Adult Hematopoietic Cell Transplantation Survivors Research Articles

Long-Term Outcomes In Survivors of Childhood Cancer Treated with Hematopoietic Cell Transplantation (HCT) Versus Conventional Therapy: a Report From the Bone Marrow Transplant Survivor Study (BMTSS) and Childhood Cancer Survivor Study (CCSS)

AbstractAbstract 217 Introduction:HCT is used with curative intent in children with cancer at risk for relapse. Improvements in transplantation strategies have contributed to increments in survival approximating 10% per decade. Adult HCT survivors are at increased risk for chronic health conditions (Sun, Blood 2010). The magnitude of risk of these conditions in childhood HCT survivors compared with the general population is not defined. Furthermore, while children treated with conventional therapy carry a substantial burden of morbidity (Oeffinger, N Engl J Med 2006), little data exists regarding the added impact of HCT-related conditioning and GvHD on the prevalence of chronic health conditions and functional status. Methods:Participants were drawn from two studies: BMTSS and CCSS. BMTSS examined long-term outcomes in individuals undergoing HCT between 1976 and 1998 at City of Hope or University of Minnesota. Participants were ≤21 years of age at diagnosis of AML, ALL, HL, and NHL, had survived at least 5 yrs from primary diagnosis and 2 yrs from myeloablative HCT. CCSS is a multi-institutional cohort of five-year survivors of childhood cancer diagnosed between 1970 and 1986, and their siblings. For the current study, participation was limited to those treated conventionally with the same diagnoses as BMTSS. Participants for both studies had completed a questionnaire covering the following areas: presence of physical health conditions (endocrinopathies; central nervous system compromise; cardiopulmonary dysfunction; gastrointestinal sequelae; musculoskeletal abnormalities; and subsequent malignancies); chronic GvHD (BMTSS); and sociodemographics. Responses obtained from BMTSS were compared to conventionally treated childhood cancer survivors and sibling controls enrolled in CCSS. Chronic physical health conditions were graded using CTCAE v 3.0 (grade 1–4, ranging from mild to life-threatening/ disabling). Relative risk regression was used to identify risk of health conditions (RR) and 95% confidence interval (CI). Results:The current study included 145 BMTSS participants, 4,020 siblings, and 7,207 CCSS cancer survivors. Median age at participation – BMTSS: 24 yrs; childhood cancer survivors: 24.6 yrs; siblings: 26.6; time from diagnosis – BMTSS: 11.9 yrs; CCSS: 15.6 yrs. 79.3% of BMTSS participants reported at least one condition (grades 1–4); 59.3% multiple (≥2); and 25.5% severe or life-threatening conditions (grade 3–4). Prevalence and severity of these conditions was significantly greater for BMTSS when compared with cancer survivors or siblings (Figure). BMTSS vs. Siblings: After adjustment for age at questionnaire, gender, and ethnicity, BMTSS participants were significantly more likely than sibling controls to report chronic health conditions: grades 1–4: RR=2.7 (95% CI, 2.4–3.0, p<0.01); grades 3–4: RR=6.4 (4.6-8.8, p<0.01); multiple conditions: RR=5.9 (5.0-7.0, p<0.01). In addition, BMTSS participants were significantly more likely to report compromised functional status: adverse general health: RR=3.4 (2.1-5.3, p<0.01); activity limitations: RR=6.8 (5.0-9.3, p<0.01); and functional impairment: RR=7.8 (5.1-12.0, p<0.01). BMTSS vs. CCSS cancer survivors: After adjustment for age, follow-up, gender, ethnicity/race, diagnosis, pre-HCT therapeutic exposures (dose-specific chemotherapy, radiation), and treatment era, BMTSS participants were 1.5 (1.3-1.7, p<0.01) times as likely as conventionally treated patients to report a chronic condition; 2.3 (1.5-3.5, p<0.01) times as likely to report severe/ life-threatening conditions; and 2.2 (1.7-2.8, p<0.01) times as likely to report multiple conditions. Allogeneic HCT recipients with a history of chronic GvHD were at a modestly higher risk of reporting multiple chronic health conditions (Table). [Display omitted] RR (95% CI) Grades 1-4RR (95% CI) Grade 3 or 4RR (95% CI) Multiple (≥2) ConditionsConventionally treated (CCSS)1.01.01.0Autologous HCT (BMTSS)1.3 (1.0–1.7)1.7 (0.7–3.9)1.5 (0.9–2.2)Allogeneic HCT, no GvHD (BMTSS)1.5 (1.2–1.7)2.5 (1.6–3.9)2.2 (1.7–2.8)Allogeneic HCT, GvHD (BMTSS)1.7 (1.4–2.0)2.7 (1.3–5.3)2.9 (2.1–3.9) Conclusions:Childhood HCT survivors carry a significantly higher burden of morbidity when compared with the general population, as well as children treated with conventional therapy, providing evidence for a critical need for close monitoring of this high-risk population. Disclosures:No relevant conflicts of interest to declare.

Total Body Irradiation (TBI) Increases Cardio-Metabolic Risk and Induces Carotid Vascular Stiffness in Survivors After Hematopoietic Cell Transplant (HCT) for Childhood Hematologic Malignancies.

Abstract 3329Poster Board III-217▪▪This icon denotes an abstract that is clinically relevant. BackgroundCardiovascular disease, hypertension and diabetes all contribute to the increased risk of late non-relapse mortality after HCT and lead to diminished life expectancy compared to the general population. An association between TBI exposure and cardio-metabolic (C-M) risk factors in adult HCT survivors has been described but this association has not been well characterized in children. MethodsMeasures of insulin resistance (euglycemic hyperinsulinemic clamp adjusted for lean body mass [Mlbm], low Mlbm represents insulin resistance), fasting glucose, insulin, lipids, anthropometry, blood pressure (BP), and carotid artery compliance and distensibility (lower values represent arterial stiffness) were determined in 106 children and young adults (current age 26.6 yr, 60.4% male) who had received HCT for hematologic malignancy during childhood (mean age at HCT 9.9 yr) and 72 healthy sibling controls (current age 23.7 yr, 51.4% male). Subjects were compared in 3 radiation exposure groups, all received myeloablative preparative regimens; 79 received allogeneic HCT and 27 received autologous HCT. Diagnoses included AML (n=50), ALL (n=30), myelodysplastic syndrome, n=8, Hodgkin's (n=10) and non-Hodgkin's lymphoma (n=8). Sixty two (58.5%) received TBI, 20 (18.9%) received cranial radiation (CRT) prior to TBI (TBI+CRT), and 24 (22.6%) received no TBI or cranial radiation (noXRT) before or during HCT. Linear regression models were used to evaluate risk factors between groups after adjusting for age, gender, pubertal stage, body mass index (BMI), and carotid lumen diameter (stiffness measures only). ResultsMetabolic syndrome (MS) (ATP III criteria for adults, modified criteria for children) was present in 15 (15.6%) HCT survivors and 4 (5.6%) controls (OR 2.3, 95% CI 0.7-7.7, p=0.16). Two or more components of the MS were present in 39 (37.1%) survivors and 10 (14.5%) controls (OR, 2.7, 95% CI 1.2-5.9, p=0.015). Compared to siblings, there were no differences between groups for glucose, BMI, waist circumference, percent body fat, or BP. However, HCT survivors who had TBI or TBI+CRT all had significantly higher cholesterol, LDL cholesterol, triglycerides and insulin. Those who received TBI+CRT had significantly lower HDL cholesterol and were also more insulin resistant (Table). However, for the noXRT group there were no differences in any of the C-M risk factors compared to controls. Carotid artery distensibility was decreased in survivors who received TBI compared to controls with even greater negative impact in those who received TBI+CRT. There was not a significant difference in distensibility in the noXRT group compared to controls. Only the TBI+CRT group had lower compliance compared to controls. ConclusionsEven at a relatively young age, and independent of obesity, HCT survivors of childhood hematologic malignancies have increased C-M risk factors present as well as adverse vascular changes, which are associated with exposure to TBI +/- CRT. These abnormalities may ultimately contribute to a higher risk of early cardiovascular morbidity and mortality thus early screening and management of modifiable C-M risk factors should be considered in HCT survivors.Cardiometabolic Risk FactorsControlTreatment Groups, mean (SD)P-values(A) TBI(B) TBI +CRT(C) noXRTA vs. controlB vs. controlC vs. controlBMI (kg/m2)22.9(1.2)21.5(1.1)21.1(1.4)23.4(1.4)0.150.170.71Waist circumference (cm)78.9(1.2)78.6(1.1)79.4(1.4)80.3(1.5)0.690.70.3Systolic BP (mmHG)113.4(2.7)112.9(2.5)119.0(3.2)110.4(3.3)0.850.060.29Fasting glucose (mg/dL)88.5(2.3)91.5(2.1)92.3(2.7)87.3(2.8)0.110.140.62Fasting insulin (mU/L)13.9(2.4)21.1(2.2)26.1(2.8)16.2(2.9)<0.001<0.0010.38Total cholesterol (md/dL)155.5(7.8)176.2(7.2)199.8(9.4)157.7(9.6)0.001<0.0010.78LDL-cholesterol (mg/dL)89.1(6.7)98.6(6.1)114.6(8.6)92.5(7.9)0.07<0.0010.61HDL-cholesterol (md/dL)45.3(2.5)43.8(2.3)38.3(2.9)44.2(3.0)0.440.010.67Triglyderides (md/dL)113(26.3)172(23.7)266(30.9)114(31.5)0.006<0.0010.98Insulin resistance [Mlbm]12.2(1.1)10.5(1.0)8.0(1.4)10.5(1.4)0.070.0020.17Carotid distensibility (%)12.1(0.6)10.2(0.6)8.5(0.7)10.9(0.8)<0.001<0.0010.14Carotid compliance (mm2/mmHg)0.14(0.009)0.13(0.008)0.10(0.01)0.14(0.01)0.15<0.0010.85 DisclosuresNo relevant conflicts of interest to declare.

Impact of Long-Term Sequelae Diagnosed after Hematopoietic Cell Transplantation (HCT) on Health-Related Quality of Life (HRQL): A Report from the Bone Marrow Transplant Survivor Study.

Patients surviving HCT are at risk of developing complications that can potentially impact on their HRQL; the magnitude of this impact is not clear. We examined the HRQL reported by 1013 adult survivors of HCT with and without long-term sequelae diagnosed after HCT. Participants had undergone HCT at City of Hope or University of Minnesota, and survived two or more years. Mailed questionnaires were used to assess HRQL (COH-QOL tool) and long-term complications. HRQL was assessed in the following domains – Physical, Psychological, Social and Spiritual well-being and overall QOL. Long-term sequelae examined included impaired hearing, ocular complications, speech difficulties, orodental issues, cardiac dysfunction, stroke, avascular necrosis, pulmonary complications, gastrointestinal and neurologic complications. We estimated least square means of overall QOL and specific domain scores adjusted for age at HCT, sex, marital status; presence of chronic GVHD in the past 12 months; ability to return to work; subject's pain or anxiety level, and physical activity level in the past 7 days. Effect size was calculated as the difference of the adjusted group means (Scoreunaffected−Scoreaffected) divided by the overall standard deviation (SD). Effect size was examined for clinical significance (>0.33) and statistical significance (p<0.05). The 1013 HCT survivors (71% participation) enrolled in the study included 54% males, 81% Caucasians, 55% with allogeneic HCT. The median age at HCT was 35 years; length of follow-up 7.3 years. The table shows the adjusted effect size associated with long-term complications. Orodental problems, speech difficulties, gastrointestinal, neurological and pulmonary compromise had a clinically and statistically significant impact on overall QOL. Physical well being was affected by impaired hearing, speech difficulties, orodental issues, cardiopulmonary compromise, gastrointestinal and neurological dysfunction. Social well being was affected by speech difficulties, orodental problems, gastrointestinal and neurological complication. Adjustment for pain accounted for the negative impact of AVN on QOL scores. This study describes the most vulnerable HRQL domains, and magnitude of impact of sequelae on HRQL, thus setting the stage for supportive interventions in this growing population.Impact of Long-term Sequelae on HRQLLong-term SequelaeNumber with/without eventOverall QOLPhysicalPsychologicalSocialSpiritualEffect SizeEffect SizeEffect SizeEffect SizeEffect SizeHearing123/7130.270.53 *0.250.160.0Ocular322/5030.140.290.190.160.11Speech15/9190.34 *0.59 *0.250.57 *−0.43Orodental221/1910.41 *0.47 *0.250.41 *0.21Cardiac165/6260.270.35 *0.190.050.16Stroke147/6120.140.180.060.050.69 *Avascular Necrosis60/7110.00.0−0.060.050.16Pulmonary147/6120.34 *0.41 *0.190.310.0Gastrointestinal71/7800.41 *0.59 *0.310.36 *0.11179/5920.41 *0.53 *0.190.190.36 *0.16* denotes p<0.05

Health-Risk Behaviors among Long-Term Hematopoietic Cell Transplant (HCT) Survivors: A Report from the Bone Marrow Transplant Survivor Study.

Health-risk behaviors such as smoking could potentially interact with therapeutic exposures, increasing the risk of long-term sequelae, and have been understudied after HCT. The current study characterizes self-reported health-risk behaviors in 886 adult HCT survivors, who underwent HCT for hematologic malignancies or other diagnoses at City of Hope or University of Minnesota between 1974 and 1998, were 21 years (yr.) or older at HCT, and had survived two or more yr. after HCT. Stem cell donor type included autologous (n=428), related donor (n=372) and unrelated donor (n=86). Median age at HCT was 38.2 yr.; median age at survey, 46.3 yr.; and median length of follow-up, 6.5 yr.; 55% were males. Study participants completed a 255-item health questionnaire that contained items on health-risk behaviors, including current or past smoking (ever smoked at least 100 cigarettes); alcohol use (women: >7 drinks/week; men: >14/week); exercise (<5 days/week of vigorous >20-minute exercise); and having ever had a mammogram for women >40 yr. at survey. Of the 886 survivors, 44% reported ever having smoked (median age at initiation 17 yr., range 8–41) and 14% reported being current smokers. Factors associated with smoking initiation included white race (RR=1.85, 95%CI, 1.3–2.7), and annual household income $20-60,000 compared with >$60,000 [RR=1.4 (1.0–1.9)]. Median age at smoking cessation was 32 yr. (16–60), and factors included higher yearly household income [>$60,000: RR=1.6 (1.1–2.3)], age <45 yr. at HCT [RR=1.5 (1.2–1.9)], age >18 yr. at smoking initiation [RR=1.58 (1.2–2.1)], and smoking rate ≤10 cigarettes /day [RR=1.54 (1.2–2.0)]. Excessive alcohol consumption was reported by 5% of the cohort, and lower income (<$20,000: RR=0.13) and presence of cGVHD (RR=0.4) were associated with reduced risk. Recommended amount of exercise was reported by only 13% of the cohort. Allogeneic HCT survivors were more likely to report lower levels of exercise [RR=1.88 (1.2–2.9)]. Finally, 96.5% of women >40 yr. had received a mammogram ever. Reported risk behaviors among survivors were compared to those of 311 siblings with similar age, sex, and race distributions. No differences were identified between survivors and siblings in the prevalence of smoking initiation, excessive alcohol use, or frequent exercise. However survivors were more likely to stop smoking [RR=1.38 (1.1–1.8)] when compared with siblings, and female survivors ≥40 yr. were more likely than siblings to report a mammogram [RR=3.26 (1.3–8.4)]. In conclusion, 14% of the survivors report current tobacco use, and the large majority of long-term HCT survivors report less than recommended amounts of physical activity. However, when compared with the sibling comparison group, the rates of smoking cessation are higher among survivors, and survivors are more likely to report having undergone at least one mammographic screening. These health-risk behaviors may provide targets for future interventions to minimize the prevalence of preventable health complications in this vulnerable population.

Health Care Utilization by Hematopoietic Cell Transplantation (HCT) Survivors: A Report from the Bone Marrow Transplant Survivor Study.

HCT is increasingly being used to successfully treat a variety of malignant and nonmalignant disorders with an attendant growing population of survivors. We determined the type of outpatient medical care reported by adult survivors of HCT and examined factors associated with limited medical care. Eligible subjects were individuals who had undergone HCT at either City of Hope Cancer Center or the University of Minnesota between 1974 and 1998, were age 21 years or older at time of transplant, and had survived two or more years after HCT. We analyzed data from 755 adult HCT survivors enrolled in this retrospective cohort study who had completed a 255-item health questionnaire (Allogeneic HCT: n=424; autologous HCT: n=331), representing over 70 percent participation among those successfully contacted. Because of the widely divergent health-related issues among the autologous and allogeneic HCT recipients, the results of the analysis for the two groups are presented separately. Median age at HCT for the allogeneic and autologous HCT survivors was 35.4 and 39.5 years respectively, and the median length of follow-up 7.3 and 6.2 years respectively. Four self-reported outcome measures were used to determine outpatient medical care in the most recent 2-year period: general contact with health care system, general physical examination, HCT-related medical visit, and medical visit at a cancer center, with the percentage of patients reporting such visits shown in the Table below. Among allogeneic HCT recipients, the risk of not reporting a general physical examination, HCT-related visit, or a cancer center visit was decreased among male survivors (OR=0.46, 95% CI, 0.29–0.73) when compared with females, and among patients who received cyclosporine as part of their GVH prophylaxis (OR=0.42, 95% CI, 0.24 to 0.74), when compared with those who had not. Among autologous HCT recipients, the risk of not reporting a medical visit was increased among patients who reported a lack of concern for future health (OR=6.3, 95% CI, 1.4–27.8) and decreased among older survivors (>45 yr. at HCT, OR=0.47, 95% CI, 0.3–0.8). The likelihood of reporting a general physical examination increased as the interval from HCT to questionnaire completion increased (p<0.001), while the likelihood of reporting an HCT-related or cancer center visit decreased (p<0.001). This study demonstrates that although 20% of the allogeneic survivors continued to report a cancer-center visit 18 years on average from HCT, primary care physicians provide health care for most of this growing high-risk population, necessitating effective and ongoing communication between cancer centers and primary care physicians.Health care Utilization by HCT SurvivorsHCT TypeGeneral Medical ContactGeneral Physical ExaminationHCT-related visitCancer center visitAllogeneic HCT98%67.8%81.5%54.3%Autologous HCT97%73.3%80.8%53.3%