ALBERT

Description: BACKGROUND: Hematopoietic cell transplantation (HCT) survivors have high risks of mortality and late complications compared with the general population. Few analyses have compared the magnitude of these risks against those experienced by a matched non-HCT cancer population where the primary difference may be exposure to HCT. METHODS: The Fred Hutchinson Cancer Research Center (FHCRC) performs most of the HCTs in Washington State (WA), including all allogeneic HCTs. We linked medical records of all 2+ year HCT survivors who were WA residents treated at FHCRC from 1992-2009 (n=1,929; 53.3% allogeneic; 83.8% hematologic malignancies) to the state’s hospital discharge and death registries. Individuals randomly selected from the state’s cancer registry (n=5,806) and the driver’s license files (n=16,340) who also survived 2+ years formed 2 comparison groups, frequency-matched by age, sex, year of HCT, and underlying diagnosis (HCT and cancer registry subjects only). Based on hospital and death registry coding (per International Classification of Diseases [ICD-9 and 10]), the cumulative incidence and the relative hazards (HR; Cox models) of experiencing specific organ-based complications (time to first event) were estimated for each group. Subanalyses involving HCT survivors alone examined the relationship between adverse outcomes occurring 2+ years after HCT and any chronic graft versus host disease (cGVHD) and/or original disease relapse prior to 2 years. RESULTS: With a median age at HCT of 43 years (range 0-79), HCT recipients experienced 3,011 hospitalizations and 399 deaths over a median follow-up time of 6.3 years (range 2.0-20.0) following HCT. Compared with non-HCT cancer survivors, HCT survivors had markedly higher rates of hospitalizations or deaths related to infections (10-year cumulative incidence 30.5 vs. 21.5%; HR 1.6, 95% CI 1.4-1.7), in particular respiratory infections (17.7 vs. 11.4%; HR 1.8, 95% CI 1.5-2.0). Among 688 hospitalizations with a primary infection code (ICD9 codes 1-139), a bacterial source was identified in 63% (gram-negative species 16%; staphylococcus 14%; clostridium difficile 7%), virus in 31% (herpes zoster 8%), and fungus in 24% (aspergillus 8%). Among hospitalizations for a respiratory infection (n=511), bacterial pneumonia was common (21%), followed by viral (8%) and fungal (7%) pneumonias; most pneumonias had no pathogen coded (n=228 of 511; 45%). HCT survivors also had greater 10-year cumulative incidence rates for circulatory (25.5 vs. 22.8%), gastrointestinal (19.2 vs. 16.4%), genitourinary (18.1 vs. 15.5%), nervous system (13.5 vs. 11.6%), musculoskeletal (16.9 vs. 13.3%), dermatologic (7.2 vs. 5.6%), and non-infectious respiratory (15.5 vs. 11.8%) complications, with HRs 1.2-1.4 and p10 percentage points lower in the general population. Among HCT recipients, history of chronic graft versus host disease (cGVHD) and relapse of one’s original disease were risk factors for most outcomes. Risks among allogeneic and autologous HCT recipients otherwise were similar. Adjustment for cGVHD status attenuated the risks between HCT and non-HCT cancer survivors, but HCT status remained a significant risk factor for many outcomes including infections and respiratory disease. CONCLUSIONS: Compared with similar non-HCT cancer survivors, 2+ year HCT survivors were at greater risk of multiple adverse late complications, in particular late respiratory infections. Greater awareness and earlier intervention, along with improvements in cGVHD treatment, may reduce some of these disparities. Disclosures No relevant conflicts of interest to declare.

Description: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune regulation leading to widespread lymphocytic and hemophagocytic infiltration of vital organs. Apparent cure has only been achieved with allogeneic bone marrow transplantation (BMT). This report describes 20 consecutive patients, who underwent either matched sibling donor (n = 4) or unrelated donor (URD; n = 16) BMT. Age at the time of BMT was 0.4 to 5.3 years (median, 0.8 years). Central nervous system disease was present at diagnosis in 13 patients. At BMT, 14 patients were in a clinical remission, whereas 6 patients had active HLH. All patients were engrafted after cytoreduction with busulfan, cyclophosphamide, and etoposide. The probability of grade II-III acute graft-versus-host disease (GVHD) for all patients was 57% (95% confidence limit [CL], 0.28, 0.86), and 73% (95% CL, 0.44, 1.0) in URD patients. The overall probability of survival at 3 years was 45% (95% CL, 0.23, 0.67) and 44% (95% CL, 0.19, 0.68) when URD BMT was evaluated separately. Favorable BMT outcome was associated with clinical remission status at the time of BMT. The preparative regimen was well tolerated, and in the 9 surviving patients it provided durable engraftment and was effective at eradicating the underlying disease.

Description: Prior studies suggest that success of HCT varies by race and ethnicity. This study examined whether disparate outcomes in URD-HCT are explained by socioeconomic status (SES), HLA disparity or other factors. Patients (n=6207) with acute or chronic leukemia or MDS, receiving myeloablative conditioning and URD HCT in the U.S., with available valid ZIP code, and reported to the CIBMTR between 1995–2004 were included. Patients were reported by the transplant center to be Caucasian (CC, n=5253), African American (AA, n=368), Asian/Pacific Islander (AP, n=141), or Hispanic (HS, n=445). We used 3 distinct HLA groupings with significantly different outcomes identified in another study to adjust for HLA disparity while accounting for best available resolution of typing. Well matched patients had no identified mismatches at HLA-A,B,C and DRB1 with low/intermediate or high resolution data available at HLA-A,B and high resolution DRB1. Partial matched patients had a single locus mismatch at any of the 4 loci and/or missing HLA-C data. Mismatched included any patient with 2 or more allele or antigen mismatches. Ethnic minorities were more likely than CC to have partially matched or mismatched donors. Patient income was estimated from reported residential ZIP code. The median follow-up of survivors ranged from 48 (AA and HS) to 66 months (CC). By Kaplan-Meier estimate, 1-year overall survival (OS) was 47% in CC, 32% in AA, 43% in AP, and 41% in HS (p

Description: 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

Description: Abstract 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

Description: Abstract 3320 Poster Board III-208 Late mortality in children who have undergone hematopoietic stem cell transplantation (HCT) for severe combine immunodeficiency (SCID), non-SCID immune diseases and inborn errors of metabolism (IEM) has not been studied. The goals of the current analyses were to: 1) determine the probability of long-term survival after HCT in patients who survive the first 2 years after HCT; 2) identify risk factors for late deaths; and 3) determine excess mortality relative to rates in an age and sex-matched general population. Nine hundred and sixty patients with 〉95% donor chimerism or recovery of T-cell function who survived at least 2 years after their transplantation were included in the study. Two hundred and one patients had SCID, 407, non-SCID immune diseases and 352, IEM. Seventy percent of SCID transplant recipients received grafts from an HLA-matched sibling or mismatched relative. Fifty six percent of non-SCID and IEM transplant recipients received grafts from unrelated donors, 32% from a matched sibling and 12% from a mismatched relative. All transplantations occurred in 1980 – 2003; the median follow-up of surviving patients was 7 years. Median ages of long-term survivors were 7, 9 and 10 years for SCID, non-SCID immune diseases and IEM, respectively. Because of differences in biologic features and transplant strategies for SCID, non-SCID immune diseases and IEM, the disease groups were analyzed separately. The 7-year probabilities of overall survival were 93%, 96% and 90% for SCID, non-SCID immune diseases and IEM, respectively. No patient, disease or transplant characteristic was associated with late deaths in patients with SCID. For non-SCID immune diseases, late deaths were higher in recipients of T-cell depleted grafts (RR 4.63, p=0.003). For IEM, late deaths were higher after unrelated donor (RR 2.75, p=0.018) and mismatched related donor (RR 2.77, p=0.042) transplants compared to matched sibling donor transplant. There were 69 late deaths with 52 occurring 2 – 6 years after transplantation and 17 after 6 years. Causes of death in patients who died between 2 – 6 years included: chronic graft-versus-host disease [CGVHD] (n=12), infection including encephalitis (n=11), organ failure (n=12), post-transplant lymphoproliferative disease (n=4), primary disease (n=5), acute abdomen (n=1), status epilepticus (n=1), acute myeloid leukemia (n=1), accidental death (n=1) and not reported (n=3). Causes of death beyond 6 years included CGVHD (n=1), infection including encephalitis (n=3), organ failure (n=4), primary disease (n=2), acute abdomen (n=1), brain stem glioma (n=1) and not reported (n=5). The table below shows the estimated excess deaths per 1000 compared to an age- and sex-matched general population at 2 – 6 years and beyond 6 – 10 years after HCT. Though the risk of late deaths in this population is in excess of that for the general population for several years after transplantation, with extended follow up, the risk appears to decrease towards normal rates. Beyond 6 years after HCT, among patients transplanted for SCID and non-SCID immune diseases, the risk of mortality does not differ significantly from the general population whereas for patients with IEM, mortality rates continue to be higher than that in the general population. Screening programs aimed at identifying late complications together with planned intervention may improve long-term survival in these patients. Excess deaths per 1000 (95% confidence interval) SCID Non-SCID IEM 2 – 6 years after HSCT 54 (28, 79)* 41 (28, 53)* 95 (82, 109)* 6 – 10 years after HSCT 25 (0, 51) 16 (0, 39) 45 (27, 62)* * Significant differences in mortality risks compared to the general population Disclosures No relevant conflicts of interest to declare.

Description: Abstract 3818 Although the adherence to recommended preventive care practices in hematopoietic cell transplantation (HCT) survivors is reported to be high, on average 25% of recommended preventive care is not delivered to this vulnerable population. We explored factors associated with lower adherence, with particular attention to modifiable factors, in a cross-sectional study of HCT long-term follow up (LTFU) patients. A 45- item supplementary module with questions about adherence to preventive care guidelines and financial concerns was added to the 236- item questionnaire that is mailed annually to LTFU patients who were alive at least 2 years after their first transplant in our center. 1550 (51%) of 3069 mailed questionnaires were returned. We have previously reported that the median adherence to recommended guidelines was 75%. Among other clinical and demographic factors associated with lower adherence, concern about medical costs and lack of knowledge about recommended tests emerged as major modifiable predictors. Of these respondents, 98% had medical insurance coverage, but 26% reported concerns about medical costs which were reflected by attempts to limit medical costs with one or more potentially deleterious avoidance behaviors (e.g., not taking a prescribed medicine, not having a medical test performed). Twenty-six percent worried that medical expenses would reach their lifetime limit. Only 27% of the respondents reported knowing recommended tests for transplant survivors, even though general guidelines are included with each annual questionnaire. 46% of the respondents indicated a desire to acquire this knowledge while 26% indicated that they relied on their treating physicians to be familiar with recommended guidelines. Multivariable logistic regression models were constructed for binary outcomes of “concerns about medical costs” and “lack of knowledge about recommended tests for LTFU patients” (Table). These models showed that concerns about medical costs were associated with lower physical and mental functioning, age less than 65 years, being female and not having chronic GVHD. Males, autologous transplant recipients, allogeneic transplant recipients who did not develop chronic GVHD, and patients surviving more than 15 years after HCT were more likely to report lack of knowledge about recommended tests for LTFU patients. When asked how they wished to receive information about recommended preventive care, patients favored mailed information (64%) over in-person evaluation (24%) or phone calls (27%). These results suggest that provision of comprehensive survivorship care plans might improve adherence to recommended preventive care practices by addressing lack of patient and provider knowledge. The increased support for preventive care by requiring health plans to cover preventive services and eliminating cost-sharing by the recent Affordable Care Act could also improve adherence by addressing financial concerns of this so-called ‘highly insured’ HCT LTFU population. Table: Multivariable logistic regressions for concern about medical costs and lack of knowledge about recommended tests Outcome: Concern about Medical Cost Covariates OR (95% CI) p-valuea p-valueb Physical functioning 〈 −1 STD 2.70 (2.04,ü3.56)

Description: Abstract 1400 Poster Board I-422 Introduction: Childhood cancer survivors have increased risk for cardiovascular disease and insulin resistance. Methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism and low folate are associated with higher levels of homocysteine and changes in methylation status; these factors, in particular the TT and CT genotypes have been associated with insulin resistance in animal and human models. The CT genotype is present in about 25 % of the healthy US population. Vitamin B12 is an important co-factor in this association. The homocysteine/methionine ratio has been used as an indirect marker of methylation status and MTHFR function. Population and Methods: This analysis includes children (n=156) who survived ≥ 5-yrs following diagnosis of acute lymphoblastic leukemia (ALL) (n=55), acute myeloid leukemia (AML) (n=4), and non-Hodgkin's lymphoma (NHL) (n=13), central nervous system tumors (38) and other cancers (n=46). Mean age at diagnosis was 10.3 yrs (5.7-15.8) and mean age at evaluation was 15.0 yrs (9.9-17.9). Anthropometric measurements, blood pressure (BP), fasting glucose, insulin, lipids, folate, vitamin B12, homocysteine, and methionine were collected. Insulin resistance was assessed by euglycemic hyperinsulinemic clamp, adjusted for lean body mass (low Mlbm represents insulin resistance, less than 50% of distribution). Genetic polymorphisms, of MTHFR CC (wildtype) CT (heterozygous) and TT (homozygous) were identified; comparisons between MTHFR polymorphisms were adjusted for age, gender, and Tanner stage. Results: CC genotype was present in 44%, CT in 47.3 %, and TT in 8.7 % of survivors. Folate and B12 levels were lowest in the TT group, although not statistically significant (P value 〉0.05). Insulin resistance was most prevalent in the CT group and least prevalent in the TT group. The homocysteine/ methionine ratio was lowest in the CT group and highest in the TT group. Measures of adiposity were similar in all three groups (Table). Conclusion: This study suggests an increased frequency of the CT genotype in this study population of childhood cancer survivors compared to the healthy US population. Insulin resistance was most prevalent in the CT group; however, this was not associated with low levels of folate, B12, or high homocysteine/methionine ratio. The low frequency of insulin resistance in the TT group likely reflects the small number of participants with this genotype. Further study of these variables in larger populations is needed to provide sufficient power in assessing these relationships in childhood cancer survivors. Disclosures: No relevant conflicts of interest to declare.

Description: Allogeneic hematopoietic cell transplantation (HCT) is the standard of care for pediatric patients with acute lymphoblastic leukemia (ALL) with early bone marrow relapse. However, the role of HCT is less clear in patients with isolated central nervous system (CNS) relapse where intensive chemotherapy followed by craniospinal irradiation is often offered. To determine the potential role of HCT, we evaluated the transplant outcomes of 116 patients with relapsed ALL with and without CNS involvement, 1–18 years of age, treated at the University of Minnesota between 1991 and 2006. Patients not in remission at transplant, and those with isolated extramedullary disease not involving the CNS were excluded. Relapse site prior to HCT was CNS in 14 patients, bone marrow (BM) in 85 patients and both marrow and CNS (BM+CNS) in 17 patients. Forty-eight underwent HCT from 1991–1995, 39 from 1996–2000 and 29 from 2001–2006. There were no significant differences among groups in median age at diagnosis (CNS: 3.7 years, range 1.2–7.7; BM: 4.5, 1–16; BM+CNS 3.7, 1.4–17), median age at transplant (CNS: 8 years, range 3.2–17.3; BM: 8.3, 3.5–17.9; BM+CNS 7.8, 3–17.9), or length of CR1 (CNS: 22.8 months, range 8.6–58; BM: 26.9, 0.8–74; BM+CNS: 34.2, 3.3–74). Remission status was similar in all groups (CNS: 7 CR2, 14 CR3+; BM: 73 CR2, 92 CR3+; BM+CNS: 14 CR2, 17 CR 3+; p=.06). Graft source was also similar between groups with 44 patients (38%) having a related donor and 72 patients having an unrelated donor (36% marrow and 25% umbilical cord blood). The majority of patients received cyclophosphamide 120 mg/kg and total body irradiation 1320–1375 cGy alone (n=69), or with etoposide (n=38) or fludarabine (n=8). Preparative regimen had no effect on outcomes. The incidence of grade II–IV GVHD (CNS 51%, 95% CI 24–68; BM 36%, 26–46; BM+CNS 18%, 1–35; p=.27) and grade III–IV GVHD (CNS 21%, 95% CI 0–42%; BM 16%, 8–24%; BM+CNS 0%; p=.21) was similar between groups. Hazard ratios using Cox multiple regression analysis demonstrated reduced survival in recipients with T cell leukemia or BCR-ABL gene rearrangement, history of marrow relapse, or receipt of HLA mismatched marrow from an unrelated donor. Patients with isolated CNS relapse had the least transplant related mortality at 2 years (CNS: 0%; BM: 35%, 95% CI 11–59%, BM+CNS: 34, 24–44; p=.05) and the lowest incidence of relapse (CNS: 0%; BM: 12%, 95% CI 0–27%, BM+CNS: 30%, 20–40; p=.01). The probability of leukemia-free survival at 5 years was greatest for patients with isolated CNS relapse (CNS: 91%, 95% CI 51–99; BM: 35, 25–45; BM+CNS: 46, 22–.68; p

Description: By age 2 years, 90% of children will have had primary infection with human herpesvirus 6 (HHV-6), which then becomes latent. HHV-6 can subsequently reactivate and cause disease in an immunosuppressed person. To investigate the effect of high-dose acyclovir as a prophylaxis against HHV-6 infection and to investigate the risk factors for having a positive HHV-6 quantitative polymerase chain reaction (PCR) assay, we identified a cohort of hematopoietic cell transplant (HCT) patients who had clinical indications for obtaining a HHV-6 PCR assay from 2003–2005 and evaluated their prospectively collected data. A total of 442 patients, including children and adults, obtained a hematopoietic cell transplantation from 2003–2005. Of this cohort, 137 were tested for HHV-6 with a PCR assay (median age 19 years; range 0.3–68 years). A positive HHV-6 PCR assay was found in 38 of the patients. The cell source included single (n=26) or double umbilical cord blood (UCBT, n=67), bone marrow (BM, n=25) and peripheral blood (PB, n=19). The median age was not significantly different for patients who tested positive compared to those patients who tested negative for HHV-6. About 50% of the patients received high-dose acyclovir. There was no significant difference in the cumulative incidence of a positive HHV-6 PCR assay by post-transplant day 100 in patients who received high-dose acyclovir (1500mg/m2/day) compared to those who did not receive high-dose acyclovir (p=0.8). Double umbilical cord blood transplant patients had 6 times higher risk of a positive HHV-6 PCR assay compared to BM or PB transplant patients, after adjusting for the transplant conditioning regimen (Hazard ratio=6.2, 95%CI 1.79–21.35, p=0.004). Compared to single UCBT patients, double UCBT patients still had 2 times higher risk of a positive HHV-6 PCR assay (95%CI 1.1– 7.4, p=0.03). For double UCBT, a significantly higher rate of positive HHV-6 PCR assay was found for those patients who received a myeloablative conditioning regimen compared to a non-myeloablative regimen (p=0.01). The use of Fludarabine was not significantly different between myeloablative and non-myeloablative conditioning regimens in those patients who received a double UCBT. In summary, we did not find statistical evidence that high-dose acyclovir was an effective prophylaxis against HHV-6 infection, though the analysis may be hampered by low power. We did find that double umbilical cord blood transplant patients are at high risk of having a positive HHV-6 PCR assay compared to BM, PB and single UCBT patients. The underlying reason for this increased risk is unclear and further investigation will be clinically valuable.