The current study demonstrates that HL and NHL survivors treated with autologous HCT have a higher prevalence of a wide spectrum of medical late complications and functional limitations and are more likely to have a negative perception of their overall health status compared to their siblings. Furthermore, medical late effects can lead to considerable functional impairments as evidenced by a significantly large proportion of survivors being unable to attend work or school due to health problems and grading their overall health status as only poor to fair.
Non-neoplastic late effects of autologous HCT in lymphoma survivors have not been well characterized previously. Ruiz-Soto et al studied late toxicity, defined as adverse events occurring 30-days after transplantation, in 158 recipients of autologous HCT for aggressive NHL.12
Forty-three patients developed late toxicity; common late adverse events included infections (19%), neurological (18%), digestive tract (15%), endocrine (9%) and pulmonary (9%) problems. However, inclusion of patients in their early post-transplant period, a short duration of post-transplant followup (median followup was 3 years, range 0.2-10 years) and a lack of a control group were limitations of their study. Lavoie et al have reported long-term outcomes of 53 HL survivors followed for at least 10 years or more following autologous HCT.13
In this retrospective analysis, common non-malignant late complications included hypothyroidism (38%), hypogonadism (38%), infections (34%), anxiety or depression (13%) and cardiac diseases (9%).
Survivors of HL and NHL treated with chemotherapy and/or radiation therapy are at an increased risk for developing late onset cardiovascular and pulmonary complications, primarily due to toxicity associated with the use of anthracyclines, bleomycin and mediastinal irradiation.14-22
Lymphoma survivors in our study reported a higher prevalence of congestive heart failure, exercise induced shortness of breath and blood clot in the extremities. However, the risk of myocardial infarction, coronary artery disease, angina, valvular heart disease, stroke and lung fibrosis was comparable to that of siblings. This low prevalence of specific cardiopulmonary outcomes could be due to the relatively young age of our study participants, both subjects and siblings, and the relatively short duration of followup after transplantation.
Female lymphoma survivors were at an increased risk of developing congestive heart failure and osteoporosis. In a previous study, we have observed female autologous HCT recipients to have a 4-fold higher risk of late death due to cardiac complications compared to age- and sex-matched general population controls.1
Although previous studies have not demonstrated a gender preference in the risk of osteoporosis after autologous HCT,23,24
ovarian ablation secondary to high-dose chemotherapy and TBI could possibly explain the increased risk of this late effect in females. Nonetheless, modifiable risk factors for cardiac disease and osteoporosis should be identified early and appropriately managed in lymphoma survivors of autologous HCT, especially females.
Compared to siblings, survivors in our study had a greater likelihood of having functional impairments and an adverse perception of their overall health status. Although no other study has specifically characterized functional limitations in lymphoma survivors, similar observations have been described previously in studies that have included recipients of autologous HCT for hematologic disorders.25-27
In a self-reported survey administered serially over the first two years post-transplant by Lee et al,26
a large proportion of autologous HCT survivors were observed to have persistent functional restrictions over time.
Thirty-five percent of the eligible cohort did not participate in this study, and the participants were older at study participation than the non-participants; this could be a potential source of bias for our study. However, comparison with the siblings was age-adjusted. Furthermore, the results of this study are based on self-reported medical information and could possibly result in misclassification of the outcomes of interest. In order to overcome this limitation, a validation study was conducted on HCT recipients at City of Hope National Medical Center, and demonstrated that self-report of complications using the BMT-SS questionnaire has good to excellent agreement with data abstracted from medical records.10
Additionally, the sibling comparison group also self-reported data, hence eliminating any systematic differences in bias between the two comparison groups. There is also a potential for over-detection bias in our study, with more vigilance for specific late effects in HCT survivors compared to healthy sibling controls. Finally, we did not account for other known risk factors for several outcomes, such as family history, smoking history, activity level and pre-transplant therapy, in our analyses. These pre-transplant exposures, especially prior chemotherapy and radiation therapy, can independently increase the risk of developing specific late complications in lymphoma survivors. However, the risk of these late complications may be further compounded by the high-dose chemotherapy and TBI routinely used as a part of conditioning regimen for autologous HCT.
These limitations notwithstanding, our study comprehensively describes the magnitude of risk of medical late effects and functional limitations and evaluates risk factors for these outcomes in HL and NHL survivors of autologous HCT. This study demonstrates that long-term survivors are at increased risk of late effects that results in functional limitations and therefore provides the justification for continued monitoring and surveillance of this population using published guidelines.28