo BMT, and for targeted risk-based interventions to mitigate their risk of late-occurring adverse health outcomes.