Long-term Survivors Of Hematopoietic Cell Transplantation Research Articles

Recovery of Pulmonary Function after Allogeneic Hematopoietic Cell Transplantation in Children is Associated with Improved Survival

Abnormal pulmonary function is prevalent in survivors of allogeneic hematopoietic cell transplantation (HCT). Post-transplantation recovery of pulmonary function, and its effect on survival, in children are not known. This retrospective cohort study of 308 children followed for 10 years after HCT at a single institution included 2 groups of patients. Group 1 comprised 188 patients with 3 or more pulmonary function test (PFT) results, of which at least 1 was abnormal, and group 2 comprised 120 patients with 3 or more PFTs, all of which were normal. Pulmonary function normalized post-transplantation in 51 patients (27%) in group 1. Obstructive lung disease, restrictive lung disease, mixed lung disease, and normal pattern were seen in 43%, 25%, 5%, and 27% of patients, respectively, at a median of 5 years (range, 0.5 to 11.9 years) post-transplantation. Lung volumes recovered better than spirometric indices. Pulmonary complications were seen in 80 patients (43%) in group 1. Patients who recovered pulmonary function had better overall survival (P = .006), which did not differ significantly from that in patients in group 2 with normal lung function post-transplantation (P = .80). After adjusting for duration of follow-up, pulmonary complications (P = .01), and lower pretransplantation forced vital capacity z-scores (P = .01) were associated with poor recovery. T cell depletion (P < .001), lower pretransplantation forced expired volume in 1 second z-scores (P = .006), and chronic graft-versus-host disease (P < .001) increased the risk for pulmonary complications. Nonrecovery of lung function with pulmonary complications (P = .03), acute graft-versus-host disease (P = .004), and mechanical ventilation (P < .001) were risk factors for nonrelapse mortality. Normalization of pulmonary function is possible in long-term survivors of allogeneic HCT. Strategies to decrease the risk of pulmonary complications may improve outcomes.

Provision of Long-Term Monitoring and Late Effects Services Following Hematopoietic Cell Transplantation (HCT): A Survey of European Programs By the Complications and Quality of Life Working Party of the EBMT

Introduction:Wider indications and improvements in outcome continue to increase the number of HCT recipients requiring long term post-HCT survivorship care. The Institute of Medicine of the US National Academy of Sciences specifically recognizes the importance of coordination of care to optimize delivery in cancer survivors. HCT recipients have particularly complex clinical needs (Majhail et al; Bone Marrow Transplant 2012), but existing evidence on which to base models of care is weak in relation to either cost-effectiveness or quality of care. Additional complexity occurs where models of care require transition from pediatric to adult services.Methods:We undertook an online survey of 430 centers within 48 countries registered with the EBMT as of February 2016. This included questions about service organization including transition models, access to non-hematological specialist services, and perceived barriers to improving services.Results:74 centers (17%) responded including data from 28 countries (58%). 83% centers were JACIE accredited or else working towards it. 41 centers included pediatric patients and follow up was until age 14-25 (median 18) years. Several models of transition were cited, the most frequent being for children to go into an adult transplant or haem-oncology clinic . Although 5 models included transfer to a different town/city, the majority transitioned within the same hospital.Late effects services were not invariably led by a single individual and sometimes occurred within the unit as part of good practise. Co-ordinated models, were most likely to be led by medical consultants (60/72 ) and the minority (only 6/72, 8%) by nurse specialists. The most frequent model of care was review within a dedicated transplant clinic that also included new patients (34/74; 46%). Management was frequently guided by a dedicated internal structured guideline (45/74; 61%). 12 centers only (16%) had a dedicated clinic for patients with chronic GVHD.Almost two thirds of responding centers (45) had a late effects mutli-disciplinary team (MDT) and for 19 centers this applied to all ages. Composition of the MDT varied. Most frequent components were: consultant hematologist (n=36), psychologist (31), endocrinologist (28), social workers (26) and nurses (20). There was widespread access (80% or more) to endocrine, cardiology, respiratory, dermatology, gastroenterology and ophthalmology.Less than half of the specialist consultant support services available had an interest in late effects however.Systematic screening for medical problems occurred within 2 years for more than 80% of centers for at least one parameter (e.g. endocrine), however some centers did not initiate routine surveillance until 10 years or more post SCT. Only 5 centers incorporated psychological assessment into their follow up.The number of responding centers with well-coordinated late effects services was high. However,notably the number of centers following up the majority (>90% ) of their patients declined substantially with time.The biggest perceived barrier to late effects services was resources: either clinical staffing or costs of investigations. Financial barriers arose from policy decision making at a National or hospital level rather than departmental level.Conclusions:This hospital based survey has identified frequent examples of good practice including dedicated clinics, clear transition services for pediatric patients undergoing HCT and the use of MDT. Notably, however, these services only cover the very long term survivors who remain under follow up at their transplant center and systematic screening starts late (>10 years) in some models. Psychological support services were not widely available.The study indicates some variation in models of care for addressing late effects after HCT across European centers. As many of the models described do not include all of the very long term survivors of HCT, it will be important to ensure engagement of non-transplant doctors in the community or referring hospitals. With a 17% response rate it is probable that there is a bias towards reporting details of services with a particular interest in this area. Nonetheless this survey is a useful starting point to improve practice and a basis to design studies that address outcome measures linked to model of care. DisclosuresNo relevant conflicts of interest to declare.

Clinical guide to fertility preservation in hematopoietic cell transplant recipients

With broadening indications, more options for hematopoietic cell transplantation (HCT) and improvement in survival, the number of long-term HCT survivors is expected to increase steadily. Infertility is a frequent problem that long-term HCT survivors and their partners face and it can negatively impact on the quality of life. The most optimal time to address fertility issues is before the onset of therapy for the underlying disease; however, fertility preservation should also be addressed before HCT in all children and patients of reproductive age, with referral to a reproductive specialist for patients interested in fertility preservation. In vitro fertilization (IVF) and embryo cryopreservation, oocyte cryopreservation and ovarian tissue banking are acceptable methods for fertility preservation in adult women/pubertal females. Sperm banking is the preferred method for adult men/pubertal males. Frequent barriers to fertility preservation in HCT recipients may include the perception of lack of time to preserve fertility given an urgency to move ahead with transplant, lack of patient-physician discussion because of several factors (for example, time constraints, lack of knowledge), inadequate access to reproductive specialists, and costs and lack of insurance coverage for fertility preservation. There is a need to raise awareness in the medical community about fertility preservation in HCT recipients.

Intermittent Zolendronic Acid (ZA) for the Prevention of Osteoporosis After Allogeneic Hematopoietic Cell Transplantation (HCT)

AbstractAbstract 1965Bone mineral density (BMD) loss, osteoporosis, and avascular necrosis (AVN) of bone are relatively common in long term survivors of HCT with up to one half of recipients suffering post HCT bone loss. We performed a multi center phase II randomized open label trial of intravenous zolendronic acid (ZA) to prevent BMD loss in recipients of allogeneic HCT with pre-existing osteopenia prior to HCT. Methods:Eligible adult (>18 years) patients had baseline pre-transplant osteopenia defined as a T-score < −1 SD and > −2.5 SD (WHO definifition) at either the lumbar (L) spine and/or the proximal femur at a pre HCT screening evaluation with a dual energy X-Ray absorptiometry (DEXA) scan. Patients were eligible irrespective of donor source, stem cell type, or conditioning regimen intensity. Patients with myeloma, baseline renal dysfunction or concomitant active dental or endocrine issues precluding the use of ZA were excluded. Subjects were allocated by block randomization stratified by center and type of conditioning (myeloablative vs. non-myeloablative) to the treatment or control arms.Both treatment and control groups received 1000 mg of calcium and 400 – 500 IU of vitamin D orally daily and were encouraged to remain active and refrain from tobacco smoking and alcohol. Additionally subjects randomized to the treatment arm received ZA 4 mg iv over 15 minutes within 28 days pre-HCT and at 3 and 6 months (mo) after HCT. Control subjects did not receive ZA or other additional therapy for bone strength. ZA dose was modified for post HCT renal dysfunction.Primary outcome measure was change in BMD from baseline to 12 mo after HCT. Serum osteocalcin, serum bone specific alkaline phophatase (BSAP), and urinary N telopeptide (UNTX) were measured at baseline and at 6 and 12 mo. Results:Between 2006 and 2010, 61 patients were randomized – 32 to the ZA treatment cohort and 29 to the control arm. Cohorts were balanced for age, sex, performance score, donor type, diagnoses and conditioning regimen intensity. HCT co-morbidity index (HCTCI) was significantly worse in the ZA arm (50% with high risk scores > 3). Baseline BMD, T scores at the femoral neck and lumbar spine, urinary NTX, serum osteocalcin and BSAP were similar in both cohorts.Differences between cohorts in bone density and bone specific laboratory parameters at 12 mo post HCT are summarized in Table 1. There was significant increase in BMD at the femoral neck and lumbar Spine; with concomitant decease in bone resorption markers for the treatment group (ZA cohort). Incidences of acute and chronic graft vs. host disease and relapse rates were similar between cohorts. There was significantly higher 1 year mortality in the ZA cohort (15 deaths vs. 6 in the control cohort). Thus overall survival was inferior in the ZA cohort 43% vs. 75% at 2 years post HCT. Grade 3–4 adverse events were similar. Conclusions:We randomized HCT recipients at high risk of post transplant bone loss to receive 3 doses ZA starting prior to HCT. ZA prevented further bone loss and resulted in improvement in BMD and T scores as well the bone resorption marker, urinary NTX. Lower survival was observed in the ZA cohort likely related to baseline imbalance in pretransplant HCTCI scores. ZA was well tolerated and not associated with any cases of osteonecrosis of jaw, renal impairment or other serious adverse events. We conclude that intermittent ZA is effective in preserving long term bone health in HCT recipients at risk for osteoporosis.Table 1ParameterDifference from baseline to 12 moP ValueZA cohortStandard of CareBMD L Spine0.048−0.057<0.01T score L Spine0.55−0.45<0.01Z score L Spine0.50−0.200.06BMD Femoral0.018−0.0540.04T score Femoral0.20−0.400.02Z score Femoral0.30−0.300.03S. Osteocalcin−11−4.10.44S.BSAP−3−30.66Urine NTX−56−90.04 Disclosures:Hari:Novartis: Research Funding. Vesole:Novartis: Research Funding. Burns:Novartis: Research Funding.

Cardiovascular Risk Factors in Hematopoietic Cell Transplantation (HCT) Survivors: Role in Development of Subsequent Cardiovascular Disease

Abstract 330 Introduction:Advances in transplantation strategies and supportive care have resulted in a growing number of long-term HCT survivors. In the general U.S. population, cardiovascular disease is a leading cause of morbidity and mortality, and cardiovascular risk factors (CVRFs), including diabetes hypertension and dyslipidemia are well-established modifiers of the risk. There is increasing evidence that HCT survivors may be at risk for CVRFs that can potentially result in an increased risk of cardiovascular morbidity. However, there is a paucity of knowledge regarding the magnitude of risk and associated risk factors for CVRFs after HCT, and the role these CVRFs play in the subsequent development of cardiovascular disease such as stroke, myocardial infarction, and congestive heart failure, in long-term survivors of HCT. Methods: A retrospective cohort study design was used to describe the cumulative incidence of CVRFs and cardiovascular disease in 1+year survivors of HCT, taking into consideration the competing risk of death. Cox proportional hazards regression analysis was used to calculate relative risk (RR) estimates and 95% confidence intervals (CI), adjusted for relevant covariates. Definition of CVRFs was per the National Cholesterol Education Program Adult Treatment Panel III criteria. Survivors taking immunosuppressant medication for management of graft vs. host disease (GvHD) at the time of CVRF diagnosis were excluded from the regression analysis. Cardiovascular disease was defined per the American College of Cardiology established case definitions. Results: 2041 consecutive one-year survivors who underwent HCT for hematologic malignancies between 1995 and 2004 at City of Hope were included in the analysis. Median age at HCT was 44.1 years (0.6–78.9); 57.6% were female; 62.5% were non-Hispanic white and 24.5% were Hispanic; 41% underwent allogeneic HCT; 26.5% of allogeneic HCT survivors had a history of chronic GvHD; 49.9% received total body irradiation (TBI). Cardiovascular risk factors: After 12,551 person-years of follow-up, the 10-year cumulative incidence of diabetes, hypertension, and dyslipidemia was 16.8%, 36.1% and 43.5%, respectively; 10-year cumulative incidence for multiple (2+) CVRFs was 29.5%. The cumulative incidence of CVRFs was significantly higher for allogeneic HCT recipients (Table). Multivariate analysis adjusted for gender, race/ethnicity, diagnosis, and conditioning-related exposures, revealed older age at HCT and obesity to be risk factors for all three CVRFs. Allogeneic HCT survivors with a history of chronic GvHD were at highest risk for diabetes (RR=32.4, 95% CI: 16.6–63.2, p<0.01), hypertension (RR=12.0, 95% CI: 5.5–26.1, p<0.01), and dyslipidemia (RR=7.2, 95% CI: 4.2–12.3, p<0.01) when compared to autologous HCT recipients. Cardiovascular disease occurred in 117 individuals, at a median 3.8 years following HCT (range 0.1–13.9). The 10-year cumulative incidence of cardiovascular disease was 7.4%, and was highest among survivors with multiple CVRFs (10.9% vs. 5.9% in those with <2 CVRFs, p=0.02). Furthermore, survivors with multiple CVRFs were at 1.8-fold risk (95% CI: 1.1–3.3, p=0.04) of subsequently developing cardiovascular disease when compared to survivors with <2 CVRFs. Conclusions: Allogeneic HCT survivors are at a substantially increased risk for CVRFs following HCT, and chronic GvHD and/or its treatment are critical modifiers of this risk. Survivors with multiple CVRFs are at highest risk for development of cardiovascular disease following HCT. These findings provide rationale for close monitoring and aggressive interventions for this high-risk population in order to reduce cardiovascular morbidity and mortality.DiabetesHypertensionDyslipidemiaMultiple (2+)Cumulative incidence5-yr10-yrP5-yr10-yrP5-yr10-yrP5-yr10-yrPAuto-HCT11.6%13.9%25.8%29.0%35.3%39.3%18.0%23.1%Allo-HCT17.7%21.0%<0.0141.3%46.6%<0.0145.6%49.6%<0.0131.1%38.9%<0.01 Disclosures:No relevant conflicts of interest to declare.

Adverse psychological outcomes in long-term survivors of hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study (BMTSS)

AbstractLittle information exists regarding long-term psychological health of hematopoietic cell transplantation (HCT) survivors. Using resources offered by the Bone Marrow Transplant Survivor Study (BMTSS), we evaluated adverse psychological outcomes in 1065 long-term HCT survivors and a healthy comparison group composed of siblings. Psychological health status was evaluated using the Brief Symptom Inventory-18. Twenty-two percent of the HCT survivors reported adverse psychological outcomes, compared with 8% of the siblings. Exposure to prednisone was associated with psychological distress across all domains (anxiety, depression, and somatic distress). Fifteen percent of the HCT survivors reported somatic distress, representing an almost 3-fold higher risk comparing to siblings. Among survivors, in addition to low annual household income and self-reported poor health, having severe/life-threatening conditions and presence of active chronic GVHD were associated with a 2-fold increased risk for somatic distress. Seven percent of the HCT survivors expressed suicidal ideation; patients with higher scores on depression subscale were most vulnerable. This study demonstrates that somatic distress is the biggest challenge faced by survivors long after HCT. These results identify vulnerable subpopulations and provide patients, families, and healthcare providers with necessary information to plan for post-HCT needs many years after HCT.

Genomic instability after allogeneic hematopoietic cell transplantation is frequent in oral mucosa, particularly in patients with a history of chronic graft-versus-host disease, and rare in nasal mucosa

AbstractGenomic instability (GI) of cells may lead to their malignant transformation. Carcinoma after hematopoietic cell transplantation (HCT) frequently involves some (eg, oral) but not other (eg, nasal) epithelia. We examined GI in oral and nasal mucosal specimens from 105 subjects, including short-term (7-98 days, n = 32) and long-term (4-22 yrs, n = 25) allogeneic HCT survivors. Controls included autologous HCT survivors (n = 11), patients treated with chemotherapy without HCT (n = 9) and healthy controls (n = 27). GI was detected in 60% oral versus only 4% nasal specimens in long-term allogeneic HCT survivors (P < .001). None of the controls showed GI. In oral specimens, GI was significantly associated with history of oral chronic graft-versus-host disease (cGVHD). We conclude that GI after HCT is frequent in some (oral) but rare in other (nasal) epithelia. This may explain why some epithelia (especially those involved with cGVHD) are prone to develop cancer.

Late Hospitalizations in Long-Term Survivors of Hematopoietic Cell Transplantation (HCT): Report From the Bone Marrow Transplant Study (BMTSS).

Abstract 807Long-term survival is now an expected outcome after HCT. However, high intensity chemo-radiotherapy for conditioning, coupled with prolonged immune suppression after HCT are associated with the risk of developing endocrinopathies (diabetes), musculoskeletal disorders (osteonecrosis, osteoporotic fractures), and cardiopulmonary complications (congestive heart failure, pulmonary fibrosis), which could necessitate hospitalization for their management. Although hospitalization needs in the immediate post-HCT period are well-described, details for long-term survivors are lacking. An in-depth study of hospitalization patterns among long-term HCT survivors would help healthcare providers and patients/caregivers in developing resources for the long-term care of survivors. This study describes the prevalence and patterns of late hospitalization among long-term HCT survivors; compares this outcome with siblings; and identifies subpopulations at increased risk. Data are derived from the BMTSS, and include 1022 individuals, who had undergone HCT between 1974 and 1998, and survived at least two years, and 309 unaffected siblings. Primary diagnoses included AML, CML, ALL, HL, NHL, and SAA. Median age at HCT was 35 years (range 0.4-69); median time since HCT 7.3 years (2-28); 55% had received an allogeneic HCT. A total of 436 (43%) survivors required one or more hospitalizations in the two years prior to study participation, compared with 29% of the siblings (p<0.001). Age-, sex-, race/ethnicity-, SES-, education-, and insurance-adjusted analysis revealed that HCT survivors were at a 1.7-fold (95%CI=1.3-2.3) increased risk of hospitalizations compared with their siblings. Among HCT survivors, the prevalence of hospitalizations declined with time since HCT (2-5 years: 49%; 6-10 years 39%; and 11+ years 37%, p for trend<0.001). Multivariate analysis adjusted for sociodemographic factors including health insurance showed that compared with autologous HCT survivors, allogeneic HCT survivors were more likely to report late hospitalizations (related donor: odds ratio [OR]=3.2, 95%CI, 1.1-9.4; unrelated donor: OR=4.1, 95%CI=1.3-13.5); age at HCT >45 years was associated with a higher risk of late hospitalizations (OR=2.3, 95% CI=1.3-4.0); and, patients with chronic graft vs. host disease (cGvHD) were more likely to report late hospitalizations (OR=1.5, 95%CI=1.0-2.1). The major reasons for hospitalization included gastrointestinal (GI) problems (n=93), ocular complications (n=58), infection (n=51), endocrine dysfunction (n=41), musculoskeletal complications (n=40), cardiac (n=37), and pulmonary (n=33) events. After adjusting for SES and insurance status, older age at HCT was associated with hospitalization for musculoskeletal (OR=9.9, 95%CI, 1.1-88.2) and GI problems (OR=3.9, 95%CI, 1.5-10.1); survivors of allogeneic HCT were more likely to be hospitalized for endocrinopathies (related HCT: OR=7.4, 95%CI, 1.4-38.9; unrelated HCT: OR=3.8, 95% CI, 0.4-37.6) and GI problems (related HCT: OR=7.57, 95%CI, 1.8-31.5; unrelated HCT: OR=9.67, 95% CI=1.9-49.6); and patients with cGvHD were more likely to be hospitalized for infection (OR=2.7, 95%CI, 1.2-6.0), ocular (OR=2.8, 95%CI, 1.2-6.4) and pulmonary problems (OR=2.7, 95%CI, 1.0-7.4). This study demonstrates that over 40% of long-term HCT survivors require late hospitalizations; that older individuals, those who underwent allogeneic HCT and those who developed cGvHD continue to be at an increased risk for late hospitalizations; and that attention needs to focus on instituting targeted follow-up to proactively minimize the need for these hospitalizations. Furthermore, ongoing healthcare issues emphasize the requirement for comprehensive health insurance coverage, even many years after HCT. Disclosures:No relevant conflicts of interest to declare.

The Preventive Health Behaviors of Long-Term Survivors of Cancer and Hematopoietic Stem Cell Transplantation Compared with Matched Controls

Little is known about the health promotion, prevention, and disease screening behaviors of cancer survivors treated with hematopoietic cell transplantation (HCT), who undergo arduous treatment and may be at particular risk for late effects and secondary malignancies. The purposes of this study were to examine the current health and secondary prevention behaviors of long-term HCT survivors compared with matched controls without cancer, and to identify sociodemographic and clinical factors associated with appropriate preventive practices. HCT survivors (n = 662) were drawn from 40 North American transplantation centers. Peer-nominated acquaintances of survivors matched on sex, age, education, and marital status served as controls (n = 158). Data were collected a mean of 6.7 years post-HCT (range, 1.8-22.6 years). Despite a greater frequency of physical exams, the HCT survivors had similar health and screening behaviors as the matched controls. Sociodemographic factors were associated with health prevention behaviors in expected ways. Some differences between disease group and type of transplant were found, with survivors of acute leukemia less likely to report regular exercise, autologous transplant survivors more likely than allogeneic transplant survivors to report screenings for breast and cervical cancer, and allogeneic transplant survivors more likely than autologous transplant survivors to report undergoing a skin exam in the previous year. Despite higher levels of engagement with health care providers, HCT survivors had similar health behaviors as matched controls and comparable to those reported by cancer survivors who did not undergo HCT. There remains considerable room for improvement. These findings support the need for further education of both HCT survivors and health practitioners.

Ethnic Differences in the Prevalence of, and Predictors for Anxiety, Depression, and Somatic Distress in Long-Term Survivors of Hematopoietic Cell Transplantation (HCT): A Report from the Bone Marrow Transplant Survivor Study (BMTSS)

Hispanics are the largest minority group in the US, constituting 14% of the entire population. Compared to non-Hispanic whites, Hispanics are conceivably at a higher risk for adverse mental health outcomes, due to socioeconomic, cultural, and language barriers as well as barriers within the healthcare system. Depressive symptoms and psychological distress are frequently observed in HCT survivors. But little is known regarding the ethnic differences in the magnitude and nature of psychosocial distress experienced by long-term HCT survivors. The purpose of this study was to determine the prevalence of and risk factors for psychosocial distresses in Hispanic HCT survivors as compared with non-Hispanic white HCT survivors. BMTSS, a collaborative effort between City of Hope National Medical Center and University of Minnesota, examined self-reported psychosocial distresses in individuals who underwent HCT between 1976 and 1998, and survived two or more years. Psychosocial distress was measured using the 18-item Brief Symptom Inventory (BSI-18). This measure provides a global severity index and symptom-specific subscales for depression, somatization, and anxiety. Participants were considered to have had psychosocial distress if they scored in the highest 10% of population norms on any of the 3 symptom-specific subscales or the global index. Logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). The current study included 984 HCT survivors; 443 had received autologous HCT and 541 allogeneic HCT for hematological malignancies (463 leukemia, 286 lymphoma, and 135 other). Median length of follow-up from HCT to study participation was 7.4 years (range 2, 27.8). Of the 984 survivors, 825 (83.8%) were self-reported non-Hispanic whites, while 159 (16.2%) were Hispanics. Median age at study participation was 44.5 years (range, 18.2–73.0) for whites and 41.5 years (range 20.0–67.4) for Hispanics, and median follow-up for was 7.3 years (range 2.0–27.8) and 8.0 years (range 2.5–25.2), respectively. When compared with non-Hispanic whites, Hispanics were significantly less likely to have completed high school (55.1% vs. 96.6%, p<0.001), and to be currently insured (75.9% vs. 93.7%, p<0.001). Hispanics were significantly more likely to have undergone allogeneic HCT (67.9% vs. 52.5%; P<0.01); to report their current health as fair or poor (25.8% vs. 17.9%, p=0.02); and to report a low household income (<=$20k: 45.4% vs. 10.0%, p<0.001). There were no differences between the two ethnic groups with respect to gender, risk of relapse at HCT, exposure to total body irradiation (TBI), and chronic graft vs. host disease. Overall, 21% of the long-term HCT survivors experienced at least one adverse mental health symptom (anxiety [6%], depression [11%], somatization [15%] and global index [10%]). Univariate analysis revealed that Hispanics were more likely to report mental health problems, and this was most apparent for the monolingual Spanish-speaking Hispanics. After adjustment for age at HCT, gender, type of HCT, primary diagnosis, time since HCT, exposure to TBI, current health status, and current insurance status, Hispanics were 3.4 times as likely as non-Hispanic whites to report anxiety (95% CI, 1.8–6.3). The comparable risks were 1.99 (1.2–3.3) for depression, 1.5 (0.95–2.5) for somatization and 3.13 (1.9–5.3) for global distress. However, adjustment for education, household income and language spoken, resulted in a mitigation of the ethnic differences in mental health problems, and the residual differences between non-Hispanic whites and Hispanics were statically non-significant (OR=1.94 [0.9–4.4] for anxiety, 0.86 [0.4–1.7] for depression, 1.09 [0.6–2.0] for somatization, and 1.82 [0.9–3.6] for global distress). Poor current health was significantly associated with increased risk of mental health problems (OR=11.3 [4.1–31.2] for anxiety, 4.5 [2.5–8.1] for depression, 12.4 [7.0–22.0] for somatization, and 13.0 [6.2–27.5] for global distress). This study demonstrates that mental health problems are prevalent in long-term HCT survivors, and that the differences in magnitude of mental health problems reported by non-Hispanic whites and Hispanics are a function of differences in socioeconomic status and ability to communicate in English.

Health care utilization by adult Hispanic long‐term survivors of hematopoietic stem cell transplantation

Long-term hematopoietic cell transplantation (HCT) survivors have a high prevalence of severe and chronic health conditions, placing significant demands on the healthcare system. The objective of the current study was to evaluate and compare the healthcare utilization by adult Hispanic and non-Hispanic white long-term survivors of HCT. A mailed questionnaire was used to assess self-reported healthcare utilization in 3 domains: general contact with healthcare system, general physical examination outside cancer center (GPE), and cancer/HCT center visit. Eligible individuals had undergone HCT between 1974 and 1998, at age > or =21 years, and had survived > or =2 years after HCT. The cohort included 681 non-Hispanic white and 137 Hispanic survivors. The median age at HCT was 38.3 years, and the median length of follow-up was 6.6 years. Hispanic survivors had lower family income and education and were more likely to lack health insurance. The prevalence of GPE increased significantly over time among non-Hispanic whites (67% at 2-5 years to 76% at 11+ years) but remained unchanged among Hispanics (66% to 61%). Cancer/HCT center visits declined over time among both Hispanics and non-Hispanic whites, but a higher proportion of Hispanics reported cancer/HCT center visits at 11+ years after HCT (81% vs 54%). Compared with non-Hispanic whites, Hispanic survivors are less likely to establish contact with primary care providers years after HCT and to continue to receive care at cancer/HCT centers. Future studies of this population are needed to establish the factors responsible for this pattern of healthcare utilization.

Chronic Kidney Disease After Hematopoietic Cell Transplantation: A Systematic Review

Advances in hematopoietic cell transplantation (HCT) have broadened its indications for use and resulted in more long-term HCT survivors. Some survivors develop chronic kidney disease (CKD); however, the incidence and risk factors are unclear. We performed a systematic review of studies identified from databases (MEDLINE, EMBASE, Science Citation Index), conference abstracts and reference lists from selected manuscripts. From 927 manuscripts, 28 patient cohorts were identified in which 9317 adults and children underwent HCT and 7317 (79%) survived to at least 100 days, permitting inclusion of 5337 (73% of survivors) in quantitative analyses. Although definitions and measurements varied widely, approximately 16.6% of HCT patients developed CKD and estimated glomerular filtration rate (eGFR in mL/min/1.73 m(2)) decreased by 24.5 after 24 months. This decrease was greater amongst patients undergoing allogeneic HCT (DeltaeGFR = -40.0 versus -18.6 for autologous transplants). Several commonly reported risk factors for CKD were investigated, including acute renal failure, total body irradiation, graft versus host disease and long-term cyclosporine use. In conclusion, CKD following HCT is likely to be common; however, prospective studies with uniform definitions of CKD and risk factors are needed to confirm these findings and better define the underlying mechanisms to promote therapies that prevent this complication.

Health care utilization by adult Hispanic long term survivors of hematopoietic cell transplantation (HCT): report from the bone marrow transplant survivor study

6608 Background: A third of long-term HCT survivors report severe or life-threatening chronic health conditions, placing significant demands on the healthcare system for a prolonged period of time. However, utilization patterns of healthcare services among minorities differ from those of non-Hispanic whites in the general population. The aim of this study was to evaluate healthcare utilization by adult long-term Hispanic HCT survivors. Methods: A mailed questionnaire was used to assess self-reported health care utilization in three domains: general contact with healthcare system, general physical examination (GPE), and cancer/HCT-related visit. Eligible individuals had undergone HCT between 1974 and 1998, at 21 years of age or older and survived 2 or more years after HCT. Results: The entire cohort consisted of 818 individuals, including 137 Hispanic survivors. The median age at HCT was 38.3 years (range: 21–68 years) and the median length of follow-up was 6.6 years (range: 2–24 years). A larger proportion of Hispanic survivors had family income < $20,000 (45.6% vs. 8.8% in non-Hispanics, p<0.001), high school or lower education (37.5% vs. 6%, p<0.001), and lacked health insurance (22.4% vs. 4.6%, p<0.001). Overall, 97% of non-Hispanic whites and 92% of Hispanics reported medical contact 11+ years after HCT (p=0.15). Compared to 2–5 years after HCT, the prevalence of GPE increased among non-Hispanic whites (67% to 76%, p for trend =0.05) but remained unchanged among Hispanics (66% to 61%, p for trend=0.68) 11+ years after HCT. On the other hand, while the proportion of non-Hispanic white survivors reporting a Cancer/HCT-related visit decreased from 94% at 2–5 years after HCT to 54% 11+ years after HCT (p for trend<0.001), the comparable figures in Hispanics were 96% and 81% (p for trend=0.03). Conclusion: As compared to non-Hispanic whites, Hispanic survivors are less likely to establish contact with a primary care provider years after the HCT and continue to receive care primarily at Cancer/HCT center for many years following HCT. Future studies of this population are needed to establish the factors responsible for this pattern of healthcare utilization. No significant financial relationships to disclose.

One-year acyclovir prophylaxis for preventing varicella-zoster virus disease after hematopoietic cell transplantation: no evidence of rebound varicella-zoster virus disease after drug discontinuation

AbstractNo consensus exists on whether acyclovir prophylaxis should be given for varicella-zoster virus (VZV) prophylaxis after hematopoietic cell transplantation because of the concern of “rebound” VZV disease after discontinuation of prophylaxis. To determine whether rebound VZV disease is an important clinical problem and whether prolonging prophylaxis beyond 1 year is beneficial, we examined 3 sequential cohorts receiving acyclovir from day of transplantation until engraftment for prevention of herpes simplex virus reactivation (n = 932); acyclovir or valacyclovir 1 year (n = 1117); or acyclovir/valacyclovir for at least 1 year or longer if patients remained on immunosuppressive drugs (n = 586). In multivariable statistical models, prophylaxis given for 1 year significantly reduced VZV disease (P < .001) without evidence of rebound VZV disease. Continuation of prophylaxis beyond 1 year in allogeneic recipients who remained on immunosuppressive drugs led to a further reduction in VZV disease (P = .01) but VZV disease developed in 6.1% during the second year while receiving this strategy. In conclusion, acyclovir/valacyclovir prophylaxis given for 1 year led to a persistent benefit after drug discontinuation and no evidence of a rebound effect. To effectively prevent VZV disease in long-term hematopoietic cell transplantation survivors, additional approaches such as vaccination will probably be required.

Health Care Utilization by Adult Long-term Survivors of Hematopoietic Cell Transplant: Report from the Bone Marrow Transplant Survivor Study

The high intensity of therapy and prolonged immune suppression after hematopoietic cell transplantation (HCT) increase the risk of long-term complications and health care needs among survivors. The aim of this study was to evaluate the current status of health care utilization by long-term HCT survivors and to identify factors associated with lack of utilization. A total of 845 individuals who had undergone HCT between 1974 and 1998 at age 21 years or older and survived 2 or more years after HCT participated in the study. Health care utilization was assessed through a mailed questionnaire in three domains: general contact with health care system, general physical examination, and cancer/HCT-related visit. The median age at HCT was 38.2 years, and the median length of follow-up was 6.4 years. Overall, 98% of allogeneic and 94% of autologous HCT survivors reported medical contact 11+ years after HCT. Cancer/HCT-related visits decreased with increasing time from HCT (allogeneic HCT, 98-57%; autologous HCT, 94-63%). The prevalence of general physical examination increased with time (allogeneic HCT, 56-74%; autologous HCT, 72-81%). Primary care physicians provide health care for an increasing number of adult long-term survivors of HCT, emphasizing the need for increased awareness of the long-term follow-up needs of the HCT survivors by the health care providers.

125: Preventive health behaviors of long-term hematopoietic cell transplant survivors

125: Preventive health behaviors of long-term hematopoietic cell transplant survivors

Delayed Chronic Kidney Disease (CKD) after Hematopoietic Cell Transplantation (HCT).

Exposure to pre-transplant nephrotoxic agents, total body irradiation (TBI), and presence of chronic graft-versus-host disease (cGVHD) have been identified as risk factors for developing CKD after HCT. However, small sample size, short follow-up post-HCT, and varying definitions of CKD have precluded a precise estimation of the magnitude of risk and associated risk factors. The aim of the current study was to describe the incidence and risk factors associated with the development of delayed CKD in HCT survivors. Eligible subjects underwent HCT for hematological malignancies or severe aplastic anemia at City of Hope, survived at least one year post-transplant, and were free of CKD at one year post-HCT. Information on pre-transplant therapeutic exposures and post-transplant CKD was obtained via medical record abstraction. All CKD cases were defined according to the National Kidney Foundation's definition based on glomerular filtration rate (GFR) values. The endogenous filtration marker creatinine was used to estimate GFR values. CKD was defined as a sustained elevation of serum creatinine which infer a GFR of less than 60 mL/min/1.73 m2 for 3 months or longer. The equation used to calculate GFR was as follows: GFR = 186 x (Pcr) −1.154 x (age) − 0.203 (x 0.742 if female) (x 1.210 if African American). Totally, 1,546 eligible subjects were identified (median age at HCT of 34.4, median length of follow-up 6.2 years; autologous HCT in 718 patients [46%], related donor HCT in 726 patients [47%], and unrelated donor HCT in 102 patients [7%]; 59% of subjects (n=913) were male). A total of 65 patients were identified with CKD, resulting in a cumulative incidence of 3.6% [95% confidence interval (CI), 2.6% to 4.6%] at five years post–HCT and 4.8% at 10 years (autologous HCT: 2.9% at five years; matched sibling HCT: 4.1%; matched unrelated donor HCT: 10.5%, p<0.05). In allogeneic transplant recipients, older age at HCT (RR per increase of five years, 1.34; 95% CI, 1.30 to 1.38), prophylaxis/treatment of GvHD with cyclosporine and/or tacrolimus (RR, 4.32; 95% CI, 1.25 to 14.89), and a primary diagnosis of Multiple Myeloma (RR=5.38, 95% CI=1.79 to 16.15) were associated with increased risk. For autologous transplant recipients, older age at HCT was associated with increased risk (RR per increase of five years, 1.33; 95% CI, 1.29 to 1.38). Of note, use of TBI, and chemotherapeutic agents for conditioning, and a history of fungal infection were not associated with risk of delayed CKD development. This study describes the magnitude of risk of delayed chronic kidney disease in a large cohort of long-term survivors of autologous and allogeneic HCT, as well as identifies high risk groups in this population, thus setting the stage for appropriate long-term follow-up of the vulnerable sub–groups. [Display omitted] [Display omitted]

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.

Pulmonary function in long‐term survivors of pediatric hematopoietic cell transplantation

The purpose of this study was to determine the prevalence of pulmonary dysfunction in pediatric hematopoietic cell transplant (HCT) survivors and to identify associated risk factors. In a cross-sectional study, patients surviving at least 5 years after pediatric HCT were requested to undergo pulmonary function testing (PFT). Risk factors for restrictive lung disease (RLD) and obstructive lung disease (OLD) were analyzed using multivariate analysis. Among 472 patients contacted, 260 (55%) participated and 215 were selected for analysis. These patients were transplanted at a median age of 8.3 (0.3-18.0) years; 175 for hematologic malignancies and 40 for non-malignant diseases. The preparative regimens for 133 patients included fractionated TBI (FTBI), 29 single-fraction TBI (SFTBI), and 53 non-TBI regimens. PFT was performed at a median of 10 (5.0-27.5) years after HCT. Forty percent of patients had either RLD or OLD (28% RLD, 9% OLD, 3% mixed RLD/OLD) and at least 15% had an isolated low-DLCO. Moderate-to-severe impairment was present in 45% of patients with RLD or OLD. In multivariate analysis, risk factors associated with RLD included transplant regimen, transplant diagnosis, scleroderma/contracture, and donor relation. Patients treated with SFTBI had the highest risk of RLD. Risk factors for OLD included chronic graft-versus-host disease, transplant regimen, and time after HCT. Patients surviving 20 or more years after HCT had the highest risk of OLD. Fifty-five percent of long-term pediatric HCT survivors had pulmonary dysfunction. These findings stress the need for long-term follow-up to detect pulmonary dysfunction.

Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study

AbstractWe assessed late mortality in 854 individuals who had survived 2 or more years after autologous hematopoietic cell transplantation (HCT) for hematologic malignancies. Median age at HCT was 36.5 years, and median length of follow-up was 7.6 years. Overall survival was 68.8% ± 1.8% at 10 years, and the cohort was at a 13-fold increased risk for late death (standardized mortality ratio [SMR] = 13.0) when compared with the general population. Mortality rates approached those of the general population after 10 years among patients at standard risk for relapse at HCT (SMR = 1.1) and in patients undergoing transplantation for acute myeloid leukemia (AML; SMR = 0.9). Relapse of primary disease (56%) and subsequent malignancies (25%) were leading causes of late death. Relapse-related mortality was increased among patients with Hodgkin disease (HD; relative risk [RR] = 3.6), non-Hodgkin lymphoma (NHL; RR = 2.1), and acute lymphoblastic leukemia (ALL; RR = 6.5). Total body irradiation (RR = 0.6) provided a protective effect. Nonrelapse-related mortality was increased after carmustine (RR = 2.3) and with use of peripheral blood stem cells (RR = 2.4). Survivors were more likely to report difficulty in holding jobs (RR = 9.4) and in obtaining health (RR = 7.7) or life insurance (RR = 8.4) when compared with siblings. Although mortality rates approach that of the general population after 10 years in certain subgroups, long-term survivors of autologous HCT continue to face challenges affecting their health and well-being.