ALBERT

Description: 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; 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.

Description: Key Points CMV reactivation after HCT is associated with a reduced risk of early relapse in patients with AML but not other disease groups. The benefit, however, is offset by an increased risk of nonrelapse mortality.

Description: 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.

Description: 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.

Description: We showed previously that the presence of aberrant marrow myeloblasts, as determined by flow cytometry immediately pre-transplant had predictive value for post-transplant outcomes in patients undergoing hematopoietic cell transplantation (HCT) for Myelodysplastic Syndrome (MDS). The characteristics of phenotypically abnormal myeloblasts in MDS include decreased expression of CD45, presence of non-lineage lymphoid antigens including CD56, and differences in the intensity of various myeloid antigens in comparison to healthy controls. In the present study, the bone marrow aspirates of 156 patients with MDS were analyzed before HCT for the presence of abnormal myeloblasts with the aim of determining whether myeloid dyspoiesis by flow cytometry was predictive of post-transplant outcomes, specifically in patients who were considered good risk by currently accepted criteria. All patients received ”myeloablative” conditioning, which in most patients (78%) consisted of busulfan (targeted) and cyclophosphamide followed by HLA-identical related (52%), HLA-matched unrelated (39%), or alternative donor (9%) stem cell infusions. In agreement with our initial report, patients with severe flow scores (≥4) had an increased hazard of relapse (HR=2.7, 95% CI_1.1–6.3, p=0.017) in comparison to patients with normal flow scores. In addition, even among patients with less than 5% marrow myeloblasts, dyspoietic characteristics of the blasts, as assessed by flow cytometry criteria were associated with an increased hazard of relapse (HR=4.0, 95% CI 1.4–12.1, p=0.013) as compared to patients without dyspoiesis by flow. The cumulative incidence of relapse in MDS patients with flow cytometrically normal marrow myeloblasts was 11.7%, compared to 28.1% in patients with less than 5% but phenotypically aberrant myeloblasts; the latter was not different from a relapse incidence of 31.4% in patients with 5% or more abnormal marrow myeloblasts. Furthermore, patients with intermediate-1 risk disease by the International Prognostic Scoring System, who showed flow cytometric aberrancies were at significantly increased risk of relapse (HR=4.2, p=0.01) in comparison to patients with intermediate-1 risk disease and no or mild dyspoiesis by flow cytometry. Thus, the presence of dyspoietic changes was more relevant than the proportion of marrow myeloblasts in predicting the risk of relapse, suggesting that flow cytometry is a powerful tool to select high risk patients from cohorts of patients who by established criteria would be considered to have good risk MDS.

Description: 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

Description: 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).

Description: NM-HCT makes use of graft-versus-tumor effects and has been applied to treat pts with hematological malignancies who were ineligible for conventional myeloablative (M)-HCT. The current study retrospectively analyzed platelet and RBC transfusion requirements within the first 100 days after HCT in 365 consecutive pts given NM- HCT from HLA-matched related (MRD; n=187) or unrelated donors (URD; n=178) between December 1997 and January 2005. Diagnoses included NHL and HD (29.5%), MM (19.4%), acute leukemias (20%), chronic leukemias (14.8%) and others (16.3%). Pts’ age ranged from 9 months to 74.5 (median 50.1) years. We also asked whether ABO incompatibility increased transfusion requirements in NM recipients, and whether there were differences in transfusion requirements between related and unrelated recipients within the subgroup of ABO-mismatched recipients. Further, overall transfusion requirements were compared to those among 1430 concurrent HLA-matched recipients given M-HCT. Among NM recipients, a higher percentage of unrelated recipients required transfusions than of related recipients (48% vs.25% for platelets p

Description: 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.