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Abstract Total body irradiation (TBI)-based conditioning regimens are considered the standard of care for patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic cell transplantation (HCT). However, due to concerns regarding acute and long-term toxicities, non-TBI regimens, commonly including busulfan (BU), have been increasingly explored. We performed a retrospective cohort analysis with the hypothesis that there would be equivalence of these two myeloablative approaches by reviewing outcomes for adult patients (pts), aged 18-60 years, undergoing a first, well-matched sibling, related or unrelated donor HCT in CR1 or CR2 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 2005-2014. Eight hundred nineteen pts received TBI (63% 9-12 Gy, 37% ≥13 Gy) combined with etoposide (25%) or cyclophosphamide (Cy) (75%) and 299 pts received intravenous BU combined with a second alkylator Cy (15%) or melphalan (Mel) (13%), or a nucleoside analogue fludarabine (Flu) (41%) or clofarabine (Clo)(30%). The majority of the BU-based pts were treated at the Moffitt or MD Anderson Cancer Center. The BU-based regimens were grouped together for analyses since no significant differences in basic outcomes among the different chemotherapy-only regimens were noted. Patients in the BU-containing group were older but had better performance status, took longer to achieve CR1 and longer to receive HCT; more received peripheral blood than marrow grafts, peri-HCT ATG, pre- and post HCT tyrosine kinase inhibitors ( TKI), and were treated more recently than pts in the TBI-based group (Table 1). With median follow-up of 3.6 years for the BU-based group and 5.3 years for the TBI-based group, adjusted 3 year outcomes showed treatment-related mortality (TRM) BU 19% vs. TBI 25% (p=.04); relapse BU 37% vs. TBI 28% (p=.007); disease-free survival (DFS) Bu 45% vs. TBI 48% (p=.35); and overall survival (OS) BU 57% vs. TBI 53% (p=.35) (Figures A-B). Patients in the BU group had significantly more grade II-IV acute GVHD (47% vs. 40%, p=.025), but marginally less chronic GVHD (49% vs. 55% at 3 years, p=.073). In multivariate analysis, the BU group had a significantly higher rate of acute GVHD after day 50 (RR 1.75, 95% CI 1.19-2.58, p=.004), but marginally less chronic GVHD (RR 0.83, 95% CI 0.68-1.01 p=.059) and higher risk of relapse (RR 1.46, 95% CI 1.15-1.85 p=.002) compared with TBI-based regimens. Despite the observed higher risks of acute GVHD and relapse, BU-based conditioning led to similar TRM, OS, and DFS following HCT for ALL. Table 1 Table 1. Figure Figure. Disclosures Ciurea: Spectrum Pharmaceuticals: Other: Advisory Board; Cyto-Sen Therapeutics: Equity Ownership. Seftel:Otsuka: Research Funding. Pulsipher:Medac: Other: Housing support for conference; Chimerix: Consultancy; Jazz Pharmaceutical: Consultancy; Novartis: Consultancy, Other: Study Steering Committee. Champlin:Ziopharm Oncology: Equity Ownership, Patents & Royalties; Intrexon: Equity Ownership, Patents & Royalties.

Abstract Abstract 4217 Background: AHCT improves survival (OS) in newly diagnosed MM patients (pts) in large randomized trials. These trials have limited eligibility to younger, healthier pts. Selection of older pts and those with co-morbid illness for AHCT is problematic. HCT-CI, originally developed as predictor of post-allogeneic transplant outcomes, maybe valuable in stratifying risk of transplant related mortality (TRM) risk and OS in the AHCT setting. We investigated the relative impact of HCT CI along with other patient and MM related variables on outcomes after AHCT in a large cohort of transplant recipients. Methods: Outcomes of 1156 MM pts receiving AHCT after high dose Melphalan (MEL) between 2007 and 2010 reported to the CIBMTR (Center for International Blood and Marrow Transplant Research) were analyzed. HCTCI scores and individual comorbidities were prospectively reported at time of AHCT. Median follow up of survivors was 26 month. The impact of HCTCI and other potential prognostic factors including Karnofsky performance status (KPS) on OS were studied in multivariate Cox regression models. Results: HCTCI score was 0, 1, 2, 3, >3 in 42%, 18%, 13%, 13% and 14% respectively. Most common co-morbidities included pulmonary, diabetes, obesity, psychiatric, cardiac, renal and prior solid tumor. Using consolidated HCTCI scores, patients were stratified initially into 3 risk groups – HCTCI 0 (42%) vs. HCTCI 1–2 (32%) vs. HCTCI >2 (26%). Males and Caucasians were more likely to have greater HCTCI score. Higher HCTCI was associated with lower KPS <90 (33% in HCTCI 0 cohort vs. 50% in HCTCI >2). HCTCI score >2 was associated with MEL dose reduction to 140 mg/m2 (22% vs. 10% in score 0 cohort). Cytogenetic risk and MM related factors were not correlated with HCTCI. TRM at 12 month was 2%, 2%, and 3% for 3 risk groups. With extremely few TRM events, multivariate analysis did not suggest an impact of HCTCI. OS was 95%, 92%, 92% at 1 year and 87%, 81%, 80% at 2 year, respectively. OS was inferior for HCTCI >2 cohort (RR of death 1.48, p=0.02) and HCTCI cohort 1–2 (RR 1.37, p=0.04) compared with HCTCI 0 cohort. There was no significant difference in OS between HCTCI >2 vs. HCTCI 1–2 (p=0.64). Therefore the latter 2 groups were combined as the HCTCI >0 cohort [N=667] and compared with HCTCI=0 [N=489] in multivariate models. HCTCI >0 predicted inferior OS (RR of death= 1.41, p=0.01). Other significant predictors of inferior survival were KPS <90 (RR of death 1.61, p<0.01), IgA subtype (RR 1.64, p<0.01), >1 pretransplant regimen (RR 1.47, p<0.01), resistant MM at AHCT (RR 1.78, p<0.01). Major cause of death in both groups was progressive MM. Conclusion: In clinical practice, higher HCTCI score was associated with MEL dose reduction. Mortality after AHCT is predominantly related to MM progression/relapse with low incidence of TRM. Higher HCTCI scores were independently associated with inferior OS. KPS remains an important tool for risk stratification. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 597 Back-ground: Planned upfront AHCT after initial induction improves both overall and progression free survival (OS and PFS) for patients with MM in randomized trials. However, it is unclear whether patients with less than partial response after a finite period of initial therapy should receive AHCT immediately or undergo salvage therapy to improve the level of response pre-AHCT. Methods: We addressed this question by querying the CIBMTR (Center for International Blood and Marrow Transplant Research) database. Between 1995 and 2010, 575 patients received upfront AHCT (within 12 mo of diagnosis) for MM after failing to achieve partial or complete response (PR/CR) to initial induction therapy. The 2326 patients who achieved CR/PR pre- AHCT had superior survival and were excluded (Fig 1). The study groups included: the 324 who received additional salvage chemotherapy after non-response to first line therapy (SALVAGE) and then proceeded to AHCT; and 251 who had no additional salvage chemotherapy but proceeded to AHCT immediately (NOSALVAGE). Outcomes of non-relapse mortality (NRM), relapse, PFS, and OS were compared measuring overall survival from diagnosis. Multivariate analysis using Cox proportional hazard models incorporated the following variables: age, gender, Karnofsky performance score, immunoglobulin isotype, stage, serum creatinine at diagnosis, disease status pre-AHCT, conditioning regimen, time from diagnosis to transplant, type of transplant (single/tandem), novel agents (thalidomide/bortezomib/lenalidomide), time-period of transplant and number of lines of pre-transplant therapy (= or &gt; 1 line) on outcomes. Results: Study cohorts were well balanced with respect to age, gender, Karnofsky performance status, immunoglobulin isotype, disease stage. More pts in NOSALVAGE received VAD (60% vs. 47%, p=0.002) for first line therapy and had a base-line creatinine &gt; 1.5mg/dl (27% vs. 17%, p=0.008). In the SALVAGE cohort, 245 (75%) received one, 65 (20%) two and 14 (4%) three salvage regimens. 197/245(61%), 47/65(59%), 2/14 (14%) were sensitive to 1st, 2nd and 3rd line salvage therapies prior to transplant resulting in 55% in SALVAGE achieving CR/PR pre-AHCT. In NOSALVAGE, 93% were in a minimal response or stable disease state and 7% with progressive disease. In SALVAGE, 55% received AHCT after 2004 compared with 38% in NOSALVAGE likely reflecting additional agents available for salvage. The majority of patients in either cohort (&gt;90%) received Melphalan based AHCT and a minority (&lt;20%) planned tandem AHCT. In the SALVAGE cohort, 44% had AHCT &lt;8 months after diagnosis as compared to 74% in NOSALVAGE (P&lt;0.001). Median follow-up for survivors was 61 mo and 68 mo, respectively. Six year NRM (p=1.0), relapse (p=0.2), PFS (p=0.2) or OS (p=0.5) were no different between the two cohorts). On multivariate analysis, a higher creatinine at diagnosis (&gt; 1.5 vs &lt; 1.5) predicted for higher NRM (p=0.008) and inferior OS (p=0.003), and the use of novel agents predicted for lower risk of NRM (HR = 0.37, P=0.04). Since more time elapsed between diagnosis and transplant among patients who received additional salvage chemotherapy, a left-truncated multivariate analysis was performed to reduce this potential waiting time bias. This multivariate analysis produced similar outcomes for TRM, relapse, treatment failure and OS irrespective of whether or not salvage regimens were used (Fig 2). Conclusions: In the setting of upfront AHCT, no additional benefit could be demonstrated for salvage regimens to upgrade response prior to AHCT. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 596 Background Large population-based studies have demonstrated a significant improvement in survival (OS) for patients (pts) with multiple myeloma (MM) over time since the mid-1990s. The improvement has mostly affected younger patients suggesting a beneficial impact of AHCT. The availability of novel drugs within the last decade and their impact on the utilization and outcomes of AHCT recipients is unknown. Methods We retrospectively reviewed the characteristics and outcomes of 20,278 patients undergoing AHCT within 12 months of diagnosis in USA and Canada and reported to CIBMTR in the periods of 1995–1999 (n=2226), 2000–2004 (n=6408) and 2005–2010 (n=11644) including a subgroup of 4373 individuals with detailed patient, disease and treatment information. We subsequently compared survival and analyzed patient, disease and treatment characteristics across the three periods with the time period serving as a surrogate for pre- and post-transplant exposure to novel agents. Results Across the 3 time periods, there was a marked increase in the number of upfront transplants across all age groups (Figure 1a). Patients receiving upfront HSCT in the more recent period were older, less likely to have stage 3 MM at diagnosis and more likely to have received thalidomide (<1 % vs. 22% vs. 52%), lenalidomide (0% vs. <1% vs. 21%) or bortezomib (0% vs. 2% vs. 35%) and have chemosensitive disease at the time of AHCT. The proportion of African-American patients remained low and stable across the three periods (14 vs. 13 vs. 15%). Over the 3 periods, there was a decrease in chemotherapy based stem cell mobilization and increase of single agent G-CSF based mobilization (24% vs. 24% vs. 41%). The use of single agent Melphalan conditioning increased from 54% in 1995–1999 to nearly 100% in the latest period concomitant with near disappearance of total body irradiation-based and multi-drug conditioning regimens. Compared with 1995–99 cohort, survival was superior in the 2000–04 and 2005–09 cohorts at 24 (72% vs. 79% vs. 84%, P<0.001), 48 (54% vs. 60% vs. 64%, P<0.001) and 60 months (47% vs. 52% vs. 55%, P<0.001) (Figure 1b). In multivariate analysis, we found that transplant in the 2000–04 period (HR=0.77, 95% C.I. 0.67–0.89) or in the 2005–10 period (HR=0.68, 95% C.I. 0.59–0.79) along with Karnofsky performance score of 80–100 (HR=0.59, 95% CI 0.51–0.70) and chemosensitivity (HR= 0.76, 95% C.I. 0.66–0.87) were associated with lower risk of death. Factors associated with higher risk of death were age 50–65 (HR=1.29 95% 1.13–1.47), age 65–80 (HR=1.45, 1.23–1.72), Durie-Salmon or ISS stage III at diagnosis (HR 1.56, 95% C.I. 1.39–1.76) and more than one prior line of therapy (HR=1.15, 95% C.I. 1.03–1.28). In comparison to patients transplanted in 1995–99, post relapse survival was superior for patients transplanted in 2000–04 and 2005–10 at 24 months (58% vs. 65% vs. 72%, P=0.005 and <0.001 respectively) and 48 months (33% vs. 39% vs. 40%, P=0.023 and 0.033 respectively). The use of maintenance therapy has changed with 27% in 1995–99 receiving planned interferon vs. 23% in 2005–09 receiving planned thalidomide, lenalidomide or bortezomib maintenance. Conclusions Utilization of upfront AHCT is increasing in the USA, particularly in older patients. Improvement in survival for MM patients seen in population studies results not only from greater utilization of AHCT but also from the improvement in outcomes after AHCT and a significant recent improvement in post-relapse survival. Pre- and post-transplant exposure to novel agents likely contributes to survival. AHCT and novel agents are complementary and should be combined for the optimal management of newly diagnosed MM. Disclosures: No relevant conflicts of interest to declare.

Abstract HLA-haploidentical hematopoietic cell transplantation (Haplo-HCT) using posttransplantation cyclophosphamide (PT-Cy) has improved donor availability. However, a matched sibling donor (MSD) is still considered the optimal donor. Using the Center for International Blood and Marrow Transplant Research database, we compared outcomes after Haplo-HCT vs MSD in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Data from 1205 adult CR1 AML patients (2008-2015) were analyzed. A total of 336 patients underwent PT-Cy–based Haplo-HCT and 869 underwent MSD using calcineurin inhibitor–based graft-versus-host disease (GVHD) prophylaxis. The Haplo-HCT group included more reduced-intensity conditioning (65% vs 30%) and bone marrow grafts (62% vs 7%), consistent with current practice. In multivariable analysis, Haplo-HCT and MSD groups were not different with regard to overall survival (P = .15), leukemia-free survival (P = .50), nonrelapse mortality (P = .16), relapse (P = .90), or grade II-IV acute GVHD (P = .98). However, the Haplo-HCT group had a significantly lower rate of chronic GVHD (hazard ratio, 0.38; 95% confidence interval, 0.30-0.48; P &lt; .001). Results of subgroup analyses by conditioning intensity and graft source suggested that the reduced incidence of chronic GVHD in Haplo-HCT is not limited to a specific graft source or conditioning intensity. Center effect and minimal residual disease–donor type interaction were not predictors of outcome. Our results indicate a lower rate of chronic GVHD after PT-Cy–based Haplo-HCT vs MSD using calcineurin inhibitor–based GVHD prophylaxis, but similar other outcomes, in patients with AML in CR1. Haplo-HCT is a viable alternative to MSD in these patients.

1562 Background: In Caucasian-predominant populations, overweight or obese NSCLC pts (BMI≥25-kg/m2) have better prognosis while underweight (BMI≤18.5-kg/m2) pts have a worse prognosis. A large pooled sample allowed us to evaluate the role of ethnicity in this BMI-NSCLC OS relationship. Methods: Using individual data, survival analysis was performed on 15 ILCCO studies, assessing the interactions between ethnicity and BMI on overall survival (OS). Adjusted Hazard Ratios (aHR) from Cox models and adjusted penalized smoothing spline plots were generated. Results: Among 13416 (77%) Caucasian, 2975 (17%) Asian, and 935 (5%) Black NSCLC pts analyzed, we confirmed that for all pts, being underweight at NSCLC diagnosis was associated with worse OS (aHR=1.68, CI 1.5-1.8, p<0.001), while overweight/obese pts had improved survival (aHR 0.89, CI 0.8-0.9, p<0.001), when compared to pts with normal BMI. In general, Black pts had poorer OS than Caucasian pts (aHR 1.26 CI 1.1-1.4, p<0.001). However, the BMI-OS relationship differed according to ethnicity (BMI-ethnicity interaction, p=0.009): Caucasian underweight pts had poorer OS (aHR 1.67, CI 1.5-1.8, P<0.001) while overweight/obese pts had improved OS (aHR 0.89, CI 0.8-0.9, P<0.001). In Asian pts, these two associations were aHR 1.15, CI 0.8-1.5, P=0.33, and aHR 0.91, CI 0.7-1.1, P=0.32, respectively. In Black pts, these two associations were aHR 1.06, CI 0.7-1.5, p=0.73 and 0.75, CI 0.6-0.8 p<0.001, respectively. For overweight/obese patients, as BMI rises from 25-kg/m2 through 45-kg/m2, the prognosis worsens for Caucasian pts, remains stable for Asian pts, but improves for Black pts. Conclusions: InCaucasian pts, being underweight had a greater negative impact on OS than for Asian or Black pts, while being obese had a greater beneficial impact in Blacks than in other ethnic groups. These ethnic differences likely reflect genetically-informed muscle/adipose tissue distributions, where Black pts may have less sarcopenic obesity than other ethnicities. In future prognostic studies, BMI relationships must account for ethnic differences.

How dipeptide repeats cause pathology A repeat expansion in the chromosome 9 open reading frame 72 ( C9orf72 ) gene is the most common known cause of two neurodegenerative diseases: frontotemporal dementia and amyotrophic lateral sclerosis. This expansion leads to the abnormal production of proteins of repeating dipeptides, but their contribution to disease pathogenesis remains unclear. Zhang et al. engineered a mouse model to study the consequences of one of these dipeptides—prolinearginine dipeptide repeat protein, poly(PR)—in the brain. They found that poly(PR) caused neuron loss as well as motor and memory impairments. These detrimental effects resulted from poly(PR)-induced perturbation of heterochromatin function, a tightly packed form of DNA that represses gene expression. Science , this issue p. eaav2606

Interleukin (IL)-17 is a T helper 17 cytokine implicated in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). Although IL-17A has a well-established role in murine pulmonary fibrosis models, its role in the tissue remodeling and fibrosis occurring in idiopathic pulmonary fibrosis (IPF) and RA-associated interstitial lung disease (RA-ILD) is not very well defined. To address this question, we utilized complimentary studies to determine responsiveness of human normal and pathogenic lung fibroblasts to IL-17A and used lung biopsies acquired from patients with IPF and RA-ILD to determine IL-17A receptor (IL-17RA) expression. Both normal and pathogenic IPF lung fibroblasts express functional IL-17RA and respond to IL-17A stimulation with cell proliferation, generation of extracellular matrix (ECM) proteins, and induction of myofibroblast transdifferentiation. Small interfering RNA (siRNA) silencing of IL-17RA attenuated this fibroblast response to IL-17A on ECM production. These fibroblast responses to IL-17A are dependent on NF-κB-mediated signaling. In addition, inhibiting Janus activated kinase (JAK) 2 by either siRNA or a selective pharmacological inhibitor, AZD1480—but not a JAK1/JAK3 selective inhibitor, tofacitinib—also significantly reduced this IL-17A-induced fibrogenic response. Lung biopsies of RA-ILD patients demonstrate significantly higher IL-17RA expression in areas of fibroblast accumulation and fibrosis, compared with either IPF or normal lung tissue. These observations support a direct role for IL-17A in lung fibrosis that may be particularly relevant in the context of RA-ILD.

This study examines the importance of four psychosocial factors—personality, cognitive appraisal of quality of life, social support, and current reserve-building—in predicting treatment burden in chronically ill patients. Chronically ill patients ( n = 446) completed web-based measures. Structural equation modeling was used to investigate psychosocial factors predicting treatment burden. Reserve-building activities indirectly reduced treatment burden by: (1) reducing health worries appraisals, (2) reducing financial difficulties, (3) increasing calm and peaceful appraisals, and (4) increasing perceived social support. These findings point to key behaviors that chronically ill people can use to attenuate their treatment burden.

Abstract Motivation Recent studies have revealed a complex interplay between environment, the human microbiome and health and disease. Mediation analysis of the human microbiome in these complex relationships could potentially provide insights into the role of the microbiome in the etiology of disease and, more importantly, lead to novel clinical interventions by modulating the microbiome. However, due to the high dimensionality, sparsity, non-normality and phylogenetic structure of microbiome data, none of the existing methods are suitable for testing such clinically important mediation effect. Results We propose a distance-based approach for testing the mediation effect of the human microbiome. In the framework, the nonlinear relationship between the human microbiome and independent/dependent variables is captured implicitly through the use of sample-wise ecological distances, and the phylogenetic tree information is conveniently incorporated by using phylogeny-based distance metrics. Multiple distance metrics are utilized to maximize the power to detect various types of mediation effect. Simulation studies demonstrate that our method has correct Type I error control, and is robust and powerful under various mediation models. Application to a real gut microbiome dataset revealed that the association between the dietary fiber intake and body mass index was mediated by the gut microbiome. Availability and implementation An R package ‘MedTest’ is freely available at https://github.com/jchen1981/MedTest. Supplementary information Supplementary data are available at Bioinformatics online.