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We determined the prevalence of self-reported late-effects in survivors of autologous hematopoietic-cell transplantation (HCT) for Hodgkin’s lymphoma (HL, n=92) and non-Hodgkin’s lymphoma (NHL, n=184) using a 255-item questionnaire and compared them to 319 sibling controls in the Bone Marrow Transplant Survivor Study. Median age at HCT was 39 years (range, 13-69) and median post-transplant followup was 6 years (range, 2-17). Median age at survey was 46 years (range, 21-73) for survivors and 44 years (range, 19-79) for siblings. Compared to siblings, HCT survivors reported a significantly higher frequency of cataracts, dry mouth, hypothyroidism, bone impairments (osteoporosis and avascular necrosis), congestive heart failure, exercise-induced shortness of breath, neurosensory impairments, inability to attend work or school and poor overall health. Compared to those receiving no total-body irradiation (TBI), patients treated with TBI-based conditioning had higher risks of cataracts (odds-ratio (OR) 4.9, 95%CI 1.5-15.5) and dry mouth (OR 3.4, 95%CI 1.1-10.4). Females had a greater likelihood of reporting osteoporosis (OR 8.7, 95%CI: 1.8-41.7), congestive heart failure (OR 4.3, 95%CI 1.1-17.2) and abnormal balance, tremor or weakness (OR 2.4, 95%CI 1.0-5.5). HL and NHL survivors of autologous HCT have a high prevalence of long-term health-related complications and require continued monitoring for late-effects of transplantation.
Autologous hematopoietic cell transplantation (HCT) is standard therapy for patients with aggressive or advanced Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL) and can lead to durable long-term remissions. Although autologous HCT is associated with low rates of early transplant-related morbidity and mortality, the high-dose chemotherapy and total body irradiation (TBI) used as part of conditioning regimens can potentially increase the risk of late complications of therapy. Lymphoma survivors treated with autologous HCT are at a significantly higher risk for premature death compared to the general population,1 and for developing secondary solid tumors, leukemia and myelodysplastic syndrome.1-6 However, the incidence and risk factors for non-malignant late effects in lymphoma autologous HCT survivors have not been systematically investigated.
The current analysis from the Bone Marrow Transplant Survivor Study (BMT-SS) was conducted to describe the prevalence of, and predictors for a broad spectrum of medical late complications, functional impairments and overall general health in survivors of HL and NHL treated with autologous HCT.
The BMT-SS is a collaborative retrospective cohort study established in 2000 between the City of Hope National Medical Center and University of Minnesota to examine the long-term outcomes of HCT survivors. The present report from the BMT-SS was restricted to subjects who met the following eligibility criteria: (1) autologous HCT for HL or NHL between January 1, 1974 and December 31, 1998, (2) age 18 years or older at the time of survey, and (3) survival of at least 2 years from HCT. The analysis compared late-effects of transplant in 276 survivors of autologous HCT for lymphoma (HL=92, NHL=184) with a sample of 319 siblings. For comparison purposes, a group of siblings was enrolled into the study by assembling a random sample of study participants stratified on the basis of diagnosis, age, sex, ethnic background; asking these participants to recruit their siblings into the study; and then asking the siblings to complete the same questionnaire as the participants.7 The comparative evaluations for this analysis were not limited to siblings of HL or NHL participants, but included siblings of all patients who were enrolled in the study and had completed a study questionnaire. The study protocol was reviewed and approved by the Human Subjects Research Review Committee of the participating institutions and all subjects provided informed consent prior to participation in the study.
Participants completed the BMT-SS questionnaire, a 255-item survey assessing medical late effects, current medical conditions, medication use, health status, health behaviors, pregnancy history, demographic characteristics, socioeconomic indicators, insurance coverage, and other information. The BMT-SS questionnaire also asks participants to report impairment of organ systems, limitations that interfere with daily function and the impact of these impairments and/or functional limitations on daily life either at home, school or work. The questionnaire was originally developed for use by the Childhood Cancer Survivor Study8 and was subsequently modified to address topics specifically related to the HCT survivor population. The questionnaire has a yes/no/don’t know format for the majority of questions or a Likert scale9 or ordinal response to score degree of impairment or dysfunction. The BMT-SS questionnaire was validated on a sample of 100 HCT survivors, and the agreement with medical records was excellent (percentage agreement adjusted for chance, kappa >0.8) for musculoskeletal, cardiovascular, pulmonary, and endocrine impairments, and moderate (kappa 0.4-0.7) for second cancers, central nervous system disorders, and eye problems.10 Data on therapeutic exposures were abstracted from databases at the two participating institutions which prospectively collect HCT-related information.
The prevalence of medical late effects was calculated by tabulating the yes responses to specific questions in the BMT-SS questionnaire. Descriptive statistics including means, medians, standard deviations, frequencies and ranges were calculated for demographic variables for the sibling comparison group and for demographic and treatment variables for participating and non-participating HCT survivors. Two sample t-test, Chi-square test or Fisher’s exact test, as appropriate, were used to compare differences between survivors and siblings and between lymphoma types among survivors.
Frequencies and percentages were calculated for medical late effects among siblings and HCT survivors as totals and by lymphoma type (HL vs. NHL). The prevalence of each medical late effect, after adjusting for age at survey and gender, was compared between cases and siblings by calculating odds ratios and 95 percent confidence intervals using generalized estimating equations (GEE) with a binomial distribution and a logit link. GEE methods were used in all models to account for the possible correlation between survivors and siblings from the same family.11 In an analysis limited to survivors only, gender, lymphoma type and the use of TBI were evaluated in relation to the outcome variables in unconditional logistic regression models. These three variables were adjusted for each other in the models with further adjustment for age at transplant and age at survey. Race/ethnicity, stem cell source (peripheral blood vs. bone marrow) and institution were not identified as independent predictors of the outcomes, nor did they appreciably alter the estimates, so they were not included in the final models. SAS version 9.1 was used for all analyses (SAS Institute, Cary, N.C.).
A total of 425 patients with HL or NHL met the eligibility criteria. Of these, 34 (8%) were lost to follow-up and 115 either actively or passively refused participation (27%). Participants did not differ from non-participants by time since transplant, stem cell source, sex, treating institution, or diagnosis. Participants were more likely to have received TBI as part of their conditioning regimen (69.1% vs. 59.1%, p=0.04), and were older at the time of interview (median age 46 (range, 21-73) years vs. 42 (range, 18-73) years) than non-participants.
Characteristics of the study participants are shown in Table 1. Compared to siblings (median age 44 (range, 19-79) years), HL survivors were younger (median age 40 (range, 22-63) years) while NHL survivors were older (median age 51 (range, 23-73) years) at the time of survey administration. There were no race/ethnicity differences between siblings and NHL survivors; however HL survivors were more likely to be of non-white race/ethnicity compared to siblings (14% vs. 7%, p=0.04). Both HL and NHL survivors were more likely to be males.
When compared to NHL, the demographic and treatment characteristics of HL group were similar, except HL survivors were younger in age both at the time of interview and at HCT, and a higher proportion of NHL survivors received TBI as a part of their conditioning regimen (83% vs. 40%, p<0.001). Overall, 66% of the patients received peripheral blood derived stem cells.
Table 2 lists the prevalence of selected medical late effects in HL and NHL HCT survivors. Compared to siblings, lymphoma survivors (HL and NHL combined) were more likely to develop the following organ-system and organ impairments: eye impairments (19.2% vs. 11.3%, p=0.01) including cataracts (14.5% vs. 3.8%, p<0.001), oral health impairments (17.8% vs. 12.9%, p=0.05) including dry mouth (13.8% vs. 0.9%, p<0.001) and problems chewing or swallowing (4.7% vs. 1.3%, p=0.009), endocrine impairments (22.5% vs. 11.3%, p<0.001) including hypothyroidism (18.8% vs. 7.2%, p<0.001), bone impairments (7.2% vs. 2.5%, p=0.007) including osteoporosis (4.3% vs. 2.2%, p=0.05) and avascular necrosis (3.3% vs. 0.3%, p=0.04), neurosensory impairments (32.6% vs. 20.4%, p=0.002) including abnormal sense of taste or smell (12.3% vs. 0.6%, p<0.001) and abnormal sense of touch (20.7% vs. 9.7%, p<0.001) and neuromotor impairments (9.8% vs. 6.3%, p=0.06) including abnormal balance, tremor or weakness (9.8% vs. 5.4%, p=0.02). Although lymphoma survivors were no more likely than siblings to report overall cardiopulmonary impairments, they did have a higher risk of developing congestive heart failure (4% vs. 0.3%, p=0.009), exercise induced shortness of breath (9.8% vs. 2.5%, p<0.001) and blood clots in the extremities (4.7% vs. 1.3%, p=0.03). There was no significant difference between HL and NHL survivors in the reported prevalence of any medical late effects.
The prevalence of functional impairments following HCT is detailed in Table 3. Lymphoma survivors were more likely than siblings to report that their current health prevented them from attending work or school (15.6% vs. 2.2%). Lymphoma survivors were also less likely than siblings to rate their present health as good, very good or excellent (83.7% vs. 94.7%). There was no significant difference between HL and NHL survivors in the reported frequencies of various functional limitations and overall health.
Table 4 shows multivariate models with the relative odds of developing selected late effects and functional limitations based on lymphoma type (HL vs. NHL), use of TBI as a part of conditioning regimen and gender. After adjusting for age at transplantation and age at survey, females had a higher risk of developing osteoporosis (odds ratio (OR) 8.7, 95% CI 1.8-41.7), congestive heart failure (OR 4.3, 95% CI 1.1-17.2) and balance impairment, tremor or weakness (OR 2.4, 95% CI 1.0-5.5) compared to males. The relative odds of developing cataracts and dry mouth were 4.9 times (95% CI 1.5-15.5) and 3.4 times (95% CI 1.1-10.4) higher, respectively, in survivors who had received TBI as a part of their conditioning regimen compared to those who did not. The type of lymphoma had no impact on the risk of developing any organ specific late effects or functional limitations.
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
This study was supported in part by grants from the National Cancer Institute (R01 CA078938) (S.B.), the Leukemia Lymphoma Society (2192) (S.B.) and the National Institutes of Health (K23 CA85503-01) (K.S.B.).
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