Search

We designed a prospective, observational study enrolling patients presenting for treatment of acute myeloid leukemia (AML) at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life (QOL), and function in: the entire cohort, those aged ≥65 years, those with high comorbidity burden, intermediate cytogenetic risk, adverse cytogenetic risk, and first complete remission with or without measurable residual disease. Patient were assessed 8 times over 2 years. Time-dependent regression models were used. Among 692 patients that were evaluable, 46% received HCT with a 2-year survival of 58%. In unadjusted models, HCT was associated with reduced risks of mortality most of the subgroups. However, after accounting for covariates associated with increased mortality (age, comorbidity burden, disease risks, frailty, impaired QOL, depression, and impaired function), the associations between HCT and longer survival disappeared in most subgroups. Although function, social life, performance status, and depressive symptoms were better for those selected for HCT, these health advantages were lost after receiving HCT. Recipients and nonrecipients of HCT similarly ranked and expected cure as main goal of therapy, whereas physicians had greater expectations for cure than the former. Accounting for health impairments negates survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is mostly owing to selection of the healthier candidates. Considering patients’ overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

We designed a prospective, observational study enrolling patients presenting for treatment of AML at 13 institutions to analyze associations between hematopoietic cell transplantation (HCT) and survival, quality of life (QOL), function and geriatric health, in 6 groups: 1) the entire cohort, 2) ≥65 years old, 3) high comorbidity burden, 4) intermediate cytogenetic-risk, 5) adverse cytogenetic-risk, and 6) first complete remission with or without measurable residual disease. Patient health and preferences were assessed eight times across 2 years. Time-dependent regression models were used. Among 692 evaluable patients, 46% received HCT with 2-year survival of 58%. In unadjusted models, HCT was associated with reduced risks of mortality in the entire group and most of the subgroups. However, after accounting for covariates associated with increased mortality (age, comorbidity-burden, disease risks, frailty, impaired QOL, depression, and impaired function), the associations between HCT and longer survival disappeared in all groups. While function, social life, performance status, and depressive symptoms were better for those selected for HCT compared to those who were not, these health advantages were lost after receiving HCT. Recipients and non-recipients of HCT similarly ranked and expected cure as main goal of therapy, while physicians expected more cure for the formers. Accounting for health impairments negate survival benefits from HCT for AML, suggesting that the unadjusted observed benefit is due mostly to selection of the healthier candidates. Considering patients' overall expectations of cure but also the QOL burdens of HCT motivate the need for randomized trials to identify the best candidates for HCT.

Five-year survival following childhood acute myeloid leukemia (AML) has increased following improvements in treatment and supportive care. Long-term health outcomes are unknown. To address this, cumulative incidence of late mortality and grades 3 to 5 chronic health condition (CHC) were estimated among 5-year AML survivors diagnosed between 1970 and 1999. Survivors were compared by treatment group (hematopoietic cell transplantation [HCT], chemotherapy with cranial radiation [chemo + CRT], chemotherapy only [chemo-only]), and diagnosis decade. Self-reported health status was compared across treatments, diagnosis decade, and with siblings. Among 856 survivors (median diagnosis age, 7.1 years; median age at last follow-up, 29.4 years), 20-year late mortality cumulative incidence was highest after HCT (13.9%; 95% confidence interval [CI], 10.0%-17.8%; chemo + CRT, 7.6%; 95% CI, 2.2%-13.1%; chemo-only, 5.1%; 95% CI, 2.8%-7.4%). Cumulative incidence of mortality for HCT survivors diagnosed in the 1990s (8.5%; 95% CI, 4.1%-12.8%) was lower vs those diagnosed in the 1970s (38.9%; 95% CI, 16.4%-61.4%). Most survivors did not experience any grade 3 to 5 CHC after 20 years (HCT, 45.8%; chemo + CRT, 23.7%; chemo-only, 27.0%). Furthermore, a temporal reduction in CHC cumulative incidence was seen after HCT (1970s, 76.1%; 1990s, 38.3%; P = .02), mirroring reduced use of total body irradiation. Self-reported health status was good to excellent for 88.2% of survivors; however, this was lower than that for siblings (94.8%; P < .0001). Although HCT is associated with greater long-term morbidity and mortality than chemotherapy-based treatment, gaps have narrowed, and all treatment groups report favorable health status.

Decreased cytomegalovirus (CMV)-specific immunity after hematopoietic cell transplantation (HCT) is associated with late CMV reactivation and increased mortality. Whether letermovir prophylaxis-associated reduction in viral exposure influences CMV-specific immune reconstitution is unknown. In a prospective cohort of allogeneic HCT recipients who received letermovir, we compared polyfunctional CMV-specific T-cell responses to those of controls who received PCR-guided preemptive therapy before the introduction of letermovir. Thirteen-color flow cytometry was used to assess T-cell responses at 3 months after HCT following stimulation with CMV immediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) antigens. Polyfunctionality was characterized by combinatorial polyfunctionality analysis of antigen-specific T-cell subsets. Use of letermovir and reduction of viral exposure were assessed for their association with CMV-specific T-cell immunity. Polyfunctional T-cell responses to IE-1 and pp65 were decreased in letermovir recipients and remained diminished after adjustment for donor CMV serostatus, absolute lymphocyte count, and steroid use. Among letermovir recipients, greater peak CMV DNAemia and increased viral shedding were associated with stronger CD8+ responses to pp65, whereas the CMV shedding rate was associated with greater CD4+ responses to IE-1. In summary, our study provided initial evidence that letermovir may delay CMV-specific cellular reconstitution, possibly related to decreased CMV antigen exposure. Evaluating T-cell polyfunctionality may identify patients at risk for late CMV infection after HCT.

Less-intensive induction therapies are increasingly used in older patients with acute myeloid leukemia (AML). Using an AML composite model (AML-CM) assigning higher scores to older age, increased comorbidity burdens, and adverse cytogenetic risks, we defined 3 distinct prognostic groups and compared outcomes after less-intensive vs intensive induction therapies in a multicenter retrospective cohort (n = 1292) treated at 6 institutions from 2008 to 2012 and a prospective cohort (n = 695) treated at 13 institutions from 2013 to 2017. Prospective study included impacts of Karnofsky performance status (KPS), quality of life (QOL), and physician perception of cure. In the retrospective cohort, recipients of less-intensive therapies were older and had more comorbidities, more adverse cytogenetics, and worse KPS. Less-intensive therapies were associated with higher risks of mortality in AML-CM scores of 4 to 6, 7 to 9, and ≥10. Results were independent of allogeneic transplantation and similar in those age 70 to 79 years. In the prospective cohort, the 2 groups were similar in baseline QOL, geriatric assessment, and patient outcome preferences. Higher mortality risks were seen after less-intensive therapies. However, in models adjusted for age, physician-assigned KPS, and chance of cure, mortality risks and QOL were similar. Less-intensive therapy recipients had shorter length of hospitalization (LOH). Our study questions the survival and QOL benefits (except LOH) of less-intensive therapies in patients with AML, including those age 70 to 79 years or with high comorbidity burdens. A randomized trial in older/medically infirm patients is required to better assess the value of less-intensive and intensive therapies or their combination. This trial was registered at www.clinicaltrials.gov as #NCT01929408.

Introduction Infections cause substantial morbidity and mortality in patients with acute myeloid leukemia (AML) and other high-grade myeloid neoplasms. The contemporary regimen of CLAG-M (cladribine, high-dose cytarabine, G-CSF, mitoxantrone) has favorable hematologic outcomes compared to '7+3' (standard-dose cytarabine, anthracycline) in some studies but may be more myelosuppressive. The aim of this investigation was to determine and compare the incidence and spectrum of infections after CLAG-M and 7+3. Methods For this retrospective cohort study, we identified microbiologically documented moderate to severe infections (grade ≥2 infections; Blood and Marrow Transplant Clinical Trials Network Technical Manual of Procedures (BMT CTN MOP) guideline) after the first cycle of CLAG-M for newly-diagnosed (ND) or relapsed/refractory (R/R) AML or other high-grade myeloid neoplasms (≥10% blasts in marrow or peripheral blood) and compared these findings to adults receiving 7+3 for ND disease. We recorded infections for up to 90 days from the start of chemotherapy or until the start of a second cycle or death, whichever occurred first. We compared the cumulative incidence probability of time-to-first infection between cohorts using Gray's test with start of additional therapy and death as competing risk events. Infection rates, defined as average number of infections per 1000 patient days-at-risk, were compared between cohorts using Poisson regression. Results The study included 442 individuals consisting of 196 with ND disease and 131 with R/R disease receiving CLAG-M, and 115 with ND disease receiving 7+3 (Table 1). Fifty-four (28%), 65 (50%), and 19 (17%) individuals per cohort had one or more moderate to severe microbiologically documented infection, respectively. The absolute neutrophil count was Conclusions Moderate to severe microbiologically documented infections are common after the first cycle of chemotherapy for ND or R/R AML or other high-grade myeloid neoplasms. CLAG-M may be associated with more moderate to severe microbiologically documented infections than 7+3 for ND disease. Individuals with R/R disease are at the highest risk. Invasive fungal infections were relatively frequent but may be significantly reduced by mold-active azole prophylaxis. New approaches to improve neutrophil recovery and function may reduce infection risk. Figure 1 Figure 1. Disclosures Halpern: Abbvie: Consultancy; Tolero Pharmaceuticals: Research Funding; Agios: Consultancy; Gilead: Research Funding; Agios Pharmaceuticals: Research Funding; Bayer: Research Funding; Novartis: Research Funding; Imago Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Nohla Therapeutics: Research Funding; Pfizer: Research Funding. Delaney: Deverra Therapeutics: Current Employment, Other: Founder, CSO. Pergam: Chimerix, Inc: Research Funding; Global Life Technologies, Inc: Research Funding; Merck & Co.: Research Funding; Sanofi Aventis: Research Funding. Boeckh: Merck: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; AlloVir: Consultancy; SymBio Pharmaceuticals: Consultancy; Helocyte: Consultancy; Evrys Bio: Consultancy; Moderna: Consultancy; GSK: Consultancy. Walter: BMS: Consultancy; Astellas: Consultancy; Agios: Consultancy; Amphivena: Consultancy, Other: ownership interests; Selvita: Research Funding; Pfizer: Consultancy, Research Funding; Jazz: Research Funding; Macrogenics: Consultancy, Research Funding; Immunogen: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy; Janssen: Consultancy; Kite: Consultancy; Aptevo: Consultancy, Research Funding; Amgen: Research Funding. Hill: Gilead: Consultancy, Research Funding; Karius: Research Funding; Octapharma: Consultancy; Allovir: Consultancy, Research Funding; Amplyx: Consultancy; Takeda: Consultancy, Research Funding; Allogene therapeutics: Consultancy; CRISPR therapeutics: Consultancy; CLS Behring: Consultancy; OptumHealth: Consultancy.

Background: Long-term survivors of childhood Hodgkin lymphoma (HL) are at significant risk for cardiovascular, pulmonary, and endocrine morbidity in addition to subsequent cancers. Emerging evidence suggests that HL survivors may also experience persistent neurocognitive impairment, however the prevalence of neurocognitive impairment has not been well characterized. Further, little work has been done to examine how specific treatments or comorbidities are associated with these impairments. Methods: The current study included 1,760 survivors (52.0% female, mean[sd] 37.5 [6.0] years old, 23.6 [4.7] years from diagnosis) of childhood Hodgkin lymphoma and 3,180 sibling controls (54.5% female, 33.2 [8.5] years old) from the Childhood Cancer Survivor Study. Participants completed questionnaires assessing four domains of neurocognitive impairment (task efficiency, emotional regulation, organization, and memory). Impairment for each domain was defined as a score worse than the 90th percentile of community controls. Treatment exposures were abstracted from the medical record. Second malignancies (SMN) were self-reported and subsequently confirmed by pathology findings or medical record review. Chronic health conditions were self-reported and systematically graded according to the NCI CTCAE v4.3 (Grade 1 mild, Grade 2 moderate, Grade 3 severe/disabling, Grade 4 life-threatening). Generalized estimating equations were used to calculate risk of impairment in survivors compared with siblings adjusted for age, sex, and race. Among HL survivors, multivariable log-binomial regression was used to calculate risk of impairment associated with demographic, clinical, and treatment factors. Separate models examined risk associated with Grade 2+ chronic health conditions adjusted for age, sex, and race. Results: 10.8% of HL survivors reported impaired task efficiency (vs. 7.7% in siblings), 16.6% emotional regulation (vs. 11.5% in siblings), 12.1% organization (vs. 10.3% in siblings), and 8.1% memory (vs. 5.7% in siblings). Compared with siblings, survivors reported significantly higher risk of impairment in each of the four neurocognitive domains after adjusting for age, sex, and race (Table). Female survivors had elevated risk of impairment on emotional regulation (RR [95%CI] 1.4 [1.1,1.9)) and memory (2.0 [1.3,3.0]). Compared with white survivors (91.8% of the population), non-white survivors had higher risk of impairment in task efficiency (2.1 [1.2, 3.5]) and emotional regulation (1.7 [1.0,2.7]). Current smokers (12.3%) had higher risk of impairment in task efficiency (1.9 [1.2, 3.1]), emotional regulation (2.5 [1.7,3.7]), and memory (1.7 [1.0,3.0]). Having a late-relapse (>5 years from diagnosis) or a second malignancy (20.0%) was associated with elevated risk of impairment in task efficiency (1.6 [1.06,2.3]). While not statistically significant, anthracycline exposure (39.8%) was associated with higher risk of impairment in task efficiency (1.3 [0.7,2.2]) and memory (1.6 [0.9,3.0]). No statistically significant associations were noted for bleomycin, corticosteroids, or chest radiation. HL survivors with pulmonary morbidity (8.5%) had a higher risk of impairment on task efficiency (1.9 [1.2,3.0]) compared to those without. Cardiovascular conditions (32.9%) were associated with elevated risk of impairment in all domains (RR range from 1.5 to 2.1, all p Conclusions: Survivors experienced significantly more neurocognitive impairment compared to sibling controls. Among survivors, potentially modifiable risk factors such as smoking and chronic health conditions were associated with neurocognitive impairment while treatment exposures showed little association. Mitigation or prevention of smoking and chronic health conditions may improve neurocognitive functioning in HL survivors Table Disclosures No relevant conflicts of interest to declare.

Introduction Herpes zoster (HZ) after hematopoietic cell transplant (HCT) is a well-known complication with a peak incidence during the first year post-HCT. Cord blood transplant (CBT) recipients are at increased risk for viral infections and historically have a cumulative incidence of HZ approaching 80% by 2.5 years in the context of short-term peri-HCT antiviral prophylaxis. In 2009, international guidelines for prevention of infections after HCT recommended maintaining HZ prophylaxis for at least 1 year after HCT. We retrospectively studied the impact of longer-term antiviral prophylaxis on the incidence of HZ after CBT. Methods Between 2006 and 2016, we performed 360 CBT at our Institution. Patients who were seronegative for varicella zoster virus (VZV) or received the live varicella vaccine (i.e. Varivax®) pre-CBT without a history of chickenpox or HZ were excluded. From 2006-2008, CBT recipients received acyclovir (ACV) 800 mg BID or valacyclovir (VACV) 500 mg BID for HSV and VZV prophylaxis. From 2008-2016, patients who were CMV seropositive received higher-dose prophylaxis with VACV 2g TID through day +100. Before 2009, institutional guidelines recommended to continue prophylaxis until the end of immunosuppression; after 2009, prophylaxis was recommended for at least 1 year and until 8 months after immunosuppression ends. For patients discharged from our center, data were collected through standardized questionnaires and medical records. We abstracted HZ events and other variables for up to 5 years post-CBT. We calculated the cumulative incidence of HZ after CBT, treating death and second HCT as competing risk events. Variables were evaluated for an association with development of HZ using Cox proportional hazards regression; those of biological interest and with a P value ≤ 0.3 in univariable analyses were considerate for multivariable model. Results The study cohort consisted of 227 CBT recipients with a median follow up of 25.4 months (interquartile range [IQR], 6.8 - 49). Follow up time was truncated at the time of death (n=113), second HCT (n=13) or last available records (n=32). Cohort characteristics are shown in Table 1. Among 1-year survivors, 91% were still receiving prophylaxis for a median duration of 20.6 months post-CBT (IQR, 14.1 - 29.4). HZ occurred in 44 patients (19%) at a median of 23.6 months (IQR, 16.1 - 30.3). Most patients (n=31/44, 70%) were not taking antiviral prophylaxis when HZ developed. The cumulative incidence of HZ by 1-year post-CBT was low (1.8%; 95% CI, 0.1%-4%) but increased starting from the second year and reached 26% (95% CI, 19%-33%) by 5 years (Figure 1). Disseminated HZ occurred in 5 cases (11%), and post-herpetic neuralgia occurred in 14 cases (31.8%). Of the 13 HZ episodes that occurred in patients reportedly taking antiviral prophylaxis, 6/13 had clear documentation of ongoing antiviral prophylaxis and 5/13 were still receiving immunosuppressive treatment for graft-versus-host disease (GvHD). All patients responded to antiviral treatment, which consisted of ACV (n=18), VACV (n=16), and famciclovir (n=1). In a multivariable analysis, patients who received myeloablative conditioning or had acute GvHD grades 2-4 had a higher risk of HZ, whereas the use of antiviral prophylaxis was associated with a lower risk of HZ (Table 2). Among 35 patients who discontinued prophylaxis before completing immunosuppressive therapy, 28.5% developed HZ. We found no association between CD4+ T cell counts at 1-year after-CBT and HZ risk. Conclusions In this cohort of 227 CBT recipients with up to 5 years of follow up, the cumulative incidence of HZ was 26% at 5 years, despite antiviral prophylaxis for >1 year in the majority of patients. Furthermore, these patients had high rates of post-herpetic neuralgia and disseminated VZV. Antiviral prophylaxis protected against HZ but there were breakthrough cases. Given that a high number of patients interrupted prophylaxis while still receiving immunosuppressants, adherence to antiviral prophylaxis should be emphasized by health care providers. Based on our findings, the lack of alternative prophylactic strategies at this time, and the safety of ACV/VACV, longer duration of prophylaxis should be considered, especially in patients with ongoing immunosuppression. Recent data demonstrating the safety and efficacy of the HZ subunit vaccine after autologous HCT support future study of HZ vaccination after allogeneic HCT. Disclosures Delaney: Nohla Therapeutics: Employment, Equity Ownership; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees. Boeckh:Chimerix: Research Funding; GSK: Other: Personal fees; GSK: Research Funding; Merck: Research Funding; Merck: Other: Personal fees; Clinigen: Other: Personal fees. Milano:ExCellThera: Research Funding; Amgen: Research Funding. Hill:Takeda: Other: research support; Karius: Other: research support; Amplyx: Consultancy; Nohla Therapeutics: Consultancy, Other: research support.

Strategies to prevent active infection with certain double-stranded DNA (dsDNA) viruses after allogeneic hematopoietic cell transplantation (HCT) are limited by incomplete understanding of their epidemiology and clinical impact. We retrospectively tested weekly plasma samples from allogeneic HCT recipients at our center from 2007 to 2014. We used quantitative PCR to test for cytomegalovirus, BK polyomavirus, human herpesvirus 6B, HHV-6A, adenovirus, and Epstein-Barr virus between days 0 and 100 post-HCT. We evaluated risk factors for detection of multiple viruses and association of viruses with mortality through day 365 post-HCT with Cox models. Among 404 allogeneic HCT recipients, including 125 cord blood, 125 HLA-mismatched, and 154 HLA-matched HCTs, detection of multiple viruses was common through day 100: 90% had ≥1, 62% had ≥2, 28% had ≥3, and 5% had 4 or 5 viruses. Risk factors for detection of multiple viruses included cord blood or HLA-mismatched HCT, myeloablative conditioning, and acute graft-versus-host disease (P values < .01). Absolute lymphocyte count of

HSCT is being increasingly offered as a curative option for children with hematologic malignancies. Although survival has improved, the long-term morbidity ascribed to the HSCT procedure is not known. We compared the risk of chronic health conditions and adverse health among children with cancer treated with HSCT with survivors treated conventionally, as well as with sibling controls. HSCT survivors were drawn from BMTSS (N = 145), whereas conventionally treated survivors (N = 7207) and siblings (N = 4020) were drawn from CCSS. Self-reported chronic conditions were graded with CTCAEv3.0. Fifty-nine percent of HSCT survivors reported ≥ 2 conditions, and 25.5% reported severe/life-threatening conditions. HSCT survivors were more likely than sibling controls to have severe/life-threatening (relative risk [RR] = 8.1, P < .01) and 2 or more (RR = 5.7, P < .01) conditions, as well as functional impairment (RR = 7.7, P < .01) and activity limitation (RR = 6.3, P < .01). More importantly, compared with CCSS survivors, BMTSS survivors demonstrated significantly elevated risks (severe/life-threatening conditions: RR = 3.9, P < .01; multiple conditions: RR = 2.6, P < .01; functional impairment: RR = 3.5, P < .01; activity limitation: RR = 5.8, P < .01). Unrelated donor HSCT recipients were at greatest risk. Childhood HSCT survivors carry a significantly greater burden of morbidity not only compared with noncancer populations but also compared with conventionally treated cancer patients, providing evidence for close monitoring of this high-risk population.

Previous investigations of cancer survivors report that the cumulative incidence of subsequent leukemia plateaus between 10 and 15 years after primary therapy. Risk beyond 15 years has not been comprehensively assessed, primarily because of lack of long-term follow-up. Among 5-year survivors from the Childhood Cancer Survivor Study cohort, 13 pathologically confirmed cases of subsequent leukemia occurred ≥ 15 years after primary malignancy, with a mean latency of 21.6 years (range, 15-32 years). Seven were acute myeloid leukemia (2 acute promyelocytic leukemia with t(15;17), 2 with confirmed preceding myelodysplastic syndrome), 4 acute lymphoblastic leukemia (2 pre-B lineage, 1 T cell, 1 unknown), and 2 other. Two acute myeloid leukemia cases had the 7q− deletion. The standardized incidence ratio was 3.5 (95% confidence interval, 1.9-6.0). Median survival from diagnosis of subsequent leukemia was 2 years. This is the first description of a statistically significant increased risk of subsequent leukemia ≥ 15 years from primary diagnosis of childhood cancer.

A total of 152 patients with myelodysplastic syndrome (MDS) receiving a first stem cell transplant had marrow cells prospectively analyzed to calculate the flow cytometric scoring system (FCSS) score. The FCSS scores were retrospectively compared with patient outcomes in both univariate and multivariate models. The cumulative incidence of posttransplantation relapse at 3 years was 15%, 10%, and 36% for patients with mild, moderate, and severe FCSS scores, respectively, with the hazard for relapse of 2.8 (P = .02) for severe scores in comparison to patients with mild or normal FCSS scores. In multivariate analyses, the FCSS score was associated with relapse even after accounting for International Prognostic Scoring System (IPSS) score or for marrow myeloblast percentage. Among patients with intermediate-1 risk by IPSS, severe FCSS scores were associated with an increased hazard of relapse (3.8; P = .02) compared with patients with normal/mild/moderate FCSS scores. Among patients with less than 5% marrow myeloblasts, myeloblast dyspoiesis was associated with an increased hazard of relapse (3.7; P = .02). This analysis confirmed that FCSS scores are predictive of posttransplantation outcomes in patients with MDS even after adjusting for risk factors such as marrow myeloblast percentage and IPSS score.

Survivors of childhood acute lymphoblastic leukemia (ALL) are at risk for late effects of cancer therapy. Five-year ALL survivors (< 21 years at diagnosis; n = 5760 eligible, 4151 participants), diagnosed from 1970 to 1986 were compared with the general population and a sibling cohort (n = 3899). Cumulative mortality of 5760 5-year survivors was 13% at 25 years from diagnosis. Recurrent ALL (n = 483) and second neoplasms (SNs; n = 89) were the major causes of death. Among 185 survivors, 199 SNs occurred, 53% in the CNS. Survivors reported more multiple chronic medical conditions (CMCs; odds ratio [OR], 2.8; 95% CI, 2.4-3.2) and severe or life-threatening CMCs (OR, 3.6; 95% CI, 3.0-4.5) than siblings. Cumulative incidence of severe CMCs, including death, 25 years from diagnosis was 21.3% (95% CI, 18.2-24.4; 23.3% [95% CI, 19.4-27.2] and 13.4% [95% CI, 8.4-18.4] for irradiated and nonirradiated survivors, respectively). Survivors reported more adverse general and mental health, functional impairment, and activity limitations compared with siblings (P < .001). Rates of marriage, college graduation, employment, and health insurance were all lower compared with sibling controls (P < .001). Long-term survivors of childhood ALL exhibit excess mortality and morbidity. Survivors who received radiation therapy as part of their treatment or had a leukemia relapse are at greatest risk for adverse outcomes.

As risk for secondary breast cancer is elevated among cancer survivors treated with conventional therapy, we sought to determine the risk among 3337 female 5-year survivors who underwent an allogeneic hematopoietic cell transplantation (HCT) at the Fred Hutchinson Cancer Research Center or at one of 82 centers reporting to the European Bone Marrow Transplant Registry. Risk was calculated using standardized incidence ratios (SIRs), and risk factors were evaluated with a multivariable Cox proportional hazards model. Fifty-two survivors developed breast cancer at a median of 12.5 (range: 5.7-24.8) years following HCT (SIR = 2.2). Twenty-five–year cumulative incidence was 11.0%, higher among survivors who received total body irradiation (TBI) (17%) than those who did not receive TBI (3%). In multivariable analysis, increased risk was associated with longer time since transplantation (hazard ratio [HR] for 20+ years after transplantation = 10.8), use of TBI (HR = 4.0), and younger age at transplantation (HR = 9.5 for HCT < 18 years). Hazard for death associated with breast cancer was 2.5 (95% CI: 1.1-5.8). We conclude that female survivors of allogeneic HCT are at increased risk of breast cancer and should be educated about the need for regular screening.

Prophylactic fluconazole prevents candidiasis; however, this drug has no activity against molds. We performed a randomized trial to determine whether prophylactic itraconazole prevents invasive mold infections (IMIs). A total of 304 patients receiving allogeneic stem cell transplants (SCT) were randomized to receive fluconazole (400 mg/d) or itraconazole (oral solution 2.5 mg/kg 3 times daily, or intravenous 200 mg daily) for 180 days after SC transplantation, or until 4 weeks after discontinuation of graft-versus-host disease (GVHD) therapy. Proven or probable invasive fungal infections (IFI) were evaluated by intent-to-treat and “on-treatment” analyses. More patients in the itraconazole arm developed hepatotoxicities, and more patients were discontinued from itraconazole because of toxicities or gastrointestinal (GI) intolerance (36% versus 16%, P < .001). Intent-to-treat analysis demonstrated no difference in the incidence of IFI during the intended study period (fluconazole 16% versus itraconazole 13%, P = .46); however, fewer patients in the itraconazole arm developed IFI on treatment (fluconazole 15% versus itraconazole 7%, P = .03). Itraconazole provided better protection against IMI (fluconazole 12% versus itraconazole 5%, P = .03), but similar protection against candidiasis (3% versus 2%, P = .69). There was no difference in overall or fungal-free survival. Itraconazole appears to prevent IMI in the subset of patients who tolerate the drug; however, toxicities and poor tolerability limit its success as prophylactic therapy.

Marrow cells of myeloid lineage from 115 patients with myelodysplastic syndrome (MDS) were characterized by multidimensional flow cytometry and compared with findings in 104 patients with various disorders and 25 healthy donors. Based on phenotypic and scatter characteristics, a flow cytometric scoring system (FCSS) was developed that allowed for a simple numerical display of results. The flow cytometric scores were categorized as normal/mild (0-1), moderate (2-3), or severe (≥ 4). Most flow cytometric abnormalities were significantly (P < .05) more frequent in patients with MDS than in the control cohort. Flow cytometric scores in MDS patients were then retrospectively compared with marrow blast counts assessed by morphology, cytogenetics, hematologic parameters, and International Prognostic Scoring System (IPSS) risk categorization. The flow cytometric scores correlated inversely with leukocyte and absolute neutrophil counts (P < .01) and correlated directly with IPSS scores (P < .01) and with IPSS cytogenetic risk categories (P < .01). In 111 MDS patients who underwent allogeneic hematopoietic stem cell transplantation, flow scores correlated with posttransplantation outcome. The probabilities of posttransplantation relapse were 3%, 15%, and 33% for patients with mild, moderate, and severe FCSS scores, respectively (P < .01), and overall survival was 74%, 40%, and 36%, respectively, for the 3 groups (P < .01). In multivariate analyses, there was a significant contribution of the flow score independent of the IPSS in predicting survival and relapse (P < .01, P = .02, and P = .03, respectively). These data suggest that FCSS is useful in assessing marrows for diagnosis of MDS and in determining the prognostic outcome in patients with this disorder. (Blood. 2003;102:394-403)

Results of previous studies have suggested that transplantation-related mortality among patients with chronic graft-versus-host disease (GVHD) may be reduced by combined treatment with cyclosporine (CSP) and prednisone rather than by prednisone alone. In a randomized trial, we assessed the efficacy of cyclosporine plus prednisone versus prednisone alone as initial therapy for chronic GHVD among patients whose platelet counts were higher than 100 000/μL. Prednisone was administered initially at a dose of 1.0 mg/kg per day orally, followed by a prolonged taper, and cyclosporine was administered at 6 mg/kg orally twice daily every other day. The cumulative incidence of transplantation-related mortality at 5 years from enrollment was 17% (95% CI, 0.11-0.23) in the CSP plus prednisone arm and 13% (95% CI, 0.08-0.19) in the prednisone arm. The hazards of transplantation-related mortality, overall mortality, recurrent malignancy, secondary therapy, and discontinuation of all immunosuppressive therapy were not significantly different between the 2 arms, but survival without recurrent malignancy was lower in the 2-drug arm (P = .03). Avascular necrosis developed in 18 (13%) of the 142 patients in the CSP plus prednisone arm and in 32 (22%) of the 145 patients in the prednisone arm (P = .04). Treatment with CSP plus prednisone may reduce the risk for steroid-related toxicity, but results of the current study do not substantiate the hypothesis that the administration of CSP reduces transplantation-related mortality among patients with chronic GVHD.

Introduction: Since the mid-1990's, overall survival rates for children diagnosed with mature B-cell non-Hodgkin lymphoma (B-NHL) have exceeded 90%, due in large part to the widespread utilization of the LMB chemotherapy regimen. As a result, a population of survivors living beyond 5 years from diagnosis and treatment with this regimen is emerging, providing the first opportunity to study late-occurring and chronic health outcomes following contemporary B-NHL therapy. Methods: Late health outcomes and health status were self-reported among CCSS participants who were 5-year survivors of childhood B-NHL and whose treatment exposures were consistent with LMB-defined risk-groups (A - low; B - intermediate; and C - high risk). Combinations of individual chemotherapy agents (cyclophosphamide [CPM], vincristine, prednisone, doxorubicin [doxo], high-dose methotrexate [HD-MTX], cytarabine, and etoposide) and respective cumulative doses (for CPM, doxo, HD-MTX, and etoposide) were abstracted from medical records. Chronic health conditions occurring ≥5 years from cancer diagnosis were graded per the Common Terminology Criteria for Adverse Events (version 4.03). Decreased fertility was defined as failure to achieve or sire a pregnancy after ≥1 year of trying among survivors of childbearing age (15-44 years). Health status outcomes were obtained from validated questionnaires. Standardized mortality ratios (SMRs) were estimated. Cox and logistic regression models (adjusted for age, sex, and race) provided hazard (HR) and odds ratios (OR) and 95% confidence intervals (CI) of health conditions and status compared to a sibling comparison group (n=4,023). Results: We identified 94 B-NHL survivors (median age 10 [range 2-20] years at diagnosis, 24 [10-39] years at evaluation, 14 [7-26] years post diagnosis), for which pertinent LMB treatment exposures are included in Table 1. Compared to siblings, survivors were more likely to be male (79% vs. 48%, p0.1) or sociodemographic differences (educational level less than a college degree, p's>0.1; household income less than $60,000/year, p's>0.1) were identified in any Groups. Cancer-related pain and anxiety did not differ in Groups B or C compared to survivors in Group A (p=0.9 and 0.2, respectively). Conclusions: Despite excellent survival rates, children diagnosed with B-NHL and treated with contemporary LMB chemotherapy regimens are at risk for chronic health conditions and health status limitations by 14 years from diagnosis. Studies exploring the trajectory of these findings and the impact of early interventions are needed to inform future frontline treatment protocols. Disclosures No relevant conflicts of interest to declare.

High-dose therapy with autologous peripheral blood stem cell (PBSC) rescue is widely used for the treatment of malignant disease. CD34 selection of PBSC has been applied as a means of reducing contamination of the graft. Although CD34 selection results in a 2 to 3 log reduction in contaminating tumor cells without significantly delaying engraftment, many other types of cells are depleted from the CD34-enriched grafts and immune reconstitution may be impaired. In the present study, 31 cytomegalovirus (CMV)-seropositive patients who received myeloablative therapy followed by the infusion of CD34-selected autologous PBSC were assessed for the development of CMV disease in the first 100 days posttransplant. Seven patients (22.6%) developed CMV disease and 4 patients (12.9%) died from complications of their infection. In a contemporaneous group of 237 CMV-seropositive patients receiving unselected, autologous PBSC, only 10 patients (4.2%) developed CMV disease, with 5 deaths (2.1%). In a multivariate logistic regression analysis, the use of CD34-selected autologous PBSC after high-dose therapy was associated with a marked increase in the incidence of CMV disease and CMV-associated deaths.

Between 1970 and 1996, 333 patients with severe aplastic anemia underwent HLA-matched related marrow transplant after conditioning with cyclophosphamide (CY). Thirty-five percent of patients transplanted between 1970 and 1976 (group 1), 12% of those transplanted between 1977 and 1981 (group 2), and 9% of patients transplanted between 1982 and 1997 (group 3) had graft rejection. Graft rejection occurred later among group 3 patients (median, 180 days) than among those in groups 1 and 2 (medians, 28 and 47 days, respectively; P < .001 group 3 v 2). In group 3, 92% of rejecting patients underwent a second transplant, compared with 78% and 77% in groups 1 and 2, respectively. Group 1 patients received various conditioning regimens before second transplant, whereas most patients of groups 2 and 3 received CY combined with antithymocyte globulin (ATG). Graft-versus-host disease (GVHD) prophylaxis after second transplant consisted of methotrexate (MTX) for all group 1 and 2 patients, whereas group 3 patients received MTX combined with cyclosporine (CSP). Over the three time periods studied, first graft rejection decreased from 35% to 9%, and the proportion of rejecting patients undergoing second transplants increased from 77% to 92%. The 10-year probability of survival after second transplants increased from 5% to 83%. Multivariate analysis showed MTX/CSP GVHD prophylaxis to be a significant factor accounting for the increase in patient survival after second transplant. © 1998 by The American Society of Hematology.

We reviewed the records and reevaluated 212 patients with aplastic anemia transplanted at the Fred Hutchinson Cancer Research Center (FHCRC) between 1970 and 1993 who survived ≥2 years and who have been followed for up to 26 years. Parameters analyzed included hematopoietic function, chronic graft-versus-host disease (GVHD), skin disease, cataracts, lung disease, skeletal problems, posttransplant malignancy, depression, pregnancy/fatherhood, and the return to work or school, as well as patient self-assessment of physical and psychosocial health, social interactions, memory and concentration, and overall severity of symptoms. Survival probabilities at 20 years were 89% for patients without (n = 125) and 69% for patients with chronic GVHD (n = 86) (the status was uncertain in 1 surviving patient). All patients had normal hematopoietic parameters. Skin problems occurred in 14%, cataracts in 12%, lung disease in 24%, and bone and joint problems in 18% of patients. Eleven patients (12%) developed a solid tumor malignancy and 19% of patients experienced depression. Chronic GVHD was the dominant risk factor for late complications. Seventeen patients died at 2.5 to 20.4 years posttransplant; 13 of these had chronic GVHD and related complications. At 2 years, 83% of patients had returned to school or work; the proportion increased to 90% by 20 years. At least half of the patients preserved or regained the ability to become pregnant or father children. Patients rated their quality of life as excellent and symptoms as minimal or mild. In conclusion, marrow transplantation in patients with aplastic anemia established long-term normal hematopoiesis. No new hematologic disorders occurred. The major cause of morbidity and mortality was chronic GVHD. However, the majority of patients who survived beyond 2 years returned to a fully functional life.

Patients with a lymphohematopoietic malignancy considered to be at high risk for posttransplant relapse were enrolled in a study to compare the use of cyclosporine (CSP) as a single agent with a combination of methylprednisolone (MP) and CSP for graft-versus-host disease (GVHD) prophylaxis after marrow transplantation from an HLA-identical sibling donor. Sixty patients were randomized to receive CSP only and 62 were randomized to receive CSP plus MP. Daily CSP was started on day −1 (5 mg/kg/d intravenously) and administered at gradually reduced doses until day 180. MP was started on day 7 at 0.5 mg/kg/d, increased to 1.0 mg/kg/d on day 15, started on a taper schedule on day 29, and discontinued on day 72. All 104 evaluable patients (surviving ≥28 days) had sustained engraftment. The incidence rates of grades II-IV acute GVHD were 73% and 60% for patients receiving CSP and CSP plus MP, respectively (P = .01). No difference was seen for grades III-IV GVHD. However, chronic GVHD occurred somewhat more frequently in patients receiving CSP plus MP (44%) than in patients receiving only CSP (21%; P = .02). The incidence of de novo chronic GVHD was marginally higher in patients receiving CSP plus MP (P = .08). No significant differences in the risk of infections were observed. There was a suggestion that the risk of relapse was lower in patients receiving CSP plus MP (P = .10) and, although the overall survival in the two groups was not different (P = .44), there was a slight advantage in favor of CSP plus MP-treated patients for relapse-free survival (P = .07). These results suggest that prophylactic MP, when combined with CSP, has only limited efficacy in acute GVHD prevention and may increase the probability of chronic GVHD.

Postgrafting cyclosporine (CSP) given for 35 days resulted in establishment of stable marrow grafts from DLA-identical canine littermates after otherwise suboptimal, but nevertheless, lethal conditioning with 450 cGy of total body irradiation (TBI). We now asked whether sustained allografts could be achieved after sublethal TBI or without TBI. Five groups of recipients were studied. Dogs in group 1 were given 200 cGy TBI and postgrafting CSP, 15 mg/kg twice daily by mouth on days −1 to 35 posttransplant. Dogs in group 2 were given 200 cGy TBI and methotrexate (MTX), 0.4 mg/kg intravenously (IV) on days 1, 3, 6, and 11 along with CSP. Dogs in group 3 were given 200 cGy TBI and CSP along with mycophenolate mofetil (MMF ), 10mg/kg twice daily subcutaneously (SC) on days 0 to 27 after transplant, a novel immunosuppressive combination. Dogs in group 4 were given 100 cGy TBI and MMF/CSP. Dogs in group 5 were not given TBI and they received MMF/CSP posttransplant. Allografts were assessed by (Ca)n dinucleotide repeat polymorphism studies in cells from peripheral blood, lymph nodes, and marrow. Dogs in group 1 had transient mixed donor-host hematopoietic chimerism for no more than 4 weeks. Three of six dogs in group 2 had transient mixed chimerism for 3 to 11 weeks, and three have remained stable mixed chimeras for up to 60 weeks now. Four of five dogs in group 3 have remained stable mixed chimeras for 54 to 57 weeks now, while one lost the allograft after 12 weeks. All dogs in groups 4 and 5 rejected their allografts after 2 to 12 weeks. In summary, the establishment of stable mixed hematopoietic chimerism following nonmyelosuppressive and nontoxic conditioning programs has remained a difficult goal. Here we present evidence in a large random-bred animal species that this goal may be achievable with pharmacological immunosuppression postgrafting, capable of inhibiting both host-versus-graft (HVG) and graft-versus-host (GVH) reactions in the setting of DLA-identical grafts.

We performed a randomized trial to compare the safety and efficacy of itraconazole with fluconazole in preventing fungal infections in patients undergoing allogeneic stem cell transplantation (SCT). Itraconazole (intravenous 200 mg daily, or oral solution 2.5 mg/kg 3 times daily) and fluconazole (intravenous or oral, 400 mg daily) were administered with the start of conditioning therapy, until at least 120 days after SCT. After enrollment of the first 197 patients, a data and safety monitoring board reviewed potential drug-related toxicities. Patients who received itraconazole developed higher serum bilirubin and creatinine values in the first 20 days after SCT, with highest values in patients who received itraconazole concurrent with cyclophosphamide (CY) conditioning. Analysis of CY metabolism in a subset of patients demonstrated higher exposure to toxic metabolites among recipients of itraconazole compared with fluconazole. These data suggest that azole antifungals, through differential inhibition of hepatic cytochrome P-450 isoenzymes, affect CY metabolism and conditioning-related toxicities.

Marrow samples from 89 patients with aplastic anemia (AA) were evaluated for their ability to grow stromal layers in standard long- term marrow cultures (LTMCs). Results were highly variable: 6.8% failed to grow any stromal cells (group I); 42.5% either failed to grow to confluency or appeared to have a decreased number of adipocytes and/or macrophages (group II); and 52.8% appeared as normal confluent cultures with fibroblasts, adipocytes, and macrophages (group III). Analyses of patient data suggested that group I patients had a longer disease duration and poorer survival (P = .07). Enzyme-linked immunosorbent assay analysis of cytokine production was performed on 20 of the normal- appearing AA LTMCs and 12 LTMCs established from normal donors. Significant differences between the AA and control groups were apparent for macrophage inflammatory protein-1 alpha (MIP-1 alpha), interleukin- 1 receptor antagonist (IL-1ra), granulocyte-macrophage colony- stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G- CSF), and leukemia-inhibitory factor (LIF). The most dramatic differences observed were elevated levels of MIP-1 alpha and GM-CSF and decreased levels of IL-1ra, particularly after IL-1 alpha stimulation. In contrast, IL-1 alpha stimulation of AA LTMCs produced levels of IL- 6, LIF, and G-CSF comparable with those of controls. These data suggest that defects exist within the microenvironment of some AA marrows. Whether the majority of these defects are the cause or consequence of aplasia is not clear. However, we speculate that some of these abnormalities may contribute to the maintenance of the hypoplastic state and, in extreme cases, prevent engraftment of donor marrow.

Background: Idiopathic pneumonia syndrome (IPS) is a non-infectious pulmonary complication with diffuse lung injury that develops in 5-10% of patients who undergo hematopoietic cell transplantation (HCT) and the mortality rate remains high at 50-90%. IPS is difficult to distinguish from occult pneumonia after HCT, because it is hard to exclude all infectious etiologies. There are currently no laboratory tests to aid physicians in the early detection of IPS and other pulmonary infections. The aim of this study was to identify prognostic biomarkers of future occurrence of IPS and compare their profiles to that for subjects with infectious pneumonia. Patients and methods: Among patients transplanted between 1988 and 2014 at FHCRC, we identified 42 patients with IPS based on radiographic findings and exclusion of possible pathogens using frozen bronchoalveolar lavage (BAL) samples of occult viral infections as recently reported (Blood 2015: 24: 3789-97). HCT recipients who did not require bronchoscopic examination and who did not grow any bacterial or fungal blood cultures within 100 days after HCT were considered as controls (n=163) and samples were collected at similar timepoints as IPS cases. We examined cases of viral pneumonia confirmed by positive BAL: human rhinovirus (HRV, n=18) and parainfluenza (PIV, n=21). A set of 1129 plasma samples from pre-HCT, day 7, day 14, day 21 post-HCT and at onset of each event was analyzed. The "onset sample" for controls was the sample closest to day 24 (median day of onset for patients with pulmonary symptoms). We measured six proteins by ELISA: Suppressor of tumorigenicity 2 (ST2), tumor necrosis factor receptor 1 (TNFR1), interleukin-6 (IL-6), lymphocyte vessel endothelial receptor (LYVE)-1, endothelial protein C receptor (EPCR), and herpes virus entry mediator (HVEM). TNFR1, LYVE-1, EPCR and HVEM were discovered through a proteomics approach, and ST2 and IL-6 were also measured due to their associations with endothelial processes and IPS (Blood 2015: 15: 2435-44), respectively. Multivariable logistic regression was used to evaluate the association of each protein with IPS vs. controls and IPS vs. HRV+PIV. Protein concentrations were log10 transformed and values below the lower limit of detection were replaced with that value (this occurred in 28% of the IL-6 measurements only). All analyses were adjusted for age, sex, transplant year, and acute GVHD status (grade 0-1 vs 2-4). Odds ratios indicate an increase in the odds of IPS for a tenfold increase in the protein concentration (Table 1). Receiver Operating Characteristic (ROC) curves were generated for each marker and if the area under the ROC (AUC) was greater than 0.7, then the analyte was considered an informative predictor of IPS. Results: Patients' characteristics are detailed in Table 1. Of the six proteins, TNFR1, ST2, LYVE-1, HVEM, and IL-6 were significantly elevated at the onset of IPS compared to controls at similar time point (adjusted, Table 2). ST2 and IL-6 were also elevated in infectious cases, although to a lesser degree. However, the biomarkers were able to distinguish IPS cases from viral infections (HRV and PIV) occurring approximately at the same time post HCT (Figure 1A). We also evaluated the prognostic value of the proteins by analyzing samples measured at day 7 post-HCT. All six proteins were elevated in IPS cases versus controls as early as day 7 with AUC from 0.85 to 0.75 (data not shown), and distinguished IPS from HRV and PIV infections (Figure 1B). Conclusion: Five proteins, TNFR1, ST2, LYVE-, HVEM, and IL-6 were significantly elevated at the onset of respiratory failure in IPS patients as compared to patients without pulmonary injury. Although the markers were also elevated in viral pulmonary infections, they were able to distinguish IPS from HRV and PIV. Importantly, these markers were elevated as early as day 7 after HCT, prior to the clinical signs of IPS. Additional analyses combining proteins together to form a composite panel are currently ongoing. Disclosures Paczesny: Viracor laboratories: Patents & Royalties: "Methods of detection of graft-versus-host disease" (US- 13/573,766).

Background: DNA viral infections remain important causes of morbidity following cord blood transplantation (CBT). The cumulative incidence, risk factors, and kinetics of reactivation of multiple double-stranded (ds)DNA viruses after CBT are unknown. This lack of understanding limits development of strategies for broader prophylaxis. Methods: Weekly plasma samples through 100 days post-CBT were retrospectively tested by quantitative PCR for HHV-6B, HHV-6A, BK, adenovirus (ADV), and EBV; twice-weekly tests for CMV were performed prospectively. Children and adults with ≥1 year of follow up and availability of >60% of samples while alive, with Results: Cohort characteristics are presented in Table 1: 95% of patients had ≥1 virus. Detection rates were: CMV, 58%; HHV-6B, 74%; HHV-6A, 0%; BK, 62%; ADV, 10%; and EBV, 3% (Table 2). Detection of multiple viruses at any time and concurrently was frequent (Fig. 1); ≥3 viruses were detected in 39% of the cohort at any time and in 14% concurrently. The proportion of patients with detection of any and multiple viruses peaked by wk 4 and persisted through wk 14. Grade 3-4 acute GVHD increased risk for detection of ≥2 (aHR, 3.1; p=0.01) and ≥3 (aHR, 3.1; p=0.08) viruses. Median time to detection was similar for all viruses (3-4 wks) except EBV (7.6 wks; Table 2). Median time to peak viral load from first detection was longest for BK (7 wks) and shortest for HHV-6B (3 days). Despite preemptive therapy for CMV, median time to peak viral load was 3 weeks. Among patients with ≥5 samples tested, the median proportion of positive samples after first detection was Median viral loads after reactivation ranged from 2.3 (CMV) to 3.4 (BK) log10 copies/ml; CMV was mitigated by treatment. Max viral loads were significantly higher than first for all except EBV; mean differences ranged from 0.1 (EBV) to 1.6 (BK) log10 copies/ml (Table 2, Fig. 3). Viral load did not markedly differ if viruses were detected alone or concurrent with other viruses (Fig. 3). Conclusions: We demonstrate frequent and persistent detection of multiple dsDNA viruses through day 100 after CBT. BK demonstrated the greatest and most sustained expansion, whereas HHV-6B reached max levels soon after first detection. These findings provide the rationale to study the impact of multiple virus reactivations on organ disease, health care utilization, and mortality in larger cohorts. These data will be critical to design trials using novel, safer therapies (e.g. CMX001 [brincidofovir], multi-virus-specific T cells) for broad prevention of viral reactivation. Disclosures Hill: Chimerix, Inc.: Research Funding. Delaney:medac: Research Funding; Novartis: Other: Chair, DSMB; Biolife Solutions: Membership on an entity's Board of Directors or advisory committees. Nichols:Chimerix, Inc.: Employment, Equity Ownership. Zerr:Chimerix, Inc.: Research Funding.

The contribution of specific cancer therapies, comorbid medical conditions, and host factors to mortality risk after pediatric Hodgkin lymphoma (HL) is unclear. We assessed leading morbidities, overall and cause-specific mortality, and mortality risks among 2742 survivors of HL in the Childhood Cancer Survivor Study, a multi-institutional retrospective cohort study of survivors diagnosed from 1970 to 1986. Excess absolute risk for leading causes of death and cumulative incidence and standardized incidence ratios of key medical morbidities were calculated. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of risks for overall and cause-specific mortality. Substantial excess absolute risk of mortality per 10 000 person-years was identified: overall 95.5; death due to HL 38.3, second malignant neoplasms 23.9, and cardiovascular disease 13.1. Risks for overall mortality included radiation dose ≥ 3000 rad ( ≥ 30 Gy; supra-diaphragm: HR, 3.8; 95% CI, 1.1-12.6; infradiaphragm + supradiaphragm: HR, 7.8; 95% CI, 2.4-25.1), exposure to anthracycline (HR, 2.6; 95% CI, 1.6-4.3) or alkylating agents (HR, 1.7; 95% CI, 1.2-2.5), non–breast second malignant neoplasm (HR, 2.6; 95% CI 1.4-5.1), or a serious cardiovascular condition (HR, 4.4; 95% CI 2.7-7.3). Excess mortality from second neoplasms and cardiovascular disease vary by sex and persist > 20 years of follow-up in childhood HL survivors.

Long-term survival is now an expected outcome after hematopoietic cell transplantation (HCT). However, the burden of morbidity long-term after HCT remains unknown. We examined the magnitude of risk of chronic health conditions reported by 1022 HCT survivors and their siblings (n = 309). A severity score (grades 1 [mild] through 4 [life-threatening]) was assigned to each health condition using the Common Terminology Criteria for Adverse Events, Version 3. Sixty-six percent of the HCT survivors reported at least one chronic condition; 18% reported severe/life-threatening conditions; comparable values in siblings were 39% and 8%, respectively (P < .001). The cumulative incidence of a chronic health condition among HCT survivors was 59% (95% confidence interval [CI], 56%-62%) at 10 years after HCT; for severe/life-threatening conditions or death from chronic health conditions, the 10-year cumulative incidence approached 35% (95% CI, 32%-39%). HCT survivors were twice as likely as siblings to develop a chronic condition (95% CI, 1.6-2.1), and 3.5 times to develop severe/life-threatening conditions (95% CI, 2.3-5.4). HCT survivors with chronic graft-versus-host disease were 4.7 times as likely to develop severe/life-threatening conditions (95% CI, 3.0-7.2). The burden of long-term morbidity borne by HCT survivors is substantial, and long-term follow-up of patients who received transplantation is recommended.

Algorithms for grading acute graft-versus-host disease (GVHD) are inaccurate in assessing mortality risk. We developed a method to predict mortality by using data from 386 patients with acute GVHD. From the onset of GVHD to day 100, GVHD manifestations were scored for the skin, liver, and upper and lower gastrointestinal tract, and data were recorded for immunosuppressive treatment, performance, and fever. Logistic regression models predicting nonrelapse mortality (NRM) at day 200 were developed with data from 193 randomly selected patients and then validated in the remaining 193 patients. Clinical parameters were grouped to optimize predictive accuracy measured as the area under a receiver-operator characteristic (ROC) curve. The optimal model included the total serum bilirubin concentration, oral intake, need for treatment with prednisone, and performance score. When the overall burden of GVHD was measured by using average Acute GVHD Activity Index (aGVHDAI) scores for each patient in training and validation data sets, areas under ROC curves were 0.87 and 0.85, respectively. Contour lines were generated to reflect the predicted NRM at day 200 as a function of current aGVHDAI scores. These results demonstrate that clinical manifestations of GVHD severity can be used to accurately predict the risk of NRM in real time.

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.

Syngeneic graft-versus-host disease (sGVHD) has been described after hematopoietic cell transplantation (HCT) but remains poorly defined. We retrospectively reviewed adult syngeneic HCTs at our center (1980-2002) for sGVHD to investigate incidence, morbidity, and risk factors with a primary focus on parity. Among 119 transplantations, there were 21 cases of biopsy-proven sGVHD. The cumulative incidence was 18%, with multiorgan involvement in 6 cases and 1 death. sGVHD was more frequent when the donor was parous (32%) than nulliparous (9%) or male (13%; P = .03) and when the recipient was parous (31%) than nulliparous (7%) or male (13%; P = .02). Other univariable risk factors included older age (P < .01), busulfan/melphalan/thiotepa conditioning (P < .01), interleukin-2 (P = .02), HLA-A26 (P = .03), and more recent transplantation year (P < .01). Overall, risk factors were similar to those described in GVHD. Although an independent effect of parity could not be completely separated from other factors, donor and recipient pregnancy history merits further investigation.

It is unknown whether the severity, timing, and quality of graft-versus-host disease (GVHD) may be different after nonmyeloablative as compared with myeloablative hematopoietic stem cell transplantation (HSCT). Therefore, GVHD incidence, morbidity of skin, liver, and gut, requirements for immunosuppressive therapy, and survival were retrospectively analyzed in 44 patients who underwent nonablative HSCT and 52 who underwent ablative HSCT (median ages, 56 and 54 years, respectively). The nonablative transplantation regimen consisted of low-dose total body irradiation (TBI), preceded in some patients by fludarabine administration and followed in all patients by immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). Those who underwent myeloablative HSCT were prepared with different TBI- and non-TBI–containing regimens and received CSP plus methotrexate or MMF for GVHD prophylaxis. The cumulative incidence of grades II-IV acute GVHD was lower after nonablative transplantation (64% vs 85%; P = .001), but there were no differences in the cumulative incidence of chronic GVHD requiring treatment (73% vs 71%; P = .96). Nonablative transplantation was associated with the delayed initiation of steroid treatment for GVHD (0.95 months vs 3.0 months; P < .001) and with the use of fewer systemic immunosuppressants in the first 3 months after transplantation (P ≤ .04). This corresponded to more prevalent skin and more severe gut morbidity 6 to 12 months after nonablative transplantation. Our results show that nonablative HSCT is associated with a syndrome of acute GVHD occurring after day 100 in many patients. This “late-onset acute GVHD” should be taken into consideration in the design of prospective studies comparing GVHD resulting from the two types of transplantation procedures.

Ganciclovir effectively prevents cytomegalovirus (CMV) disease in the first 100 days after allogeneic hematopoietic stem cell transplantation (HSCT), but late-onset CMV disease is increasingly observed. We designed a prospective cohort study to define the incidence and risk factors for late CMV infection in patients who undergo HSCT. CMV-seropositive patients were studied prospectively for CMV infection (quantitative pp65 antigenemia, quantitative CMV-DNA, blood culture), T-cell immunity (CMV-specific CD4+ T-helper and CD8+ cytotoxic T-lymphocyte responses, CD4 and CD8 T-cell count, absolute lymphocyte count), and other transplantation-related factors. Univariate and multivariable analyses were used to assess the risk for late CMV infection and disease and to assess overall survival. Late CMV disease developed in 26 of 146 (17.8%) patients a median of 169 days after transplantation (range, 96-784 days); the mortality rate was 46%. Thirty-eight percent of patients surviving late disease had a second episode a median of 79 days after the first episode. At 3 months after transplantation, preceding detection of CMV pp65 antigenemia, CD4 T-cell counts lower than 50 cells/mm3, postengraftment absolute lymphopenia levels lower than 100 lymphocytes/mm3, undetectable CMV-specific T-cell responses, and graft-versus-host disease (GVHD) were associated with late CMV disease or death. After 3 months, continued detection of pp65 antigenemia or CMV DNA in plasma or peripheral blood leukocytes and lymphopenia (fewer than 300 lymphocytes/mm3) were strong predictors of late CMV disease and death. In conclusion, CMV viral load, lymphopenia, and CMV-specific T-cell immunodeficiency are predictors of late CMV disease and death after allogeneic stem cell transplantation. Prevention strategies should be targeted at patients in whom CMV reactivated during the first 3 months and those with poor CMV-specific immunity or low CD4 counts.

The gradual disappearance of host antidonor isohemagglutinins after major ABO-mismatched hematopoietic stem cell (HSC) allografts has been attributed to the gradual destruction of host plasma cells by graft-versus-host effects. To corroborate this hypothesis, we retrospectively analyzed results from 383 major or major/minor ABO-mismatched unrelated and related HSC allografts performed between 1983 and 1998. All patients were conditioned by high-dose pretransplant therapy and given methotrexate/cyclosporine for graft-versus-host disease (GvHD) prophylaxis. Of the 383 patients, 155 had HLA-matched related and 228 had unrelated grafts. We asked whether unrelated recipients experienced a more rapid disappearance of isohemagglutinins than related recipients, and whether, within the groups of related and unrelated recipients, the titer disappeared faster in patients with GvHD than in those without GvHD. The median time to reach undetectable antidonor IgG and IgM titers was significantly shorter in unrelated recipients (46 versus 61 days; P = .016). In addition, related recipients with GvHD had a 2.2-fold increased likelihood (1.12-4.39,95% CI; P = .02) of reaching undetectable titers within 100 days than patients without GvHD. The persistence of antidonor isohemagglutinins led to significantly increased red blood cell (RBC) transfusion requirements in the ABO-mismatched related patients compared with ABO-matched counterparts. However, time to neutrophil and platelet engraftment, incidence of GvHD, and survival were not influenced by ABO incompatibility. In conclusion, our results corroborate the hypothesis that the rate of disappearance of antidonor isohemagglutinins after ABO-mismatched allogeneic HSC grafts is influenced by the degree of genetic disparity between donor and recipient, suggesting a graft-versus-plasma cell effect.

A retrospective analysis of cytomegalovirus (CMV) genotype was conducted on 281 CMV isolates obtained from marrow transplant recipients. The genotyping was based on sequence variations in the gene encoding envelope glycoprotein B (gB) as detected by restriction analysis of polymerase chain reaction (PCR)-amplified gB DNA. Among all isolates studied, the distribution of gB types 1-4 was 48.4%, 16.4%, 24.6%, and 8.2%, respectively, with only 2.5% of all isolates containing more than one gB type. The association of gB types with acute graft-versus-host-disease (GVHD) and death related to myelosuppression was examined using appropriate multivariable regression models. Covariables in addition to gB type included underlying disease type, donor-recipient HLA matching, donor CMV serostatus, and age as a continuous variable. Death associated with myelosuppression occurred in 2.9% or 4 of 136 patients with gB1, 0% or 0 of 46 patients with gB2, 21.7% or 15 of 69 patients with gB3, and 17.4% or four of 23 patients with gB4. The significant association of CMV gB type with death due to myelosuppression was maintained in a multivariable analysis (P < .001). In addition, the data also suggested that gB types 3 and 4 may be associated with a reduced hazard of grades II to IV acute GVHD.

Background Parainfluenza virus (PIV) is a respiratory virus that infects approximately 10% of hematopoietic cell transplantation (HCT) recipients. A substantial proportion of patients with lower respiratory tract disease (LRD) present without prior upper respiratory tract infection (URI), but reasons for the lack of early detection are poorly understood. Since the definition of LRD differs among studies, we previously proposed a classification of LRD (possible, probable, and proven) that correlates with clinical outcomes (54thASH meeting; abstract #458). The classification demonstrated that patients with PIV detection in lungs (probable and proven LRD) had significantly worse survival than those with PIV detection in a nasopharyngeal (NP) sample alone (possible LRD and URI), with day 90 overall survival 50% vs. 90%, respectively. The purpose of the study was (1) to evaluate risk factors for progression to proven and probable LRD and (2) to determine factors associated with LRD without preceding URI. Patients and methods This retrospective cohort study included 391 HCT recipients with PIV infection transplanted between 1990 and 2011 at FHCRC. PIV detection was performed by conventional culture, direct fluorescent antibody testing, and/or polymerase chain reaction. Categories of PIV infection were defined according to site of PIV detection and radiography: URI: PIV detection in NP sample without new pulmonary infiltrates; possible LRD: detection in NP sample with new pulmonary infiltrates; probable LRD: detection in lung (BAL or biopsy) sample without new pulmonary infiltrates; and proven LRD: detection in lung sample with new pulmonary infiltrates. Patients diagnosed with LRD ≥ 2 days after URI diagnosis were considered to have progression to LRD. Risk factors for progression to proven/probable LRD were analyzed using Cox proportional hazards models, and comparisons between LRD cases with or without prior URI were performed by logistic regression models. Results Among 391 patients, 344 had a positive NP sample at diagnosis of PIV infection and 47 were diagnosed with a positive lung sample alone. Among 344 patients, 61 progressed to LRD and median time to progression was 7 days (range, 2–40). The cumulative incidence of progression by 30-days among patients who presented with URI was 19%; 5%, 4% and 11% of patients progressed to possible, probable and proven LRD, respectively, and 28% of patients with possible LRD further progressed to proven LRD. In a multivariate model among the 344 patients, bone marrow (BM) or cord blood (CB) as cell source (aHR, 3.1; 95% CI, 1.6-5.9, p < 0.001), lymphocyte count less than 100/µL at time of PIV infection (aHR, 2.7; 95% CI, 1.5-4.8, p = 0.001), steroid use greater than 1mg/kg/day before PIV infection (aHR, 2.1; 95% CI, 1.1-4.1, p = 0.035), and PIV type 3 (aHR, 10.0; 95% CI, 1.4-100, p = 0.021) were significantly associated with progression to proven/probable LRD. New pulmonary infiltrates in patients with upper respiratory viral detection (possible LRD) was also associated with progression to proven/probable LRD (aHR, 5.2; 95% CI, 2.8-9.5, p < 0.001). Among 56 patients with possible LRD, all patients who had BM or CB as cell source and high-dose steroids progressed to proven/probable LRD while patients receiving peripheral blood stem cells (PBSCs) with low or no steroid exposure rarely progressed. Among 94 proven/probable LRD cases, 47 presented with LRD without prior URI. PBSCs as cell source (aOR, 4.20; 95% CI, 1.7-10, p = 0.002) and inpatient status at diagnosis (aOR, 3.86; 95% CI, 1.5-9.7, p = 0.004) were significantly associated with progression to LRD without prior URI. Overall, 9 / 47 patients (19%) without virologically proven prior URI had NP tests that were negative or non-interpretable. Conclusion Progression from URI to proven/probable LRD occurs in 21% of PIV-infected patients. Risk factors for progression include PIV-3 subtype, high-dose steroids, BM or CB as cell source and lymphopenia. Progression rates are also high in patients with possible LRD. These data provide important information for clinical trial design as new antivirals are being developed. Strategies are needed to improve detection of PIV prior to progression. Disclosures: Seo: Ansun BioPharma: Research Funding. Boeckh:Ansun BioPharma: Research Funding.

Background Childhood hematopoietic cell transplant (HCT) survivors have been shown to be at increased risk for a variety of long-term cardiometabolic sequelae. However, it is unclear if genetic factors can modify the levels of various quantitative cardiometabolic traits in this population. Methods Prospective cross-sectional study of ≥2-year survivors of pediatric allogeneic (n=47) or autologous (n=27) HCT recruited from two centers. Allogeneic HCT survivors had to be free of chronic GVHD and off immunosuppression at time of assessment. All participants underwent detailed physiologic measurements (euglycemic insulin clamp, body composition assessments, blood pressure, fasting lipids) and also provided DNA samples (both donor and host if allogeneic HCT recipient). A panel of carefully annotated genes and respective single nucleotide polymorphisms (SNPs) associated with each cardiometabolic trait (fat mass, body mass index, insulin resistance, triglyceride, HDL and LDL cholesterol) was assembled based on evidence from the general population using the Human Genome Epidemiology (HuGE) Navigator (accessed March 2013). For each trait, we estimated the least square mean values and determined the overall and pairwise p-values among genotypes. Multiple comparisons were controlled for using Benjamini and Hochberg’s false discovery rate. For initial validation, a separate dataset of 134 ≥2-year pediatric allogeneic HCT survivors without active chronic GVHD and retrospectively collected phenotypes was available. Results Among the primary study participants (n=74), 73% were exposed to total body irradiation, and their median current age was 24 years (range 10-50), with median interval since HCT of 11.4 years (range 2.6-27.6). 95% of these survivors self-reported White non-Hispanic race/ethnicity. Host polymorphisms in LPL (rs319; p=0.0009) and ADRB2 (rs12654778; p=0.002) were found to be significantly associated with differences in triglyceride levels and body mass index, respectively. While several other genes (all host) had SNPs that were associated with various outcomes (e.g. ADIPOQ and insulin resistance, CETP with both HDL and LDL-cholesterol; all p Conclusion It is possible that underlying genetic factors may influence subsequent development of adverse metabolic traits, even among heavily treated childhood cancer survivors. However, any associations require further validation. Furthermore, the relatively small numbers of such patients at most centers limit the power of such genetic investigations. Future efforts should focus on developing appropriate consortia in which samples may be pooled. Application of rigorous phenotype definitions may also enhance the likelihood of identifying true genetic associations. Disclosures: No relevant conflicts of interest to declare.

Background Hodgkin lymphoma (HL) is one of the most treatable pediatric cancers; however, long-term survivors have many therapy-related late effects. As the number of survivors expands and ages, it is important to determine how aging affects the health status of pediatric HL survivors. Methods The study included 1,469 5-year HL survivors and 3,206 siblings enrolled in the Childhood Cancer Survivor Study, a multi-center study of childhood cancer survivors and siblings. Six health status domains (general health, functional impairment, activity limitation, mental health, cancer-related pain, and cancer-related anxiety) were analyzed from data longitudinally collected on the baseline and 2 follow-up surveys. Prevalence of poor outcomes (as defined by Hudson et al. JAMA 2003) for survivors and siblings in each domain were compared using multiple logistic regression models and generalized estimating equations. Separate regressions were performed by sex and included survivor/sibling status, age, race, and interaction between age and survivor status. Models were then adjusted for body mass index (BMI) and number of severe, disabling, or life-threatening medical conditions (Common Terminology Criteria for Adverse Events [CTCAE] Grade 3 or 4). Treatment effects were evaluated in survivors in subsequent analyses. Results Survivors had higher odds of poor health status outcomes than siblings across all domains, which persisted after adjustment for the number of grade 3 or 4 medical conditions (Table 1). The gap between survivors and siblings increased significantly with age in females in the domains of functional impairment (Figure 1) and mental health (Figure 2), but not in males. The odds ratios (OR) for functional impairment in female survivors versus similarly aged female siblings were 0.8 (95% confidence interval [CI] 0.3-1.9) for 18 - 29 year olds, 2.5 (95% CI 1.6-3.7) for 30 - 39 year olds, and 3.1 (95% CI 2.0-4.8) for 40 year olds and older. Female survivors also reported higher prevalence of grade 3 or 4 conditions than male survivors, with 42% of male and 70% of female survivors 40 years and older reporting 1 or more conditions. These conditions increased the odds of poor health status in both sexes (Table 1). BMI in females and race other than non-Hispanic white in males were also significant predictors of poor health status. No treatment variables were consistently associated with poor health status. Conclusions Pediatric HL survivors have increased odds of poor health status compared to siblings. Aging further increases this burden for female survivors in the domains of functional impairment and mental health. Survivors of both sexes continue to develop serious medical conditions with aging, which increase the odds of poor health status. Pediatric HL survivors require early interventions to improve health status and close screening to diagnose medical conditions before they negatively impact quality of life. Disclosures: No relevant conflicts of interest to declare.

Background Multiplex PCR assays now allow the concomitant testing of multiple respiratory viral pathogens, including viruses previously difficult to detect with traditional diagnostic methods. We present a systematic assessment of respiratory viral shedding patterns, rates of progression from upper (URI) to lower respiratory tract disease (LRD) and association of viruses with clinical disease in a large prospective cohort of allogeneic HCT recipients. Patients and Methods Between 2005 and 2011, 471 allogeneic HCT recipients were followed prospectively with PCR testing of serial nasal wash and throat swab samples and a standardized symptom survey (12 respiratory and 4 systemic symptom questions) for 1 year after HCT (day 0-100: weekly symptom survey and PCR; day 101-365, weekly symptom survey and PCR every 3 months and whenever URI symptoms occurred). Bronchoalveolar lavage testing was done when lower respiratory symptoms and/or radiographic changes occurred. PCR testing for RSV, human metapneumovirus (HMPV), parainfluenza virus (PIV) 1-4, influenza (A, B), adenovirus (ADV), human bocavirus (HBoV), human coronaviruses (HCoV, OC43, 229E, NL63, HKU1), and human rhinoviruses (HRhV) were performed in real time on all upper and lower respiratory tract samples. Viral load was quantified when possible. Results From 471 patients, a total of 7,091 samples (median 15, range 1-50 per patient) were tested and 12,709 symptom surveys (median 22, range 1-57 per patient) were collected. Overall, 70% of patients had at least one respiratory virus infection documented during follow-up. 48% of the infections resolved within one week, mostly without treatment (exceptions: all patients with influenza virus and some with RSV received treatment according accepted treatment guidelines). The most common viruses detected were HRhV (32.7%) and HCoV (19.7%), followed by PIV, ADV, RSV, influenza, HMPV and HBoV (Table). Most infectious episodes detected by PCR were associated with respiratory symptoms but completely asymptomatic episodes occurred with HRhV, HCoV, ADV and occasionally with influenza and PIV (Table). Only one patient with RSV infection was completely asymptomatic. Rates of progression from URI to LRD varied from 36% (HMPV) to 5.9% (HBoV) (Table). The time to progression to lower tract disease also varied widely, with the shortest median time observed with RSV and influenza (Table). Only 13% of patients presented initially with LRD (no prior upper respiratory tract viral detection). Conclusion In this prospective surveillance study of HCT recipients, we found that (1) asymptomatic infection may occur with HRhV, HCoV, ADV and occasionally with influenza and PIV, but is otherwise rare; (2) progression rates from URI to LRD differ substantially among viruses, with highest rates observed with HMPV and RSV; (3) the proportion of patients presenting initially with LRD was very rare in this surveillance study; and (4), viral shedding may be prolonged, especially for HRhV, HCoV, PIV-3 and influenza A. These results suggest that close monitoring of respiratory viruses in HCT patients may identify patients at risk for experiencing progression to LRD. Disclosures: Boeckh: Gilead: Consultancy; GSK: Consultancy, Research Funding; Chimeix Inc.: Consultancy, Research Funding; Genentech: Consultancy; Ansun: Research Funding. Chien:Gilead Sciences: Employment. Englund:GSK: Consultancy; Chimerix Inc.: Research Funding; Gilead: Research Funding.

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) Disclosures: No relevant conflicts of interest to declare.

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 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.

Abstract 7 Background: Hispanic children with ALL have a significantly inferior outcome compared with non-Hispanic whites (Blood, 2002). Low systemic exposure to 6MP adversely affects prognosis (N Engl J Med 1990), and red cell (RBC) levels of its metabolite (thioguanine nucleotide [TGN]) correlate with survival (Blood, 1999). Significant inter-patient variability in RBC TGN levels exists due either to inherited difference in thiopurine methyltransferase (TPMT) activity, or failure to adhere to prescribed 6MP. Non-adherence to 6MP has been reported, and could be related to differences in cultural beliefs, possibly accounting for ethnic differences in ALL survival. Methods: We tested this hypothesis in Hispanic and non-Hispanic white children with ALL diagnosed at age ≤21 yrs, and receiving maintenance therapy at 78 participating COG institutions. 6MP adherence was measured over 6 months using Medication Event Management System (MEMS) and RBC TGN. Electronic MEMS cap collected real-time data on dates/ times when the 6MP bottle was opened. Whether the bottle opening was followed by ingestion of 6MP was assessed by monthly (6 assessments/ patient) measurement of TGN. TPMT activity was also measured. Self-reported sociodemographics and reasons for non-adherence were also collected. MEMS-based adherence (outcome of interest) was defined as the ratio of days that 6MP bottle was opened to days 6MP doses were prescribed, reported as a percentage: “% adherence”. All prescribed doses were reviewed for each patient, and the period of time when 6MP was withheld by the prescriber due to toxicity/ illness taken into account. Longitudinal analysis was performed using Generalized Estimating Equations. Results: 333 patients (173 Hispanics; 160 non-Hispanic whites) contributed 54,193 person-days of observation for 6MP adherence. Median age at study participation was 6 yrs (2-20); 67% were males; 38% presented with high-risk disease per NCI criteria. While age, sex and disease characteristics did not differ by ethnicity, Hispanics were significantly more likely to report indices of lower SES (Table). Mean % adherence over the 6 month study period was significantly lower among Hispanics (86±20%) compared with non-Hispanic whites (93±9%, p Conclusion: Non-adherence to 6MP is prevalent in children with ALL. Hispanic children are more likely to be non-adherent, even after adjusting for sociodemographic variables. Non-adherence is associated with significantly inferior DFS. Non-adherence explains the ethnic differences in DFS. This study has informed a targeted intervention to reduce non-adherence to oral chemotherapy, with the goal to reduce disparities in ALL outcome. Disclosures: Relling: St. Jude Children's Research Hospital: Employment, Patents & Royalties; Enzon Pharmaceuticals: Research Funding.

In a randomized, placebo-controlled, double-blind trial, thalidomide or placebo together with glucocorticoids and either cyclosporine or tacrolimus was administered as initial therapy for clinical extensive chronic graft-versus-host disease (cGVHD). All patients had thrombocytopenia or cGVHD that evolved directly from acute GVHD as an indicator of a poor prognosis. The study drug (thalidomide or placebo) was administered initially at a dose of 200 mg orally per day, followed by a gradual increase to 800 mg/d if side effects were tolerable. Treatment with the study drug was discontinued before resolution of cGVHD in 23 (92%) of the 25 patients who received thalidomide and in 17 (65%) of the 26 patients who received placebo (P = .02). Neutropenia and neurologic symptoms were the most frequent reasons for early discontinuation of treatment with thalidomide. The duration of treatment with thalidomide was too short to assess its efficacy in controlling cGVHD.

Abstract 4633 Background Chronic health conditions are commonly reported by survivors of childhood leukemia and lymphoma. To further understand the socio-economic impact of these reported conditions, we sought to determine overall and cause-specific rates of hospitalization among survivors of childhood leukemia/lymphoma and to compare these rates with those of the U.S. population. Methods From the CCSS, 5,637 5 year survivors of childhood leukemia/lymphoma, who participated in the 2000 follow-up questionnaire, were identified. Data related to hospitalizations occurring during the years 1992-2005 were collected and hospitalization rates among survivors were determined. For comparison, hospitalization rates in the general U.S. population were obtained from the National Hospital Discharge Survey (NHDS). Indirect standardization was used to calculate age- and sex- standardized incidence ratios (SIR) and absolute excess risks (AER). The reasons for hospitalization were described and cause specific hospitalization rates were also compared with those of the general U.S. population. Results At follow up, the mean age was 29.2 years (SD: 7.6; range: 14.0-51.0) and the mean time since diagnosis was 20.8 years (SD: 4.6; range 13.3-31.7). Overall, the hospitalization rates of survivors of childhood leukemia, non-Hodgkin lymphoma (NHL) and Hodgkin disease (HD) were 1.3 (95% CI: 1.2-1.3), 1.2 (95% CI: 1.1, 1.3) and 1.9 times (95% CI: 1.8, 2.0) that of the general U.S. population, respectively. Survivors, regardless of diagnosis, were more likely than the general population to be hospitalized for infection, endocrine, cardiovascular, gastrointestinal and genitourinary reasons, as well as external causes (Figure 1). The greatest AER was associated with hospitalization for neoplasm. Survivors of leukemia and NHL were approximately 5 times [SIRleukemia: 5.4 (95% CI: 4.8; 6.2) and SIRNHL: 4.8; (95% CI: 3.6, 6.1)] and HD survivors 10.2 times (95% CI: 8.9, 11.7) more likely than the general population to be hospitalized for this reason. Survivors of HD had 6.5 times (95%CI: 5.6, 7.5) the rate of hospitalization for cardiovascular causes and 4.4 times (95% CI: 3.6, 5.2) the rate of hospitalization for pulmonary causes when compared with the general U.S. population. These findings are consistent with reports indicating an increased risk for second cancers, particularly breast cancer after chest irradiation, and conditions such as pneumonitis, lung fibrosis, cardiomyopathy and coronary artery disease among Hodgkin patients. Survivors of leukemia had 5.2 times (95% CI: 4.4, 6.2) the rate of hospitalization for neurological reasons compared with the general population, likely reflecting late effects of treatment with cranial and spinal radiation. Interestingly, survivors have a significantly lower rate of hospitalization for psychological reasons when compared with the U.S. population (Figure 1). Conclusions Long-term survivors of childhood leukemia/lymphoma experience a significantly increased rate of hospitalization. Additional research is needed to further quantify the overall healthcare utilization and economic impact of treatment-related complications as this population ages. These findings also emphasize the importance of ongoing medical surveillance that includes screening and prevention strategies, which may impact the occurrence of serious medical conditions resulting in hospitalization. Disclosures: No relevant conflicts of interest to declare.

Abstract 328 Hematopoietic cell transplantation (HCT) is utilized in the treatment of a subset of children with acute myeloid leukemia (AML). Although presence of minimal residual disease (MRD) has been associated with a high relapse rate in children with AML, the clinical implications of MRD prior to HCT have not previously been defined. We explored the clinical outcomes associated with the presence of morphologic or sub-morphologic disease prior to HCT. In the period of 1995-2007, 89 patients age 1-18 years received myeloablative conditioning and allogeneic HCT from related (N=36) or unrelated (N=53) donors at Fred Hutchinson Cancer Research Center. At the time of HCT, 63 patients received transplants in complete remission (CR) and 26 had morphologic disease. Among those in morphologic CR, 43 were in 1st CR, 17 in 2nd CR and 3 were in 3rd CR. All patients had bone marrow evaluation for MRD by multi-dimensional flow cytometry (MDF) 2-4 weeks prior to HCT. MDF testing showed that 10 of 63 patients (16%) who received transplants in morphologic CR had MRD levels ranging from 0.3% to 12% (median 3.7%) while the remaining 53 patients had no detectable MRD. The median follow up for the 38 survivors is 6 years (range 1 – 12). Actuarial overall survival at 3 years from HCT for patients who received HCT with and without morphologic disease was 12% vs. 59%, (p Disclosures: No relevant conflicts of interest to declare.

Use of contemporary risk-based therapy in children with ALL has resulted in five-year survival rates exceeding 80%. Achievement of durable remissions requires a maintenance phase composed of oral administration of antimetabolites (6-mercaptopurine and methotrexate) for approximately two years. Previous studies have shown that low systemic exposure to oral 6MP adversely affects prognosis, thus emphasizing the critical need for therapeutic levels throughout maintenance. However, significant inter-patient variability in red cell thioguanine nucleotide (6TGN – a major metabolite of 6MP) concentrations exists, and could in part be related to failure to adhere to prescribed therapy. Non-adherence in pediatric ALL patients has been reported – however, small sample sizes and varying methods of assessment make it difficult to understand the magnitude of this problem. The purpose of our study was to describe adherence to oral 6MP in a large multi-ethnic cohort of children with ALL. Patients were eligible to participate if they were diagnosed with ALL at age less than 22 years, belonged to one of four ethnic/racial groups (Asian, African-American, Caucasian, or Hispanic), and had completed at least 24 weeks of maintenance therapy. We have restricted the current report to Caucasians, where we have completed our target accrual. To measure 6MP adherence, we used the Medication Event Management System (MEMS) and supplied each patient with a MEMS TrackCap. This electronic cap allowed the collection of real-time data by recording the date and time(s) when the 6MP bottle was opened over a 6-month period. The MEMS data was downloaded at the end of the 6-month study period. Patients/parents also completed a self-administered sociodemographic questionnaire. Longitudinal analysis was performed using the Generalized Estimating Equations. A total of 173 Caucasian patients provided 26,424 person-days of observation for 6MP adherence. The median age at diagnosis was 5 years (1 to 19), and at study participation was 6 years (range, 2 to 20); median time from diagnosis was 18.8 months, and from start of maintenance, 8.1 months; 67% were males. NCI criteria for high-risk disease were present in 42% of the patients. The median annual household income was between $50K and $75K; 79% of the mothers and 72% of the fathers had received education beyond high school. The median number of household members (including patient) was 4 (range, 2 to 10). Adherence was defined as the ratio of 6MP bottle openings to actual 6MP doses prescribed, calculated as a percentage (“percent adherence”). Prescribed doses for the entire 6-month period were reviewed for each patient, and instances when 6MP was withheld by the prescriber due to toxicity or illness were taken into account for purposes of calculating adherence. The mean percent adherence over the 6-month study period was 85% (range 11% to 100%). The mean monthly percent adherence declined significantly over the 6-month study period (p=0.002). Multivariate analysis identified certain subgroups that were at increased risk of lower percent adherence (Figure): age >8 years at study entry (p=0.01); households that included members other than the mother, father, and patient ( Figure Figure

We retrospectively assessed 1) overall platelet (PLT) and red blood cell (RBC) transfusion requirements within the first 100 days after allogeneic among HCT recipients given either nonmyeloablative (n=365) or myeloablative conditioning (n=1430); 2) transfusion requirements among nonmyeloablative recipients given grafts from related (n=187) vs. unrelated donors (n=178), and grafts from ABO matched (n=203) vs. ABO mismatched donors (n=159); and 3) the impact of ABO incompatibility on HCT outcomes among nonmyeloablative recipients. Table 1 summarizes results. We confirmed that myeloablative recipients were more likely to receive both PLT and RBC transfusions than nonmyeloablative recipients (both p

We analyzed data from 38 patients (median age = 56, range: 8 – 68 years) with acute leukemia (n=15), chronic idiopathic myelofibrosis (n=6), myelodysplastic syndrome with or without myeloproliferative disorder (n=5), chronic myeloid leukemia (n=4), non- Hodgkin lymphoma (n=4), aplastic anemia (n=2), multiple myeloma (n=1) and renal cell carcinoma (n=1), who underwent salvage allogeneic hematopoietic cell transplantation (HCT) for allograft failure. In 14 cases the original donors were used for second HCT, while in 24 cases different donors were identified (Table 1). Conditioning regimens for first HCTs included total body irradiation (TBI; 2 Gy) with or without fludarabine (Flu; n=28), myeloablative regimens (busulfan-cyclophosphamide, n=6; cyclophosphamide-TBI, n=2); and other, cyclophosphamide-anti-thymocyte globulin-based regimens (n=3). Conditioning for salvage HCT consisted of Flu 30 mg/m2/day on days -4 to -2 followed by TBI of 3 (n=24) or 4 (n=14) Gy on day 0. Cyclosporine and mycophenolate mofetil were used for postgrafting immunosuppression. The median time between first and salvage HCTs was 91 (range, 29 to 1004) days. Sustained second grafts were achieved in 34 patients (89%), while grafts failed in 4 patients (11%), all of whom had idiopathic myelofibrosis. With a median follow-up among surviving patients of 2.0 (range, 0.3 to 7.8) years, the 2 and 4 year Kaplan-Meier survival estimates were 49% (95% CI: 31%, 66%) and 42% (95% CI: 23%, 61%), respectively. The 2 year relapse-rate and non-relapse mortality were 36% (95% CI: 20%, 52%) and 25% (95% CI: 11%, 41%), respectively. The cumulative incidences of grades 2–4 acute and moderate-severe chronic graft-versus-host disease (GVHD) at 2 years were 42% and 41%, respectively. Four patients with chronic GVHD discontinued systemic immunosuppressive therapy at a median of 2.5 years. Within the limitations of the small patient numbers studied, TBI dose (3 vs. 4 Gy), same vs. different donors for salvage HCT, donor type (related, unrelated, HLA-haploidentical related vs. double umbilical cord), and HCT comorbidity scores did not appear to affect outcomes. Based on this retrospective multicenter analysis, we conclude that graft failure following allogeneic HCT can be effectively overcome by second transplantation using conditioning with Flu and low dose TBI (3 or 4 Gy), which should be further investigated in a prospective manner. Table 1. Donors in 1st and 2nd HCTs. HLA-MURD: HLA-matched unrelated donor; HLA-MMURD: HLA-mismatched unrelated donor, UCB: umbilical cord blood. | | 2nd HCT | |:---------------------:| ---------- | --------------- | | | | Different Donor | | 1st HCT | Same Donor | HLA-MURD | HLA-MMURD | Double UCB | HLA-haploidentical | | HLA-identical sibling | 11 | 11 | - | - | - | - | | HLA-MURD | 17 | 3 | 10 | 4 | - | - | | HLA-MMURD | 8 | - | 1 | 7 | - | - | | Double UCB | 2 | - | - | - | 1 | 1

We conducted a matched cohort analysis comparing relapse rates and outcomes for patients receiving transplants from cord blood, matched unrelated donors, and mismatched unrelated donors following myeloablative conditioning in our center’s recent experience. Between April 2006, when our current cord blood protocols opened, and February 2008, 26 consecutive patients underwent CBT following conditioning with 13.2 Gy TBI, 120 mg/kg cyclophosphamide (CY), and 75 mg/m2 fludarabine (FLU) for acute leukemias in morphologic CR (n=24) or chronic myeloid leukemia not in blast crisis (n=2). Twenty-three patients received two units (5 of whom had one of the two units ex vivo expanded) and three received single units. Matching between units and patient was 4/6:4/6 (n=10), 4/6:5/6 (n=5), 5/6:5/6 (n=7), 6/6:6/6 (n=1), and single 5/6 (n=3). For paired analysis with each cord patient, waiver of consent was obtained from the IRB and one matched 10/10 unrelated donor patient (MURD) and one mismatched (9/10 n=23, 8/10 n=3) unrelated donor patient (MMURD) was selected from our center’s database on the basis of identical disease status and similar age without knowledge of transplant outcome. All unrelated donor patients underwent myeloablative transplantation following conditioning with CY/TBI or busulfan (BU)/CY between November 2001 and February 2008 (median April 2005). Patients were matched for disease type, cytogenetic risk status, minimal residual disease status (MRD), and, for patients beyond CR1, time from diagnosis to relapse. Specific diseases and disease status were ALL n=10: CR1 n=8 (MRD n=3), CR2 n=1, CR3 n=1 (MRD n=1), Philadelphia chromosome positive n=3; AML n=14: CR1 n=8 (MRD n=1), CR2 n=6 (MRD n=2); CML n=2 (CP1 n=1, CP2 following blast crisis n=1). Median ages and range for patients were: CBT 23 (0.6–42), MURD 25 (1–41), and MMURD 25 (1–48), and median differences in age between the cord recipient and their unrelated donor matched pairs were 7.8 and 4.6 years for MMURD and MURD, respectively. Median follow-up for surviving cord patients is 16 months (range 7.5–26). There has been only 1 relapse among cord patients versus 8 relapses among MURDs and 5 relapses among MMURDs. Transplant related mortality (TRM) between each group is comparable. Cause specific hazard for relapse is significantly decreased when comparing cords to MURDs by logrank test (p=0.014) and trends toward decrease when comparing cords to MMURDs (p=0.068) (Figure 1). Two year cumulative incidence (CI) of relapse is 3.8% (95% CI 0.3–16.4) for cord patients, 31.4% (95% CI 14.9–49.6) for MURDs, and 21% (95% CI 7.6–38.9) for MMURDs. Two year CI of TRM is 21.6% (95% CI 7.5–40.4) for cord patients, 22.9% (95% CI 8.3–41.8) for MURDs, and 31.8% (95% CI 15–50.1) for MMURDs. Previous data suggest that double unit CBT, as compared to single unit CBT, may markedly reduce relapse rates. The majority of CBT patients included in this analysis underwent double unit CBT, and this strategy may contribute to our observations. Additionally, myeloablative MURD and MMURD TBI regimens at our center involve 12 Gy in contrast to the 13.2 Gy in our CBT regimens. This may also account to some degree for lower relapse rates. Larger numbers and longer follow-up will be needed to confirm these observations, but the possibility of decreased relapse rates without increased TRM is promising. Growing inventories of high quality cord blood units coupled with ongoing improvements in supportive care for CBT patients should lead to continued expansion of the role of CBT. Figure 1: Relapse and TRM following transplantation. Figure 1:. Relapse and TRM following transplantation.